RxPG News : Antihypertensives

ACE 2- Potential treatment for hypertension

Fri, 30 Jan 2009 14:47:36 PST

( from http://www.rxpgnews.com ) Huijing Xia, PhD, a postdoctoral research associate in the lab of Eric Lazartigues, PhD, Assistant Professor of Pharmacology at LSU Health Sciences Center New Orleans, is the lead author on a paper reporting that a recently identified enzyme in the brain plays a critically important role in the central regulation of blood pressure. The LSUHSC research team showed that Angiotensin-converting enzyme 2 (ACE2) helps preserve the function of a key spontaneous reflex involved in blood pressure regulation and confirms its potential as a target for the prevention or treatment of High Blood Pressure. The research is published in the February 1, 2009 issue of the peer reviewed journal, Hypertension, and the cover of the issue features images of ACE2 expression from the Lazartigues laboratory at LSU Health Sciences Center New Orleans.

The LSUHSC researchers had previously identified ACE2 in the mouse brain in areas involved in the central regulation of cardiovascular function. In this study, they wanted to clarify the role it plays.

Beat-to-beat short term regulation of blood pressure is provided by a spontaneous reflex called the baroreceptor reflex. Receptors in the arteries sense blood pressure and relay the information to the central nervous system where a network of brain stem cells adjust vascular resistance and heart rate. Action of a hypertensive hormone – Angiotensin II – is known to interfere with that process.

First, the researchers demonstrated that chronically hypertensive mice showed dramatically decreased baroreceptor reflex sensitivity and ACE2 activity. Following treatment with compounds to block both Angiotensin II receptors, the researchers found that by blocking one of these receptors – AT1Rs – ACE2 activity increased. In order to determine the relationship between AT1Rs blockade and ACE2, as well as the significance of ACE2, the LSUHSC researchers generated a triple-transgenic mouse model with increased ACE2 on a background of chronic hypertension. In this model, they observed that the impaired baroreceptor reflex and other critical functions normalized, as did blood pressure.

"We now have evidence that brain ACE2 plays a critical role in baroreceptor reflex function and , consequently, in the prevention of hypertension," says Dr. Xia.

"Blood pressure" is the force of blood pushing against the walls of the arteries as the heart pumps out blood. If this pressure rises and stays high over time, it can damage the body in many ways. According to the National Institutes of Health, in the United States, about 72 million people have hypertension or High Blood Pressure (HBP). This is about 1 in 3 adults. HBP itself usually has no symptoms. Rarely, headaches may occur. Some people only learn that they have HBP after it causes health problems, such as coronary heart disease, stroke, or kidney failure.

"Beyond our discovery of ACE2, we have now confirmed its potential as a target for the treatment of hypertension and other cardiovascular diseases," concludes Dr. Lazartigues.

CCB and ACE inhibitors reduce diabetes risk in Hispanic patients

Thu, 08 Jun 2006 16:38:37 PST

( from http://www.rxpgnews.com ) The combination of drugs traditionally used to control blood pressure might not be ideal for Hispanic patients, University of Florida researchers warn.

While beta-blockers and diuretics have long been used to treat patients with hypertension, Hispanic patients appear to benefit from a tailor-made strategy that includes other medications, particularly calcium antagonists and angiotensin-converting, or ACE, inhibitors.

Not only does the approach effectively lower blood pressure in many Hispanic patients, it has an extra benefit: It dramatically cuts their risk of developing diabetes. UF researchers reported the findings in this May issue of the American Heart Journal.

"We can successfully lower blood pressure in Hispanic patients with heart disease with medications that include beta-blockers like atenolol or calcium antagonists like verapamil plus the ACE inhibitor trandolapril, especially when compared with non-Hispanic patients," said Rhonda Cooper-DeHoff, Pharm.D., a research assistant professor and associate director of the clinical research program in cardiovascular medicine at UF's College of Medicine. "Lower blood pressure translated into fewer heart attacks and fewer strokes, which is very important for reducing cardiovascular risk in both Hispanics and non-Hispanics.

