Sildenafil Shows Promise as Adjunct Therapy for Severe Pulmonary Hypertension

NEW YORK (Reuters Health) Jul 02 - Adding sildenafil (Viagra) to inhaled iloprost therapy improves exercise capacity and lung hemodynamics in patients with severe pulmonary arterial hypertension (PAH), according to a new report by German researchers.

"The potential of sildenafil for the treatment of patients with PAH, either as a single therapy or as an adjunct therapy, is very high," lead author Dr. Hossein A. Ghofrani, from Justus-Leibig-University in Giessen, said in a statement.

Dr. Ghofrani noted that in most PAH patients there comes a time when "the initial therapy either loses effectiveness or the disease will progress despite ongoing therapy. It is my personal view that future therapeutic approaches will focus more and more on combination therapy with substances that are compatible."

The new findings, which are published in the July 2nd issue of the Journal of the American College of Cardiology, are based on a study of 14 patients with deteriorating PAH despite ongoing treatment with inhaled iloprost. The subjects were instructed to continue their iloprost regimen unchanged, but to add oral sildenafil therapy for up to 12 months.

Sildenafil therapy was tied to a significant improvement in 6-minute walking distance compared with baseline scores (p = 0.002). Furthermore, this improvement, which was first observed after three months of therapy, was maintained for up to 12 months (p = 0.002).

Treatment with sildenafil was also tied to a downgrading of the New York Heart Association functional class, the researchers point out.

Lastly, sildenafil therapy had a beneficial effect on pulmonary hemodynamics. For example, a significant drop in the pulmonary vascular resistance occurred after just a few months of treatment (p = 0.036).

Although two patients died from pneumonia during the study period, no serious adverse effects were linked to treatment with sildenafil, the authors note.

The finding that sildenafil therapy can rescue PAH patients failing prostanoid therapy is quite remarkable given that these patients are usually considered urgent candidates for lung transplantation, the researchers state. Still, controlled clinical trials are warranted to verify the current findings, they add.

J Am Coll Cardiol 2003;42:158-164.

Nebulized Epinephrine Not Helpful for Infants With Acute Bronchiolitis

Laurie Barclay, MD

July 2, 2003 — Nebulized epinephrine is not helpful for infants with acute bronchiolitis, according to the results of a multicenter, randomized, double-blind trial published in the July 3 issue of the New England Journal of Medicine.

"The treatment of infants with bronchiolitis is largely supportive," write Claire Wainwright, MB, BS, MD, from Royal Children's Hospital in Brisbane, Australia, and colleagues. "The role of bronchodilators is controversial."

Among 194 infants with bronchiolitis admitted to four Australian hospitals, length of hospital stay and the time until the infant was ready for discharge were not significantly different in those treated with 1% nebulized epinephrine or with normal saline. However, the time until the infant was ready for discharge was significantly longer in the epinephrine group (P = .02) among infants requiring supplemental oxygen and intravenous fluids.

The need for supplemental oxygen at admission was the strongest predictor of illness severity score, length of stay, and the time until the infant was ready for discharge (P < .001). Although heart rate increased significantly after each 4-mL treatment with epinephrine, there were no significant changes in respiratory rate, blood pressure, or respiratory effort scores.

Because more infants with moderately severe illness were assigned to the epinephrine group, this difference could have influenced the apparent effect of epinephrine, the authors note.

"This trial mirrors the reality of clinical practice in both tertiary care and district hospitals, and our results are therefore applicable to the majority of hospitalized infants with acute broncholitis," the authors write. "The evidence from this trial points clearly to a lack of benefit, in either short-term or long-term clinically relevant outcomes, of nebulized epinephrine in infants hospitalized with acute bronchiolitis."

In an accompanying editorial, Mary Ellen B. Wohl, MD, and Victor Chernick, MD, from Harvard Medical School in Boston, Massachusetts, point out that no bronchodilator reduces length of stay and that treatment of hospitalized infants with either albuterol or epinephrine therefore cannot be recommended.

