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Fen Phen and Primary Arterial Hypertension News - October
Philadelphia Jury Reaches Split Fen-Phen Verdicts
Fri Oct 22
NEW YORK (Reuters) - Wyeth on Friday said a Philadelphia jury refused to award damages to a woman who claimed she was harmed by the company's recalled "fen-phen" diet drug Pondimin, but that the same jury in a separate case awarded $41,000 to another woman who had taken the drug.
Wyeth said the Court of Common Pleas of the First Judicial District of Pennsylvania refused to award damages to Julia Feagins, 47, of Corinth, Texas, following trial. But the Madison, New Jersey-based drugmaker said the jury awarded over $41,000 to Ida Dupree, of Port Arthur, Texas. A Wyeth spokesman said the company is considering whether to appeal the award to Dupree, but declined further comment. Wyeth in 1997 recalled Pondimin and a second drug used in the fen-phen slimming cocktail after the appetite suppressants were linked to heart damage. The company has taken charges of over $16 billion to cover liabilities to former users of the drugs.
Pfizer and Wyeth see earnings rise
Thursday, October 21
BY DAVID SCHWAB
Star-Ledger Staff
Pharmaceutical companies Pfizer and Wyeth yesterday reported solid earnings. Pfizer, the world's biggest drug maker, said net earnings rose 50 percent and Wyeth added it erased a loss from the year before. But both companies raised some caution flags. New York-based Pfizer said third-quarter revenue grew 4 percent, to $12.83 billion, helped by an 11 percent rise in sales of cholesterol medicine Lipitor. Profit reached $3.34 billion, or 44 cents per share, due to cost cutting after its purchase of Pharmacia last year. Pfizer's earnings a year ago were depressed due to more than $1 billion in merger-related charges. For the quarter, sales of Pfizer's Celebrex rose 14 percent and Bextra sales jumped 37 percent. Both arthritis-pain medicines are similar to Vioxx, which Merck withdrew from the market three weeks ago for safety reasons. Celebrex and Bextra "are responding to new challenges," said Karen Katen, president of Pfizer global pharmaceuticals. The two medicines are expected to continue exceeding sales projections, she said. Madison-based Wyeth said revenue rose 10 percent, to $4.5 billion and net earnings were $1.42 billion, or $1.06 per share, reversing a year- earlier loss of $426 million due to charges for its diet-pill litigation. Wyeth reported sales of antidepressant Effexor jumped 38 percent and sales of Enbrel for rheumatoid arthritis doubled. But for next year, Pfizer warned sales will likely be hurt by generic competition for Pfizer's antifungal drug Diflucan, epilepsy treatment Neurontin, antibiotic Zithromax and hypertension treatment Accupril. Shares yesterday fell more than 2 percent. "We believe that investors will focus on Pfizer's foreboding 2005 guidance," said Leerink Swann analyst Andrew Oh. Pfizer said it will issue specific earnings estimates for 2005 early next year. Cost savings from the Pharmacia merger are expected to begin leveling off in 2005. For 2004, Pfizer expects to achieve $3.5 billion in Pharmacia-related cost savings, with savings of $4 billion next year. At Wyeth, Kenneth Martin, the company's chief financial officer, warned the company may need to set aside additional financial reserves "in the next few months" to cover liability to former users of its two recalled fen-phen diet drugs. The company has already taken more than $16 billion in fen-phen charges since the two medicines were recalled in 1997 after being linked to heart-valve damage among some of the 6 million Americans who had taken them. Reuters contributed to this report. David Schwab can be reached at dschwab@starledger.com or (973) 392-5835.
Fargoan receives new set of lungs
By Erin Hemme Froslie,The Forum
October 19
Nearly two years to the day he was diagnosed with a rare debilitative disease, Jack Keller received the new lungs that promise him a better future. Friday the 25-year-old Fargo man underwent surgery for a double lung transplant. By Monday he was sitting in a chair next to his hospital bed at the Mayo Clinic in Rochester, Minn. "Overall he's doing great," said Jack's younger brother, Josh Keller, who is a youth pastor in Fargo. "It been a journey, but right now the prognosis is very good." Jack was diagnosed with primary pulmonary hypertension in October 2002. The incurable disease occurs when the blood pressure in the vessel between heart and lungs is higher than normal. For Keller, the best treatment was a lung transplant. He expected to wait at least another year before a set became available.
But last Thursday Jack received a call shortly after 9 p.m. The Mayo Clinic had lungs for him. Fifteen minutes later, a second call revealed there might be a problem, Josh said.
It took two hours before doctors told Jack to get to the hospital as soon as possible. Jack and his mother, Marlys, were flown by MeritCare Hospital to Rochester. They arrived shortly after 1 a.m. Friday. Jack immediately started taking anti-rejection drugs. Around 9 a.m. the 5½-hour surgery started. "It was flawless," Josh said. "God has been so true and faithful in all of this." Jack will spend the next three months recovering at a transplant house in Rochester, said Josh, who with other family members drove to Rochester early Friday morning. Six months from now Josh expects to be lifting weights with his big brother again. "We feel so blessed," he said. Jack's coworkers at First International Bank and Trust in Fargo also are thrilled things are going well and faster than expected. "It's an answered prayer, to be honest," said Cory Thompson, assistant vice president. Jack was supposed to speak at a Thursday benefit for him sponsored by his coworkers. It's a silent auction from 6:30 to 8:30 p.m. at Bethel Free Evangelical Church. His colleagues will let him off the hook this time. "He has a new set of lungs and we couldn't be happier," Thompson said.