"The use of trandolapril and verapamil, however, also significantly reduced the risk of developing diabetes in Hispanic patients," she said.

Researchers involved in the landmark International Verapamil SR-Trandolapril study, known as INVEST, were intrigued by the finding in part because patients with high blood pressure and cardiovascular disease - in particular those of Hispanic descent, the fastest-growing ethnic minority in the United States - are much more likely to develop diabetes. Those who do are twice as likely to suffer serious complications associated with heart disease.

UF researchers tracked more than 22,500 patients from 14 countries - including about 8,000 Hispanics - for two to five years. The study enrolled more Hispanic patients than any other hypertension trial to date, Cooper-DeHoff said, and included Hispanic participants from the mainland United States, Puerto Rico, Cuba, Mexico, Canada, Guatemala, Panama and El Salvador.

Participants were randomly assigned to receive a sustained-release form of the calcium antagonist verapamil or the beta-blocker atenolol. Both groups also could receive the ACE inhibitor trandolapril and the diuretic hydrochlorothiazide.

Researchers found that both treatment strategies controlled high blood pressure exceptionally well, safely lowering it below 140/90 in 72 percent of INVEST participants, who were mostly elderly. On average, it took at least two medications to lower blood pressure in Hispanic patients, compared with three in non-Hispanic patients.

Overall, Hispanic patients had a 19 percent increased risk of developing diabetes during the study's follow-up period, but those in the verapamil group were actually 15 percent less likely to develop diabetes, and the addition of trandolapril to verapamil was linked to the decreased risk.

UF researchers said that one or two out of every 100 hypertensive heart disease patients treated with a verapamil SR-trandolapril strategy for at least three years could potentially avoid diabetes - an advance that would affect thousands.

Use of ACE inhibitors has been shown to improve the body's ability to use sugar for fuel, Cooper-DeHoff said.

"Because trandolapril was used more frequently in verapamil strategy, this is likely why we saw a reduced rate of new diabetes," she said, adding that preventing diabetes would have tremendous public health implications and could greatly cut related health-care costs.

UF researchers also will continue to analyze DNA they have collected from Hispanic study participants to evaluate the role of genes and environmental factors such as diet on diabetes development.

Regardless of race or ethnicity, lowering blood pressure is extremely important in reducing future cardiovascular risk, Cooper-DeHoff said.

"Even lowering blood pressure two or three millimeters of mercury is associated with significant reduction in the risk of subsequent stroke," she said. "It's very important even for those with mild hypertension to seek treatment. And if we can choose medications in Hispanic patients that reduce the risk of developing diabetes, that's an important thing for physicians prescribing blood pressure-lowering medications to keep in mind."

ACE inhibitors implicated in birth defects

Thu, 08 Jun 2006 16:36:37 PST

( from http://www.rxpgnews.com ) The Food and Drug Administration is examining study data from Vanderbilt University Medical Center researchers, published this week in the New England Journal of Medicine, to determine if new warnings should be placed on common blood pressure medications indicating an increased risk of birth defects for babies whose mothers take these medications during the first trimester of pregnancy.

The study, led by William Cooper, M.D., M.P.H., associate professor of Pediatrics at the Monroe Carell Jr. Children's Hospital at Vanderbilt, found infants born to mothers who took angiotensin converting enzyme inhibitors (ACE inhibitors) during the first trimester of pregnancy had an increased risk of major birth defects, compared with infants whose mothers did not take these medications.

Out of 29,507 infants whose TennCare records were examined for the study, 209 were exposed to ACE inhibitors in the first trimester only. When those babies were compared to the rest of the population, including babies exposed to other types of antihypertensive medications, they had more than double the risk of major birth defects, especially of the heart and central nervous system.

"We knew ACE inhibitors were a possible cause of adverse fetal outcomes when exposure occurred later in pregnancy, but it has not been well studied in the first trimester," Cooper said. "We were very surprised that even after controlling for other risk factors, the TennCare records we examined showed a clear increase in a broad range of birth defects following first-trimester-only exposures."

