Recently use of antihypertensive drug

INTRODUCTION:-
High blood pressure, termed "hypertension," Hypertension is common and often symptomless. Hypertensions a condition that afflicts almost 1 billion people worldwide and is a leading cause of morbidity and mortality. More than 20% of Americans are hypertensive, and one-third of these Americans are not even aware they are hypertensive. Therefore, this disease is sometimes called the "silent killer." This disease is usually asymptomatic until the damaging effects of hypertension (such as stroke, myocardial infarction, renal dysfunction, visual problems, etc.) are observed.
Hypertension, or high blood pressure (HBP), is the most important cardiovascular risk factor worldwide, contributing to one half of the coronary heart disease and approximately two thirds of the cerebrovascular disease burdens.1 In the United States, the estimated prevalence of hypertension (defined as systolic blood pressure [BP] 140 mm Hg and/or diastolic BP 90 mm Hg and/or receiving antihypertensive medication) derived from the 1988–1994 Third National Health and Nutrition Examination Survey (NHANES III) was 42 million adults. An additional 8 million Americans reported having been told twice by a health professional that they have HBP, but their BP was <140/90 mm Hg at the NHANES III examination.2–4 This subgroup, termed "twice told," increased the hypertension prevalence estimate to 50 million persons. In 1999–2000, prevalence was estimated as 59 million among US adults.4 There were an additional 6 million persons twice told, yielding a total estimate of 65 million persons based on the NHANES 1999–2000 data.4
Since the 1960s, national examination surveys (including NHANES) conducted by the National Center for Health Statistics have been the principal means to track progress in preventing, treating, and controlling hypertension and have been benchmarks for the National High Blood Pressure Education Program and related health objectives for the nation.5,6 These data have generally indicated favorable trends, ie, improvements in hypertension prevalence, awareness, treatment, and control rates. Except for prevalence, these trends persisted through 1999–2000. There was an 8.3% relative increase in the prevalence rate during the 1990s, partially attributable to the epidemic of overweight and obesity occurring in the United States during the past 2 decades.7
In addition to articles describing hypertension trends through the year 2000,4,7 there have been several other reports using more recent NHANES data. A National Center for Health Statistics data brief updated the overall trends in hypertension through 2006 but did not address trends in awareness, treatment, and control and did not address changes in BP distributions or mean values.8 A report by Ostchega et al9 analyzed trends through 2004 but only in older persons and without the level of detail in this report. A recent publication by Gu et al10 investigated data through 2004 but was focused primarily on hypertension treatment patterns. This current report adds to these previous findings through a detailed analysis of NHANES 1999–2004 related to trends in prevalence; trends in awareness, treatment, and control; evaluation of the role of changes in body mass index (BMI) in the changes in hypertension prevalence; and analysis of changes in the mean values and distributions of BP values.
Methods
Data from the NHANES are used to assess the health and nutritional status of the civilian, noninstitutionalized US population. A nationally representative sample is obtained using a complex, stratified, multistage probability cluster sampling design. Selected subpopulations are oversampled, thereby providing a larger subsample size to yield more reliable estimates for these groups. The data used in this article are from NHANES III (1988–1994) and NHANES 1999–2004. Informed consent was obtained from all of the participants, and the protocol was approved by the institutional review board of the National Center for Health Statistics.
NHANES data were collected through a standardized household interview with additional interviewing and a physical examination in a mobile examination center. Respondents who were pregnant or for whom no BP data were available were excluded from the analysis. Because of coding changes, pregnant women could not be excluded from the 2003–2004 portion of the data. From previous estimates, this has an insignificant effect and would alter the prevalence of hypertension by approximately one tenth of a percent. In both surveys, the protocol called for 3 BP measurements at the mobile examination center by a physician using a mercury sphygmomanometer after a 5-minute rest. For NHANES III, 99% of the study population had 3 BP measurements; for NHANES 1999–2004, the figure was 91%. The final analytic sample consisted of 16 351 respondents for NHANES III and 14 430 respondents for NHANES 1999–2004, all age 18 years. Additional information about overall NHANES methodology and BP measurement is available elsewhere.11–13
Respondents were defined as having hypertension if their average systolic BP was 140 mm Hg, their average diastolic BP was 90 mm Hg, or they reported current use of antihypertensive medication. Awareness was defined as hypertensive respondents having been told at least once by a health professional that they had hypertension. Hypertensive adults were included in the treatment category if they reported the use of a prescribed medicine for hypertension. Among hypertensive persons, control was defined as a systolic BP <140 mm Hg and a diastolic BP <90 mm Hg.
BMI was defined as measured weight in kilograms divided by squared height in meters. There were 3 BMI categories: underweight/normal, defined as a BMI <25 kg/m2; overweight, 25 to <30 kg/m2; and obese, 30 kg/m2. Respondents were grouped into 6 age groups: 18 to 29, 30 to 39, 40 to 49, 50 to 59, 60 to 69, and 70 years of age. Respondents were categorized into 4 racial/ethnic groups according to self-reported race and ethnicity: non-Hispanic white (NHW), non-Hispanic black (NHB), Mexican American (MA), and other. Because the "other racial/ethnic" category is a diverse group, separate results for this group are not shown.
SAS for Windows14 (SAS Institute, Inc) and SUDAAN15 (Research Triangle Institute) were used for data management and statistical analysis. All of the estimates were weighted according to the inverse probability of being sampled for the examination. Sampling weights provided with the data were also adjusted for person-level nonresponse and a poststratification adjustment to the estimated US population.16 Age standardization was done using the year 2000 standard17 and the age groups defined above.
Comparisons of the differences in means and percentages between the 2 surveys were performed using linear contrasts in the SUDAAN descript procedure. Differences between surveys for population distributions among BP categories as defined in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure were evaluated using 2 tests. P values <0.05 were considered statistically significant. To examine the effect of BMI on the trends in hypertension, logistic regression models were examined within each racial/ethnic gender subgroup. Each model included age as a continuous variable and the time period of the surveys (1988–1994 or 1999–2004) as a categorical variable. Two sets of models were compared, first without and then with BMI (as a continuous variable). Adjusted odds ratios were calculated using the logistic procedure in SUDAAN. Odds ratios of which the 95% CI did not include unity were considered significant.
Qualifications and Limitations
Hypertension prevalence rates reported in this study are for the overall nonpregnant, noninstitutionalized, nonmilitary US population. Accordingly, a potential underestimation bias may exist in view of the fact that a relatively high proportion of adults in nursing homes, hospices, chronic disease hospitals, and other chronic care facilities have hypertension. Although this effect is offset by exclusion of adults likely to have normal BP (eg, many military personnel), the extent of the offset was not estimated.
Estimates are provided that both exclude and briefly include a subpopulation that has been traditionally overlooked: those who were nonhypertensive at the time of the survey but who have been told at least twice that they have hypertension. Exclusion of this subpopulation permits a more direct comparison with previous studies that only evaluated adults who were hypertensive by direct measurement or reported use of antihypertensive medication. Inclusion of this subpopulation who reported previously confirmed hypertension but whose BP was controlled by means other than antihypertensive medication (eg, nonpharmacologic therapy or diminished left ventricular function) is more representative of the overall population.41,42
Each data collection period occurred over 6 years. This approach ensures a large enough sample size and represents a strength of this study. However, trends occurring within each 6-year period were not evaluated in these analyses.
Although the sample size for the MA subpopulation was smaller than for the other racial/ethnic groups in NHANES III, it was actually larger than for the NHB subpopulation in the 1999–2004 survey. Accordingly, the historical difficulties with achieving large enough sample sizing by oversampling some groups were not as severe as in past studies.
Perspectives
Effective prevention, detection, treatment, and control of HBP continue to be important goals for health policy, public health, and medical care decision makers, as well as advocates and individuals at risk for hypertension.43 A positive impact of their aggregate efforts, interventions, and health behaviors will likely be reflected in improvements in key BP-related trends (or vice versa). For example, hypertension control rates have risen progressively from 1976 to 1980 to 1999 to 2004. However, the same data underscore the fact that there is still much that needs to be accomplished to further improve hypertension control rates for the US population.44
The overall hypertension prevalence trend for 1988–1994 to 1999–2004 is upward, driven primarily by a rise among women. This is contrary to the Healthy People 2010 objective that set as a goal to reduce the percentage of hypertension to an overall age-standardized prevalence in adults of 14%.45 The fact that rates are rising in the context of progressive rise in age and BMI of the overall population is of particular concern from a public health policy, as well as a medical care perspective. There are important unanswered questions about why the proportion of women with hypertension is rising 2 times faster than for men.
Although important progress continues to be made in the area of awareness, treatment, and control, the need continues to be high for interventions that will ultimately halt and reverse this rising tide of hypertension prevalence. The rapid improvements in BP control in some groups does suggest that the Health People 2010 objective to achieve a goal of 68% under control may have a chance of succeeding, eg, in NHW men. However, the very low control rates in some groups, such as 21% in MA men, indicate continued critical disparities in health care access and implementation. A better understanding of what is impeding further progress in the treatment of hypertension in women, especially NHW women, is needed. To the extent that it reflects a lack of appreciation of the importance of cardiovascular disease in women, progress may be stimulated by campaigns launched since 2003 by the federal government, voluntary agencies, and advocacy groups focusing on raising public and clinician awareness regarding the importance of preventing, detecting, and treating heart disease in women.
Definition of hypertension.
Blood pressure is the force of blood against the walls of arteries. Blood pressure has two components-the systolic pressure (It is the force that blood exerts on the artery walls when the heart is pumping) over the diastolic pressure (it is the residual force that remains when the heart relaxes between beats). The measurement is written one above or before the other, with the systolic number on top and the diastolic number on the bottom. For example, a blood pressure measurement of 130/85 mm Hg (millimeters of mercury) is expressed verbally as "130 over 85."Hypertensive is defined as an abnormal elevation in diastolic pressure and/or systolic pressure; mean arterial pressure is also elevated in hypertension, but it is not usually measured in people. In past years, the diastolic value was emphasized in assessing hypertension. However, elevations in systolic pressure ("systolic hypertension") are also associated with increased incidence of coronary and cerebrovascular disease (e.g., stroke). Therefore, we now recognize that both systolic and diastolic pressure values are important to note.
Acuturial studies show that the standardized mortality and morbidity increase proportionally to the systolic as well as the diastolic blood pressure (Fig. 1). This means that a subject with a B. P. of 140/90 mmHg., which is considered normal by the W.H.O. definition of hypertension, has a lower life expectancy compared with one whose B.P. is 120/80 mmHg. So, epidemiologically, there is no clearcut line drawn between a normal and an abnormal B.P. The decision to treat hypertension, therefore, would depend on
clinical studies of the benefits of treatment, The many possible side effects of drug treatment of hypertension emphasize the importance of clinical evidence of benefit before embarking on a life-long treatment which is not without risk.The controlled trial of Hamilton in 1964 showed clear benefit in lowering the blood pressure with the diastolic. > 110 mmHg. The U.S. Veterans Administration


Co-op Study (1967 and 1970) also showed benefits of treatment in patients with diastolic B.P. > 105 mmHg. (Fig. 2) So at present, we can consider it well established that patients with DBP of
105 - 110 mmHg warrants adequate control of their blood pressure if it is found to be persistently elevated.Large scale controlled studies are now being carried out in the U.S., U.K., Australia
and Scandinavia to try to solve the controversial issue of whether patients with borderline or mild hypertension (DBP 90 - 105 mmHg) warrants any treatment. Until results of these studies are known, it will remain controversial as to the value of active treatment of blood pressure in this
range when the subject is totally asmptomatic. When there is evidence of target organ damage such as retinopathy, angina, congestive heart failure, cerebral thrombosis, dissecting or enlarging aneurysm and renal damage or failure, drug treatment would be indicated even with mild hypertension.


According to the latest U.S. national guidelines (JNC 7 Report)), the following represents different stages of hypertension:
Classification Systolic
(mmHg) Diastolic
(mmHg)
Normal <120 <80
Prehypertension 120-139 80-89
Stage 1 140-159 90-99
Stage 2 >160 >100
Two classes of of hypertension. In 90-95% of patients presenting with hypertension, the cause is unknown. This condition is called primary (or essential) hypertension. The remaining 5-10% of hypertensive patients have hypertension that results secondarily from renal disease, endocrine disorders, or other identifiable causes. This form of hypertension is called secondary hypertension.
Hemodynamic basis of hypertension. Regardless of the origin of hypertension, the actual increase in arterial blood pressure is caused by either an increase in systemic vascular resistance (SVR) or an increase in cardiac output (CO). The former is determined by the vascular tone (i.e., state of constriction) of systemic resistance vessels, whereas the latter is determined by heart rate and stroke volume. Therefore, in order to understand how arterial blood pressure can become elevated, it is necessary to understand the mechanisms that regulate both SVR and CO.
Treatment of hypertension. Most people with hypertension are treated with antihypertensive medications. In most forms of hypertension, the hypertensive state is maintained by an elevation in blood volume, which in turn increases cardiac output by the Frank-Starling relationship. Diuretic drugs, which enhance the removal of sodium and water by the kidneys and thereby decrease blood volume, are very effective in the treatment of hypertension. Hypertension is also commonly treated with drugs that decrease cardiac output. These cardioinhibitory drugs either block beta-adrenoceptors on the heart (i.e., beta-blockers) or L-type calcium channels (i.e., calcium-channel blockers), which decreases cardiac output by decreasing heart rate and contractility (inotropy). Vasodilator drugs, which decrease systemic vascular resistance, are also used to treat hypertension. Included in these drugs are alpha-adrenoceptor antagonists (alpha-blockers), direct-acting vasodilators, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.
Secondary Hypertension
Secondary hypertension accounts for approximately 5-10% of all cases of hypertension, with the remaining being primary hypertension. Secondary hypertension has an identifiable cause whereas primary hypertension has no known cause (i.e., idiopathic).
There are many known conditions that can cause secondary hypertension. Regardless of the cause, arterial pressure becomes elevated either due to an increase in cardiac output, an increase in systemic vascular resistance, or both. When cardiac output is elevated, it is generally due to either increased neurohumoral activation of the heart or increased blood volume.
Patients with secondary hypertension are best treated by controlling or removing the underlying disease or pathology, although they may still require antihypertensive drugs.








Some causes for secondary hypertension are listed below:
• Renal artery stenosis
• Chronic renal disease
• Primary hyperaldosteronism
• Stress
• Sleep apnea
• Hyper- or hypothyroidism
• Pheochromocytoma
• Preeclampsia
• Aortic coarctation
Renal artery stenosis (renovascular disease)
Renal artery disease can cause of narrowing of the vessel lumen (stenosis). The reduced lumen diameter increases the pressure drop along the length of the diseased artery, which reduces the pressure at the afferent arteriole in the kidney. Reduced arteriolar pressure and reduced renal perfusion stimulate renin release by the kidney. This increases circulating angiotensin II (AII) and aldosterone. These hormones increase blood volume by enhancing renal reabsorption of sodium and water. Increased AII causes systemic vasoconstriction and enhances sympathetic activity. Chronic elevation of AII promotes cardiac and vascular hypertrophy. The net effect of these renal mechanisms is an increase in blood volume that augments cardiac output by the Frank-Starling mechanism. Therefore, hypertension caused by renal artery stenosis results from both an increase in systemic vascular resistance and an increase in cardiac output.
Chronic renal disease
Any number of pathologic processes (e.g., diabetic nephropathy, glomerulonephritis) can damage nephrons in the kidney. When this occurs, the kidney cannot excrete normal amounts of sodium which leads to sodium and water retention, increased blood volume, and increased cardiac output by the Frank-Starling mechanism. Renal disease may also result in increased release of renin leading to a renin-dependent form of hypertension. The elevation in arterial pressure secondary to renal disease can be viewed as an attempt by the kidney to increase renal perfusion and restore glomerular filtration.
Primary hyperaldosteronism
Increased secretion of aldosterone generally results from adrenal adenoma or adrenal hyperplasia. Increased circulating aldosterone causes renal retention of sodium and water, so blood volume and arterial pressure increase. Plasma renin levels are generally decreased as the body attempts to suppress the renin-angiotensin system; there is also hypokalemia associated with the high levels of aldosterone.
Stress
Emotional stress leads to activation of the sympathetic nervous system, which causes increased release of norepinephrine from sympathetic nerves in the heart and blood vessels, leading to increased cardiac output and increased systemic vascular resistance. Furthermore, the adrenal medulla secretes more catecholamines (epinephrine and norepinephrine). Activation of the sympathetic nervous system increases circulating angiotensin II, aldosterone, and vasopressin, which can increase systemic vascular resistance. Prolonged elevation of angiotensin II and catecholamines can lead to cardiac and vascular hypertrophy, both of which can contribute to a sustained increase in blood pressure.
Sleep Apnea
Sleep apnea is a disorder in which people repeatedly stop breathing for short periods of time (10-30 seconds) during their sleep. This condition is often associated with obesity, although it can have other causes such as airway obstruction or disorders of the central nervous system. These individuals have a higher incidence of hypertension. The mechanism of hypertension may be related to sympathetic activation and hormonal changes associated with repeated periods of apnea-induced hypoxia and hypercapnea, and from stress associated with the loss of sleep.
Hyper- or hypothyroidism
Excessive thyroid hormone induces systemic vasoconstriction, an increase in blood volume, and increased cardiac activity, all of which can lead to hypertension. It is less clear why some patients with hypothyroidism develop hypertension, but it may be related to decreased tissue metabolism reducing the release of vasodilator metabolites, thereby producing vasoconstriction and increased systemic vascular resistance.
Pheochromocytoma
Catecholamine secreting tumors in the adrenal medulla can lead to very high levels of circulating catecholamines (both epinephrine and norepinephrine). This leads to alpha-adrenoceptor mediated systemic vasoconstriction and beta-adrenoceptor mediated cardiac stimulation, both of which contribute to significant elevations in arterial pressure.. Despite the elevation in arterial pressure, tachycardia occurs because of the direct effects of the catecholamines on the heart and vasculature. Excessive beta-adrenoceptor stimulation in the heart often leads to arrhythmias. The pheochromocytoma is diagnosed by measuring plasma or urine catecholamine levels and their metabolites (vanillylmandelic acid and metanephrine).
Preeclampsia
This is a condition that sometimes develops during the third trimester of pregnancy that causes hypertension due to increased blood volume and tachycardia. The former increases cardiac output by the Frank-Starling mechanism.
Aortic coarctation
Coarctation, or narrowing of the aorta (typically just distal to the left subclavian artery), is a congenital defect that obstructs aortic outflow leading to elevated pressures proximal to the coarctation (i.e., elevated arterial pressures in the head and arms). Distal pressures, however, are not necessarily reduced as would be expected from the hemodynamics associated with a stenosis. The reason for this is that reduced systemic blood flow, and in particular reduced renal blood flow, leads to an increase in the release of renin and an activation of the renin-angiotensin-aldosterone system. This in turn elevates blood volume and arterial pressure. Although the aortic arch and carotid sinus baroreceptors are exposed to higher than normal pressures, the baroreceptor reflex in blunted due to structural changes in the walls of vessels where the baroreceptors are located. Also, baroreceptors become desensitized to chronic elevation in pressure and become "reset" to the higher pressure.
Simple Steps For Controlling High Blood Pressure Effectively
High blood pressure, or the hypertension, as it is commonly named, is a condition that can affect us without even knowing its specific symptoms, because there are none. The silent killer can be controlled with the proper medicated treatment and by following the doctor advises. The first thing you have to do after you have been diagnosed with hypertension, is to be aware and to learn how to live with it, because the faster you take some measures, the faster you can stop it from threatening your life.
Being a chronic disease, there is nothing yet that can cure it. We can only try to ameliorate it and to control it by making drastic changes in our lives. Begin with changing the way you eat, change the lifestyle you have and make sure you follow the medicated treatment prescribed by your doctor: these are the right steps towards healing hypertension. Hypertension can lead to major breakdowns of our body's systems if we do not take the right measures and the consequences are very serious: complicated heart attacks, strokes or the failure of your kidneys.