Readers can reach Forum reporter Erin Hemme Froslie at (701) 241-5534
We have a dangerous faith in animal models
Jared Milrad
Speaking at one of the largest pharmaceutical conferences in the world, Dr. Mark Levin, CEO of Millenium Pharmaceuticals, startled the compendium of drug testers before him with a single slide. Of the 22 drugs that advanced to human trials from liver toxicity tests in rats, only two of 11 drugs found to be toxic in rats were also toxic in humans, and only eight of the 17 supposedly safe drugs were also safe in humans. These results, Levin concluded, make the animal model about as predictable as a "coin toss"- and this man is no animal rightist. The most ardent supporters of animal research -- i.e. any drugs, chemicals or genetic modifications tested in non-humans that seek to model human disease -- propose claims highly more predictable than the methodologies they defend. Vivisectors hail the crucial scientific milestones that, in their view, depended on the animal model, such as the development of penicillin, the polio vaccine or a basic understanding of gross human anatomy and physiology. Sure enough, the penicillin and polio vaccine discoveries may have depended on animal models, though even penicillin inventor Alexander Fleming argued that animal models delayed "the whole field of antibiotics" and vaccine developer Albert Sabin criticized misleading monkey models. When early scientists compared the gross structure and function of the dog heart to the human heart, animal research worked. Decades later, however, when today's scientists consider knowledge about genes, gene regulation, complex biochemical pathways and current technologies, animal research doesn't work. In fact, it harms and sometimes kills the very species it seeks to protect. We now know that humans have about 30,000 genes, of which 99.4 percent of our "working DNA" is shared with chimpanzees and 97.5 percent with mice. Many species share thousands of genes, in fact, but the ways in which these genes are regulated (or turned "on" or "off") differs extensively from species to species, individual to individual. Gene regulation and sequence are the main reasons why most, but not all, humans develop lung cancer from prolonged smoking and why mice have tails but humans don't. Further, since genes interact in a complex system unique to each individual, one cannot simply "knock out" or add a gene to a mouse and then consistently predict the function of that same gene in humans. As one might expect, these slight differences have failed the animal model. The National Cancer Institute, for example, found that successful anti-cancer drugs were useless in mice growing human tumors. The Food and Drug Administration, which mandates animal testing for all new drugs, recalled or relabeled most new medications under study because of adverse, unexpected side effects. Today, 20 compounds harmless in humans are carcinogenic in mice. Cerestat, recalled because it killed potential stroke patients, joins hormone replacement therapy, Thalidomide, fen-Phen, Rezulin and other treatments as the collective human harms of animal research. Not only do animal models kill, they siphon time, money and scientific knowledge away from the human patients who need it most. According to The Washington Post, the pharmaceutical industry spends nearly $75 million each year lobbying in Washington and the industry has strong connections to the FDA, medical journals and academic institutions. These vested interests steal the spotlight from successful and widely used non-animal technologies. Epidemiology (the study of human populations), in-vitro research, gene assays, mathematical models and improved clinical research all summarize the past, present, and future of biomedical research. The potential of pharmacogenomics (or personalized medicine) and the success of the Human Genome Project, for example, emphasize the benefits of these modalities. There are no alternatives, much less refinements, to a scientifically inept model. We have a clear choice: not whether to save a child or dog, but whether to use our resources wisely or merely expend them on tradition. Terminally-ill patients deserve a better future, but only sound science, not mice, can take them there.
Jared Milrad is the president of Student Protecting Animals Responsibly and Compassionately. E-mail him at viewpoint@technicianonline.com.
Pulmonary Hypertension, Primary
April 13
Synonyms and related keywords: idiopathic pulmonary arterial hypertension, IPAH, idiopathic pulmonary hypertension, elevated pulmonary artery pressure, thrombotic pulmonary arteriopathy, TPA, plexogenic pulmonary arteriopathy, primary pulmonary hypertension, PPH, precapillary pulmonary hypertension, prostacyclin analogues, endothelin receptor antagonists, ERAs, endothelin-receptor antagonists, pulmonary hypertension, portal hypertension, pulmonary arteriopathy, pulmonary artery hypertension, PAH, pulmonary arterial hypertension AUTHOR INFORMATION Section 1 of 11
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Author: Ronald J Oudiz, MD, Director of Pulmonary Hypertension, Assistant Professor, Department of Medicine, Division of Cardiology, Harbor-UCLA Medical Center, University of California at Los Angeles School of Medicine
Ronald J Oudiz, MD, is a member of the following medical societies: American College of Cardiology, American College of Physicians, and American Heart Association
Editor(s): Oleh Wasyl Hnatiuk, MD, Program Director, National Capital Consortium, Pulmonary and Critical Ca, Walter Reed Army Medical Center; Associate Professor, Department of Medicine, Uniformed Services University of Health Sciences; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, Pharmacy, eMedicine; Robert S Crausman, MD, MMS, Associate Professor of Medicine, Brown University School of Medicine; Chief, Division of Geriatrics, Program Director, Department of Medicine, Memorial Hospital of Rhode Island; Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine; and Zab Mohsenifar, MD, Director, Division of Pulmonary/Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center; Professor, Department of Internal Medicine, University of California at Los Angeles School of Medicine
INTRODUCTION Section 2 of 11
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Background: Primary pulmonary hypertension (PPH) is a rare disease characterized by elevated pulmonary artery pressure with no apparent cause. PPH is also termed precapillary pulmonary hypertension or idiopathic pulmonary arterial hypertension. The diagnosis is usually made after excluding other known causes of pulmonary hypertension. Dresdale and colleagues first reported a hemodynamic account of PPH in 1951. Pathophysiology: The pathophysiology of PPH is poorly understood. An insult (eg, hormonal, mechanical, other) to the endothelium may occur, resulting in a cascade of events characterized by vascular scarring, endothelial dysfunction, and intimal and medial (smooth muscle) proliferation. At least 10-15% of patients with PPH have a familial form, which has only recently been characterized. Some cases may be related to sporadic genetic defects. Early in the disease, as the pulmonary artery pressure increases and the right ventricle must perform extra work, thrombotic pulmonary arteriopathy occurs. Thrombotic pulmonary arteriopathy is characterized by in situ thrombosis of small muscular arteries of the pulmonary vasculature. In later stages, as the pulmonary pressure continues to rise, plexogenic pulmonary arteriopathy develops. This is characterized by a remodeling of the pulmonary vasculature with intimal fibrosis and replacement of normal endothelial structure. Associated conditions PPH can be associated with portal hypertension (sometimes called portopulmonary hypertension), suggesting that patients with shunting of splanchnic blood, with or without liver disease, have a higher risk of developing PPH. Additionally, exposure of the pulmonary circulation to substances in the splanchnic circulation, which normally are detoxified via the liver, may contribute to the development of pulmonary hypertension. More research is necessary to better understand this relationship. Patients with connective-tissue diseases, namely the CREST (calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia) variant of scleroderma, systemic lupus erythematosus, and mixed connective-tissue disease, are also predisposed to developing PPH-like disease. However, the pathophysiologic nature of this predisposition is unclear. Most experts term these types of pulmonary hypertension secondary pulmonary arterial hypertension, indicating that, similar to PPH, the process involves the precapillary circulation but is somehow caused by the underlying disease. Other associations with PPH include exposure to anorexigens and other alpha-adrenergic stimulants (eg, cocaine, amphetamines) and HIV seropositivity. How these associated conditions predispose to or cause PPH remains unknown. Frequency: In the US: PPH is responsible for approximately 125-150 deaths per year and has an incidence rate of approximately 1-3 cases per million population per year. The incidence and prevalence of PPH-like secondary pulmonary hypertension are considerably higher than those for pure PPH.