This research is important because of an increase in the number of women of childbearing age who develop high blood pressure and are prescribed ACE inhibitors. These drugs already carry a warning that they may cause injury and even death to the developing fetus when used during the second and third trimesters of pregnancy. The warning states that a woman should discontinue use of ACE inhibitors as soon as possible once she becomes pregnant.

Latest Data on Nebivolol, the Investigational Beta-Blocker Compound

Thu, 19 May 2005 13:06:38 PST

( from http://www.rxpgnews.com ) Mylan Laboratories Inc.,(NYSE: MYL) announced today that the results of new data on nebivolol, an investigational compound currently under review by the Food and Drug
Administration for the treatment of hypertension, were presented at the 20th Annual Scientific Meeting of The American Society of Hypertension (ASH) held in San Francisco.

Four separate posters were presented including Phase III clinical results of nebivolol in the treatment of hypertension and the results of pre-clinical studies on the compound's antioxidant properties, its ability to stimulate nitric oxide (NO) release from endothelial cells in White and African American donors, and its high degree of beta-1 adrenergic receptor selectivity, as demonstrated in laboratory studies.

The first abstract, Nebivolol in the Treatment of Patients with Stage 1 and Stage 2 Hypertension: Results of a Randomized, Double-Blind, Placebo-Controlled Study [Abstract #633], was presented by Dr. Robert Weiss, M.D.,
Director of Research, Cardiovascular Consultants of Maine, Auburn, Maine. The trial was a double-blind, multicenter, randomized, placebo-controlled,parallel-group, dose-ranging study of nebivolol in patients with mild-to-moderate hypertension.

Eligible patients (n=909) were randomized to treatment
with nebivolol (1.25, 2.5, 5, 10, 20, or 40 mg) or placebo once daily for 12 weeks. The primary efficacy variable was the change from baseline to the end of double-blind treatment (Day 84) in average trough sitting diastolic blood
pressure (DBP) for all groups up to and including 20 mg. Safety was assessed by monitoring adverse events (AEs), vital signs (including heart rate), physical examination, electrocardiograms, and laboratory evaluations.

Statistically significant reductions in trough sitting DBP and trough sitting systolic blood pressure (SBP) occurred in the primary and secondary analyses at all doses studied (1.25 mg to 40 mg). Placebo-subtracted reductions in trough sitting blood pressure (SBP/DBP) ranged from 6.6/5.1 mm
Hg to 11.7/8.3 mm Hg, in a dose dependent manner. The incidence of adverse events with nebivolol was slightly higher than in placebo treated patients (46.1% vs. 40.7%, respectively.) The most frequently reported treatment-
emergent adverse events across all nebivolol doses combined (1.25 mg to 40 mg)were:

headache (7.1% vs. 7.4% placebo),
fatigue (3.6% vs. 2.5% placebo),
nasopharyngitis (2.9% vs. 7.4% placebo)
diarrhea (2.8% vs. 2.5% placebo) and
dizziness (2.8% vs. 3.7% placebo.)

In general, beta blocker related adverse events were low including

erectile dysfunction (0.2% vs. 0.0% placebo),
depression (0.2% vs. 0.0% placebo),
decreased libido (0.1% vs. 0.0% placebo),
dyspnea (1.0% vs 0.0% placebo), and
bradycardia (0.7% vs. 0.0% placebo).

There were significant reductions in heart rate which were dose related. There were few changes in laboratory parameters and mean laboratory values generally
remained within normal limits.

A second abstract, Characterization of Beta-1-adrenergic Receptor Selectivity of Nebivolol and Various Other Beta-Blockers in Human Myocardium [Abstract # 322], was presented by Michael R. Bristow, M.D., Ph.D. of University of Colorado Health Sciences Center. In this study cardioselectivity ratios were measured in radioligand assays for nebivolol and seven other beta blocking agents.