"However, epinephrine does reduce airway resistance and improves the clinical score as compared with albuterol," they write. "We speculate that the same benefits might be achieved by the administration of alpha-adrenergic nose drops, particularly before feeding. How simple."

N Engl J Med. 2003;349:27-35, 82-83

Reviewed by Gary D. Vogin, MD

Diabetes Drugs Inappropriately Prescribed for Patients With Concomitant Heart Failure

NEW YORK (Reuters Health) Jul 01 - Despite explicit warnings on package inserts, metformin and thiazolidinediones are often given to diabetics hospitalized with heart failure, according to a report published in the July 2nd issue of the Journal of the American Medical Association.

Moreover, the findings indicate that inappropriate use of these drugs is rapidly increasing.

Metformin is contraindicated for diabetics treated with heart failure medications because of the increased risk of potentially fatal lactic acidosis. Thiazolidinediones are not recommended for diabetics with advanced heart failure, out of concern that such agents could increase the intravascular volume and worsen the cardiac condition, the authors note.

To investigate the inappropriate use of these drugs, Dr. Harlan M. Krumholz, from Yale University in New Haven, Connecticut, and colleagues analyzed data from Medicaid beneficiaries with diabetes who were hospitalized with heart failure between April 1998 and March 1999 or between July 2000 and June 2001.

In the 1998-1999 cohort, 7.1% of patients received a metformin prescription, 7.2% received a thiazolidinedione prescription, and 13.5% received a prescription for either drug, the investigators note. In the 2000-2001 group, the corresponding rates were all significantly higher -- 11.2%, 16.1%, and 24.4% (p < 0.001 for all).

"National guidelines do not focus extensively on the treatment of diabetes in heart failure patients," the authors emphasize. "Future guidelines should provide more explicit guidance in defining the safe treatment" of these patients.

JAMA 2003;290:81-85.

Excessive Zinc Supplementation May Increase Prostate Cancer Risk

Laurie Barclay, MD

July 1, 2003 — Zinc supplementation may increase prostate cancer risk, according to the results of a study published in the July 2 issue of the Journal of the National Cancer Institute. Reviewing data from the Health Professionals Follow-up Study, the investigators suggest that zinc supplementation of 100 mg/day or more or use of supplements for more than 10 years can more than double the risk of prostate cancer.

"The high concentration of zinc in the prostate suggests that zinc may play a role in prostate health," write Michael F. Leitzmann, MD, from the National Institutes of Health in Bethesda, Maryland, and colleagues. "Whether dietary zinc intake affects intraprostatic zinc levels is unknown. However, ingestion of 150 mg/day or more of zinc has undesirable metabolic effects, such as immune dysfunction and impaired antioxidant defense that are potentially related to prostate cancer."

During follow-up from 1986 through 2000 of 46,074 U.S. men enrolled in the Health Professionals Follow-up Study, 2,901 developed prostate cancer, including 434 cases of advanced cancer.

Although supplemental zinc up to 100 mg/day was not associated with prostate cancer risk, men who consumed more than 100 mg/day of supplemental zinc had more than double the risk of advanced prostate cancer compared with nonusers (relative risk, 2.29; 95% confidence interval [CI], 1.06 - 4.95; P = .003 for trend). In men who used zinc supplements for at least 10 years, relative risk was 2.37 (95% CI, 1.42 - 3.95; P <.001 for trend).

"Excessively high zinc intake was associated with an increased risk of advanced prostate cancer," the authors write. "Although we cannot rule out residual confounding by supplemental calcium intake or some unmeasured correlate of zinc supplement use, our findings, that chronic zinc oversupply may play a role in prostate carcinogenesis, warrant further investigation."

J Natl Cancer Inst. 2003;95:1004-1007

Reviewed by Gary D. Vogin, MD

Novel Contraceptive Device Effective, Reliable

NEW YORK (Reuters Health) Jul 01 - A phase-III study of a novel birth control system confirms previous findings of rapid recovery after insertion and high patient satisfaction, the Selective Tubal Occlusion Procedure 2000 Investigators Group reports in the July issue of Obstetrics and Gynecology. No pregnancies occurred after nearly 10,000 woman-months of follow-up.