Internationally: The worldwide incidence of PPH approximates that observed in the United States.
Mortality/Morbidity: PPH has no cure. Untreated, PPH leads to right-sided heart failure and death. The overall survival rate in one study was approximately 30% at 3 years. Prior to the 1990s, therapeutic options were limited. The recent emergence of prostacyclin analogues, endothelin receptor antagonists, and other novel drug therapies has greatly improved the outlook for patients with PPH and PPH-like diseases. In one study, the use of long-term prostacyclin agents resulted in a 5-year mortality rate greater than 65%. With newer therapies, perhaps in combination, these figures are expected to further improve. Race: No racial predilection is recognized. Sex: PPH occurs at a female-to-male ratio ranging from 2-9:1, depending on the treatment center sampled; however, the reasons for this female predilection remain unknown. Age: Typically, younger women of childbearing age develop PPH. However, it can also affect women in their fifth and sixth decades of life or older. CLINICAL Section 3 of 11
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History: The average time from symptom onset to diagnosis has been reported to be approximately 2 years. Early symptoms are nonspecific. Often, neither the patient nor physician recognizes the presence of the disease, which leads to delays in diagnosis. Complicating matters, PPH requires an extensive workup in an attempt to elucidate an identifiable cause of the elevated pulmonary artery pressure.
The most common symptoms reported in a national prospective study by Rich et al in 1987 are as follows:
Dyspnea is present in 60%.
Weakness is present in 19%.
Recurrent syncope is present in 13%.
Women are more likely to be symptomatic than men.
Physical: Physical findings in persons with PPH can be quite variable. Physical examination of the cardiovascular system often reveals the following findings:
The pulmonic component of the second heart sound may be increased, which may demonstrate fixed or paradoxic splitting in the presence of severe right ventricular dysfunction. Occasionally, the second heart sound may be palpable.
Pulmonic regurgitation (Graham Steell murmur) may also be apparent.
A murmur of tricuspid regurgitation can be present, and a right ventricular lift (heave) may be noted.
Jugular venous pulsations may be elevated in the presence of volume overload, right ventricular failure, or both.
Other findings may include (1) hepatomegaly with palpable pulsations of the liver and (2) an abnormal abdominal-jugular reflex.
Lung examination findings are usually normal.
Extremity examination may reveal pitting edema of varying degrees.
Causes: The strict definition of PPH is pulmonary hypertension with no known cause. However, associations have been recognized (eg, liver cirrhosis, stimulant abuse, HIV infection; see Associated conditions).
DIFFERENTIALS Section 4 of 11
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Apnea, Sleep
Cardiomyopathy, Dilated
Cor Pulmonale
Hypothyroidism
Mitral Stenosis
Mixed Connective-Tissue Disease
Portal Hypertension
Pulmonary Edema, Cardiogenic
Pulmonary Embolism
Pulmonary Hypertension, Secondary
Pulmonic Stenosis
Scleroderma
Systemic Lupus Erythematosus
Other Problems to be Considered:
Anorexigen-associated pulmonary hypertension
Hypertension Resource Center
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Author Information
Introduction
Clinical
Differentials
Workup
Treatment
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Follow-up
Miscellaneous
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Apnea, Sleep
Cardiomyopathy, Dilated
Cor Pulmonale
Hypothyroidism
Mitral Stenosis
Mixed Connective-Tissue Disease
Portal Hypertension
Pulmonary Edema, Cardiogenic
Pulmonary EmbolismPulmonary Hypertension, Secondary
Pulmonic Stenosis
Scleroderma
Systemic Lupus Erythematosus Patient Education
WORKUP Section 5 of 11
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Lab Studies: Antinuclear antibody: When performing a workup on a patient with possible PPH, excluding autoimmune disorders is important. However, up to 40% of patients with PPH are positive for antinuclear antibodies and have no other clinical manifestations of autoimmune disease. Further, most connective-tissue diseases associated with pulmonary artery hypertension are diagnosed based on clinical results, with serology results used as adjunctive confirmation of the disease.
Thyroid-stimulating hormone: Screen for thyroid abnormalities during the initial workup for PPH because these abnormalities are common in patients with PPH. Thyroid abnormalities may be the cause of or contribute to symptoms similar to PPH. In addition, hyperthyroidism itself may lead to an elevation in pulmonary artery pressure.
HIV testing: HIV-positive patients have a higher rate of PPH compared with the general population; therefore, include an HIV test as part of the routine evaluation.
Imaging Studies: Chest radiograph: The chest radiograph may be the first diagnostic step in the evaluation of a patient with dyspnea; however, for many patients with pulmonary artery hypertension, the findings do not help reveal the underlying etiology of the pulmonary hypertension. Chest radiographs are useful for excluding interstitial and alveolar processes that may cause hypoxia-mediated pulmonary vasoconstriction.
Echocardiography: This is extremely useful for assessing right and left ventricular function, estimating pulmonary systolic arterial pressure, and excluding congenital anomalies and valvular disease. Findings from echocardiography may demonstrate right-to-left shunting across a patent foramen ovale in approximately 33% of patients.
High-resolution chest CT scans and ventilation-perfusion lung scans: These are frequently obtained to help exclude interstitial lung disease and thromboembolic disease.
Pulmonary angiogram: This test is occasionally required to help definitively exclude thromboembolic disease. While considered a high-risk procedure in patients with elevated pulmonary arterial pressures and/or right ventricular failure, a carefully performed study is generally safe.
Other Tests:
ECG: Results are often abnormal in patients with PPH, revealing right atrial enlargement, right axis deviation, right ventricular hypertrophy, and characteristic ST depression and T-wave inversions in the anterior leads. Some patients have few or no abnormal ECG findings; thus, normal ECG findings do exclude a diagnosis of PPH.