Binding to beta-1 and beta-2 adrenergic receptors was
investigated using 50 pM final concentration of the non-selective beta receptor radioligand [125 I]iodocynanopindolol in the presence or absence of varying cold beta receptor ligand concentrations in membranes prepared from explanted human left ventricular myocardium. The beta-1/beta-2 ratio for each beta blocker investigated was: 321 for nebivolol; 103 for bisoprolol; 93 for
betaxolol; 69 for celiprolol; 74 for metoprolol; and 1.0 for the non-selective beta blockers bucindolol, propanolol and carvedilol.

Two additional in vitro studies were presented by Preston Mason, Ph.D. of Brigham and Women's Hospital, Harvard Medical School, entitled: Nebivolol Improves eNOS Function and Nitric Oxide Bioavailability in Endothelial Cells
from African Americans [Abstract # 389]; and Membrane Location of Nebivolol Contributes to Antioxidant Activity and Endothelial Nitric Oxide Release in Stroke-Prone Hypertensive Rats [Abstract # 388].

Metoprolol Shows Promise in Pediatric Hypertension

Tue, 17 May 2005 08:34:38 PST

( from http://www.rxpgnews.com ) AstraZeneca announced new data for beta-blocker TOPROL-XL® (metoprolol succinate) extended-release tablets in treating hypertension in pediatric patients. The data was presented today in a press briefing at the 20th annual scientific meeting of the American Society of Hypertension (ASH) in San Francisco.

This study adds to the established data on TOPROL-XL in the treatment of hypertension in adults. Hypertension affects one in three adults and approximately one in 100 children in the United States.(1,2)

"Hypertension in children is becoming increasingly common, in part related to the rise in childhood obesity. There is limited data on the treatment of pediatric hypertension. This study helps fill an unmet need by exploring new treatment options for children with hypertension," said lead investigator Bonita Falkner, M.D., Department of Medicine and Pediatrics, Thomas Jefferson University in Philadelphia and Chair of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents.

The trial was a double-blind, placebo-controlled, randomized, parallel group study of 144 children, ages six to sixteen, with primary hypertension. Each patient was randomized to one of four treatment arms (placebo or TOPROL- XL 0.2 mg/kg "low," 1.0 mg/kg "medium," or 2.0 mg/kg "high") for four weeks. Systolic blood pressure served as the primary measure.

The mean systolic blood pressure was reduced with TOPROL-XL (low/medium/high doses pooled) by 6.2 mm Hg versus placebo 1.9 mm Hg (p=0.03). None of the patients receiving TOPROL-XL required discontinuation because of an adverse event. The most common adverse events for TOPROL-XL versus placebo were headache (11.7% vs. 16.7%), upper respiratory tract infection (6.8% vs. 4.2%), dizziness (4.2% vs. 4.2%), and cough (2.5% vs. 8.3%).

Important Information About TOPROL-XL

TOPROL-XL is a beta1-selective (cardioselective) adrenoceptor-blocking agent, for oral administration, available as extended-release tablets. TOPROL-XL has been formulated to provide a controlled and predictable release of metoprolol succinate for once-daily administration. TOPROL-XL currently is available in 25-mg, 50-mg, 100-mg, and 200-mg tablets.

Indications for TOPROL-XL include the treatment of hypertension, alone or in combination with other antihypertensives; the long-term treatment of angina pectoris; and the treatment of stable, symptomatic (NYHA Class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin. It was studied in patients already receiving ACE inhibitors, diuretics, and, in the majority of cases, digitalis.

TOPROL-XL is contraindicated in severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, and sick sinus syndrome (unless a permanent pacemaker is in place).

Patients taking TOPROL-XL should avoid abrupt cessation of therapy. Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have occurred. The dosage should be reduced gradually over a one-to-two week period and the patient should be carefully monitored.

As with other beta-blockers, TOPROL-XL should be used with caution in patients who have diabetes, bronchospastic disease, thyrotoxicosis, peripheral vascular disease, who are undergoing major surgery, or who take calcium channel blockers of the verapamil and diltiazem type.