This article will provide you with a simple 3-steps program that can help you reduce and regulate your high blood pressure and prevent it from taking over your life.

Step 1: Eat Healthy!
Eating healthy might seem easy for someone who hasn't tried it yet. It involves changing your whole way of life and you must forget and put away your old eating habits and apply the new rules of healthy eating. You can begin with a small step, like reducing the quantity of salt you used to prepare the meals. A higher quantity of salt can produce edema, the retention of water. Normally, the water from our body must be eliminated through the urine. The salt interferes in the process and a big part of the water that should be eliminated is blocked within our bodies, creating excess. This will cause a pressure on the walls of the blood vessels, the main reason for the occurrence of hypertension.

If you feel you can't live without salt, you can replace it with salt substitutes or tasty combinations of other seasonings. The taste of the food might not be the same as before, but your hypertension will slowly lose its power.
Changing the way you eat and the things you eat, will determine you to begin lose the excess of weight too. It is a common fact that hypertension is caused by obesity, by the fat accumulated in our body which thickens the walls of the blood vessels and increases the blood pressure as a consequence.
To guide the people in finding the right way to control hypertension through healthy eating, in 1997, the Journal of Medicine from New England published a work that was lately approved by the US government as an excellent method to prevent hypertension. This amazing writing was the DASH diet, which means Dietary Approaches To Stop Hypertension. This is a diet based on healthy food, tasty and beneficial for our body too, including all the proteins, vitamins, fibers and minerals necessary to our body.
Step 2: Quit Smoking And Reduce The Amount Of Alcohol
If you are a smoker or you are used to have more than a couple of drinks daily, you might take a minute and think about how this affects your health. It is hard to leave behind those nasty habits, and the best way to do it isn't to go through it by yourself. You will not make it. Search for advice and counselling in your personal physician and you will have professional support while you will improve your life.

Step 3: Be Active!
A sedentary way of life will certainly not help you in reducing the risqu of hypertension. Our busy schedules don't leave us much choice when it comes to our free time. We prefer to relax and watch a movie instead of exercising our bodies. Do not worry; you do not have to spend hours at the gym. Ten minutes a day can work wonders on your blood circulation, by reducing the negative effect of hypertension on our bodies.
There is the case though, when we inherit hypertension. At the periodic check-up, tell your doctor if you ever had a history of hypertension in your family; it is possible that you might have it too. The only thing you can do is to protect yourself by avoiding the things that allow the hypertension to become serious in the first place. There are also drugs included in the category of antihypertensive; not every one of them might work for your type of body, and you will have to try a whole list of drugs until you find the one that works on your hypertension. Pay attention, though! If you take the drugs and still go on with your old lifestyle, do not expect any results! The right combination of hypertension inhibitors includes: healthy food, exercises and a healthy way of life (no cigarettes or alcohol).
Clinical Evaluation of Hypertensive Patients
While a. random finding of elevated blood pressure may have a prognostic significance, the well known wide variation of B.P. that can occur with changing environment makes it necessary to obtain
repeated B.P. recordings to establish a basal hypertensive state before embarking on a life-long treatment. When there is malignant hypertension or severe hypertension with complications such as congestive heart failure, treatment should be started early. In taking the history of the patient,
during the physical examination and later investigation of the patient, the doctor should bear in mind the following considerations:-
1. The cardiovascular risk factors
2. Evidence and extent of target organ damage.
3. Possibility of secondary hypertension.
4. Co-existance of other diseases and factors that may influence management
The initial investigation should include:
1. Urine analysis.
2. Serum urea and/or creatinine.
3. Serum uric acid.
4. Serum glucose (fasting).
5. Serum potassium.
6. Serum cholesterol.
7. Electrocardiogram.
8. C.X.R.
Other tests may be ordered when
indicated.
Nondrug Management of Hypertension
Nondrug Management of Hypertension should always be utilized to the maximum and in many mild or borderline hypertensive patients, this may eliminate the need for drug therapy.
1. Smoking
Although there is no evidence that suggests it may cause sustained hypertension, smoking is a definite
independent risk factor in cardiovascular disease. It increases the risk of acute myocardial infarction and
also the incidence of sudden deaths. The risk is markedly aggravated in the presence of hypertension.
Cessation of smoking has been shown to reduce mortality. Every effort should therefore be made to encourage patients to stop smoking or to cut it down. In patients over the age of 55, the difference in the risk of smoking
is less dramatic assumed to be due to selective survival. And so the doctor would assess individual
patient and advise accordingly after balancing the benefit to be gained against the psychological stress that
some of these patients may suffer in attempting to give up smoking.
2. Hypercholesterolemia
Controversy still exists as to the value and risk of the control of hypercholesterolemia either by diet
restriction or more so by drug control. However, general opinion at present still favours reasonable
restriction of diet cholesterol and saturated fat with the precaution against possible malnutrition. Drug
control should generally be restricted to those with highly elevated serum cholesterol values resistent to
diet control.
3. Body weight control
Overweight or obesity increases overall mortality by about 11/2 times and a higher prevalence of hypertension
has been found in obese subjects. Reduction of body weight in obese subject reduces the cardiac work load and decreases B.P. The Framingham Study in obesity shows that a 10% reduction of body weight results in a lowering of
systolic B.P. by 5 mmHg., serum cholesterol by 11 mg%, serum glucose by 2 mg% and serum uric acid by 0.4 mg%.
Weight reduction should therefore be advised for all obese hypertensive subjects.
4. Sodium Intake
Epidemiological study shows that excessive salt intake is associated with a high prevalence of hypertension
(Fig. 3). This is well demonstrated in the example of Northern Japan where the incidence of hypertension was as high as 40% with an average daily salt intake of 30 gm/day. In Eskimos taking practically salt free diet, hypertension
was hardly a problem. In clinical practice, a low salt diet can lower B.P. in a third of patients with essential ypertension
while excessive salt intake definitely raises the B.P., although the raise may be relatively minor. So, it is quite clear that excessive salt intake should be discouraged. The practice of stringent lifelong salt restriction, however, is not
any easy task makes life miserable for those accoustomed to a relatively high salt diet habit. The use of diuretics certainly has eased the necessity for strict dietary salt control.