Pulmonary function and cardiopulmonary exercise testing: Assessment of ventilatory efficiency and mechanical lung function can help differentiate intrinsic pulmonary vascular disease from cardiac deconditioning and restrictive or obstructive lung disease. In patients with PPH, values for peak exercise oxygen consumption, oxygen pulse, and ventilator equivalents (ratio of expired volume to carbon dioxide output at the anaerobic threshold) during exercise are abnormal to varying degrees.
Diagnostic algorithms: Several diagnostic algorithms have been proposed in the literature that are useful for helping complete a thorough workup, which may be necessary to help exclude all reasonable causes of secondary pulmonary hypertension.
Sleep study: Sleep apnea must be excluded as a contributor or cause of pulmonary hypertension if the patient?s history suggests this diagnosis.
Procedures:
Cardiac catheterization: This is the criterion standard test to definitively confirm a PPH diagnosis. Excluding left-sided heart disease, including diastolic dysfunction, is especially important in these patients because of major treatment implications. Catheterization is also performed to determine vasoreactive status, which may have implications in the initiation and titration of high-dose calcium channel blocker (CCB) therapy.
Catheter placement for long-term therapy: The initiation of intravenous therapy with epoprostenol (EPO) requires placement of a central venous catheter and detailed instruction on the long-term use of vasodilator therapy.
Lung biopsy: When the etiology of pulmonary hypertension is still in doubt, a lung biopsy may be necessary.
Histologic Findings: Several histologic subtypes are associated with pulmonary arteriopathy in PPH, one of which involves in situ thrombosis. Thrombotic pulmonary arteriopathy may be observed, with or without plexiform lesions. It is characterized by in situ thrombosis of small muscular arteries of the pulmonary vasculature. Thrombotic pulmonary arteriopathy is often present at earlier stages of PPH (ie, before the development of plexogenic pulmonary arteriopathy) or as an irreversible lesion in later stages. Platelet activation and increased circulating procoagulant factors are observed.
Staging: Traditionally, New York Heart Association/World Health Organization functional classification is used to grade PPH disease severity. This grading system has obvious limitations because it is subjective. Other means to characterize disease severity include hemodynamic findings after right-sided heart catheterization, exercise capacity (eg, peak exercise oxygen consumption, 6-min walk distance), and clinical severity of heart failure signs found during the physical examination. More recent studies show that the echocardiographically determined eccentricity index, a marker of interventricular septum flattening, is a prognostic indicator. Positive findings for serum troponin and the presence of a pericardial effusion are also of prognostic utility, indicating a worse prognosis.
TREATMENT Section 6 of 11
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Medical Care: Anticoagulation Several studies, using both univariate and multivariate analyses, show that survival is increased when the patient is treated with anticoagulant therapy, regardless of histopathologic subtype. Use warfarin to maintain an international normalized ratio of 1.5- to 2-times the control value, provided the patient has no contraindications to anticoagulation.
Other oral agents Use digoxin therapy to improve right ventricular function in patients with right ventricular failure. However, no randomized controlled clinical study has been performed to validate this strategy for patients with PPH. Use diuretics to manage peripheral edema. The use of loop diuretics (eg, furosemide, bumetanide) requires potassium supplementation and close monitoring of serum potassium. Potassium-sparing diuretics may have a role in ameliorating the sometimes-intractable hypokalemia observed with daily diuretic use. Use oxygen supplementation in those patients with resting or exercise-induced hypoxemia. Use caution if patients have a left-to-right shunt via a patent foramen ovale (see Imaging Studies) because supplemental oxygen in these instances may provide little or no benefit.
Conventional oral vasodilator therapy
CCBs are the most widely used class of drugs for PPH. These drugs are thought to act on the vascular smooth muscle to dilate the pulmonary resistance vessels and lower the pulmonary artery pressure. Several studies report clinical and hemodynamic benefits from the use of long-term calcium channel blockade. The use of these drugs produces a reduction in pulmonary vascular resistance by increasing the cardiac output and decreasing pulmonary artery pressure. It also improves the quality of life and survival rate. Only use CCBs on patients without overt evidence of right-sided heart failure. A cardiac index of less than 2 L/min/m2 or elevated right atrial pressure above 15 mm Hg is evidence that CCBs may worsen right ventricular failure and, thus, are of no benefit. This is potentially harmful to patients with PPH. In general, high doses of CCBs are used in patients with PPH; however, only patients with an acute vasodilator response to an intravenous or inhaled pulmonary vasodilator challenge (eg, with adenosine, EPO, nitric oxide) derive any long-term benefit from CCBs (this corresponds to <20% of patients with PPH and probably <10% of patients with secondary, PPH-like pulmonary artery hypertension). Similarly, patients without an acute vasodilator response to a vasodilator challenge have a worse prognosis on long-term oral vasodilator therapy compared with those who have an initial response. Importantly, realize that the absence of an acute response to intravenous or inhaled vasodilators does not preclude the use of intravenous vasodilator therapy. In fact, continuous intravenous vasodilator therapy is strongly suggested for these patients because CCBs are contraindicated. This illustrates the importance of performing vasoreactivity testing in patients with PPH. Intravenous EPO or adenosine or inhaled nitric oxide are used most commonly for acute vasodilator testing. Oxygen, nitroprusside, and hydralazine should not be used as pulmonary vasodilator testing agents. Only up to 25% of patients with PPH demonstrate significant pulmonary vasoreactivity. If patients demonstrate vasoreactivity and are candidates for high-dose CCB therapy, administer a CCB challenge to stable patients to determine the vasodilator response. Perform this in the critical care unit with a balloon flotation catheter in the pulmonary artery. Administer oral nifedipine every hour (diltiazem can be used if resting tachycardia is present) until a 20% decrease in pulmonary artery pressure and pulmonary vascular resistance is observed or systemic hypotension or other adverse effects preclude further drug administration. Calculate the daily dosage requirement at half the total initial effective dose, and administer this every 6-8 hours. Typical doses of nifedipine and diltiazem can reach 240 mg/d and 900 mg/d, respectively. Use caution when withdrawing CCBs because rebound pulmonary hypertension has been reported with the cessation of vasodilator therapy. Three approved pulmonary vasodilator therapies currently available for PPH are as follows: Epoprostenol (Flolan) Treprostinil (Remodulin) Bosentan (Tracleer) EPO and treprostinil are given parenterally (see Medication), and bosentan is given orally.
