In a five-year laboratory study, UC surgeon-scientist Karyn Butler, MD, found that when the heart experiences short periods of stress, either from reduced blood flow or high blood pressure, it activates a protective molecular pathway – known as JAK-STAT – that protects the heart muscle. The pathway, which is normally dormant in the heart, was originally identified in disease-fighting white blood cells as a mediator of infection and has recently been targeted for its role in heart health.

Butler says when the JAK-STAT pathway is active and functioning, it can help precondition and protect the heart from damage caused when blood flow is restored after a period of decreased flow, as occurs after a heart attack.

“These mini stress tests appear to push the heart muscle into an adaptive state where it gets used to how long-term stress feels,” Butler explains. “This preconditioning helps the heart muscle better tolerate longer episodes of compromised blood flow.”

Her team reports their findings in the January 2008 issue of the American Journal of Physiology: Heart and Circulatory Physiology.

A trauma/critical care surgeon at University Hospital in Cincinnati, Butler wanted to determine how she could help patients with heart disease from high blood pressure tolerate cardiac ischemia, which occurs when vessels become narrowed or blocked and results in a dangerous reduction of blood flow to the heart.

To study the heart’s response to restored blood flow after cardiac ischemia and in the presence of hypertension, Butler developed a hypertrophied (enlarged) animal heart model to mimic the conditions of heart enlargement and congestive heart failure in humans.

The enlarged heart model was then subjected to preconditioning – a series of short periods of blood flow blockage – to simulate what happens in humans with serious heart disease.

Butler found that these mini stress tests activated the dormant JAK-STAT pathway, and helped protect the muscle from injury when blood flowed back into the heart.

“The concept is similar to how we approach a new physical fitness regimen: incremental steps. You wouldn’t try to condition yourself for a marathon by running 10 miles on your first day of training. You’d prepare yourself incrementally,” explains Butler, an associate professor of surgery at UC and corresponding author of the study.

“The body appears to be doing the same thing when it comes to the heart. Patients often endure short periods of reduced blood flow before the blockage causes irreversible cardiac damage,” she adds. “When the JAK-STAT pathway is activated, however, it appears to have a protective effect and may help the heart recover.”

By revealing the underlying molecular mechanisms, Butler says, scientists may be able to develop drugs designed to selectively harness the protective benefits of the JAK-STAT pathway and help patients avoid debilitating heart injuries.

Butler’s next step is to compare the effects of the JAK-STAT pathway in normal hearts with diseased hearts similar to those of patients at higher risk for heart attack.

The Harold Amos award was created to increase the number of academic medicine faculty from historically disadvantaged ethnic, financial or educational backgrounds. The awards identify researchers who have excelled in their education and who have completed or are completing formal clinical training. Recipients are committed to pursuing academic careers, serving as role models for students and fellow faculty, decreasing health disparities, and improving the health and well-being of the underserved.

A native of New Jersey, Dr. Ravenell completed medical school at the University of Chicago, where he first became interested in academic medicine and in treating underserved patients.

“I had the opportunity to work on a black men’s health project where we did focus groups with underserved patients,” said Dr. Ravenell, who completed his residency at the University of Pennsylvania and a clinical epidemiology fellowship at Cornell University Medical Center. “The results of that study were used to get funding to start a black men’s health clinic.”

He was recruited to UT Southwestern in 2005 by Dr. Ronald Victor, professor of internal medicine and principal investigator of the Barbershop Project, a barber-run program aimed at improving diagnosis and treatment of hypertension in black men. Dr. Ravenell said the Barbershop Project is key in linking clinical work and research designed to benefit underserved patients.

Dr. Ravenell said funding from the Harold Amos award will allow him to study a phenomenon known as “physician inertia,” where doctors may be reluctant to aggressively treat hypertension in African-American men.

“I’m interested in studying reasons why doctors may not be more aggressive in initiating or intensifying therapy for high blood pressure,” he said. “Poorly controlled hypertension in patients can have severe and devastating consequences.”

The award was named in honor of Dr. Harold Amos, who was the first African-American to chair a department, now the Department of Microbiology and Medical Genetics, at Harvard Medical School.

Dr. Ravenell is the seventh UT Southwestern researcher to win this prestigious grant. Other UT Southwestern winners and the years grants were received include: Dr. Richard King, assistant professor of neurology (2006); Dr. Ohwofiemu Nwariaku, associate professor of surgery (2002); former faculty members Dr. Edsel Arce-Hernandez (1999), Dr. Carmela Morales (1996) and Dr. Ivor Benjamin (1985); and former fellow Dr. David Wilkes (1992).

The approval is based on data from two clinical trials involving more than 1,200 patients with moderate or severe high blood pressure.

In the first double-blind, active-controlled, seven-week trial, patients with severe hypertension (mean baseline 172/113 mm Hg SBP/DBP) were randomly treated with either AVALIDE 150/12.5 mg (n=468) or irbesartan 150 mg monotherapy (n=227). After one week, all doses were doubled.

At five weeks, AVALIDE® (irbesartan-hydrochlorothiazide) 300/25 mg demonstrated mean blood pressure reductions of 30.8/24.0 mm Hg versus 21.1/19.3 mm Hg (SBP/DBP) for irbesartan 300 mg alone (P<.0001).