In any case, the amount of salt that we take every day is just an acquired taste and habit. So, it is
well worth an effort to adivse the general public to refrain from excessively salted food items such
as preserved food, canned food, salted nuts and peanuts, salted fish, ham, potato chips etc. When the
daily salt intake is reduced to around 5 gm/day, the Australian Study in mild hypertension has
shown that there is significant lowering of the B.P. with a diastolic B.P. 90 mmHg in 32% of patients
compared with 16% of patients on no restriction.
5. Exercise
Regular exercise is generally recommended to maintain physical fitness with an augmentation of cardio-pulmonary reserve. But isometric exercises such as weight lifting should be avoided especially for hypertensive subjects because of an immediate increase in cardiac work before the heart can compensate. Undue exertion is known to transiently elevate the B.P. Sexual intercourse likewise can increase the systolic and diastolic B.P. by
30 - 80 and 20 - 40 mmHg respectively.
6. Environmental Temperature and Emotional Stress
Dipping hands into ice-cold water can elevate the B.P. due to reflex vasoconstriction. In a cold weather, the B.P. generally higher. Cerebral vascular accident occurs more frequently in Winter. So in very cold weather and especially for the elderly, patients should be advised to keep themselves warm and avoid abrupt changes of temperature such as getting up from a warm bed in a cold night to go to a cold toilet. The bedroom and the
toilet should be kept warm. Diving into cold water or taking a cold shower after a sauna bath should
definitely be avoided. Emotional stress can transiently increase the B.P. on acute situation but is has not been proven that
chronic stress can cause persistent
hypertension.
7. Contraceptive Pills
With the use of contraceptive pills, hypertension may appear within 6 months and return to normal within 3 - 6 months after discontinuation. So contraceptive pills should be avoided in patients with hypertension and the B.P. of subjects on the pill should be checked periodically at least during the first 6 months of therapy.
Drug Management
With the numerous hypotensive agents available, the drug of choice is one that is effective, simple, with
minimal side effects and inexpensive.Being a life-long undertaking, the patient should be well informed of the
necessity of a good B.P. control and the inevitable side effects of medication. Although the doctor should try to
reduce it to the minimum with the use of alternative medication or other precautions.Home monitoring of the B.P. helps to encourage the patient to appreciate the result of treatment; and the involvement of the family members in a team effort also improves the patient compliance
World Hypertension Day 2008
Saturday, May 17, 2008, marked World Hypertension Day, the fourth time this day has been observed since it was initiated by the World Hypertension League (WHL), a division of ISH, in 2005. The purpose of World Hypertension Day is "to promote public awareness of hypertension and its serious medical complications and to encourage citizens of all countries to avoid or control hypertension by providing information on prevention, detection, and treatment." This year's theme was "Measure Your Blood Pressure -- At Home."[6] "By focusing public attention on the benefits of controlling high blood pressure we want to help people better protect themselves against heart attack, stroke, and kidney failure," said Arun Chockalingam, PhD (Simon Fraser University, Vancouver, Canada), secretary-general of the WHL . "We hope World Hypertension Day will motivate people to be screened and to make blood pressure monitoring and management part of their general health management."
According to Professor M Mohsen Ibrahim, MD (University of Cairo, Egypt), an advisor to the WHL, "People often think high blood pressure is only a 'western' disease; but it is not. It is on the rise in developed and developing nations, and if we do not get it under control, it will grow by 50% in the next 15 years. This would leave a lot of people at risk, but World Hypertension Day can help to motivate people and slow this epidemic." World Hypertension Day is supported globally by Novartis, Omron, and sanofi-aventis.
A record-setting number of World Hypertension Day events were set to take place around the world this year. More than 35 countries hosted public events to provide free blood pressure screenings and information about high blood pressure. May 17, 2008 also marked the launch of the largest-ever international survey to draw increased attention to the links between hypertension and heart disease. The '"Do You Know Your Numbers?" survey is designed to quantify how aware the general public is about high blood pressure, as well as cholesterol and diabetes, and how much importance they place on controlling these contributors to heart disease. The survey is sponsored in part by Novartis. The results of the survey will be released in September 28th, to coincide with World Heart Day 2008, which will focus on better high blood pressure control. "This survey is unique, because it studies how the public views key contributors to heart health." Dr Chockalingam said. "This information is important, because it will help doctors and patients to better communicate about how to improve patients' health by better managing these common, yet devastating, diseases."
New US Guidelines for Blood Pressure Monitoring at Home
People with hypertension should routinely monitor their blood pressure at home to help manage the disease, according to a new joint scientific statement from the American Heart Association (AHA), the American Society of Hypertension (ASH), and the Preventive Cardiovascular Nurses' Association. Use of a home monitor can confirm suspected or newly diagnosed hypertension and rule out the diagnosis for patients whose readings at the doctor's office do not reflect their actual pressures over time. Home monitoring can also be used to evaluate the response to antihypertensive treatment, and to motivate patients to take their medications regularly. The full statement is published online in Hypertension,[8] along with an executive summary[9] that also appears in the May issue of the Journal of the American Society of Hypertension,[10] and is scheduled for publication in the Journal of Cardiovascular Nursing.
Lead author Thomas G. Pickering, MD, DPhil (Columbia Presbyterian Medical Center, New York), who was chair of the statement writing group, stressed that high blood pressure is notoriously difficult to treat to goal and that home monitoring can help the many patients who fail to reach target levels despite treatment. "BP measurement and tracking could be improved with home monitoring by the patients themselves, in much the way people with diabetes monitor their blood sugar levels with home glucose monitors," he proposed. He said that there is strong evidence that the traditional way of measuring blood pressure in adults can be misleading. Studies indicate that between 10% and 20% of people diagnosed with high BP in the doctor's office show the white coat effect. "It is also believed that some people with normal blood pressures in their doctors' offices have pressures that spike to potentially dangerous levels in other situations," Dr. Pickering added.
The statement says that home monitoring is particularly useful in the elderly, who show both increased BP variability and white coat effect, as well as in patients with diabetes, patients with kidney disease, and in pregnant women. Dr Pickering noted that because everyone's BP is highly variable during the day, taking 1 reading at a doctor's office every few months does not give a complete picture of a patient's condition. Home monitors can take multiple measurements during each session, and can be used at different times of day. Many monitors also store and average blood pressure readings over time, providing crucial data for patients to take to their physicians so they can work as a team to diagnose and treat the condition.
Many types of home monitors are relatively inexpensive, costing less than $100. The statement recommends that patients be reimbursed for the purchase of a monitor as prescribed by their healthcare provider (physician and/or nurse practitioner) and that providers be reimbursed for services related to initial patient education regarding correct technique; yearly or as-needed assessments to validate that individuals' technique; interpretation of BP readings stored in the monitor memory; and personal, telephone, and/or e-mail consultation to deliver medical advice-based on analysis of home BP readings. Monitors should be renewable after 5 years or if they are shown to be inaccurate.
"Home blood pressure monitoring also gives patients the physiologic feedback they need to see regarding blood pressure," says Nancy Houston Miller, RN, co-author and former president of the Preventive Cardiovascular Nurses Association. "Rather than 3 to 4 office blood pressure checks per year, if they measure blood pressure at home in addition to following up with their healthcare provider, patients are likely to achieve goals more quickly and be confident that medicines are working for them." She believes that nurses and nurse practitioners have a significant role to play in interpreting data from BP devices and educating patients about needed lifestyle interventions and medications.
Suzanne Oparil, MD, immediate past president of ASH, said that the society is "encouraged by this joint statement on the value of home blood pressure monitoring and confident it will be helpful in reducing the incidence of heart attack, stroke and kidney disease." The statement writing group said home BP monitoring is evidence-based healthcare that can improve the quality and lower the cost of caring for the 73 million people with hypertension.
Although earlier AHA guidelines have included home monitors, this is the first statement to have detailed recommendations on their use. They advise patients to purchase oscillometric monitors that measure BP in the brachial artery with a cuff that fits around the upper arm. Wrist monitors are not recommended. The statement notes that only a few of the home BP devices on the market have been subjected to proper validation tests such as the Association for the Advancement of Medical Instrumentation (AAMI) and British Hypertension Society (BHS) protocols, and that several devices have failed the tests. Current lists of validated monitors are available on the Web sites of the dabl® [sic] Educational Trust and the British Hypertension Society (see Resource list).
Patients are advised to consult their healthcare providers about the accuracy of their home monitor as well as their technique in using it. After 5 minutes of rest and while seated, they should take 2 to 3 readings at a time, 1 minute apart, on the nondominant arm. The arm should be supported, with the upper arm at heart level, and feet on the floor (back supported, legs uncrossed). The patient should have abstained from exercising, smoking, or drinking coffee or tea over the 30 minutes before taking the blood pressure measurement. To get a reliable estimate of the true BP, the statement recommends following the latest European Society of Hypertension guidelines on home BP measurement,[11] which suggest taking at least 2 readings in the morning and 2 in the evening every day for 1 week, but discarding the readings for the first day, so that there are 12 readings on which to make clinical decisions. The statement notes that the number of hypertensive patients monitoring their BP at home has been rising in past years, going from 38% in 2000 to 55% in 2005. "I think this is a very healthy trend," Dr Pickering said, although he stressed that "with a condition like high blood pressure, it really does depend on the patients remembering to change their lifestyles or remembering to take their pills."
No Evidence for Selection of Specific Blood Pressure-Lowering Regimens in People of Different Ages
Some national hypertension guidelines, such as those for the United Kingdom [12] and Canada,[13] recommend treatment with particular BP lowering drug classes according to age, based on possible differences in cardiovascular effects. However, according to the results of the latest meta-analysis by the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC), published in the British Medical Journal,[14] there is no strong evidence that specific classes of antihypertensive drugs are more beneficial in terms of preventing cardiovascular events in people of different ages. The BPLTTC members say that their findings "should greatly simplify decision making for millions of clinicians around the world."
For this meta-analysis, trials were eligible for inclusion if they randomized 1000 patients or more to either (a) medication to lower BP vs control (placebo or less intensive treatment), or (b) different classes of BP-lowering drugs. All trials included were completed between 1995 and 2006. The investigators compared total major cardiovascular events (stroke, coronary heart disease [CHD], and heart failure) as primary outcome in patients aged < 65 years ("younger") vs aged ≥65 years ("older"). Of 37 eligible trials, 31, including 96,466 younger individuals and 94,140 older individuals (mean age 57 and 72 years, 58% and 51% men, respectively), were included in the meta-analysis.
Results of BPLTTC Meta-analysis
Mean BP at baseline was higher in the older group in the trials and more events occurred overall in the older patients. There was no difference in reduction in primary outcome events between the 2 age groups in the trials that compared BP-lowering trials with placebo or that compared different antihypertensive drug classes, despite differences in BP reductions between the groups with some of the randomized treatments. Similarly there was no difference when secondary outcomes -- stroke, CHD, heart failure, cardiovascular death, and total mortality were compared in the 2 age groups, or in analyses of the trials for which individual patient data were available or who included only patients in 1 age group. A subsidiary analysis comparing the effects of regimens based on diuretics or beta-blockers with other drug classes (angiotensin converting enzyme [ACE] inhibitors and calcium channel blockers combined), showed no difference in proportional reduction in major cardiovascular events in the younger vs older patients.
Limitations, Implications, and Comment
These results do not completely exclude the possibility of differences in the proportional effects of blood pressure lowering regimens between age groups, but they do suggest that any such differences are likely to be small, the investigators conclude. Thus, they suggest that factors such as tolerability and cost are probably reasonable bases for choice of drug as long as an effective blood pressure reduction is achieved. They add that among the older age group there was, in almost every analysis and for almost every outcome, an estimate of effect suggesting benefit from BP lowering, with no evidence of harm and the absolute benefits of treatment in terms of serious vascular events prevented are likely to be particularly large among older individuals because of their higher average risk. "These data also provide considerable reassurance that current approaches to the use of blood pressure lowering treatments based on absolute risk, that assume constant proportional risk reductions across age groups, are an appropriate means of quantifying the likely absolute benefit to be gained from lowering blood pressure," they conclude.
In an accompanying editorial,[15] Jan A Staessen, MD, PhD, Study Coordinating Centre, Hypertension Unit, Department of Molecular and Cardiovascular Research, University of Leuven, Belgium, and colleagues say that they understand the appeal of an age-oriented strategy in the choice of first line antihypertensive drugs because it would translate certain physiologic and pharmacologic principles, such as the decrease in plasma renin with age, into clinical practice. They suggest that although the BPLTTC analysis strongly supports the early and aggressive management of hypertension, irrespective of age, it did not exclude the possibility that ACE inhibitors and other inhibitors of the renin system given as first line treatment in older people might be less efficacious than diuretics or calcium channel blockers.
No Evidence for Selection of Specific Blood Pressure-Lowering Regimens in People of Different Ages
Some national hypertension guidelines, such as those for the United Kingdom [12] and Canada,[13] recommend treatment with particular BP lowering drug classes according to age, based on possible differences in cardiovascular effects. However, according to the results of the latest meta-analysis by the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC), published in the British Medical Journal,[14] there is no strong evidence that specific classes of antihypertensive drugs are more beneficial in terms of preventing cardiovascular events in people of different ages. The BPLTTC members say that their findings "should greatly simplify decision making for millions of clinicians around the world."
For this meta-analysis, trials were eligible for inclusion if they randomized 1000 patients or more to either (a) medication to lower BP vs control (placebo or less intensive treatment), or (b) different classes of BP-lowering drugs. All trials included were completed between 1995 and 2006. The investigators compared total major cardiovascular events (stroke, coronary heart disease [CHD], and heart failure) as primary outcome in patients aged < 65 years ("younger") vs aged ≥65 years ("older"). Of 37 eligible trials, 31, including 96,466 younger individuals and 94,140 older individuals (mean age 57 and 72 years, 58% and 51% men, respectively), were included in the meta-analysis.
Results of BPLTTC Meta-analysis
Mean BP at baseline was higher in the older group in the trials and more events occurred overall in the older patients. There was no difference in reduction in primary outcome events between the 2 age groups in the trials that compared BP-lowering trials with placebo or that compared different antihypertensive drug classes, despite differences in BP reductions between the groups with some of the randomized treatments. Similarly there was no difference when secondary outcomes -- stroke, CHD, heart failure, cardiovascular death, and total mortality were compared in the 2 age groups, or in analyses of the trials for which individual patient data were available or who included only patients in 1 age group. A subsidiary analysis comparing the effects of regimens based on diuretics or beta-blockers with other drug classes (angiotensin converting enzyme [ACE] inhibitors and calcium channel blockers combined), showed no difference in proportional reduction in major cardiovascular events in the younger vs older patients.
Limitations, Implications, and Comment
These results do not completely exclude the possibility of differences in the proportional effects of blood pressure lowering regimens between age groups, but they do suggest that any such differences are likely to be small, the investigators conclude. Thus, they suggest that factors such as tolerability and cost are probably reasonable bases for choice of drug as long as an effective blood pressure reduction is achieved. They add that among the older age group there was, in almost every analysis and for almost every outcome, an estimate of effect suggesting benefit from BP lowering, with no evidence of harm and the absolute benefits of treatment in terms of serious vascular events prevented are likely to be particularly large among older individuals because of their higher average risk. "These data also provide considerable reassurance that current approaches to the use of blood pressure lowering treatments based on absolute risk, that assume constant proportional risk reductions across age groups, are an appropriate means of quantifying the likely absolute benefit to be gained from lowering blood pressure," they conclude.
In an accompanying editorial,[15] Jan A Staessen, MD, PhD, Study Coordinating Centre, Hypertension Unit, Department of Molecular and Cardiovascular Research, University of Leuven, Belgium, and colleagues say that they understand the appeal of an age-oriented strategy in the choice of first line antihypertensive drugs because it would translate certain physiologic and pharmacologic principles, such as the decrease in plasma renin with age, into clinical practice. They suggest that although the BPLTTC analysis strongly supports the early and aggressive management of hypertension, irrespective of age, it did not exclude the possibility that ACE inhibitors and other inhibitors of the renin system given as first line treatment in older people might be less efficacious than diuretics or calcium channel blockers.
Identification of Angiotensin-Converting Enzyme-2 Activators as Potential Antihypertensive Drugs
Activation of angiotensin-converting enzyme 2 (ACE 2) could lead to a new class of antihypertensive drugs that would also be effective in reversing cardiac and renal fibrosis, say University of Florida (Gainesville) researchers in the May 1, 2008 issue of Hypertension.[21] ACE 2, a homolog of ACE, is a key RAS enzyme involved in balancing the adverse effects of angiotensin II on the cardiovascular system. It is known to degrade angiotensin II (AngII) to generate angiotension[1-7] which has vasodilatory and antiproliferative effects. Blocking AngII with ACE inhibitors or angiotensin receptor blockers (ARBs) has been shown to increase cardiac ACE2 expression. Altered expression of ACE2 is associated with cardiac, renal, and vascular dysfunction.
Previous studies have suggested that pharmacologic enhancement of ACE2 activity may have beneficial effects on the cardiovascular system and protect against hypertension-induced pathophysiology. As part of research funded by the National Institutes of Health (NIH), José A Hernández Prada, PhD (Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida) and colleagues have used a structure-based drug-discovery approach to identify a compound that[21]:
• "This Enhances ACE 2 activity;
• Causes "considerable" reductions in BP; and
• Reverses cardiac and renal fibrosis in spontaneously hypertensive rats (SHRs).
Observation is remarkable, because rational drug design is traditionally directed at the discovery of enzyme inhibitors or receptor blockers that compete with the natural ligand," the researchers explain. They believe that the new approach will enable rational development of enzyme activators.
Dr Hernández Prada and colleagues used a novel rapid molecular docking approach to computationally screen approximately 140,000 small molecules, a small number of which were selected for in vitro testing for their ability to modulate ACE2 activity. The new screening approach involved rotating the molecules in thousands of different orientations to determine how they would bind to certain pockets on the enzyme's surface. After a small number of potentially active compounds had been identified, in vitro assays revealed 2 (xanthenone and resorcinolnaphthalein) that enhanced ACE2 activity by 1.8 to 2.2-3 fold. ACE2 activity was enhanced in a dose-dependent manner by the 2 compounds, with median effective concentration (EC50) values of 20.1 and 19.5 mcmol/L, respectively. Both were selective for ACE2, showing no significant effects on ACE activity. Xanthenone was selected for large-scale synthesis and in vivo testing because it was more soluble than resorcinol naphthalein.
Results With in vivo Experiments
Acute in vivo administration of xanthenone resulted in a rapid, dose-dependent transient and robust decrease in BP in SHRs and normotensive Wistar-Kyoto (WKY) rats. The antihypertensive effect was significantly greater in SHRs compared with WKY rats. At a dose of 10 mg/kg, BP sure decreased by a mean of 71 ± 9 mm Hg in SHRs compared with only 21 ± 8 mm Hg in WKY rats (P < .05). Chronic infusion of xanthenone (120 mcg/day) resulted in a significant decrease in BP in SHRs (17 mm Hg, P < .05), whereas it had no effect in WKY rats. The decrease in blood pressure was also associated with improvement in cardiac function and change of pressure over time in SHRs, but no significant changes in left ventricular (LV) systolic pressure, LV end diastolic pressure, perfusion pressure, or heart rate. Chronic infusion of xanthenone also caused a significant reversal of myocardial, perivascular, and renal interstitial fibrosis in SHRs.
The mechanism of the effect on cardiac function remains to be elucidated. It may be an indirect effect as a result of the decrease in BP, but the researchers believe that effects of xanthenone in reversing myocardial and perivascular fibrosis indicate that the improvement in heart function is more likely due to the marked reduction in collagen deposition in cardiac tissue.
Implications for New Treatments
"The clinical ramifications of this study are directly significant for cardiovascular disease and diseases associated with hypertension, such as obesity and diabetes," the researchers say. The study provides evidence suggesting that development of a new class of antihypertensive drugs (specific for ACE2) may serve as a complementary strategy in the treatment of cardiovascular disease. Study co-author David A Ostrov, PhD (Assistant Professor, Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville) added that early results also show xanthenone inhibits inflammation, which has significant implications for a number of human diseases, including autoimmune disorders such as type 1 diabetes and rheumatoid arthritis as well as other diseases involving fibrosis, such as Alzheimer's. Additional research will continue to explore the compound's effectiveness in animals and humans.
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When considering volunteering for a clinical trial, it is important to make an informed decision. Below are answers to frequently asked questions that many potential volunteers have about participating in a study.
What is a clinical trial?
A clinical trial is a research study in which volunteers receive investigational treatments under the supervision of a physician and other research professionals. These treatments are developed by pharmaceutical and biotechnology companies who select qualified physicians, also known as investigators, to conduct clinical trials to determine the benefits of investigational drugs.
Clinical trials are usually conducted in three phases (I, II, III). Only a small number of people participate in phase I trials while the later phases involve a larger number of volunteers.
Who can participate in a clinical trial?
All clinical trials have guidelines about who can participate. Before joining a clinical trial, a volunteer must qualify for the study. The factors that allow volunteers to participate in a clinical trial are called "inclusion criteria" and the factors that disallow volunteers from participating are called "exclusion criteria." These criteria can include age, gender, the type and stage of a disease, previous treatment history, and other medical conditions.
Some research studies seek participants with specific illnesses or conditions to be studied in a clinical trial, while others require healthy participants. It is important to note that inclusion and exclusion criteria are used to identify appropriate participants, promote participants' safety, and ensure that researchers learn the information they need.
How does a clinical trial work?
In a clinical trial, a volunteer is usually assigned a specific study group. Volunteers in one study group may receive an investigational treatment or study drug while other volunteers may receive a placebo or a treatment already available.
A placebo is an inactive product used to assess the experimental treatment's effectiveness. The participant, physician, and research staff may not know which volunteer receives a placebo and which receives the active treatment. Not knowing which participants are receiving the active treatment allows the physician and research staff to objectively observe the volunteers during the study. Regardless of which treatment volunteers receive, however, the level of medical attention and care that each receives is the same.
What questions should be asked before choosing to participate?
Patients considering participating in a clinical trial should talk about it with their physicians and medical caregivers. Potential volunteers should also understand the credentials and experience of the staff and the facility involved in conducting the study.
Questions to ask a physician or medical caregiver:
• How long will the trial last?
• Where is the trial being conducted?
• What treatments will be used and how?
• What is the main purpose of the trial?
• How will patient safety be monitored?
• Are there any risks involved?
• What are the possible benefits?
• What are the alternative treatments besides the one being tested in the trial?
• Who is sponsoring the trial?
• Do I have to pay for any part of the trial?
• What happens if I am harmed by the trial?
• Can I opt to remain on this treatment, even after termination of the trial?
What can volunteers expect if they choose to participate?
In some studies, participants receive a physical examination and their medical histories are reviewed by either the study physician or a research staff member once they are enrolled in the study. The volunteers' health will continue to be monitored during and after the trial. A detailed description of what's expected of volunteers will be outlined in consent forms along with specific clinical trial information.
What is informed consent?
For information about the informed consent process when participating in clinical trials, please refer to the CenterWatch publication, Understanding the Informed Consent Process.
What are the benefits and risks of joining a trial?
Volunteers in a clinical trial participate in the development of medical therapies that may offer better treatments and even cures for life-threatening and chronic diseases. However, there are risks involved.
Possible benefits for volunteers:
• Play an active role in their health care.
• Gain access to research treatments before they are widely available.
• Obtain medical care at health care facilities during the trial.
• Help others by contributing to medical research.
Possible risks for volunteers:
• There may be unpleasant, serious, or even life-threatening side effects to experimental treatment.
• The experimental treatment may not be effective.
• The protocol may require more time and attention than a non-protocol treatment, including trips to the study site, more treatments, hospital stays, or complex dosage requirements.
Please note: volunteers may withdraw from a study at any time for any reason.
Does information remain confidential and private?
Access to personal information is usually available to the investigator and research team conducting the clinical trial. In some circumstances, the IRB overseeing the research and the sponsor or contract research organization coordinating the trial will also have access to personal information. This is explained more specifically in the consent form that participating volunteers are asked to sign. As a clinical trial progresses, researchers report the results of the trial at scientific meetings, to medical journals, and to various government agencies.
What happens after the trial?
After a study phase is complete, the data is collected to determine the drug's effectiveness, if it is safe and if there are any side effects. Depending on the results, researchers then determine whether to stop testing or move to the next phase of study. After phase III of a study is complete, researchers decide if the results are medically important and may submit them to journals for peer-review. Data then may be submitted to the Food and Drug Administration (FDA) for approval.
If a drug is approved, pharmaceutical companies may continue to conduct studies that compare the new drug—in terms of its safety, effectiveness, and cost—to other drugs already on the market or assess a drug's long-term effectiveness and its impact on the quality of a person's life.

Drug Name: Cleviprex (clevidipine)
Company: The Medicines Company
Approval Status: Approved August 2008
Treatment Area: hypertension when oral therapy is not feasible or not desirable
General Information
Cleviprex is an intravenous short acting dihydropyridine calcium channel antagonist. Clevidipine acts by selectively relaxing smooth muscle cells that line small arteries. This results in widening of the arterial lumen and reduction of blood pressure since the small arterioles are the primary resistance vessel within the vasculature.
Cleviprex is specifically indicated for the reduction of blood pressure when oral therapy is not feasible or not desirable.
Cleviprex is supplied as a sterile liquid emulsion designed for intravenous administration. The recommended initial dose of the drug is 1-2 mg/hour until the desired blood pressure reduction is achieved.
Dose titration: The dose may be doubled at short (90 second) intervals initially. As the blood pressure approaches goal, the increase in doses should be less than doubling and the time between dose adjustments should be lengthened to every 5-10 minutes.
Maintenance dose: The desired therapeutic response for most patients occurs at doses of 4-6 mg/hour.
Maximum dose: Most patients were treated with maximum doses of 16 mg/hour or less. Because of lipid load restrictions, no more than 1000 mL or an average of 21 mg/hour of Cleviprex infusion is recommended per 24-hour period.
Clinical Results
FDA Approval

FDA approval of Cliviprex for perioperative hypertension was based on the results of two clinical trials. These double-blind, randomized, parallel, placebo controlled, multicenter trials enrolled cardiac surgery patients undergoing coronary artery bypass grafting, with or without valve replacement.
ESCAPE-1
This study evaluated the pre-operative use of Cleviprex. Inclusion required a systolic pressure >160 mmHg and the mean baseline blood pressure was 178/77 mmHg. Cleviprex was infused preoperatively for 30 minutes, until treatment failure, or until induction of anesthesia, whichever came first. The maximum infusion time was 60 minutes. Cleviprex was started at a dose of 1-2 mg/hour and was titrated upwards, as tolerated, in doubling increments every 90 seconds up to an infusion rate of 16 mg/hour in order to achieve the desired blood pressure-lowering effect. At doses above 16 mg/hour increments were 7 mg/hour. The average Cleviprex infusion rate in ESCAPE-1 was 15.3 mg/hour. The subjects treated with clevidipine achieved treatment success (at least a 15% reduction in blood pressure) 92.5% of the time, compared to 17.3% in the placebo arm. Cleviprex lowered blood pressure within 2-4 minutes.
ESCAPE-2
This study evlauated the post-operative use of Cleviprex. Inclusion required a systolic pressure of >140 mmHg within 4 hours of the completed surgery. The mean baseline blood pressure was 150/71 mmHg. Cleviprex was infused postoperatively for a minimum of 30 minutes unless alternative therapy was required. Infusion of Cleviprex was started at a dose of 1-2 mg/hour and was titrated upwards, as tolerated, in doubling increments every 90 seconds up to an infusion rate of 16 mg/hour in order to achieve the desired blood pressure-lowering effect. At doses above 16 mg/hour increments were 7 mg/hour. The average Cleviprex infusion rate was 5.1 mg/hour. Treatment success was achieved in 91.8% of clevidipine-treated patients compared with 20.4% of placebo-treated patients. Median time to achieving target SBP was 5.3 min with cleviprex.
ECLIPSE Studies
These three phase III open label studies enrolled 1,512 subjects who were randomized to receive Cleviprex, nitroglycerin (perioperative hypertension), sodium nitroprusside (perioperative hypertension), or nicardipine (postoperative hypertension), for the treatment of hypertension in cardiac surgery. The mean exposure was 8 hours at 4.5 mg/hour for the 752 patients who were treated with Cleviprex. Blood pressure control was assessed by measuring the magnitude and duration of SBP excursions outside the predefined pre- and post-operative SBP target range of 75-145 mmHg and the predefined intra-operative SBP range of 65-135 mmHg. In general, blood pressure control was similar with the four treatments.