Essure (Conceptus Inc., San Carlos, California) is approved for use in the US and elsewhere (see Reuters Health report November 4, 2002).

In this international prospective trial, which was funded by Conceptus, microinsert placement was attempted in 507 previously fertile women seeking sterilization. The women, who weighed 90 to 300 pounds, were given an oral nonsteroidal anti-inflammatory drug prior to the procedure, and paracervical blocks were performed in most cases.

Dr. Jay M. Cooper of Women's Health Research in Phoenix, Arizona, and colleagues observed successful bilateral placement in 92% of women. The failures were primarily due to anatomic failure, such as stenotic fallopian tubes or obscuring of the visual field by thickened endometrium.

Average pain during the procedure was rated as mild or none by 65% of women; however, 4% rated the average procedural pain as severe. Sixty-percent reported a return to normal function within one day, and more than 98% were satisfied or very satisfied at all follow-up visits.

Bilateral placement rate was high even among women with obesity or prior abdominal or pelvic surgery. Tubal occlusion was documented by three months in 96% of women in whom microinserts were successful, and by six months in 100%. Contraception was successful during an average of 21.4 months.

"Women need to be adequately counseled that successful bilateral placement may not be possible in all cases because of anatomic impediments and visualization difficulties," Dr. Cooper's team notes. This drawback is worth the attempt, they conclude, given the potential risks, side effects, and longer recovery time required for laparoscopic tubal sterilization procedures.

Obstet Gynecol 2003;102:000-000.

Mycophenolate Mofetil Helpful in Pemphigus CME

News Author: Laurie Barclay, MD
CME Author: Charles Vega, MD

Authors and Disclosures
To earn CME credit, read the news brief, the paragraphs that follow, and answer the questions below.

Release Date: June 27, 2003; Valid for credit through June 27, 2004

Credits Available
Physicians - up to 0.25 AMA PRA category 1 credit(s)

June 27, 2003 — Mycophenolate mofetil is safe and effective for adjuvant treatment for pemphigus, according to the results of a prospective trial published in the June issue of the Archives of Dermatology.

"Mycophenolate mofetil is increasingly being used as a corticosteroid-sparing agent in immunosuppressive regimens," write Daniel Mimouni, MD, and colleagues from Johns Hopkins University School of Medicine in Baltimore, Maryland. "Because of its effectiveness and safety profile, mycophenolate has now replaced azathioprine as the antimetabolite adjuvant of choice in the treatment of many autoimmune and inflammatory disorders."

Of 42 consecutive patients with pemphigus who had relapses during prednisone taper or had clinically significant adverse effects from previous drug therapy, 31 had pemphigus vulgaris and 11 had pemphigus foliaceus. Patients were allowed to continue receiving prednisone but not other medications for pemphigus. They received treatment with mycophenolate mofetil for a median of 22 months, with a median follow-up period of 22 months.

Complete remission occurred in 22 (71%) of 31 patients with pemphigus vulgaris and in five (45%) of 11 patients with pemphigus foliaceus. Median time to achieve complete remission was nine months (range, 1-13 months). One patient (3%) with pemphigus vulgaris and four patients (36%) with pemphigus foliaceus achieved partial remission.

Although 77% of patients had no adverse effects, two patients had to discontinue treatment, one because of symptomatic but reversible neutropenia, and another because of nausea.

The authors point out that dermatologic diseases may require dosages of mycophenolate mofetil from 35 to 45 mg/kg per day, higher than the recommended dosage for renal transplant recipients of 30 mg/kg per day. In the latter indication, dosage is lower because it is typically used with other immunosuppressants. Unlike azathioprine, the adverse effects of mycophenolate appear to be dose-dependent and are rarely clinically significant.