In patients with hypertension or angina pectoris, the most common side effects with TOPROL-XL are tiredness (10%), depression (5%), diarrhea (5%), itching or rash (5%), shortness of breath (3%), and bradycardia (3%).

About Hypertension in Children

Hypertension is estimated to affect more than 50 million adults. Although hypertension is more prevalent in adults, it is occurring with increasing frequency in children as well. The changing epidemiology of pediatric hypertension is attributed to a rise in childhood obesity, inactivity, and poor dietary habits. The typical pediatric patient with hypertension is most commonly an otherwise healthy child with obesity and associated cardiovascular risk factors.

These observations suggest that the trend of decreasing cardiovascular disease in adults observed over the past 50 years may be reversed as the current population of hypertensive children and adolescents grow into adulthood. Hypertension in childhood is considered a chronic medical condition and may require long-term treatment. Thus, early recognition and intervention for hypertension is recommended to begin in childhood by the National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents.

Trends in the Prescribing of Thiazides for Hypertension

Tue, 26 Apr 2005 22:25:38 PST

( from http://www.rxpgnews.com ) Hypertension is common in affluent societies and a major risk factor for heart disease. In Canada, hypertension is the leading primary diagnosis for patient visits to physicians' offices. Beyond recommending lifestyle changes such as losing weight, quitting smoking, and lowering salt and alcohol intake, prescription drugs are indicated in many patients. As a consequence, antihypertensive drugs are the leading category of prescription drugs in Canada, accounting for 20% of prescription drug sales.

Several classes of drugs are available for treatment, including diuretics, ACE inhibitors, and calcium channel blockers. First-line treatment with thiazide diureticsthe oldest and by far the cheapest drug classhas been shown in randomized trials to reduce serious cardiovascular morbidity and mortality with benefits at least as great as first-line treatment with other drug classes.

Steve Morgan and colleagues set out to examine whether prescribing practices were in accordance with this evidence. They analyzed administrative claims data from a public drug plan for seniors (residents of age 65 and older) to determine trends in first-line hypertension drug use. During the period from 1993 to 2000, over 82,000 seniors were identified as new users of hypertension drugs. Less than a third of these patients received thiazides (alone or as part of a combination regimen) as a first-line treatment.

The share of new patients receiving a thiazide increased over the study period, but did not exceed 45% at any point. Women were more likely than men, and older patients were more likely than younger ones, to receive thiazides. Comorbidities also influenced prescribing practices: patients without concurrent diagnoses were more likely to receive thiazides. While for some comorbidities (such as previous acute myocardial infarction) evidence suggested that there were good reasons to prescribe drugs other than thiazides, no such evidence existed for many of the other conditions that nevertheless were associated with lower prescription of thiazides.

Changes in drug availability and existing evidence during the period studied make it difficult to calculate the exact extent to which thiazides were under-prescribed. However, the study shows that many patients received drugs that had previously been found to be no better at treating hypertension than much cheaper alternatives. Drug prices changed over the study period as well, but even comparing the lowest price for any of the alternatives to thiazides, $0.34 per day, with the constant cost of less than $ 0.01 per day for a thiazide makes it clear that a lot of money was wasted.

On a more positive note, prescription of thiazides as a first-line therapy rose over the study periodfrom 25% to 42% in patients without comorbidities. Most of the increase occurred shortly after a specific local education campaign. This suggests that repeated targeting of prescribing physiciansmany of whom receive regular marketing material from pharmaceutical companies and subscribe to the general view that newer drugs are betterwith current evidence-based information should be considered.

One of the most influential studies comparing antihypertensive drugs, the ALLHAT study, also supported the use of thiazides as first-line drugs. ALLHAT was published in 2003, and its results widely publicized. According to Steve Morgan, Anecdotal evidence suggests that ALLHAT has had an influence on prescription practices, but I am not aware of a large-scale analysis yet.