Severe Hypertension
Cleviprex was evaluated in an open-label, uncontrolled clinical trial dubbed VELOCITY in 126 patients with severe hypertension. Cleviprex infusion was initiated at 2 mg/hour and up-titrated every 3 minutes, doubling up to a maximum dose of 32 mg/hour as required to achieve a prespecified target blood pressure range within 30 minutes (primary endpoint). The transition to oral antihypertensive therapy was assessed for up to 6 hours following cessation of Cleviprex infusion. The average infusion rate was 9.5 mg/hour. The mean duration of Cleviprex exposure was 21 hours. Transition to oral antihypertensive therapy within 6 hours after discontinuing Cleviprex infusion was successful in 91% of patients. Infusion of clevidipine reduced systolic blood pressure by 6% (12 mmHg) within 3 minutes, by 15% after 9.5 minutes and by 27% (55 mmHg) at 18 hours. Target blood pressure was reached in a median time of 10.9 minutes and 89% of patients achieved their target within 30 minutes.
Side Effects
Adverse events associated with the use of Cleviprex in the perioperative setting may include, but are not limited to, the following:
• Acute renal failure
• Atrial fibrillation
• Nausea
Adverse events associated with the use of Cleviprex for patients with severe hypertension may include, but are not limited to, the following:
• Headache
• Nausea
• Vomiting
Adverse events associated with the use of Cleviprex for patients with severe or essential hypertension may include, but are not limited to, the following:
• Myocardial infarction
• Cardiac arrest
• Syncope
• Dyspnea
Mechanism of Action
Cleviprex is an intravenous short acting dihydropyridine calcium channel antagonist. Clevidipine acts by selectively relaxing smooth muscle cells that line small arteries. This results in widening of the arterial lumen and reduction of blood pressure since the small arterioles are the primary resistance vessel within the vasculature. Clevidipine butyrate does not reduce cardiac filling pressure (pre-load), confirming lack of effects on the venous capacitance vessels.
Drug Name: Azor (amlodipine besylate; olmesartan medoxomil)
Company: Daiichi Sankyo
Approval Status: Approved September 2007
Treatment Area: Hypertension
General Information
Azor is a combination of the angiotensin II receptor antagonist olmesartan, and the calcium channel blocker amlodipine. The amlodipine component of Azor inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle, and the olmesartan medoxomil component of Azor blocks the vasoconstrictor effects of angiotensin II.
Azor is specifically indicated for the treatment of hypertension, alone or with other antihypertensive agents.
Azor is supplied as a tablet designed for oral administration. The drug comes in four strengths; the amlodipine dose is listed first and the olmesartan dose is listed second (both in mg): 5/20, 5/40, 10/20 and 10/40. The dosage may be increased after two weeks. The maximum recommended dose of Azor is 10/40.
Clinical Results
FDA Approval
FDA approval of Azor was based on the results of several clinical trials.
Azor
An 8-week, multi-center, double-blind, randomized, placebo controlled, parallel group, factorial study enrolled 1,940 subjects with mild to severe hypertension. The subjects were placed in one of 12 treatment arms to receive placebo, monotherapy treatment with amlodipine 5 mg or 10 mg, monotherapy treatment with olmesartan medoxomil 10 mg, 20 mg, or 40 mg, or combination therapy with amlodipine/olmesartan medoxomil (Azor) at doses of 5/10 mg, 5/20 mg, 5/40 mg, 10/10 mg, 10/20 mg, and 10/40 mg. Results showed that all combinations produced greater mean reductions in blood pressure than either drug alone. The highest combination dose was amlodipine 10 mg plus 40 mg olmesartan. At this dose systolic blood pressure was cut by 30.1 mm Hg, a 53% greater drop than with 10 mg amlodipine alone. Diastolic blood pressure on this dose was reduced by 19 mm Hg, compared to 12.7 for amlodipine alone.
Amlodipine
The anti-hypertensive activity of amlodipine was evaluated in 15 double-blind, placebo-controlled, randomized studies. The trials enrolled a total of 1,338 subjects with mild to moderate hypertension who were treated with amoldipine or placebo once daily. Amoldipine resulted in statistically significant placebo-corrected reductions in supine and standing blood pressures at 24 hours postdose, averaging about 12/6 mmHg in the standing position and 13/7 mmHg in the supine position. Maintenance of the blood pressure effect over the 24-hour dosing interval was observed, with little difference in peak and trough effect.
Olmesartan medoxomil
The anti-hypertensive activity of olmesartan was evaluated in 7 placebo controlled studies. A total of 2,693 subjects with essential hypertension were enrolled and received placebo or olmesartan at doses ranging from 2.5 mg to 80 mg, for 6 to 12 weeks. The blood pressure lowering effect was maintained throughout the 24-hour period, with trough-to-peak ratios for systolic and diastolic response between 60% and 80%.
Side Effects
Side effects associated with the use of Azor may include, but are not limited to, the following:
• Edema
• Hypotension
• Orthostatic Hypotension
• Rash
• Pruritus
• Palpitation
• Urinary Frequency
• Nocturia
Mechanism of Action
Azor is a combination of the angiotensin II receptor antagonist olmesartan, and the calcium channel blocker amlodipine. The amlodipine component of Azor inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle, and the olmesartan medoxomil component of Azor blocks the vasoconstrictor effects of angiotensin II.
Drug Name: Letairis (ambrisentan)
Company: Gilead
Approval Status: Approved June 2007
Treatment Area: pulmonary arterial hypertension
General Information
Letairis (ambrisentan) is a potent type-A selective endothelin receptor antagonist. Endothelin is a peptide made by the body in the endothelium. It constricts blood vessels and elevates blood pressure. Endothelin receptor antagonists (ETRAs) are a class of drugs which prevent the constriction or narrowing of blood vessels thereby enhancing blood flow throughout the body.
Letairis is specifically indicated for the treatment of pulmonary arterial hypertension in subjects with WHO class II or III symptoms to improve exercise capacity and delay clinical worsening.
Letairis is supplied as a 5 mg or 10 mg tablet designed for oral administration. The recommended initial dose of the drug is 5 mg once daily. The dose may be increased to 10 mg once daily if the 5 mg dose is tolerated.
Clinical Results
FDA Approval
FDA approval of Letairis was based on the results of two clinical trials. These 12-week, randomized, double-blind, placebo-controlled, multicenter studies were dubbed ARIES-1 and ARIES-2.
ARIES-1
Subjects in this trial received once-daily doses of Letairis (5 mg and 10 mg) or placebo. The primary endpoint was the change from baseline in the 6-minute walk distance. The mean change from baseline in the 5 mg group was 23 ± 83, in the 10 mg group 44 ± 63 versus -8 ± 79 in the placebo group. The placebo-adjusted mean change from baseline was 31 meters in the 5 mg group and 51 meters in the 10 mg group (p=0.008 and p=<0.001, respectively). The time to clinical worsening occurred in 10% of the placebo group compared to 3% of the Letairis group.
ARIES-2
Subjects in this trial received once-daily doses of Letairis (2.5 mg and 5 mg) or placebo. Again the primary endpoint was the change from baseline in the 6-minute walk test. The mean change from baseline in the 2.5 mg group was 22 ± 83, in the 5 mg group 49 ± 75 versus -10 ± 94 in the placebo group. The placebo-adjusted mean change from baseline was 32 meters in the 2.5 mg arm and 59 meters in the 5 mg arm (p=0.022 and p=<0.001, respectively). The time to clinical worsening occurred in 22% of the placebo group compared to 6% of the Letairis group.
In addtion Letairis was evaluated in an open-label long-term follow-up trial. The trial followed 383 subjects who had been previously been treated in ARIES-1 and ARIES-2. Results showed that 95% were still alive after one year and 94% were still receiving Letairis monotherapy.
Ongoing Study Commitments
• Gilead has agreed to conduct a study examining the effects of LETAIRIS on 6-minute walk distance at peak and trough plasma concentrations, and further agrees to reach agreement on an appropriate study design with the Division. Protocol Submission: October 2007Study Start: June 2008 Final Report Submission: December 2009
• Gilead has agreed to submit the results of the Phase 1 ketoconazole drug interaction study that has already been completed. Final Report Submission: October 2007
• Gilead has agreed to a post-approval commitment to explore the interaction potential of strong inhibitors of CYP2C19 (e.g. omeprazole) on ambrisentan pharmacokinetics in humans. Gilead further agreed to explore the interaction potential of cyclosporine A (strong inhibitor of OATP and P-gp) and rifampin (inhibitor of OATP and inducer of P-gp, CYPs 3A and 2C19) on ambrisentan pharmacokinetics in humans.
Protocol Submission: October 2007
• Study Start: April 2008 Final Report Submission: December 2008
Side Effects
Adverse events associated with the use of Letairis may include, but are not limited to, the following:
• Peripheral edema
• Nasal congestion
• Sinusitis
• Flushing
• Palpitations
• Nasopharyngitis
• Abdominal pain
• Constipation
Mechanism of Action
Letairis (ambrisentan) is a potent type-A selective endothelin receptor antagonist. Endothelin is a peptide made by the body in the endothelium and it constricts blood vessels and elevates blood pressure. There are two classes of endothelin receptors: Endothelin A (ET-A) and Endothelin B (ET-B). The binding of endothelin to ET-A receptors causes vasoconstriction while the binding to ET-B causes vasodilatation. Ambrisentan is a high affinity ET-A receptor antagonist with a high selectivity for the ET-A versus ET-B receptor.
Drug Name: Tekturna (aliskiren)
Company: Novartis Pharms
Approval Status: Approved March 2007
Treatment Area: hypertension
General Information
Tekturna is an orally active, nonpeptide, potent renin inhibitor. Renin is the enzyme at the beginning of the Renin Angiotensin System (RAS), one of the key regulators of blood pressure. Suppression of the RAS has been shown to treat hypertension and reduce cardiovascular events. Tekturna is specifically indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents. The use of Tekturna with maximal doses of ACE inhibitors has not been adequately studied. Tekturna is supplied as a 150 mg or 300 mg tablet designed for oral administration. The recommended initial dose of the drug is 150 mg once daily. In patients who do not have adequately controlled blood pressure, the daily dose may be increased to 300 mg.
Clinical Results
FDA Approval
FDA approval of Tekturna was based on the results of six clinical trials of aliskiren monotherapy, one trial of aliskiren alone and in combination with hydrochlorothiazide and one trial of aliskiren alone and in combination with valsartan. The six randomized, double-blind, placebo-controlled trials enrolled 2,730 subjects who received aliskiren in doses of 75-600 mg or placebo for eight weeks. Increase in response was observed for all doses studied, with reasonable effects seen at 150-300 mg, and no clear further increase at 600 mg. A substantial proportion (85%-90%) of the blood pressure lowering effect was observed within 2 weeks of treatment. Subjects in the placebo controlled trials continued in an open label trial for an additional year. A blood pressure lowering effect was demonstrated by a randomized withdrawal study, which showed a statistically significant difference between subjects kept on aliskiren and those randomized to placebo. When treatment ceased, blood pressure returned to baseline levels over a period of a couple of weeks.
Aliskiren and hydrochlorothiazide were studied alone and in combination with each-other. This randomized, double-blind, placebo-controlled, parallelgroup, 15-arm factorial study enrolled 2,776 subjects. Aliskiren was administered in doses of 75, 150, and 300 mg and hydrochlorothiazide in doses of 6.25, 12.5, and 25 mg, for eight weeks. Blood pressure reductions with the combinations were greater than the reductions with the monotherapies.
Aliskiren and valsartan were studied alone and in combination with each-other. This randomized, double-blind, placebo-controlled, parallel-group, 4-arm, dose escalation study enrolled 1,797 subjects. The dosages of aliskiren and valsartan were started at 150 and 160 mg, respectively, and increased at four weeks to 300 mg and 320 mg, respectively. Seated trough cuff blood pressure was measured at baseline, 4, and 8 weeks. Blood pressure reductions with the combinations were greater than the reductions with the monotherapies.
Ongoing Study Commitments
• Novartis has agreed to a deferred pediatric study under PREA for the treatment of hypertension in pediatric patients ages 6 to 16 years. Final Report Submission: March 5, 2009
• Novartis has agreed to submit the results of the cellular markers of proliferation and apoptosis from Study 2103 as soon as they are available, but no later than September 2007. Final Report Submission: 09/07
• Novartis has agreed to include intestinal procedures and neoplasms and angioedema as events of special interest in your proposed ALTITUDE trial as detailed in their special protocol assessment letters. You committed to providing safety information and periodic summaries during the ALTITUDE trial for the parameters of special interest. The data should be submitted when the final study report comes in. The periodic summaries will include: Monthly line listings of suspected/non suspected SAE and non serious AE (reported in the previous month) and Aggregate summaries (cumulative) of suspected/non suspected SAE and non serious AE in PSUR semi-annually for the first 2 years post-launch and annually thereafter. Protocol Submission: 09/07
Study Completion: 09/11Final Report Submission: 03/12
• Novartis has agreed to incorporate a colonoscopy substudy into their proposed long-term outcome study. The colonoscopy substudy should include colonoscopies performed at baseline and after drug treatment for 12 months or longer. This study should be powered to rule out a doubling in the rate of cancerous or precancerous lesions. They should discuss this substudy with the Agency.Protocol Submission: 09/07
Study Completion Date: 02/09 Final Report Submission: 05/09
• Novartis has agreed to provide evidence that it is not likely to be clinically useful to give aliskiren in a twice-daily dosing regimen to patients whose blood pressure is not controlled on the highest recommended dose given once daily. These data could come from a study comparing once- and twice-daily dosing, but the Division would consider alternative strategies to address this issue. Protocol Submission: 06/07
Final Report Submission: 02/09
Side Effects
Adverse events associated with the use of Tekturna may include, but are not limited to, the following
• Hand, face and/or body edema
• Diarrhea
• Abdominal pain
• Dyspepsia
• Gastroesophageal reflux
• Rash
• Elevated uric acid
• Gout
• Renal stones
Mechanism of Action
Tekturna is a renin inhibitor. Renin is secreted by the kidney in response to decreases in blood volume and renal perfusion. Renin cleaves angiotensinogen, a peptide in the blood that causes vasoconstriction and increased blood pressure, to form the inactive decapeptide angiotensin I (Ang I). Ang I is converted to the active octapeptide angiotensin II (Ang II) by angiotensin-converting enzyme (ACE) and non-ACE pathways. Ang II is a vasoconstrictor and leads to the release of catecholamines from the adrenal medulla and prejunctional nerve endings. It also promotes aldosterone secretion and sodium reabsorption, which increases blood pressure and it inhibits renin release, providing a negative feedback to the system. This cycle is known as the renin-angiotensin-aldosterone system (RAAS). Thus, as a direct renin inhibitor, Tekturna disrupts the RAAS process by decreasing plasma renin activity (PRA) and inhibiting the conversion of angiotensinogen to Ang I.
Drug Name: BiDil (isosorbide dinitrate/hydralazine hydrochloride)
Company: NitroMed
Approval Status: Approved June, 2005
Treatment Area: Heart Failure
General Information
BiDil is a single-pill, fixed-dose combination of two generic drugs, isosorbide dinitrate and hydralazine hydrochloride. The combination exerts vasodialtory effects on both arterial and veinous vascular systems.
BiDil is specifically indicated for the adjunctive treatment of heart failure in self identified black patients, in addition to standard therapy. Addition of BiDil to standard regimens is aimed at prolonging time to hospitalization, improving patient-reported functional status, and reducing all-cause mortality. BiDil was not significantly efficacious in treating broader patient populations or other self-identified racial groups.
BiDilis supplied as a biconvex film-coated orange tablet. The recommended initial dose is one tablet of BiDil (20 mg isosorbide dinitrate, 37.5 mg hydralazine hydrochloride) thrice daily. Regimens may be titrated to maximum tollerated dose as required, but should not exceed 2 tablets thrice daily.
Clinical Results
FDA Approval
Approval of BiDil was based on two placebo-controlled clinical trials (V-HeFT I and A-HeFT) and one active-controlled clinical trial (V-HeFT II), which compared BiDil to enalapril. V-HeFT I enrolled 459 men with impaired cardiac function and reduced exercise tolerance, who were randomized to receive 75 mg/40 mg qid (n=186) or placebo (n=273), in addition to continuation of standard therapy with digitalis glycosides and diuretics. Trial data from the general patient cohort yielded no significant difference in all-cause mortality between the treatment group and placebo, though a trend towards improvement was noted. Retrospective analysis showed that this trend correlated with patients’ self-identified racial group: patients who self-identified as black or African-American showed improvements in survival, while self identified white or Caucasian-American patients showed no difference from placebo.
The V-HeFT II trial enrolled 804 men with impaired cardiac function and reduced exercise tolerance, who were randomized to receive either 75 mg/40 mg or enalapril, in addition to continuation of standard therapy with digitalis glycosides and diuretics. Trial data indicated that the drug combination was inferior to enalapril. Retrospecitve analysis again indicated that efficacy correlated with self-identified race: inferiority was observed only in the white population (n=574), with no significant difference in black patients (n=215).
The A-HeFT trial enrolled 1,050 self- identified black patients (men and women) with stable symptomatic heart failure across 169 sites in the United States. Subjects were randomized to receive either BiDil (n=518) or placebo (n=532) for up to 18 months, in addition to maintained stable background therapy. BiDil dosing was initiate at 20 mg isosorbide dinitrate/37.5 mg hydralazine hydrochloride three times daily, and titrated to a target dose of 40/75 mg three times daily or to the maximum tolerated dose. Trial results yielded significant efficacy in the primary endpoint, a composite score of all-cause mortality, first-hospitalization for heart failure, and responses to the Minnesota Living with Heart Failure (MLHF) questionnaire. Specifically, BiDil produced a 43% reduction in all cause mortality (p=0.012) and 8% fewer first-hospitalizations (16.4% vs. 24.4%; p<0.001), and a highly significant reduction in MLHF score (p<0.01) at 12 months vs. placebo; these strongly positive results produced significant improvement in the composite score (p<0.021), and lead to early termination of the trial so that subjects receiving placebo could be switched to the BiDil regimen. Secondary results indicated that the drug produced a reduction in mean blood pressure (3/3 mmHg lower) compared to placebo; whether this effect contributed to improved primary patient outcomes was unknown.
Side Effects
Adverse events associated with the use of BiDil may include, but are not limited to, the following:
• Malaise
• Cholecystitis
• Hypercholesterolemia
• Angioedema
• Headache
• Dizziness
• Chest Pain
• Asthenia
• Nausea
• Bronchitis
• Hypotension
Mechanism of Action
The specific mechanism of action of the comnbination of isosorbide dinitrate and hydralazine hydrochloride has not been established. Independently, isosorbide dinitrate has been shown to exert vasodilatory effects in both arteries and veins. The drug releases nitric oxide, activating guanylyl cyclase and relaxing vascular smooth muscle. Hydralazine has also been shown to relax arterial smooth muscle, and may mitigate tolerance to nitrate therapy, thus exerting synergistic activity with isosorbide.
Drug Name: Caduet (amlodipine/atorvastatin )
Company: Pfizer
Approval Status: Approved January 2004
Treatment Area: Hypertension/Angina
General Information
Caduet combines the drugs amlodipine (Norvasc, Lotrel) and atorvastatin (Lipitor), two widely prescribed cardiovascular medications. It's the first medicine to treat two different conditions, high blood pressure and high cholesterol.
It is indicated for the treatment of hypertension, chronic stable angina and vasospastic angina (Prinzmetal’s or variant angina). It is also indicated for primary dysbetalipoproteinemia, elevated serum TG levels, hypercholesterolemia and mixed dyslipidemia. In addition, is indicated as an adjunct to diet to reduce total-C, LDL-C, and apo B levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia
The recommened initial antihypertensive oral dose of amlodipine is 5 mg once daily with a maximum dose of 10 mg once daily.
Clinical Results
FDA approval of Caduet was based on a double-blind, placebo-controlled study enrolling 1,600 subjects with co-morbid hypertension and dyslipidemia. Results showed that all combination-treatment groups of amlodipine and atorvastatin demonstrated statistically significant dose-related reductions in systolic blood pressure (SBP), Diastolic Blood pressure (DBP) and LDL-C compared to placebo.
Subjects received once daily treatment with eight dose combinations of amlodipine and atorvastatin (5/10, 10/10, 5/20, 10/20, 5/40, 10/40, 5/80, or 10/80mg), amlodipine alone (5 mg or 10 mg), atorvastatin alone (10 mg, 20 mg, 40 mg, or 80 mg) or placebo.
Side Effects
Adverse events associated with the use of Caduet may include (but are not limited to) the following:
•
• Headache
• Abdominal Pain
• Rash
• Chest pain,
• Nausea
• Insomnia
• Dizziness
Mechanism of Action
Amlodipine, a long acting calcium ion antagonist, is the active ingredient in Norvasc (Pfizer) and Lotrel (Novartis). Amlodipine inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The drug binds to dihydropyridine and nondihydropyridine binding sites. In addition, amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.
Atorvastatin, a HMGCoA reductase inhibitor indicated for lowering cholesterol, is the active ingredient in Lipitor (Pfizer). Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMGCoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell-surface to enhance uptake and catabolism of LDL.
Drug Name: Benicar
Company: Sankyo Pharma
Approval Status: Approved April 2002
Treatment Area: Hypertension
General Information
Benicar is an angiotensin II receptor blocker (ARB) approved for the treatment of hypertension. This once-daily oral tablet that may be administered alone or in combination with other antihypertensive agents.
Hypertension, the term used for abnormally high blood pressure, is the most common health problem in the United States. Over 50 million Americans suffer from hypertension, but many are unaware of the problem and remain untreated. Left untreated, it can lead to serious and life-threatening events including stroke and heart attack.
Clinical Results
Approval of Benicar is supported by 7 placebo-controlled studies, with doses ranging from 2.5 to 80 mg, given for six to 12 weeks. The trials included more than 3275 subjects with essential hypertension. All seven studies reported significant reductions in peak and trough levels of diastolic and systolic blood pressure. Response was dose-related, with 20 mg and 40 mg doses inducing the desired effect and doses over 40 mg having little additional effect. The blood pressure lowering effect from using Benicar once-daily was maintained throughout the 24 hour period, with trough-to-peak ratios for systolic and diastolic response between 60 and 80%.
Side Effects
Adverse events associated with the use of Benicar may include (but are not limited to) the following:
Dizziness
Mechanism of Action
Benicar (olmesartan medoxomil) blocks the vasoconstrictive effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT receptor in vascular smooth muscle.
Drug Name: Inspra (eplerenone tablets)
Company: Pharmacia
Approval Status: Approved September 2002
Treatment Area: Hypertension
General Information
Inspra is indicated for the treatment of hypertension (high blood pressure) and may be used alone or in combination with other anti-hypertensive agents. Inspra is also being studied for use in heart failure; as a selective aldosterone receptor antagonist, Inspra may offer advantages over currently available non-selective aldosterone antagonists.
Inspra for oral administration contains 25 mg, 50 mg, or 100 mg of eplerenone. The recommended starting dose of Inspra is 50 mg administered once daily. The full therapeutic effect of Inspra is apparent within 4 weeks.
Clinical Results
Inspra was demonstrated to be effective in lowering high blood pressure in over 3,000 patients and was generally well tolerated. Patients treated with Inspra 50 to 200 mg daily experienced significant decreases in sitting systolic and diastolic blood pressure at trough with differences from placebo of 6-13 mm Hg (systolic) and 3-7mm Hg (diastolic). These effects were confirmed by assessments with 24-hour ambulatory blood pressure monitoring (ABPM).
Blood pressure lowering was apparent within 2 weeks from the start of therapy with Inspra, with maximal antihypertensive effects achieved within 4 weeks. Stopping Inspra following treatment for 8-24 weeks in six studies did not lead to adverse event rates in the week following INSPRA withdrawal greater than following placebo or active control withdrawal. Blood pressures in patients not taking other antihypertensives rose 1 week after Inspra withdrawal by about 6/3 mm Hg, suggesting that Inspra antihypertensive effect was maintained through 8-24 weeks.
Side Effects
Adverse events associated with the use of Inspra may include (but are not limited to) the following:
• Headache
• Dizziness
• Angina pectoris/myocardial infarction
• Increased GGT
Mechanism of Action
The hormone aldosterone is a key component within the RAAS (renin angiotensin aldosterone system) and plays a significant role in the body’s regulation of the cardiovascular system. Inspra works with relative selectivity to block aldosterone receptors.Aldosterone synthesis, which occurs in the adrenal gland, is modulated by multiple factors, including angiotensin II and non-RAAS mediators such as adrenocorticotropic hormone (ACTH) and potassium. Aldosterone binds to mineralocorticoid receptors in both epithelial (e.g., kidney) and nonepithelial (e.g., heart, blood vessels, and brain) tissues and increases blood pressure through induction of sodium reabsorption and possibly other mechanisms.
Eplerenone has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with inhibition of the negative regulatory feedback of aldosterone on renin secretion. The resulting increased plasma renin activity and aldosterone-circulating levels do not overcome the effect of eplerenone on blood pressure.
Drug Name: Remodulin (treprostinil)
Company: United Therapeutics
Approval Status: Approved May 2002
Treatment Area: pulmonary arterial hypertension
General Information
Remodulin (treprostinil sodium) injection is a continuous subcutaneous infusion for the treatment of pulmonary arterial hypertension (PAH) in patients with NYHA Class II-IV symptoms. Remodulin is intended to diminish the symptoms, such as shortness of breath, associated with physical activity in PAH patients.
Remodulin is supplied in concentrations of 1.0 mg/mL, 2.5 mg/mL, 5.0 mg/mL and 10.0 mg/mL. The standard infusion rate is 1.25 ng/kg/min, but can be reduced in the event that the original dose cannot be tolerated.
Pulmonary arterial hypertension (PAH) is a disease in which blood pressure is abnormally high in the arteries between the heart and lungs. PAH is characterized by symptoms of shortness of breath during physical exertion. The condition can ultimately lead to heart failure.
Clinical Results
Two 12-week, multicenter, randomized, double-blind studies were conducted to compare Remodulin to placebo. A total of 470 subjects with NYHA Class II-IV pulmonary arterial hypertension (PAH) we enrolled in the studies. The baseline measures were 6-minute walking distance and level of shortness of breath during this physical test (Borg dyspnea score). The primary endpoint was change in 6-minute walking distance over the 12-week treatment period. There was a noteworthy change in 6-minute walking distance for those subjects treated with Remodulin, although the effects did not achieve conventional levels of statistical significance. There was a statistically significant change in subjects' Borg dyspnea scores with the Remodulin treatment. There were significant differences between Remodulin- and placebo-treated subjects in eight out of ten hemodynamic parameters that were evaluated, including cardiac index; mean pulmonary arterial pressure; pulmonary vascular resistance indexed; mean right atrial pressure; systemic vascular resistance indexed; mixed venous oxygen saturation. The two hemodynamic parameters that did not achieve statistical significance were mean systemic arterial pressure and heart rate.
At the time of FDA approval, clinical studies of Remodulin were still ongoing for the PAH indication to explore further effects and potential benefits of the drug. In addition, a post-marketing, phase IV clinical trial is expected to commence.
Side Effects
In clinical trials, infusion site pain and infusion site reaction were the most frequently reported adverse events. Both of these effects were experienced by over 80% subjects receiving Remodulin therapy.
The following adverse events were also reported in clinical trials:
• Headache
• Diarrhea
• Nausea
• Rash
• Jaw pain
• Vasodilatation
• Dizziness
• Edema
• Pruritus (itching)
• Hypotension
Mechanism of Action
The major pharmacological actions of treprostinil are direct vasodilation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation. (From prescribing information)
Drug Name: Diovan
Company: Novartis
Approval Status: Approved January 1997 (capsules); July 2001 (tablets)
Treatment Area: Hypertension
General Information
Diovan, in both capsule and tablet formulations, has been approved for the treatment of hypertension in adult subjects. It offers blood pressure control comparable to current leading antihypertensive therapies (lisinopril and enalapril) and an outstanding side effect profile.
As with other drugs that affect the renin-angiotensin system, Diovan can cause fetal and neonatal morbidity and death when administered to pregnant women. Diovan therapy should be discontinued as soon as pregnancy is detected.
Hypertension, the term used for abnormally high blood pressure, is the most common health problem in the United States. Over 50 million Americans suffer from hypertension, but many are unaware of the problem and remain untreated. Left untreated, it can lead to serious and life-threatening events including stroke and heart attack.
Clinical Results
Diovan capsules were evaluated in seven placebo-controlled, four to 12 week trials in adult subjects with baseline diastolic blood pressures of 95-115. One trial included subjects over the age of 65. In total, over 2000 subjects were randomized to various doses of the drug and about 800 were treated with placebo.
Results indicated that administration of Diovan to hypertensive subjects led to a significant decrease in sitting, supine, and standing systolic and diastolic blood pressure, usually with little or no orthostatic change.
Side Effects
Adverse events associated with the use of Diovan capsules and tablets may include (but are not limited to) the following:
•
• Headache
• Dizziness
• Viral infection
• Fatigue
• Abdominal pain
Warning - Diovan should not be taken during pregnancy.
Mechanism of Action
Diovan (valsartan) blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues. Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects including vasocantstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium.
Additional Information
Drug Name: Teveten HCT (eprosartan sylate/hydrochlorothiazide)
Company: Unimed Pharmaceuticals
Approval Status: Approved November 2001
Treatment Area: Hypertension
General Information
Teveten HCT, a combination of eprosartan mesylate and hydrochlorothiazide, has been approved by the FDA for the treatment of hypertension (high blood pressure). Eprosartan mesylate works by blocking the angiotensin II receptor. The hormone angiotensin II plays a role in hypertension by causing blood vessels to constrict, which raises blood pressure. By blocking the effects of angiotensin II, eprosartan mesylate prevents this pressure increase. Hydrochlorothiazide is also an anti-hypertensive compound; however, the way in which thiazides produce this effect is unknown.
According to the National Heart, Lung, and Blood Institute, it is estimated that one in every four American adults has hypertension. Hypertension can be defined as a sustained elevation of the force of blood against the walls of the arteries. The first line of treatment for hypertension is changing unhealthy lifestyle habits; if this is not sufficient, blood pressure medications may be utilized.
Side Effects
Side effects reported with eprosartan mesylate use in clinical trials include:
• Upper respiratory tract infection
• Rhinitis
• Pharyngitis (inflammation of the pharynx)
• Cough
• Fatigue
• Abdominal pain
• Joint pain
Mechanism of Action
Angiotensin II, a potent vasoconstrictor, is the principal pressor agent of the renin-angiotensin system. Angiotensin II also stimulates aldosterone synthesis and secretion by the adrenal cortex, cardiac contraction, renal resorption of sodium, activity of the sympathetic nervous system, and smooth muscle cell growth. Eprosartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor found in many tissues (e.g., vascular smooth muscle, adrenal gland). (from Teveten Prescribing Information)
Drug Name: Atacand HCT
Company: AstraZeneca
Approval Status: Approved September 2000
Treatment Area: For the treatment of hypertension
General Information
Atacand HCT (candesartan cilexetil-hydrochlorothiazide) has been developed for the treatment of hypertension, and may be helpful when single products are unsuccessful in reducing blood pressure. Atacand HCT consists of two active ingredients: an angiotensin II receptor antagonist and a diuretic hydrochlorothiazide. It works by inhibiting the effects of angiotensin II, which is an agent that causes vasoconstriction and high blood pressure. Additionally, hydrochlorothiazide reduces blood pressure by improving the kidneys' ability to eliminate salt and fluid from the body. Atacand HCT is available in two tablet strengths: 32 mg Atacand-12.5 mg hydrochlorothiazide and 16 mg Atacand-12.5 mg hydrochlorothiazide.
Clinical Results
Five double-blind, placebo-controlled trials evaluated candesartan cilexetil-hydrochlorothiazide. These five trials, of 8 to 12 weeks duration, consisted of 3037 hypertensive patients. Doses ranged from 2 to 32 mg candesartan cilexetil and from 6.25 to 25 mg hydrochlorothiazide administered once daily in various combinations.
The combination of candesartan cilexetil-hydrochlorothiazide resulted in placebo-adjusted decreases in sitting systolic and diastolic blood pressures of 14-18/8-11 mm Hg at doses of 16-12.5 mg and 32-12.5 mg (the two tablet stengths). In long-term studies of up to one year, the blood pressure lowering effect of the combination was maintained.
Side Effects
The most common adverse events observed with Atacand HCT use include the following:
•
• Upper respiratory infection
• Dizziness
• Back pain
• Flu-like symptoms
Atacand HCT should not be used by pregnant women and should be discontinued if pregnancy is detected.
Mechanism of Action
Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Candesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues. Its action is, therefore, independent of the pathways for angiotensin II synthesis.
Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. (from FDA Label)
Drug Name: Diltiazem HCL, Extended-Release Capsules
Company: Biovail Laboratories
Approval Status: Approved January 2000
Treatment Area: Indicated for the treatment of hypertension; for use alone or in combination with other anti-hypertensive medications
General Information
The Diltiazem Hydrochloride extended-release capsules, taken in 120 to 240 mg a day doses, are principally used to reduce high blood pressure (hypertension).
According to the American Heart Association, high blood pressure in adults defined as a blood pressure greater than or equal to 140 mm Hg systolic pressure or greater than or equal to 90 mm Hg diastolic pressure. High blood pressure has been directly linked to increases in the risk of various heart and brain conditions such as coronary heart disease and stroke.
While high blood pressure can occur in anyone, high risk groups include blacks, middle-aged and elderly adults, obese people, heavy drinkers, and women taking oral contraceptives.
Clinical Results
Clinical studies compared the Diltiazem HCL extended release capsules with the Diltiazem HCL tablets. The two forms of the drug were shown to have similar trends in half-life, despite the difference in absorption rate. It was found that 95% of the extended-release capsule is absorbed throughout the dosing interval. The capsules take effect within two to three hours and active effects are detected for 10 to 14 hours.
Side Effects
Common side effects include headache, drowsiness, swelling of feet and ankles, constipation, nausea, sudden weight gain, and fatigue.
More serious, but less common side effects include, irregular or slow heartbeat, shortness of breath, and fatigue caused by heart failure.
There may be some drug interactions between Diltiazem HCL and aspirin, beta-blockers, digitalis preparations, carbamazepine, cyclosporine, digoxin, lithium, oral diabetes agents, phenytoin, rifampin, cimetidine, fluvoxamine, or ranitidine.
Warning
Suddenly discontinuing use of this drug may cause serious health problems. Any discontinuance of the drug should be in gradual dosage reductions.
Mechanism of Action
Diltiazem interferes with the movement of calcium into heart muscle cells and the smooth muscle cells in the walls of the arteries. This action relaxes blood vessels (causing them to widen), which lowers blood pressure, increases the blood supply to the heart, and decreases the hearts overall workload. "from www.DiscoveryHealth.com"
Drug Name: Micardis (hydrochlorothiazide; telmisartan) Tablet
Company: Boehringer Ingelheim
Approval Status: Approved November 2000
Treatment Area: Hypertension
General Information
Micardis is a pill containing 2 drugs composed of hydrochlorothiazide and telmisartan. Hydrochlorothiazide is a diuretic and telmisartan is an orally active angiotensin II antagonist acting on the AT1 receptor subtype. Micardis is available by prescription only.
Clinical Results
Clinical trials involving more than 2500 patients were conducted to test the effects of telmisartan and hydrochlorothiazide in combination for the treatment of hypertension. 1017 patients were given telmisartan (20 to 160 mg) and concomitant hydrochlorothiazide (6.25 to 25 mg). One factorial trial was included where patients were given combinations of telmisartan (20, 40, 80, 160mg or placebo) and hydrochlorothiazide (6.25, 12.5, 25mg and placebo). For patients who did not experience adequate control of their condition with the randomized monotherapy dose or had not achieved adequate response after completing the up-titration of telmisartan, four other studies were held of at least six months duration which allowed the add-on of hydrochlorothiazide.
The combination of telmisartan and hydrochlorothiazide resulted in additive placebo-adjusted decreases in systolic and diastolic blood pressure at trough of 16-21/9-11 mmHg at 40/12.5 mg and 80/12.5 mg, compared to 9-13/7-8 mmHg for telmisartan 40 mg to 80 mg and 4/4 mmHg for hydrochlorothiazide 12.5 mg alone.
In active controlled studies, the addition of 12.5 mg hydrochlorothiazide to titrated doses of telmisartan in patients who did not achieve or maintain adequate response with telmisartan monotherapy further reduced systolic and diastolic blood pressure.
The antihypertensive effect was independent of age or gender.
There was essentially no change in heart rate in patients treated with the combination of telmisartan and hydrochlorothiazide in the placebo controlled trial. (From FDA Label)
Side Effects
Micardis has been found to cause fetal and neonatal morbidity and death when taken by pregnant women. Numerous birth defects have been reported associated with angiotensin II receptor antagonists. Pregnant mothers should discontinue use of Micardis as soon as possible and physicians should warn them of all the risks to their fetus if the decision is made to continue treatment.
Possible side effects of Micardis include, but are not limited to:
• fatigue
• flu-like symptoms
• dizziness
• diarrhea
• nausea
• sinusitis
• upper respiratory tract infection
In clinical trials side effects have generally been mild and have not required discontinuation of therapy. For more information on side effects associated with telmisartan or hydrochlorothiazide
Mechanism of Action
Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principle pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Telmisartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis.
There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Telmisartan has much greater affinity (>3,000 fold) for the AT1 receptor than for the AT2 receptor.
Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because telmisartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Telmisartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of telmisartan on blood pressure.
Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium salt and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases n serum potassium. The renin-aldosterone link is mediated by angiotensin II, so coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics.
The mechanism of the antihypertensive effect of thiazides is not fully understood.
(From FDA Label)
Drug Name: Prinivil or Zestril (Lisinopril)
Company: Merck, Zeneca
Approval Status: Approved November 24, 1995
Treatment Area: hypertension, heart failure, acute myocardial infarction
General Information
This drug is being marketed by both Merck and Zeneca. The Merck product is called Prinivil; Zeneca's product is called Zestril.
Prinivil is indicated for the treatment of hypertension, heart failure, and acute myocardial infarction. It may be used alone as initial therapy or concomitantly with other classes of antihypertensive agents. It is indicated as adjunctive therapy in the management of heart failure in subjects who are not responding adequately to diuretics and digitalis. It is also indicated for the treatment of hemodynamically stable subjects within 24 hours of acute myocardial infarction, to improve survival.
Clinical Results
In most hypertensive subjects studied, onset of antihypertensive activity was seen at one hour after oral administration of an individual dose of Prinivil, with peak reduction of blood pressure achieved by six hours. Although an antihypertensive effect was observed 24 hours after dosing with recommended single daily doses, the effect was more consistent and the mean effect was considerably larger in doses of 20 mg or more than with lower doses. However, at all doses studied, the mean antihypertensive effect was substantially smaller 24 hours after dosing than it was six hours after dosing.
During baseline-controlled clinical trials in subjects receiving digitalis and diuretics, single doses of Prinivil resulted in decreases in pulmonary capillary wedge pressure, systemic vascular resistance, and blood pressure accompanied by an increase in cardiac output and no change in heart rate.
A multicenter, controlled, randomized, unblinded clinical trial was conducted in 19,394 subjects with acute myocardial infarction admitted to a coronary care unit. The trial was designed to examine the effects of short-term (6-week) treatment with Prinivil, nitrates, their combination, or no therapy. Subjects receiving Prinivil alone or with nitrates had an 11% lower risk of death compared to patients receiving no Prinivil at 6 weeks.
Side Effects
Prinivil was found to be generally well tolerated in controlled clinical trials. For the most part, the following adverse effects were mild and transient: fatigue, diarrhea, nausea, headache, and dizziness.
Mechanism of Action
The effects of Prinivil in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin-aldosterone system. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion.
Additional Information
When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, Prinivil should be discontinued as soon as possible.
Drug Name: Tiazac (diltiazem hydrochloride)
Company: Forest Laboratories
Approval Status: Approved February 1996