Future therapies
Clinical trials are underway to determine the safety and efficacy of several new drugs that include inhaled therapy (ie, prostacyclins, nitric oxide) and orally active drugs. Efforts are currently focused on prostacyclin analogues, newer endothelin antagonists, and phosphodiesterase-5 inhibitors.
Surgical Care: A single- or double-lung transplant is indicated for patients who do not respond to medical therapy. Simultaneous cardiac transplantation may not be necessary even with severe right ventricular dysfunction; however, this is dependent on the transplant institution.
Atrial septostomy is a palliative procedure that may afford some benefit to patients with deteriorating conditions. This procedure works by allowing interatrial right-to-left shunting to occur, thus delivering more overall oxygen content to the respiring tissues, albeit with a lower overall saturation.
Diet: No specific diet is recommended; however, a low-sodium and low-fluid diet is recommended for those with significant volume overload due to right ventricular failure.
Patients taking warfarin must limit their intake of vitamin K?containing foods, such as green leafy and coliform vegetables.
L-arginine supplementation (a precursor to nitric oxide) may be helpful; however, more studies are needed to confirm its role in the management of PPH.
Activity: Few data are available on cardiopulmonary rehabilitation. The generally accepted recommendation is that patients with pulmonary hypertension and heart failure perform mild symptom-limited aerobic activity and avoid complete bed rest. Isometric exercises (weight-lifting) are contraindicated. MEDICATION Section 7 of 11
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Current pulmonary vascular therapies appear to exert their actions on the pulmonary circulation by mechanisms that remain poorly defined. Clearly, the magnitude of the pulmonary vasodilator actions of prostanoids and endothelin antagonists do not account for the degree of clinical benefit observed with these drugs. Rather, additional effects on the endothelial health of the pulmonary circulation and on the inhibition of pathologic intimal fibrosis and smooth muscle proliferation are likely to be the predominant mechanisms involved in the treatment responses. Drug Category: Parenteral vasodilators -- For patients in whom CCBs fail to respond or with an inability to tolerate CCBs with NYHA types III and IV right-sided heart failure.
Drug Name
Epoprostenol (Flolan) -- An analogue of PGI2 that was approved by the FDA in 1995 for use in patients with PPH. Has potent vasodilatory properties, an immediate onset of action, and a half-life of approximately 5 min. In addition to its vasodilator properties, also contributes to inhibition of platelet aggregation and plays a role in inhibition of smooth muscle proliferation. Latter effect may have implications for beneficial remodeling of pulmonary vascular bed. EPO is only FDA-approved medication for treatment of PPH.
Adult Dose Continuous IV infusion via permanent indwelling central venous catheter using a small, battery-powered infusion pump worn at the hip or carried in a backpack
Beginning dose: 2-4 ng/kg/min; depending on initial response; initiate under close observation in the ICU with right-sided heart flotation catheter in place
Subsequent dose: Titrate based on follow-up outpatient evaluation; currently, no upper limit has been defined; most patients derive optimal benefit with doses of 25-40 ng/kg/min; doses exceeding 40 ng/kg/min after 1 y of therapy are not uncommon
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity; hyaline membrane disease, dominant left-to-right shunt, respiratory distress syndrome
Interactions Coadministration with anticoagulants may increase bleeding risk because of shared effects on platelet aggregation
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Coadminister with anticoagulants whenever possible to reduce risk of thromboembolism; sudden discontinuation or reduction in therapy may result in rebound pulmonary hypertension
Drug Name
Treprostinil (Remodulin) -- Used to treat PAH. Structurally very similar to EPO but stable at room temperature and has much longer half-life; therefore, can be given as an SC continuous infusion via a much smaller pump. Elicits direct vasodilation of pulmonary and systemic arterial vessels and inhibits platelet aggregation. Vasodilation reduces right and left ventricular afterload and increases cardiac output and stroke volume.
Adult Dose 1.25 ng/kg/min SC via continuous infusion initially; may increase by 1.25 ng/kg/min qwk for 4 wk, then may increase by 2.5 ng/kg/min qwk; if initial dose not tolerated, decrease to 0.625 ng/kg/min, then slowly titrate upward; must slowly taper if discontinued (potential for severe rebound pulmonary hypertension and death)
Subsequent dose: Titrate based on follow-up outpatient evaluation; currently, no upper limit has been defined; most patients derive optimal benefit with doses of 25-40 ng/kg/min; doses exceeding 40 ng/kg/min after 1 y of therapy are not uncommon
Pediatric Dose Not established
Contraindications Documented hypersensitivity
Interactions Additive hypotensive effect with antihypertensive agents or diuretics; may increase risk of bleeding with other antiplatelet drugs (eg, aspirin) or anticoagulants (eg, warfarin, heparin)
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions May cause infusion site pain and irritation; common adverse effects include diarrhea, jaw pain, edema, vasodilatation, and nausea; do not discontinue abruptly
Drug Category: Oral pulmonary hypertension agents -- ERAs and are alternative therapy to parenteral prostacyclin agents. Given PO. Competitively bind to ET-1 receptors endothelin-A and endothelin-B, causing reduction in PAP, PVR, and mean RAP. Indicated for treatment of PAH in patients with WHO class III or IV symptoms to improve exercise ability and decrease rate of clinical deterioration.Drug Name
Bosentan (Tracleer) -- First PO PPH therapy to be approved in United States. A mixed endothelin-A and endothelin-B receptor antagonist indicated for PAH, including PPH. In clinical trials, improved exercise capacity, decreased rate of clinical deterioration, improved functional class, and improved hemodynamics.
Improves pulmonary arterial hemodynamics by competitively binding to ET-1 receptors endothelin-A and endothelin-B in pulmonary vascular endothelium and pulmonary vascular smooth muscle. This leads to a significant increase in CI associated with a significant reduction in PAP, PVR, and mean RAP. These changes result in an improvement in exercise capacity (as measured by the 6-min walk test) and improved PPH symptoms.
Because drug has teratogenic potential and because of need for careful scrutiny in choosing appropriate candidates for ERA therapy, Tracleer can be prescribed only through the Tracleer Access Program. Call 1-866-228-3546.