In the second double-blind, active-controlled, 12-week trial, patients with moderate hypertension (mean baseline 162/98 mm Hg SBP/DBP) were randomly treated with AVALIDE 150/12.5 mg (n=328), irbesartan 150 mg monotherapy (n=106), or hydrochlorothiazide 12.5 mg monotherapy (n=104). After two weeks, all doses were doubled. The primary endpoint was mean change in SBP from baseline to Week 8. At eight weeks, AVALIDE 300/25 mg demonstrated mean blood pressure reductions of 27.1/14.6 mm Hg (SBP/DBP), which was significantly greater than irbesartan 300 mg or hydrochlorothiazide 25 mg alone, 22.1/11.6 mm Hg (P<.01) and 15.7/7.3 mm Hg (P<.0001) (SBP/DBP), respectively.

In the severe hypertension study, the incidences of pre-specified adverse events on AVALIDE vs. irbesartan were: syncope (0% vs. 0%), hypotension (0.6% vs. 0%), dizziness (3.6% vs. 4.0%), headache (4.3% vs. 6.6%), hyperkalemia (0.2% vs. 0%), and hypokalemia (0.6% vs. 0.4%). In the moderate hypertension study, the incidences of pre-specified adverse events on AVALIDE vs. irbesartan or hydrochlorothiazide monotherapy were: hypotension (0.9% vs. 0% and 0%), dizziness (3.0% vs. 3.8% and 1.0%), headache (5.5% vs. 3.8% and 4.8%), hyperkalemia (1.2% vs. 0% and 1.0%), and hypokalemia (0.9% vs. 0% and 0%).

"Guidelines support initial combination therapy for severe hypertension based on the need to lower BP within weeks rather than months," said Dr. Joel Neutel, Professor of Medicine, University of California in Irvine.

"Now with AVAPRO® (irbesartan) and AVALIDE physicians have more therapeutic options to treat mild, moderate and severe hypertension," added Dr. Neutel.

AVAPRO is indicated for the treatment of hypertension and also helps to slow the progression of nephropathy in type 2 diabetic hypertensive patients. AVALIDE may be used in appropriate patients whose blood pressure is not adequately controlled on monotherapy and now can be used as initial therapy in appropriate patients who are likely to need multiple drugs to achieve their blood pressure goals.

"JNC 7 guidelines recommend that physicians consider starting with combination therapy for most patients with stage 2 hypertension," said Dr. Michael Weber, Professor of Medicine, SUNY Downstate College of Medicine.

"In addition, the approval of AVALIDE® (irbesartan-hydrochlorothiazide) as a first-line therapy in patients likely to need multiple drugs to achieve their blood pressure goals provides physicians with an FDA-approved therapeutic option in one tablet."

About AVAPRO® (irbesartan) and AVALIDE

In the United States, AVAPRO is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents. AVAPRO is also indicated for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (>300 mg/day) in patients with type 2 diabetes and hypertension. In this population, AVAPRO reduces the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end-stage renal disease (need for dialysis or renal transplantation).

AVALIDE is a fixed-dose combination of the angiotensin II receptor blocker (ARB) AVAPRO and a diuretic (hydrochlorothiazide).
AVALIDE is indicated for the treatment of hypertension.
AVALIDE may be used in patients whose blood pressure is not adequately controlled on monotherapy.
AVALIDE may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals.
The choice of AVALIDE as initial therapy for hypertension should be based on an assessment of potential benefits and risks.

Important Safety Information

Use In Pregnancy: When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus.

When pregnancy is detected, AVAPRO or AVALIDE should be discontinued as soon as possible. See WARNINGS: Fetal/Neonatal Morbidity and Mortality.

- Because of the hydrochlorothiazide component, AVALIDE is contraindicated in patients with anuria or hypersensitivity to sulfonamide-derived drugs

- In patients with volume or sodium depletion (eg, patients vigorously treated with diuretics or on dialysis), such depletion should be corrected prior to administration of AVAPRO® (irbesartan) or AVALIDE® (irbesartan-hydrochlorothiazide), or a lower initial dose of AVAPRO (75 mg) should be used, to avoid possible symptomatic hypotension

- Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history

- Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus

- Lithium generally should not be given with thiazides

- Thiazides should be used with caution in patients with severe renal disease and in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma

- In placebo-controlled hypertension studies, there were no significant differences in adverse events (AEs) between AVAPRO and placebo. Adverse events that occurred in at least 1% of patients treated with AVAPRO and at a higher incidence vs placebo included diarrhea (3% vs 2%), dyspepsia/heartburn (2% vs 1%) and fatigue (4% vs 3%)

- Additionally, in a study of hypertensive type 2 diabetic patients with renal disease (proteinuria ? 900 mg/day), the reported AEs for AVAPRO were similar to those seen in hypertension studies, with the exception of an increased incidence of orthostatic symptoms; AVAPRO compared to placebo (both groups received adjunctive antihypertensives): dizziness (10.2% vs 6.0%), orthostatic dizziness (5.4% vs 2.7%) and orthostatic hypotension (5.4% vs 3.2%), respectively. In patients with proteinuria, monitor serum potassium

- In placebo-controlled hypertension studies, the most common adverse experiences reported with AVALIDE that occurred in ?1% of patients and at a higher incidence vs placebo included fatigue (7% vs 3%), musculoskeletal pain (7% vs 5%), dizziness (8% vs 4%), and nausea/vomiting (3% vs 0%). Additionally, in studies of moderate and severe hypertensives where AVALIDE was used as initial therapy, the types and incidences of adverse events reported for AVALIDE were similar to monotherapy

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For full Prescribing Information including boxed WARNING regarding Use in Pregnancy, please visit: http://www.AVAPROAVALIDE.com or http://www.bms.com.