Treatment Area: hypertension
General Information
Tiazac has been approved as a treatment for hypertension. The once-daily calcium channel blocker reduces blood pressure of hypertensive subjects. Through its extended-release, osmotic diffusion system of concentrated diltiazem beads, Tiazac delivers smooth 24-hour plasma levels, which are highly correlated with blood pressure measurements. When properly dosed, Tiazac provides smooth and predictable 24-hour blood pressure control. A greater blood pressure reduction is achieved with Tiazac when blood pressure is at its highest, yet Tiazac achieves blood pressure reduction without causing hypotension during periods of lower blood pressure.
Tiazac, a highly concentrated formulation of diltiazem, enables more drug to be contained inside a smaller capsule. This formulation allows for both smaller capsules for a given dosage, relative to the same dose of other once-daily diltiazem products, and for five dosage strengths: 120, 180, 240, 300, and 360 mg.
Tiazac, as with all diltiazem formulations, should not be used in subjects with severe hypotension (less than 90 mm Hg systolic), acute myocardial infarction and pulmonary congestion documented by x-ray on admission, subjects with sick sinus syndrome or 2nd/3rd-degree AV block (unless used with a pacemaker), and subjects who have demonstrated hypersensitivity to the drug. This drug should be used with caution in subjects with impaired kidney, liver, or heart function.
Clinical Results
In a major comparative trial of single-drug therapy for hypertension, diltiazem showed blood pressure control greater than or comparable to that of six other antihypertensives from different drug classes. African-American patients in the study responded especially well to diltiazem therapy, while Caucasians responded well to all drug classes.
Doses of Tiazac up to 360 mg exhibited a side-effect profile similar to that of the lower doses, and similar to placebo. Tiazac can be safely dosed up to 540 mg. In clinical trials, absorption of Tiazac was not affected by food intake: Tiazac can be taken with or without food, even high-fat meals.
Tiazac showed no clinically significant changes in ECG readings, no increases in 2nd or 3rd-degree AV heart block and no more than a slight decrease in heart rate.
Side Effects
Tiazac was well tolerated in clinical trials. The most commonly reported side effects were headache, peripheral edema, pain, dizziness, and asthenia.
Mechanism of Action
Tiazac produces its antihypertensive effect primarily by relaxation of vascular smooth muscle and the resultant decrease in peripheral vascular resistance. The magnitude of blood pressure reduction is related to the degree of hypertension: thus hypertensive individuals experience an antihypertensive effect, whereas there is only a modest fall in blood pressure in normotensives.
Additional Information
Blood pressure normally varies throughout the day and night and is influenced by the subject’s own circadian rhythm and external stimuli. In hypertensive subjects, blood pressure needs 24-hour control to achieve blood pressure levels that approach treatment goals.
Drug Name: Micardis
Company: Boehringer Ingelheim
Approval Status: Approved November 1998
Treatment Area: Cardiology
General Information
Treatment for hypertension. It may be used alone or in combination with other antihypertensive agents.
Side Effects
Micardis has been evaluated for safety in more than 3700 patients, including 1900 treated for over six months and more than 1300 for over one year. Adverse experiences have generally been mild and transient in nature and have only infrequently required discontinuation of therapy.
Mechanism of Action
Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin- converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Telmisartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT 1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis. There is also an AT 2 receptor found in many tissues, but AT 2 is not known to be associated with cardiovascular homeostasis. Telmisartan has much greater affinity (>3,000 fold) for the AT 1 receptor than for the AT 2 receptor. Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because telmisartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Telmisartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of telmisartan on blood pressure.
Drug Name: Atacand (R) (candesartan cilexetil)
Company: Astra Merck
Approval Status: Approved June 1998