Adult Dose Starting dose: 62.5 mg PO bid for 4 wk, followed by 125 mg PO bid indefinitely
Pediatric Dose Not established; 62.5 mg PO bid recommended if <40 kg or >12 y; not to exceed 125 mg/d
Contraindications Documented hypersensitivity; coadministration with cyclosporine A or glyburide
Interactions Toxicity may increase when administered concomitantly with inhibitors of isoenzymes CYP450 2C9 and CYP450 3A4 (eg, ketoconazole, erythromycin, fluoxetine, sertraline, amiodarone, cyclosporine A); induces isoenzymes CYP450 2C9 and CYP450 3A4, causing decrease in plasma concentrations of drugs metabolized by these enzymes (including glyburide and other hypoglycemics, cyclosporine A, hormonal contraceptives, simvastatin, and, possibly, other statins); hepatotoxicity increases with concomitant administration of glyburide
Regarding cyclosporine A, during first day of concomitant administration, trough concentrations of bosentan increase approximately 30-fold; steady-state bosentan plasma concentrations are 3- to 4-fold higher than in the absence of cyclosporine A
Regarding glyburide, an increased risk of elevated liver aminotransferase levels is observed in patients receiving concomitant therapy with glyburide
Pregnancy X - Contraindicated in pregnancy
Precautions May cause a dose-related decrease in hemoglobin and hematocrit; hemoglobin levels should be monitored after 1 and 3 mo of treatment and then q3mo; overall mean decrease in hemoglobin concentration is 0.9 g/dL (change to end of treatment); most of this decrease of hemoglobin concentration is detected in first few weeks of treatment, and hemoglobin levels stabilize by 4-12 wk of treatment
In placebo-controlled studies of all uses of bosentan, marked decreases in hemoglobin (>15% decrease from baseline, resulting in values <11 g/dL) were observed in 6% of bosentan-treated subjects and 3% of placebo-treated subjects; in subjects with PAH treated with doses of 125 and 250 mg bid, marked decreases in hemoglobin occurred in 3% of bosentan-treated subjects compared with 1% in placebo-treated subjects
A decrease in hemoglobin concentration by at least 1 g/dL was observed in 57% of bosentan-treated subjects, compared with 29% of placebo-treated subjects; in 80% of subjects whose hemoglobin level decreased by at least 1 g/dL, the decrease occurred during the first 6 wk of treatment
During the course of treatment, hemoglobin concentration remained within normal limits in 68% of bosentan-treated subjects compared with 76% of placebo subjects (explanation for change in hemoglobin not determined, but hemorrhage or hemolysis did not appear to be the cause)
Check hemoglobin concentrations after 1 and 3 mo and every 3 mo thereafter; if a marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine cause and need for specific treatment
Causes at least 3-fold elevation of liver aminotransferase levels (ie, ALT, AST) in up to 11% of patients; may elevate bilirubin (serum aminotransferase levels must be measured prior to initiation of treatment and then qmo); caution in patients with mildly impaired liver function (avoid in patients with moderate or severe liver impairment)
Not recommended while breastfeeding; exclude pregnancy before initiating treatment and prevent thereafter by use of reliable contraception
Headache and nasopharyngitis may occur
FOLLOW-UP Section 8 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography
Further Inpatient Care: Patients on EPO therapy must have a central venous catheter placed surgically and receive their initial EPO dose in an inpatient setting. This allows for monitoring of acute adverse effects and provides the opportunity for the patient and support personnel to master the EPO preparation and administration technique before discharge.
Further Outpatient Care: Currently, no precise dosage adjustment algorithm is available for patients with PPH who are on vasodilator therapy.
Monitor the patient with frequent physical examinations, and focus the history on heart failure symptoms and adverse effects of medications.
Echocardiography has been used in several studies to serially monitor changes in the right ventricular?right atrial pressure gradient and the right and left ventricular chamber sizes.
Findings from other noninvasive modalities (eg, electron-beam CT measurements of cardiac chamber sizes) correlate with hemodynamic improvements in pulmonary physiology.
More recently, cardiopulmonary exercise testing, serial invasive hemodynamic testing, and 6-minute walk testing have been used to monitor the disease status of patients with PPH.
Complications: Advanced right-sided heart failure with hepatic congestion
Pedal edema
Pleural effusions
Ascites
Worsening dyspnea on exertion
Prognosis: The mortality rate for untreated PPH is approximately 50% at 3 years. With EPO therapy, this has increased to higher than 65% at 5 years. Data on long-term survival in patients treated with other pulmonary vascular therapies are emerging. Patients whose disease progresses and is unresponsive to medical treatments either undergo transplantation or die of progressive right-sided heart failure.
Patient Education: Patient and physician education about this rare fatal disease is paramount.
If applicable, instruct patients on how to administer their daily parenteral medication.
MISCELLANEOUS Section 9 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography
Medical/Legal Pitfalls: Treating PPH requires significant education in and exposure to the available therapies for PPH and the potential complications. Because PPH is rare, management is best left to expert personnel at centers with regular exposure to these patients. Failure to heed this advice can result in medicolegal pitfalls should patient outcome be less than optimal.
PICTURES Section 10 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography
Caption: Picture 1. Primary pulmonary hypertension. CADD-1 ambulatory infusion pump. Courtesy SIMS Deltec, St. Paul, Minn.
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Caption: Picture 2. Primary pulmonary hypertension. Two-dimensional short-axis echocardiogram image. Note the flattened interventricular septum due to right ventricular overload.
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BIBLIOGRAPHY Section 11 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography
Abenhaim L, Moride Y, Brenot F, et al: Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med 1996 Aug 29; 335(9): 609-16[Medline].
Barst RJ, Rubin LJ, Long WA, et al: A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med 1996 Feb 1; 334(5): 296-302[Medline].
Barst RJ, Langleben D, Frost A, et al: Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med 2004 Feb 15; 169(4): 441-7[Medline].
Dresdale DT, Schultz M, Michtom RJ: Primary pulmonary hypertension. I. Clinical and hemodynamic study. Am J Med 1951 Dec; 11(6): 686-705[Medline].
Farber HW, Loscalzo J: Prothrombotic mechanisms in primary pulmonary hypertension. J Lab Clin Med 1999 Dec; 134(6): 561-6[Medline].
Gaine S: Pulmonary hypertension. JAMA 2000 Dec 27; 284(24): 3160-8[Medline].
Galié N, Hinderliter AL, Torbicki A, et al: Effects of the oral endothelin-receptor antagonist bosentan on echocardiographic and doppler measures in patients with pulmonary arterial hypertension. J Am Coll Cardiol 2003 Apr 16; 41(8): 1380-6[Medline].