"To our knowledge, this is the largest case series of [pemphigus vulgaris] and [pemphigus foliaceus] treated with this agent," the authors write. "Mycophenolate is approximately four times more expensive than azathioprine. However, the need for more frequent routine laboratory monitoring, thiopurine methyl transferase screening, and potentially more frequent management of adverse effects in azathioprine-treated patients may warrant the use of mycophenolate as first-line adjuvant therapy."

Roche Pharmaceuticals helped support this study. The authors report no relevant financial interest in this article.

Arch Dermatol. 2003;139:739-742
Learning Objectives
Upon completion of this activity, participants will be able to:

* Review the etiology, symptoms, and treatment of pemphigus disease.
* Describe the efficacy of mycophenolate mofetil as an adjuvant treatment of pemphigus.

Clinical Context

Pemphigus diseases are rare, chronic vesiculobullous skin diseases. Vesicular formation occurs at the intraepidermal level in true pemphigus due to autoantibodies directed against the intercellular matrix that helps approximate epidermal cells. True pemphigus is distinguished from pemphigoid disease, in which vesicles form at the subepidermal level. True pemphigus is divided into either the more common pemphigus vulgaris or rarer pemphigus foliaceus. Pemphigus vulgaris usually begins in middle age with flaccid bullae that usually originate in the oropharynx and then spread to the scalp, face, chest, axillae, and inguinal area. Pemphigus foliaceus is defined by similar lesions but without involvement of the oropharynx.

The introduction of systemic steroids in the treatment of pemphigus has reduced disease mortality from 90% to 5%, according to Stanley in the 1999 edition of Fitzpatrick's Dermatology in General Medicine. Prednisone at 1 mg/kg/day is the usual first agent chosen. However, because of the adverse events associated with chronic steroid use, adjuvant treatments, such as azathioprine and cyclophosphamide, have been employed to maintain treatment efficacy while tapering or eliminating steroids. Methotrexate and cyclosporine have also been used as adjuvant agents.

This study by Mimouni and colleagues looks at another adjuvant therapy, mycophenolate mofetil, in the treatment of pemphigus. Mycophenolate inhibits purine synthesis and lymphocyte proliferation and has been previously used in transplant patients to prevent rejection.
Study Highlights

* 31 patients with pemphigus vulgaris and 11 with pemphigus foliaceus who had either a relapse of pemphigus during prednisone taper or adverse events with previous regimens were selected to participate in the open-label trial of mycophenolate mofetil.
* Mycophenolate was dosed at 35-45 mg/kg/day.
* The main outcome measure was either complete or partial remission of pemphigus. Total remission was defined as the absence of lesions for 4 or more weeks. Partial remission was defined as having 1-5 lesions lasting more than one week.
* 21 subjects were failing a prednisone dosage between 0.5-1 mg/kg/day. 10 subjects were failing prednisone at a dose of <0.5 mg/kg/day. 11 subjects were included because they could not tolerate adjuvant therapy with azathioprine.
* Median time for follow up was 22 months.
* Complete remission was achieved in 71% of subjects with pemphigus vulgaris and 45% of subjects with pemphigus foliaceus. Partial remission was achieved in 3% of pemphigus vulgaris patients and 36% of pemphigus foliaceus patients.
* 10% of subjects failed to achieve any level of remission with mycophenolate.
* The median time to remission with mycophenolate was 9 months.
* 24% of participants receiving mycophenolate reported adverse events, and 79% of those with adverse events suffered gastrointestinal symptoms. Most subjects with vague abdominal pain and/or mild diarrhea did not require dosage adjustment.
* Mycophenolate did not cause significant laboratory abnormalities, increased rates of infection, or increased rates of cancer during the study period.

Pearls for Practice

* Pemphigus diseases are vesiculobullous diseases of the skin and mucous membranes. The primary treatment for these diseases is oral corticosteroids, which have dramatically reduced the mortality of pemphigus.
* This open-label trial of mycophenolate demonstrates its efficacy and safety as an adjuvant treatment of pemphigus.