Treatment Area: hypertension
General Information
Astra Merck, Inc. announced it has received approval from the US Food and Drug Administration (FDA) to market Atacand (R) (candesartan cilexetil) for once-daily treatment of hypertension. Atacand belongs to a group of antihypertensive medications called angiotensin II receptor blockers (ARB) which represent the first new class of antihypertensive agents in the U.S. in more than a decade.
Clinical Results
In clinical trials involving more than 7000 hypertensive patients, Atacand has been shown to reduce blood pressure in a consistent and dose-dependent manner over a 24-hour period. In clinical trials, treatment with Atacand has been well tolerated with an adverse event rate similar to placebo.
Side Effects
Adverse experiences that occurred in at least one percent of patients treated with Atacand and at a higher incidence versus placebo included back pain, dizziness, upper respiratory tract infection, pharyngitis and rhinitis. Atacand should not be used in women who are pregnant or by people who are allergic to any component of the medication.
Drug Name: Atacand
Company: Astra Merck
Approval Status: Approved June 1998
Treatment Area: hypertension
General Information
Atacand has been approved for once-daily treatment of hypertension. Atacand belongs to a group of antihypertensive medications called angiotensin II receptor blockers (ARB) which represent the first new class of antihypertensive agents in the United States in more than a decade.
Clinical Results
In clinical trials involving more than 7,000 hypertensive patients, Atacand has been shown to reduce blood pressure over a 24-hour period.
Side Effects
Adverse experiences that occurred in at least one percent of patients treated with Atacand and at a higher incidence vs. placebo included back pain, dizziness, upper respiratory tract infection, pharyngitis, and rhinitis. The drug should not be used in women who are pregnant or by people who are allergic to any component of the medication.


DRUG ARE UNDER CLINICAL TRIAL:-
Hypertension Study CLCI699A2201
Novartis is conducting this clinical research study is to find out if the study drug LCI699 is safe, tolerable, and helps to lower blood pressure in participants who have mild to moderate hypertension (high blood pressure). Participants must be between 18 and 75 years old. The study drug LCI699 is considered investigational which means that it is still being tested and is not approved by the Health Authorities.
Hypertension Study CSAH100A2302
Novartis Pharmaceuticals is conducting this clinical research trial is to determine if the drug combination of aliskiren (Tekturna®), Amlodipine (Norvasc®)and hydrochlorothiazide (HCT) are safe and will effectively lower blood pressure in patients with moderate to severe high blood pressure.

Each drug used alone and the combination of aliskiren/hydrochlorothiazide are approved by the US Food and Drug Administration (FDA) and are available for sale in the U.S.

The combination of aliskiren, hydrochlorothiazide and amlodipine is considered investigational. The word investigational means that this combination is still being tested and is not approved by the FDA and is NOT available for sale in the U.S.
Hypertension Study CSPP100A2409
Novartis is conducting this clinical research trial to find out if the drug aliskiren hydrochlorothiazide (Tekturna® HCT) compared to amlodipine (Norvasc®) alone is safe and will effectively lower blood pressure in participants who have diabetes and stage 2 systolic hypertension (which occurs when systolic blood pressure is greater than or equal to 160 mm Hg or less than 200 mm Hg).Both medicines are approved by the US Food and Drug Administration (FDA) for the treatment of people with high blood pressure.
Hypertension Study CSPP100A2411
Novartis is conducting this clinical research trial to find out if the drug aliskiren hydrochlorothiazide (Tekturna® HCT) compared to hydrochlorothiazide (HCTZ) alone is safe and will effectively lower blood pressure. Patients must be 55 years or older and have stage 2 systolic high blood pressure (systolic blood pressure greater than or equal to 160 mm Hg or less than 200 mm Hg). Both the combination of aliskiren hydrochlorothiazide and hydrochlorothiazide alone are approved by the US Food and Drug Administration (FDA) and are available for sale in the U.S.
Hypertension Study CVAH631BUS08
Novartis clinical trials is performing this clinical research study to determine the efficacy and safety of the combination of the study drug valsartan plus hydrochlorothiazide (known as Diovan HCT®) compared to patients initiated with either valsartan or hydrochlorothiazide. Participants must be at least 75 years old and have high blood pressure and will be asked to visit the study center 8 to 10 times over a 16 week period. Diovan HCT® has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of high blood pressure.
Hypertension Study CSAH100A2302
Novartis Pharmaceuticals is conducting this clinical research trial is to determine if the drug combination of aliskiren (Tekturna®), Amlodipine (Norvasc®)and hydrochlorothiazide (HCT) are safe and will effectively lower blood pressure in patients with moderate to severe high blood pressure.

Each drug used alone and the combination of aliskiren/hydrochlorothiazide are approved by the US Food and Drug Administration (FDA) and are available for sale in the U.S.
Hypertension Study CSPP100A2409
Novartis is conducting this clinical research trial to find out if the drug aliskiren hydrochlorothiazide (Tekturna® HCT) compared to amlodipine (Norvasc®) alone is safe and will effectively lower blood pressure in participants who have diabetes and stage 2 systolic hypertension (which occurs when systolic blood pressure is greater than or equal to 160 mm Hg or less than 200 mm Hg).Both medicines are approved by the US Food and Drug Administration (FDA) for the treatment of people with high blood pressure.
Hypertension Study CVAH631BUS08
Novartis clinical trials is performing this clinical research study to determine the efficacy and safety of the combination of the study drug valsartan plus hydrochlorothiazide (known as Diovan HCT®) compared to patients initiated with either valsartan or hydrochlorothiazide. Participants must be at least 75 years old and have high blood pressure and will be asked to visit the study center 8 to 10 times over a 16 week period. Diovan HCT® has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of high blood pressure.
Hypertension Study CSPP100A2410
Novartis is conducting this clinical research trial to find out if a single drug (aliskiren) or a combination of 2 drugs (aliskiren hydrochlorothiazide) will control high blood pressure better, in patients high blood pressure and metabolic syndrome.
Both aliskiren hydrochlorothiazide and aliskiren are approved by the US Food and Drug Administration (FDA) for the treatment of people with high blood pressure.
Hypertension Study CSPP100A2411
Novartis is conducting this clinical research trial to find out if the drug aliskiren hydrochlorothiazide (Tekturna® HCT) compared to hydrochlorothiazide (HCTZ) alone is safe and will effectively lower blood pressure. Patients must be 55 years or older and have stage 2 systolic high blood pressure (systolic blood pressure greater than or equal to 160 mm Hg or less than 200 mm Hg). Both the combination of aliskiren hydrochlorothiazide and hydrochlorothiazide alone are approved by the US Food and Drug Administration (FDA) and are available for sale in the U.S.
Hypertension Study CLCI699A2201
Novartis is conducting this clinical research study is to find out if the study drug LCI699 is safe, tolerable, and helps to lower blood pressure in participants who have mild to moderate hypertension (high blood pressure). Participants must be between 18 and 75 years old. The study drug LCI699 is considered investigational which means that it is still being tested and is not approved by the Health Authorities.
Hypertension Study CVAH631BUS08
Novartis clinical trials is performing this clinical research study to determine the efficacy and safety of the combination of the study drug valsartan plus hydrochlorothiazide (known as Diovan HCT®) compared to patients initiated with either valsartan or hydrochlorothiazide. Participants must be at least 75 years old and have high blood pressure and will be asked to visit the study center 8 to 10 times over a 16 week period. Diovan HCT® has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of high blood pressure.
Hypertension Study CLCI699A2201
Novartis is conducting this clinical research study is to find out if the study drug LCI699 is safe, tolerable, and helps to lower blood pressure in participants who have mild to moderate hypertension (high blood pressure). Participants must be between 18 and 75 years old. The study drug LCI699 is considered investigational which means that it is still being tested and is not approved by the Health Authorities.
Hypertension (High Blood Pressure)
August 4, 2008
The Medicines Company released positive results from a phase III trial of Cleviprex for the treatment of acute hypertension after cardiac surgery. This randomized, double-blind, placebo-controlled trial, dubbed ESCAPE 2, enrolled 110 subjects with a systolic blood pressure (SBP) greater than 140 mm Hg following cardiac surgery. The subjects were randomized to a 30 to 60 minute infusion of Cleviprex or placebo. The primary end point was the incidence of treatment failure, defined as the inability to decrease SBP by 15% or more from baseline, or the discontinuation of study treatment for any reason within the 30 minute period after study drug initiation. The primary endpoint was reached: treatment success was achieved in significantly more Cleviprex-treated subjects than placebo-treated subjects (91.8% versus 20.4%, P <0.0001). The median time to achieving target systolic blood pressure with Cleviprex was 5.3 minutes. Treatment was generally well tolerated and no clinically significant increase in heart rate from baseline was observed. Adverse event rates were similar for both treatment groups. An NDA is currently under review by the FDA.
June 30, 2008
Speedel reported positive results from a phase IIa trial of SPP-635 for the treatment of hypertension. This double-blind, placebo-controlled, randomized, parallel design study enrolled 35 subjects with mild to moderate hypertension. The subjects received a single daily dose of SPP635 or placebo for 4 weeks. Sitting blood pressure and 24-hour ambulatory blood pressure (ABP) were the efficacy endpoints. Treatment with SPP635 decreased ABP compared to placebo (24-hour systolic ABP -12.5 1.70
Hypertension Study CLCI699A2201
Novartis is conducting this clinical research study is to find out if the study drug LCI699 is safe, tolerable, and helps to lower blood pressure in participants who have mild to moderate hypertension (high blood pressure). Participants must be between 18 and 75 years old. The study drug LCI699 is considered investigational which means that it is still being tested and is not approved by the Health Authorities.
Hypertension Study CSAH100A2302
Novartis Pharmaceuticals is conducting this clinical research trial is to determine if the drug combination of aliskiren (Tekturna®), Amlodipine (Norvasc®)and hydrochlorothiazide (HCT) are safe and will effectively lower blood pressure in patients with moderate to severe high blood pressure.

Each drug used alone and the combination of aliskiren/hydrochlorothiazide are approved by the US Food and Drug Administration (FDA) and are available for sale in the U.S.

The combination of aliskiren, hydrochlorothiazide and amlodipine is considered investigational. The word investigational means that this combination is still being tested and is not approved by the FDA and is NOT available for sale in the U.S.
Hypertension Study CSPP100A2409
Novartis is conducting this clinical research trial to find out if the drug aliskiren hydrochlorothiazide (Tekturna® HCT) compared to amlodipine (Norvasc®) alone is safe and will effectively lower blood pressure in participants who have diabetes and stage 2 systolic hypertension (which occurs when systolic blood pressure is greater than or equal to 160 mm Hg or less than 200 mm Hg).Both medicines are approved by the US Food and Drug Administration (FDA) for the treatment of people with high blood pressure.
Hypertension Study CSPP100A2411
Novartis is conducting this clinical research trial to find out if the drug aliskiren hydrochlorothiazide (Tekturna® HCT) compared to hydrochlorothiazide (HCTZ) alone is safe and will effectively lower blood pressure. Patients must be 55 years or older and have stage 2 systolic high blood pressure (systolic blood pressure greater than or equal to 160 mm Hg or less than 200 mm Hg). Both the combination of aliskiren hydrochlorothiazide and hydrochlorothiazide alone are approved by the US Food and Drug Administration (FDA) and are available for sale in the U.S.
Hypertension Study CVAH631BUS08
Novartis clinical trials is performing this clinical research study to determine the efficacy and safety of the combination of the study drug valsartan plus hydrochlorothiazide (known as Diovan HCT®) compared to patients initiated with either valsartan or hydrochlorothiazide. Participants must be at least 75 years old and have high blood pressure and will be asked to visit the study center 8 to 10 times over a 16 week period. Diovan HCT® has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of high blood pressure.
Hypertension Study CSAH100A2302
Novartis Pharmaceuticals is conducting this clinical research trial is to determine if the drug combination of aliskiren (Tekturna®), Amlodipine (Norvasc®)and hydrochlorothiazide (HCT) are safe and will effectively lower blood pressure in patients with moderate to severe high blood pressure.