Olschewski H, Simonneau G, Galié N, et al: Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002 Aug 1; 347(5): 322-9[Medline].
Rich S, Dantzker DR, Ayres SM, et al: Primary pulmonary hypertension. A national prospective study. Ann Intern Med 1987 Aug; 107(2): 216-23[Medline].
Rubin LJ: Primary pulmonary hypertension. N Engl J Med 1997 Jan 9; 336(2): 111-7[Medline].
Rubin LJ, Badesch DB, Barst RJ, et al: Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002 Mar 21; 346(12): 896-903[Medline].
Shapiro SM, Oudiz RJ, Cao T, et al: Primary pulmonary hypertension: improved long-term effects and survival with continuous intravenous epoprostenol infusion. J Am Coll Cardiol 1997 Aug; 30(2): 343-9[Medline].
Simonneau G, Fartoukh M, Sitbon O, et al: Primary pulmonary hypertension associated with the use of fenfluramine derivatives. Chest 1998 Sep; 114(3 Suppl): 195S-199S[Medline].
Simonneau G, Barst RJ, Galie N, et al: Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double- blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2002 Mar 15; 165(6): 800-4[Medline].
Sun XG, Hansen JE, Oudiz RJ, Wasserman K: Exercise pathophysiology in patients with primary pulmonary hypertension. Circulation 2001 Jul 24; 104(4): 429-35[Medline].
Sun XG, Hansen JE, Oudiz RJ, Wasserman K: Gas exchange detection of exercise-induced right-to-left shunt in patients with primary pulmonary hypertension. Circulation 2002 Jan 1; 105(1): 54-60[Medline].
Sun XG, Hansen JE, Oudiz RJ, Wasserman K: Pulmonary function in primary pulmonary hypertension. J Am Coll Cardiol 2003 Mar 19; 41(6): 1028-35[Medline].
Torbicki A, Kurzyna M, Kuca P, et al: Detectable serum cardiac troponin T as a marker of poor prognosis among patients with chronic precapillary pulmonary hypertension. Circulation 2003 Aug 19; 108(7): 844-8[Medline].
Wax D, Garofano R, Barst RJ: Effects of long-term infusion of prostacyclin on exercise performance in patients with primary pulmonary hypertension. Chest 1999 Oct; 116(4): 914-20[Medline].
Don't do or diet, just eat healthily Cutting calories, rather than sacrificing what you're used to eating, is a big step toward a lifestyle change. BY ELLEN KANNER
Oct. 10, 2004
Being diabetic doesn't mean being deprived. Angel Loor hasn't given up chocolate chip cookies. He pumps iron, though, and pitches a mean softball. Michael Glickstein hasn't said bye-bye to bread. He's said hello to walking. These two diabetics know their weaknesses, but manage them not with any diet du jour, but by eating less of what they love, eating balanced and exercising more. ''It's not glitzy,'' admits Sandra Woodruff, president of the Florida Diabetic Association and author of The Complete Diabetes Prevention Plan (Avery, $24.95). But it works. Obesity is a leading cause of Type 2 diabetes, which is why the American Diabetes Association and the University of Miami's Diabetes Research Institute recommends ''a good healthy diet, whether you have diabetes or you don't,'' says DRI's director, Dr. Luigi Meneghini. ''Lots of green leafy vegetables, stay away from sweets and saturated fats, maintain a caloric intake to maintain or get to a desirable body weight.'' What they don't recommend is a cast-in-stone do-or-diet. NEW GUIDELINES ''Since 1994, the guidelines for diabetes have changed,'' says Woodruff, based in Tallahassee. ``We realized one diet doesn't fit all. It really helps for people to include -- in moderation -- foods that were a no-no. They become more satisfied and still have good results.'' ''There's no way people will totally change their lifestyle and stick with it,'' says Lois Exelbert, speaking from 20 years' experience as nurse and administrative director of Baptist-South Miami Diabetes Care Centers. ``We try not to go all-out gangbusters and revamp a total lifestyle. Our approach is one step at a time.'' Every lifestyle change counts. ''If it's someone who eats a lot of white rice, beans, plantains, I will give information how to control portions, how to look at leaner choices of protein, maybe choosing brown rice instead of white rice,'' says Anna Fraker, DRI dietitian. ``Baking, broiling, not frying, different ways to improve their nutrition so they get the results they're looking for -- to cut calories but not sacrifice what they're used to eating.'' Easy to say, hard to do, but you don't have to do it alone. In fact, diabetes healthcare professionals say you shouldn't. ''You have to have some sort of education team work with you to be effective -- a nurse, a dietitian and an exercise therapist,'' says Exelbert. ``The point is, in Miami you can have it all. Florida law mandates diabetes education is covered [by insurance].'' Exelbert and Fraker follow the current trend, customizing a diet and exercise plan to fit each person and running diabetic outreach programs. In Fraker's six-week course, Miami Lite, she takes diabetic patients grocery shopping and even out for dinner to help them make healthy choices. ''Having the weekly meetings was almost like a support group,'' says Loor, one of her star pupils. Learning to limit portions was hard, he says, but keeping track of everything he put in his mouth was harder. ''The infamous food diary,'' he says, laughing. But it paid off. ``I have a better knowledge of how the types of food I eat affect my metabolism and sugar levels.'' Though Loor, 40, had lost weight on Atkins, he learned, ''On Atkins, you just eat protein and fats. It wasn't really balanced.'' By eating smaller portions of a variety of food, he's dropped 17 pounds in three months and now has his glucose levels in check. ''Proteins, carbs, fats, vegetables are really important in order to maintain a level in control,'' says the Homestead resident. ``I feel much better because of that.'' DREADFUL HEALTH Don't talk Atkins and South Beach. Don't talk diet at all. ''You name the diets, I've been on them,'' says Glickstein who has a family history of diabetes and a life-long struggle with weight. ''In '93 when I was diagnosed, I weighed in the low 300s,'' he recalls. His health was dreadful and his blood sugar was ``in the 600s -- coma level.'' Glickstein has lost 85 pounds since December by limiting portions, making healthy food choices and taking Topomax, an anti-seizure drug that suppresses appetite. He's tried other drugs including fen-phen, but Topomax, prescribed by DRI's Dr. Meneghini, has produced no dangerous side effects. Now Glickstein, 64, eats smaller amounts and enjoys ``everything in moderation.'' If he indulges in bread, it's only a few bites. Then he knows to check his sugar levels and monitor what he eats for the rest of the day. ''You have to learn your limitations,'' says Glickstein of Broward's Embassy Lakes. ``My snacks are nuts, fruit, small quantities -- eight cherries is a fruit portion. You never forget. Once you learn it, it sticks.'' As a result, Glickstein now weighs 259, his blood sugar and triglycerides are down and so is his waistline. ``I'm looking younger, feeling younger. This is as good as I have felt in over 20 years.'' STEP BY STEP Though he suffers from diabetes-caused neuropathy (nerve damage), Glickstein tries to walk two-thirds of amile four times a week for the same reason Loor works out and plays softball. ''Weight training really jump-started my metabolism,'' says Loor. ``It really helped keep my sugar levels in check. I'm below 120 now, functioning as normal.'' Baptist's Exelbert applauds them both. ''For people with diabetes, exercising every day is the best. Can everybody do that? No,'' she says. ``If you're somebody who never got off the couch, even 10 minutes to walk your dog is going to have a benefit.'' Glickstein and Loor have both embraced their new lifestyles. They confess it's not always easy. Woodruff's advice to them is, ``You don't have to be perfect all the time. If you fall off the wagon, get back on and hang in there.''