Each drug used alone and the combination of aliskiren/hydrochlorothiazide are approved by the US Food and Drug Administration (FDA) and are available for sale in the U.S.
Hypertension Study CSPP100A2409
Novartis is conducting this clinical research trial to find out if the drug aliskiren hydrochlorothiazide (Tekturna® HCT) compared to amlodipine (Norvasc®) alone is safe and will effectively lower blood pressure in participants who have diabetes and stage 2 systolic hypertension (which occurs when systolic blood pressure is greater than or equal to 160 mm Hg or less than 200 mm Hg).Both medicines are approved by the US Food and Drug Administration (FDA) for the treatment of people with high blood pressure.
Hypertension Study CVAH631BUS08
Novartis clinical trials is performing this clinical research study to determine the efficacy and safety of the combination of the study drug valsartan plus hydrochlorothiazide (known as Diovan HCT®) compared to patients initiated with either valsartan or hydrochlorothiazide. Participants must be at least 75 years old and have high blood pressure and will be asked to visit the study center 8 to 10 times over a 16 week period. Diovan HCT® has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of high blood pressure.
Hypertension Study CSPP100A2410
Novartis is conducting this clinical research trial to find out if a single drug (aliskiren) or a combination of 2 drugs (aliskiren hydrochlorothiazide) will control high blood pressure better, in patients high blood pressure and metabolic syndrome.

Both aliskiren hydrochlorothiazide and aliskiren are approved by the US Food and Drug Administration (FDA) for the treatment of people with high blood pressure.
Hypertension Study CSPP100A2411
Novartis is conducting this clinical research trial to find out if the drug aliskiren hydrochlorothiazide (Tekturna® HCT) compared to hydrochlorothiazide (HCTZ) alone is safe and will effectively lower blood pressure. Patients must be 55 years or older and have stage 2 systolic high blood pressure (systolic blood pressure greater than or equal to 160 mm Hg or less than 200 mm Hg). Both the combination of aliskiren hydrochlorothiazide and hydrochlorothiazide alone are approved by the US Food and Drug Administration (FDA) and are available for sale in the U.S.
Hypertension Study CLCI699A2201
Novartis is conducting this clinical research study is to find out if the study drug LCI699 is safe, tolerable, and helps to lower blood pressure in participants who have mild to moderate hypertension (high blood pressure). Participants must be between 18 and 75 years old. The study drug LCI699 is considered investigational which means that it is still being tested and is not approved by the Health Authorities.
Hypertension Study CVAH631BUS08
Novartis clinical trials is performing this clinical research study to determine the efficacy and safety of the combination of the study drug valsartan plus hydrochlorothiazide (known as Diovan HCT®) compared to patients initiated with either valsartan or hydrochlorothiazide. Participants must be at least 75 years old and have high blood pressure and will be asked to visit the study center 8 to 10 times over a 16 week period. Diovan HCT® has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of high blood pressure.
Hypertension Study CLCI699A2201
Novartis is conducting this clinical research study is to find out if the study drug LCI699 is safe, tolerable, and helps to lower blood pressure in participants who have mild to moderate hypertension (high blood pressure). Participants must be between 18 and 75 years old. The study drug LCI699 is considered investigational which means that it is still being tested and is not approved by the Health Authorities.
Hypertension (High Blood Pressure)
August 4, 2008
The Medicines Company released positive results from a phase III trial of Cleviprex for the treatment of acute hypertension after cardiac surgery. This randomized, double-blind, placebo-controlled trial, dubbed ESCAPE 2, enrolled 110 subjects with a systolic blood pressure (SBP) greater than 140 mm Hg following cardiac surgery. The subjects were randomized to a 30 to 60 minute infusion of Cleviprex or placebo. The primary end point was the incidence of treatment failure, defined as the inability to decrease SBP by 15% or more from baseline, or the discontinuation of study treatment for any reason within the 30 minute period after study drug initiation. The primary endpoint was reached: treatment success was achieved in significantly more Cleviprex-treated subjects than placebo-treated subjects (91.8% versus 20.4%, P <0.0001). The median time to achieving target systolic blood pressure with Cleviprex was 5.3 minutes. Treatment was generally well tolerated and no clinically significant increase in heart rate from baseline was observed. Adverse event rates were similar for both treatment groups. An NDA is currently under review by the FDA.
June 30, 2008
Speedel reported positive results from a phase IIa trial of SPP-635 for the treatment of hypertension. This double-blind, placebo-controlled, randomized, parallel design study enrolled 35 subjects with mild to moderate hypertension. The subjects received a single daily dose of SPP635 or placebo for 4 weeks. Sitting blood pressure and 24-hour ambulatory blood pressure (ABP) were the efficacy endpoints. Treatment mmHg versus +1.5 1.59 mmHg, diastolic ABP -8.4 1.09 mmHg versus -0.1 1.10 mmHg). Moreover, there was a significant decrease in ABP not only during the daytime (systolic blood pressure effects of SPP635 versus placebo: -14.4 2.01 mmHg vs. +0.9 2.17 mmHg; diastolic blood pressure lowering of SPP 635 versus placebo: -9.6 .38 mmHg versus -0.7 1.55 mmHg) but also during night-time (systolic blood pressure effects of SPP635 versus placebo: -9.7 1.80 mmHg versus +2.7 2.17 mmHg; diastolic blood pressure lowering of SPP 635 versus placebo: -6.9 1.20 mmHg vs. +2.4 2.26 mmHg). Similar results were observed for sitting blood pressure. Based on the results Speedel plans to move forward with the development of SPP-635.
November 5, 2007
Forest Laboratories issued positive results from a phase III trial of nebivolol for the treatment of hypertension. This twelve-week, randomized, double-blind trial enrolled 300 African-American subjects with stage I-II hypertension. The subjects received nebivolol (2.5, 5, 10, 20, or 40 mg) or placebo once daily. Results showed that nebivolol significantly reduced sitting diastolic and sitting systolic blood pressure at all daily doses compared to placebo. Nebivolol was well tolerated, with a low rate of the side effects commonly associated with beta blockers, including fatigue, sexual dysfunction, and depression. In addition, treatment did not lead to adverse changes in blood lipids and glucose levels. An NDA is currently under review by the FDA.
October 29, 2007
Anthera announced positive preliminary results from a phase II trial of A-002 for the treatment of cardiovascular disease. This multi-center, randomized, double-blind, placebo- controlled trial, dubbed PLASMA (Phospholipase Levels And Serological Markers of Atherosclerosis), enrolled 400 subjects with stable coronary heart disease, in the US and Ukraine. The subjects received one of four different doses of A-002 or placebo for up to eight weeks, in addition to standard of care therapies. Statistical significance was reached in the primary endpoint, a reduction in secretory phospholipase A2 (sPLA2) levels. Significant decreases in cholesterol levels (LDL-C, non-HDL and total cholesterol), as well as reductions in C-Reactive Protein, were also observed. Full results are expected in 2008, to be followed by phase III trials.
The Medicines Company announced positive results from a phase III trial of Cleviprex for the treatment of acute hypertension. This open-label, single-arm, multi-center study enrolled 126 subjects in an emergency room setting, presenting with acute hypertension (average baseline systolic blood pressure (SBP) of 203 mmHg). For each subject, the investigators determined a target SBP range to be achieved within the first 30 minutes of Cleviprex infusion. The target SBP levels were reached by a median of 10.9 minutes, with 89% of subjects achieving their target within 30 minutes. Following initial blood pressure control, Cleviprex was infused continuously for a median of 21 hours to maintain blood pressure within target limits. Among subjects who received 18 hours of continuous Cleviprex therapy, 92% did not require the addition of other intravenous antihypertensive agents during the 18-hour period. A NDA is currently under review by the FDA.
October 15, 2007
Pharmacopeia issued positive results from a phase I trial of PS433540 for the treatment of hypertension. This double-blind, placebo controlled trial enrolled 17 healthy male subjects. All the subjects received placebo and four dose levels of PS433540 (20, 100, 250 and 500 mg) and open label 300 mg of irbesartan (current standard of care) once, at weekly intervals. At baseline and 2, 4, 12 and 24 hours post-dose, subjects received a six-minute infusion of angiotensin II (AII) and had their blood pressure measured. All doses of PS433540 produced a statistically significant inhibition of the expected AII-induced increase in blood pressure when compared to placebo (p<0.01). In addition, the data showed that the 250 mg and 500 mg doses of PS433540 were at least as effective in blocking the AII response as irbesartan. It was determined that PS433540 is suitable for once-daily oral dosing provided by its ability to block AII induced blood pressure increase for 24 hours. Pharmacopeia is currently conducting phase IIa trials of PS433540.
July 2, 2007
Speedel announced positive results from a phase IIa trialof SPP-635 for the treatment of hypertension. This double-blind,placebo-controlled, randomized, parallel design trial enrolled 35 subjects inEurope. Subjects received either placebo or a single dosage level of SPP635, once-dailyfor 4 weeks. Statistically significant results were observed in blood pressurechanges after four weeks compared to placebo. Sitting systolic blood pressurewas significantly reduced by 17.9 mmHg, from 156.6±9.1 mmHg at baseline(mean ± SD) to 138.7±13.3 mmHg in the SPP635 group (p<0.001).The placebo group remained unchanged (156.1±9.0 to 153.2±8.9 mmHg;baseline vs. end of treatment). Diastolic blood pressure was also significantlyreduced by 9.8 mmHg, from 91.3±7.8 to 81.5±8.2 mmHg (p<0.001)in the SPP635 treated group compared to 95.3±5.1 to 93.3±5.4 mmHgin the placebo group. Based on the results, Speedel plans to initiate a phaseII trial in Europe later in 2007.
June 25, 2007
Cytos released positive top-line results from a phase I/IIa trial of CYT-006 for the treatment of hypertension, at the 17th European Meeting on Hypertension. This randomized, double-blind and placebo-controlled trial enrolled 72 subjects with mild to moderate hypertension. Subjects were randomized into two arms to receive one of two doses of the vaccine or placebo administered via 3 subcutaneous injections at week 0, 4 and 12. Efficacy on systolic and diastolic blood pressure was assessed by 24-hour ambulatory blood pressure monitoring at baseline and post-treatment. All subjects who received the vaccine showed a strong antibody response on the first injection which was boosted by the subsequent injections. CYT-006 showed strong efficacy in the early morning hours. The early morning rise of blood pressure starting at 5 am was suppressed by the vaccine, leading at 8 am to a change from baseline of the blood pressure of - 25 / - 13 mm Hg compared to placebo (SBP / DBP, p<0.0001 / p=0.0035). This suppression of early morning rise blood pressure was associated with an exceptionally low increase in plasma renin concentration (PRC) from a mean renin concentration of 5.1 pg/ml at baseline to 6.3 pg/ml at week 14 (p=0.02). The induced anti-angiotensin antibody levels were significantly higher at the 300 microgram than at the 100 microgram dose (p=0.0098). Blood pressure reduction was much larger and only significant at the 300 microgram dose (p=0.0498). Based on the results Cytos plans to move forward with the development of CYT-006.
May 21, 2007
NicOx and Axcan announced negative results from a phase IIa trial of NCX 1000 for the treatment of portal hypertension. This double-blind, dose-escalating trial enrolled 11 subjects who were randomized to receive either placebo or escalating doses of NCX 1000 (500mg, 1000mg and 2000mg as the first three doses during the first two days). This was followed by 2000mg (or the maximum tolerated dose) three times a day for the following 14 days. The primary endpoint was portal pressure on day 16 compared to baseline. Secondary endpoints included the same comparison after consumption of a controlled meal as well as response rate, increase of liver blood flow, safety, tolerability and pharmacokinetics. Results revealed a positive safety and tolerability profile. However, treatment with NCX 1000 did not provide the efficacy required to continue this trial or move into future trials. Based on the results NicOx and Axcan have agreed to terminate the development of NCX 1000.
April 16, 2007
Pharmacopeia announced positive results from a phase I trial of PS433540 for the treatment of hypertension and diabetic nephropathy. This randomized, placebo-controlled, dose-escalation trial enrolled healthy subjects who were placed into six groups. Each group was comprised of eight individuals, with six receiving PS433540 and two receiving placebo. Treatment was administered in doses ranging from 20 mg to 1000 mg and the doses were increased for each successive group. Treatment was well tolerated across all six doses administered. PS433540 possessed linear pharmacokinetics and a half-life consistent with once daily administration. Based on the results, Pharmacopeia plans to initiate multiple ascending dose trials later in 2007.
February 26, 2007
BioMarin reported negative results from a phase IIa trial of Phenoptin for the treatment of hypertension. This randomized, double-blind, placebo-controlled trial enrolled 116 subjects with poorly controlled hypertension. Subjects received oral doses of Phenoptin (5 mg/kg) or placebo twice daily for eight weeks. The primary endpoint, a statistically significant drop in systolic blood pressure when compared to placebo, was not met. The subjects on placebo experienced a drop of 6.4 mm Hg while those receiving Phenoptin had a drop of 4.8 mm Hg. Statistical significance was not reached for any other safety or efficacy parameter relative to placebo. BioMarin plans to further analyze the data and does not anticipate altering the course of development at this time.
February 5, 2007
Cytos released positive results from a phase IIa trial of CYT006-AngQb, a vaccine for the treatment of hypertension. This randomized, double-blind and placebo-controlled trial enrolled 72 subjects with mild to moderate hypertension. Subjects were randomized into two arms to receive one of two doses of the vaccine or placebo administered via 3 subcutaneous injections at week 0, 4 and 12. Efficacy on systolic and diastolic blood pressure was assessed by 24-hour ambulatory blood pressure monitoring at baseline and post-treatment. Treatment was safe and well tolerated, with side effects mostly transient. The most commonly reported adverse events included injection site reactions and mild flu-like symptoms lasting for 1 to 2 days. All subjects who received the vaccine showed a strong antibody response on the first injection which was boosted by the subsequent injections. The antibody response had long half-life of 3-4 months. A significant reduction in ambulatory daytime blood pressure was observed, however these differences were not significant in nighttime blood pressure. Based on these results Cytos plans to initiate future trials exploring a more aggressive treatment regimen.
January 8, 2007
Actelion reported positive results from a clinical trial, dubbed EARLY (Endothelin Antagonist Trial in mildly Symptomatic PAH patients, NYHA modified functional class II), of Tracleer for the treatment of pulmonary arterial hypertension (PAH). This double-blind, placebo-controlled, multicenter trial enrolled 185 mildly symptomatic PAH subjects internationally. Subjects received placebo or Tracleer at an initial dose of 62.5 mg b.i.d. for four weeks and a target dose of 125 mg b.i.d. for five months, for an overall exposure to either active study drug or placebo of six months. After six months, subjects could opt to continue in an open-label extension study that was ongoing at this time. The co-primary endpoints were achieved, with the subjects on Tracleer therapy showing a significant reduction in pulmonary vascular resistance (PVR) and an improvement in 6-minute-walk test compared to those receiving placebo (p less than 0.0001and p=0.076, respectively). The secondary endpoint was met as well, with Tracleer treatment resulting in a 70% reduction in the time to clinical worsening when compared to placebo (p=0.018). Results were to be fully analyzed in anticipation of worldwide filings of Tracleer to include the treatment of mildly symptomatic PAH (NYHA modified functional class II).
Nuvelo and Bayer announced negative results from two phase III trials of alfimeprase. The first trial, dubbed NAPA-2 (Novel Arterial Perfusion with Alfimeprase-2) evaluated alfimeprase in the treatment of acute peripheral arterial occlusion. This randomized, double-blind trial enrolled 300 subjects internationally, who received 0.3 mg/kg of alfimeprase or placebo. The primary endpoint, avoidance of open vascular surgery within 30 days of treatment, was not met. The second trial, dubbed SONOMA-2 (Speedy Opening of Non-functional and Occluded catheters with Mini-dose Alfimeprase-2) evaluated alfimeprase in the treatment of catheter occlusion. This randomized, double-blind trial enrolled 303 subjects who received 3 mg of alfimeprase with placebo in a 2:1 ratio. The primary endpoint, restoration of function to the occluded catheter in 15 minutes, was not met. Based on these results, Nuvelo and Bayer decided to temporarily suspended enrollment in the ongoing Phase 3 trials, NAPA-3 and SONOMA-3, pending further analysis of the results.
April 17, 2006
Myogen has issued top line results of their phase III ARIES-1 trial of ambrisentan for the treatment of pulmonary arterial hypertension. Trial data met their primary efficacy endpoint, with both doses of the drug significantly improving placebo-corrected mean change in six-minute walk distance at week 12 compared to baseline (5 mg: 30.6 m, p=0.0084; 10 mg: +51.4 m, p=0.0001). Rates of clinical worsening were generally low among all treatment arms, and differences in this measure were not significant between groups. Safety data were generally positive, with no patients developing serum aminotransferase concentrations greater than three times the upper limit of the normal. The most commonly observed adverse event was peripheral edema. This randomized, double-blind, placebo-controlled study enrolled 202 subjects in the US, who received one of two doses of the drug (5 mg or 10 mg) or placebo once daily.
January 23, 2006
Novartis and Speedel announced positive results of three phase III trials of aliskiren (SPP-100), for the treatment of hypertension. The first study, which investigated the drug (150 mg) in combination with the approved calcium channel blocker amlodipine (5 mg), found the combination to be safe and efficacious: the combination had a positive tolerability profile, showed a reduced incidence of edema compared to amlodipine alone, and showed an increased reduction in blood pressure. Results of the second study, which investigated both aliskiren monotherapy and in combination with the ACE inhibitor ramipril, were also positive: the drug produced decreases in systolic and diastolic blood pressure from baseline as a monotherapy, and significantly improved both measures when added to ramipril, vs. ramipril alone; the combination was well tolerated. The third trial indicated a positive safety and tolerability profile for long term aliskiren monotherapy (>12 months).
August 22, 2005
Myogen also reported result of a phase II trial of ambrisentan, for the treatment of pulmonary arterial hypertension (PAH), in the Journal of the American College of Cardiology. The drug met its primary efficacy endpoint, significantly increasing 6-minute walk distance across all dosing groups (mean increase: 36.1 m, range: 33.9 m - 38.1 m; p<0.0001). Secondary improvements were noted in Borg dyspnea index, WHO functional class, subject global assessment, mean pulmonary arterial pressure (-5.2 mmHg; p<0.0001), and cardiac index (+0.331/min/m2; p<0.0008). This double-blind, dose-ranging study enrolled 64 PAH patients, who received one of four daily regimens of ambrisentan (1 mg, 2.5 mg, 5 mg, or 10 mg) for 12 weeks.
Myogen has reported results of their phase IIb "DAR-201" trial of darusentan for the treatment of resistant hypertension. Administration of 300 mg daily produced significant, placebo-corrected reductions in both systolic (-11.6 mmHg; p=0.02) and diastolic (-7.0 mmHg; p<0.001) blood pressure at trial completion. Secondary efficacy was seen in reducing blood pressure at lower doses and at interim time measures. The drug did not produce significant changes in liver enzymes, with no incidences of serum aminotransferase levels above two times the upper limit of normal. This randomized, double-blind, placebo-controlled study enrolled 115 patients at 30 US sites, who were titrated up from 10 mg to 300 mg of the drug or placebo daily, with 2 week intervals between dose increases; once the 300 mg daily dose was reached, patients received treatment for 10 weeks. Based on these results, the company announced plans to initiate phase III trials of the drug in the near future.
February 22, 2005
Cardiome Pharma reported positive results of a investigator-sponsored clinical trial of oxypurinol, for the treatment of congestive heart failure. Trial data yielded significant evidence of efficacy, with patients receiving the drug demonstrating a 6.8% improvement in left ventricle ejection fraction (LVEF) vs. placebo (p=0.017). This improvement relative to placebo represented an average relative increase in cardiac output of 22.6%. Secondary efficacy was also observed, with oxypurinol producing a 17.0 mg/L decrease in serum uric acid levels, versus placebo (p<0.001). No significant improvements vs. placebo were noted in 6 minute walk distance, but improvement from baseline was seen in both treatment arms. No serious adverse events or safety concerns were noted. This double-blind, placebo controlled trial treated 47 patients with LVEFs below 40%. Subjects were randomized to receive oxypurinol or placebo via oral dosing for 28 days.
Encysive Pharmaceuticals has reported top-line results of a phase III trial of their drug Thelin (sitaxsentan), for the treatment of pulmonary hypertension. Results from the pivotal study met their primary endpoint, yielding a placebo-subtracted improvement in total distance in a 6 minute walk test of 31.4 meters at the 100 mg. trial dose (p=0.03). Patients in the bosentan group also experienced a significant improvement in placebo subtracted distance (29.5 meters, p=0.05), but neither the difference between 100 mg Thelin and bosentan nor the improvements seen with 50 mg Thelin (24.2 meters, p>0.05) were significant. Efficacy was also seen in secondary endpoints with 100 mg Thelin, including a significant improvement in WHO functional class (a mark not reached in any other study arm, p=0.04), a trend towards improvement in time to clinical worsening, and the lowest number of early discontinuations and incidences of liver enzyme abnormalities of any trial arm. This double-blind, placebo-controlled trial randomized 240 PAH patients across 55 sites in North America, Europe, Israel and Australia at a 1:1:1:1 ratio to receive one of two doses of Thelin (50 mg. or 100 mg.) or placebo once daily, or approved therapy with bosentan twice daily (per the bosentan label). Following these results, the company announced plans to file an NDA with the FDA in April 2005.
February 7, 2005
Angiogenix reported negative efficacy results from a phase II trial of Acclaim (isosorbide mononitrate plus L-arginine), for the prevention of nitrate tolerance in patients with chronic stable angina. The trial failed to meet its primary efficacy endpoint, a statistically significant increase in treadmill walking time following treatment. The trial also failed to meet secondary endpoints, though positive, non-significant trends were observed for time to onset of angina, ST-segment depression, and improvement seen with concomitant ACE inhibitor therapy. Trial data did meet their primary safety endpoint, with acceptable profiles for both incidence of serious adverse events and tolerability. This randomized, double-blinded, placebo-controlled, multi-center study enrolled 204 subjects across 7 countries. The company announced plans to continue the development of Acclaim, with a re-assessment of dosing data based on these results prior to future studies.
Speedel Pharma announced positive results from phase I studies a pair of their investigational rennin inhibitors, SPP630 and SPP635, for the treatment of hypertension and protection of end-organs including the heart and kidneys. Data from the trials met pharmacokinetic endpoints, establishing a bio-availability of roughly 30%, an elimination half-life of more than 30 hours (suitable for once daily dosing), and an improved tissue distribution profile. These micro-dosing studies of both drugs used nano-molar doses to investigate their pharmacokinetics in healthy volunteers. Speedel announced that the completion of these trials allowed for the initiation of expanded, classical phase I studies in Q3, 2005.
January 3, 2005
Cardiome Pharma and Fujisawa Healthcare reported results from a phase III trial with RSD1235, an Ion channel modulator being investigated for the treatment of atrial fibrillation (AF). The study, called ACT 1, enrolled 426 subjects with AF at 45 sites in the U.S., Canada and Scandinavia. The study examined three sub-groups, including 237 subjects with recent-onset AF (more than 3 hrs but less than 7 days), 119 patients with longer-term AF (more than 7 days but less than 45 days) and 60 patients with atrial flutter. Results showed that 52% of the 234 subjects with recent-onset AF achieved a normal heart rhythm compared with 4% of subjects given placebo. In the overall population, 38% of RSD1235 treated subjects demonstrated termination of AF, compared to 3% of placebo patients. In addition, 8% of RSD1235 treated subjects in the longer-term AF population achieved AF termination compared to 0% of placebo subjects. In the recent-onset AF population, 52% of those who were dosed with RSD1235 achieved a normal heart rhythm, as compared to 4% of placebo patients. There were no cases of drug-related "Torsades de Pointes", an arrhythmia which is an occasional side effect of many current anti-arrhythmia drugs. Serious adverse events were reported in 13% of subjects receiving RSD1235 compared to 18% subjects on placebo. Serious drug-related adverse events occurred in 0% of placebo patients and 1.4% of patients receiving RSD1235. The primary endpoint in ACT 1 was conversion of recent-onset AF to normal heart rhythm for a period of at least 1 minute.
The Medicines Company reported primary results from a phase III trial investigating Clevelox (clevidipine), an intravenous drug being evaluated for the control of blood pressure. The placebo-controlled, doubled blind, randomized study, called ESCAPE-1, enrolled subjects before they underwent cardiac surgery. Results showed that patients with high blood pressure treated with Clevelox achieved treatment success 92.5% of the time versus 17.3% with placebo, measured by at least a 15% reduction in blood pressure. In November 2004, The company reported similar primary results of ESCAPE-2, a trial of Clevelox conducted in post-operative patients. The complete Clevelox phase III program consists of five clinical trials, including three trials, know as ECLIPSE, which are currently enrolling patients. Full data will be published and presented under scientific peer review. Pending positive results, the Medicines Company plans on filing an NDA with the FDA shortly.
December 6, 2004
Penwest Pharmaceuticals announced mixed results from a pivotal phase III study of low doses of its investigational beta blocker PW2101, for the treatment of hypertension and angina. Trial data failed to meet their primary efficacy endpoint, with a non-significant change in Mean Seated Office Cuff diastolic blood pressure from baseline to week six, compared to placebo (2.4 mmHg, p>0.05). The trial did meet secondary endpoints, including a significant increase in 24-hour Mean Ambulatory diastolic blood pressure from baseline to week six, compared with placebo. A previous phase III pivotal trial of low-dose PW2101 also produced significant evidence of efficacy. This randomized, double-blind, placebo-controlled study enrolled 110 hypertensive patients, who received low dose low-dose PW2101 or placebo for 6 weeks. The company announced plans to submit these data to the FDA as an expansion of the PW2101 NDA, which is currently under review, in hopes of broadening the dosing indications for the drug.
October 11, 2004
Encysive Pharmaceuticals reported top-line results of their STRIDE-6 clinical trial of Thelin (sitaxsentan), for the treatment of pulmonary arterial hypertension (PAH) in subjects failing standard therapy with bosentan. Trial data indicated that among subjects discontinuing bosentan for lack of efficacy (n=35), 10% in the low dose Thelin group and 33% in the high-dose Thelin group achieved symptom improvement, and unchanged disease state was noted for 75% and 47% of each group, respectively. Among subjects discontinuing bosentan due to safety concerns (n=13), primarily liver function abnormalities, only one was unable to safely undergo treatment with Thelin, due to a recurrence of liver abnormality. Tolerability concerns were similar for both doses, and included nausea, fatigue, headache, edema, and upper respiratory tract infection; one subject in the study died due to progressive PAH. This blinded, dose-ranging study randomized 48 bosentan-intolerant PAH patients to receive either 50 or 100 mg Thelin once daily for 24 weeks; following completion of the STRIDE-6 study, 45 of the 48 subjects continued into the STRIDE-3 long-term extension.
April 12, 2004
Forbes Medi-Tech reported positive preliminary results from a phase II trial investigating FM-VP4, a cholesterol absorption inhibitor for the treatment of high cholesterol. Results showed that the study reached its primary efficacy endpoint of significantly lowering low-density lipoprotein (LDL) cholesterol. Data showed that the reduction in LDL cholesterol was 11% as compared to placebo, with 33% of subjects at 400 mg per day achieving a greater than 15% reduction. FM-VP4 was shown to be safe with no difference seen between dosing and placebo groups. The double blind, placebo-controlled, dose-escalation study enrolled 25 subjects with hypercholesterolemia. Subjects were treated with placebo or escalating doses of FM-VP4 from 100, 200, 400, and 800 mg daily for 28 days.
Medicure reported positive preliminary results from a phase II trial investigating MC-4232, an ACE Inhibitor plus MC-1 for the treatment of hypertension. Results showed a trend towards the reduction in glycated hemoglobin (HbA1c), the primary measure of blood glucose control. Data showed 4.9% reduction in HbA1c compared to baseline levels. HbA1c reflects average blood glucose fluctuations over a 60 to 90 day period. The 14-week study enrolled 15 subjects with diabetic hypertension. Medicure plans to proceed with additional phase II trials.
July 21, 2003
Alteon reported negative results from a phase IIb trial investigating ALT-711, a crosslink breaker for the treatment of uncontrolled systolic hypertension. Results showed that ALT-711 did not demonstrate statistical significance as compared to placebo in the primary endpoint, the reduction of systolic blood pressure by ‘office cuff pressure’ measurement. The data showed a 6-10 mm Hg drop in systolic blood pressures in all groups during the first two weeks. The dose ranging, double-blind, placebo-controlled trials, called SAPPHIRE (Systolic And Pulse Pressure Hemodynamic Improvement by Restoring Elasticity) and SILVER (Systolic Hypertension Interaction with Left VEntricular Remodeling), enrolled 768 subjects having elevated systolic blood pressure at over 60 sites nationwide. Subjects were maintained on background hypertension medication during treatment.
EPIX Medical reported positive results from two phase III trials investigating MS-324, a blood pool contrasting agent for the use with magnetic resonance angiographs (MRA). The two trials were conducted on subjects with suspected vascular disease in the renal and pedal arteries. Results demonstrated that both studies met their primary clinical endpoint, demonstrating statistically significant improvement in accuracy for detecting renal and pedal vascular disease with MS-325 compared with non-contrast MRA. The renal study enrolled 145 subjects with suspected disease in the renal arteries and administered each a 0.03 mmol/kg dose of MS-325. Data showed that three individual MRA readers achieved an accuracy of 73%, 79% and 79%, with MS-324 enhancement compared with 45%, 56% and 51% for non-contrast MRAs. The pedal study enrolled 96 subjects with suspected pedal artery stenosis and administered each a 0.03 mmol/kg dose of MS-325. The three readers showed improved specificity of 21%, 34% and 34% with MS-325-enhanced MRA compared to non-contrast MRA. Results were announced at the 11th annual meeting of the International Society of Magnetic Resonance in Medicine (ISMRM) in Toronto.
Sanofi-Synthelabo reported positive results from a general surgery study investigating Arixtra (fondaparinux), a selective factor X inhibitor for the treatment of venous thromboembolism (VTE). Results showed that Arixtra was at least as effective and as safe as the low molecular weight heparin (LMWH) dalteparin for the prevention of VTE following major abdominal surgery. In abdominal cancer surgery subjects, fondaparinux was significantly more effective than the low molecular weight heparin. The randomized, double blind study, called PEGASUS (The PEntasaccharide in GenerAl SUrgery Study) enrolled 2,927 subjects who had undergone major abdominal surgery. Results were presented at the 19th Congress of the International Society on Thrombosis and Haemostasis.
April 7, 2003
Alteon reported preliminary results from a phase IIa trial investigating ALT-711, a glycosylation end product (AGE) crosslink breaker for the treatment of diastolic heart failure. Early results showed that subjects who received treatment for 16 weeks achieved a statistically significant reduction in left ventricular (LV) mass. LV mass was 125+35 gm at baseline and decreased to 119+35 gm at follow-up. Subjects also showed improvements in LV diastolic filling. However, measurements of exercise tolerance and aortic distensibility proved to be more variable than anticipated. The open-label, outpatient trial enrolled 23 subjects at least 60 years of age who received 210 mg of ALT-711 twice daily for 16 weeks in addition to their current medications. The DIAMOND (Distensibility Improvement and Remodeling in Diastolic Heart Failure) study was conducted at Wake Forest University Baptist Medical Center and the Medical University of South Carolina.
Pharmacia reported positive results from a phase III trial investigating Inspra (eplerenone), an approved hypertension drug for the new indication of post-myocardial infarction heart failure. Results showed a 15% reduction in ‘all cause mortality’ and a 13% reduction in the combined endpoint of ‘cardiovascular death and hospitalizations’ among Inspra treated subjects compared with current standard therapy. In addition, in subjects treated with Inspra there was a 21% reduction in sudden cardiac death and 15% fewer subjects hospitalized for heart failure. Inspra was generally well tolerated compared to placebo, with similar rates observed for adverse events such as menstrual disorder, gynecomastia and impotence. The randomized, double blind, placebo-controlled study, called EPHESUS (Eplerenone Post- AMI Heart Failure Efficacy and SUrvival Study), enrolled 6,632 subjects at 671 centers worldwide. The company plans to submit a sNDA for Inspra in the treatment of post-myocardial infarction heart failure.
March 10, 2003
Biovail reported positive results from a phase IV trial investigating Cardizem LA (diltiazem), a recently approved drug for the treatment of hypertension. Results showed that Cardizem demonstrated better diastolic blood pressure control compared to the alternative drug amlodipine. There was a highly statistically significant reduction in DBP favoring Cardizem during the first four hours of awakening and between 6AM and 12 noon however over 24-hours the DBP reductions were comparable to amlodipine. The drug also showed superior reductions in the rate-pressure product, an index of myocardial oxygen demand. The randomized study enrolled African American subjects who had stage I and II hypertension.
May 20, 2002
Study results indicate that Forest Laboratories' lercanidipine provides comparable efficacy to the calcium channel blocker amlodipine while offering an improved tolerability profile. The double-blind COHORT trial included 828 hypertensive subjects and compared the tolerability of lercanidipine, lacidipine (an agent similar to lercanidipine) and amlodipine. Results showed that treatment with lercanidipine resulted in 75% fewer subject drop-outs due to edema compared to treatment with amlodipine. Furthermore, the incidence of edema was over 50% lower in subjects treated with lercanidipine compared to the incidence with amlodipine treatment.
April 8, 2002
Results from two phase III trials suggest that Pharmacia's eplerenone produces a greater reduction in proteinuria than enalapril in diabetic hypertensive subjects. Additionally, results showed that the two drugs similarly reduced left ventricular mass (LVM). Both trials evaluated treatment with eplerenone, enalapril, and eplerenone in combination with enalapril. The studies were designed to control blood pressure equally in all treatment groups to allow for evaluation of eplerenone's effect on proteinuria and left ventricular hypertrophy (LVH). In the first trial, which included diabetic subjects with hypertension and albuminuria, treatment with eplerenone resulted in a 62% reduction in proteinuria, compared to a 45% reduction with enalapril and a 74% reduction with the combination therapy. In the second trial, which included hypertensive subjects with LVH, eplerenone and enalapril treatment produced reductions of 14.5g and 19.7g in LVM, respectively. LVM reduction in the combination therapy group was 27.2g.
Overview of Clinical Trials
Clinical trials are conducted to collect data regarding the safety and efficacy of new drug and device development. There are several steps and stages of approval in the clinical trials process before a drug or device can be sold in the consumer market, if ever.
Drug and device testing begins with extensive laboratory research which can involve years of experiments in animals and human cells. If the initial laboratory research is successful, researches send the data to the Food and Drug Administration (FDA) for approval to continue research and testing in humans.
Once approved, human testing of experimental drugs and devices can begin and is typically conducted in four phases. Each phase is considered a separate trial and, after completion of a phase, investigators are required to submit their data for approval from the FDA before continuing to the next phase.
Human Clinical Trial Phases
Phase I studies assess the safety of a drug or device. This initial phase of testing, which can take several months to complete, usually includes a small number of healthy volunteers (20 to 100), who are generally paid for participating in the study. The study is designed to determine the effects of the drug or device on humans including how it is absorbed, metabolized, and excreted. This phase also investigates the side effects that occur as dosage levels are increased. About 70% of experimental drugs pass this phase of testing.
Phase II studies test the efficacy of a drug or device. This second phase of testing can last from several months to two years, and involves up to several hundred patients. Most phase II studies are randomized trials where one group of patients receives the experimental drug, while a second "control" group receives a standard treatment or placebo. Often these studies are "blinded" which means that neither the patients nor the researchers know who has received the experimental drug. This allows investigators to provide the pharmaceutical company and the FDA with comparative information about the relative safety and effectiveness of the new drug. About one-third of experimental drugs successfully complete both Phase I and Phase II studies.
Phase III studies involve randomized and blind testing in several hundred to several thousand patients. This large-scale testing, which can last several years, provides the pharmaceutical company and the FDA with a more thorough understanding of the effectiveness of the drug or device, the benefits and the range of possible adverse reactions. 70% to 90% of drugs that enter Phase III studies successfully complete this phase of testing. Once Phase III is complete, a pharmaceutical company can request FDA approval for marketing the drug.
Phase IV studies, often called Post Marketing Surveillance Trials, are conducted after a drug or device has been approved for consumer sale. Pharmaceutical companies have several objectives at this stage: (1) to compare a drug with other drugs already in the market; (2) to monitor a drug's long-term effectiveness and impact on a patient's quality of life; and (3) to determine the cost-effectiveness of a drug therapy relative to other traditional and new therapies. Phase IV studies can result in a drug or device being taken off the market or restrictions of use could be placed on the product depending on the findings in the study.