Tough medicine
Since the recall of Vioxx, Merck has lost more than $33 billion U.S. in value
But is it too late for this pharmaceutical giant to regain its righteous reputation? DAVID OLIVE
Oct. 10
"We try to remember that medicine is for the patient. We try never to forget that medicine is for the people. It is not for the profits. The profits follow, and if we have remembered that, they have never failed to appear. The better we have remembered it, the larger they have been." —George W. Merck II (1935) With the help of a catchy jingle, "It's a Beautiful Morning," pain reliever Vioxx was one of the most successful new-product launches ever, zooming to annual sales of $2.5 billion (U.S.) by 2003 — just a few years after its high-profile introduction in 1999. Developed in Canada for the New Jersey-based Big Pharma giant Merck & Co. Inc., Vioxx has been prescribed to 84 million patients in some 80 countries, including about 3.3 million Vioxx prescriptions written for Canadians last year alone. Then, a little more than a week ago, Vioxx became the biggest prescription-drug recall in history when a clinical study commissioned by Merck itself revealed that Vioxx users were at twice as great a risk for strokes and heart attacks than patients taking a placebo. With the recall, Merck loses one of its dwindling number of "blockbusters" — the industry term for drugs with annual sales of $1 billion (U.S.) or more. Merck not only loses a drug generating $2.5 billion (U.S.) in annual sales, and accounting for an estimated 18 per cent of Merck's total profits, but has been forced to set aside several billion dollars for an anticipated flood of class-action lawsuits from patients claiming to have suffered adverse effects from taking Vioxx. The recall further humbles an iconic company whose stock has languished for lack of new blockbusters in a new-product pipeline that ran dry years ago. On the day of Merck's recall announcement, the stock market wiped out more than 26 per cent of the firm's shareholder value, or about $28 billion (U.S.). And longstanding doubts about the continued tenure of CEO Ray Gilmartin, 62, were greatly accentuated. There have been previous shocking recalls — of Wyeth-Ayerst's so-called "fen-phen" obesity treatment in 1997; the diabetes drug Rezulin (Parke-Davis/Warner-Lambert) and heartburn remedy Propulsid (Johnson & Johnson Inc.) in 2000; and Bayer AG's cholesterol-reducer Baycol in 2001. But this is Merck, the world's third-largest drug firm and traditionally its most respected — with good reason. Descended from a German pharmacy opened in 1668, and an independent U.S. firm since World War I, this is the publisher of the Merck Manual, indispensable physicians' companion since 1899, which now clocks in at about 3,000 pages. It is the most R&D-oriented of its biggest peers, counting among its medicine chest of innovations many vaccines for childhood diseases and its invention of cortisone, the first steroid. Merck was named Fortune's most admired company for seven straight years beginning in 1986; and has been managed with sufficient financial acumen over the decades to even now command a triple-A debt rating — a distinction shared with just six other U.S. non-financial firms. For generations, Merck inculcated a patients-first, profits-later corporate culture, rejecting the acquisitions route so favoured by its peers because that might dilute a culture that would not be jeopardized by Merck's preferred route of internally generated growth. Successive CEOs have depicted Merck's activities as a noble calling — a sincere but opportunistic response to the snake-oil reputation of its industry in Merck's early decades. To this day, most drug industry research is conducted on university and teaching-hospital campuses and is largely financed by taxpayers. When Merck opened its own Merck Research Laboratory back in the Great Depression year of 1933 — one of the industry's first large-scale research facilities — then-CEO George W. Merck II was poetic in speaking to employees about his hope "that those who seek the Truth, that those who toil that this world may be a better place to live in, that those who hold aloft that torch of Science and Knowledge through these social and economic dark ages, shall take new courage and feel their hands supported." Fifty-eight years later, then-CEO Roy Vagelos, a physician and biochemist, and one of America's most-respected industrial leaders of the 1980s and 1990s, told employees that "Merck's dedication to fighting disease, relieving suffering, and helping people is a righteous cause." But Merck's world was changing drastically as Vagelos prepared for his 1994 retirement. With its new-product pipeline in the midst of a periodic dry spell, and with a resulting drop in revenue and profit growth rates exacerbated by downward pressure on prices exerted by the new health management organizations (HMOs), Merck broke one of its own rules in 1994 by ponying up an astonishing $6.6 billion (U.S.) for Medco Containment Services Inc., a drug wholesaler and Merck nemesis founded and run by a dealmaking crony of convicted junk-bond king Michael Milken. Medco, with its $30 billion (U.S.) in annual sales, overshadowed the smaller Merck, and was ultimately a distracting bust — a misalliance between the low-margin discount drug wholesaler and the high-margin Merck. Constantly accused of unfairly promoting Merck products at the expense of rivals' offerings, and chronically fending off U.S. authorities over accusations of improper trade practices, Medco was finally spun off last year. After a decade of alienating key constituencies in Washington, state capitals and other volume drug buyers, Merck unloaded the ugly duckling for just $6 billion or so — taking a significant after-inflation loss on its misadventure. The Merck culture was further weakened by the board's recruitment of Gilmartin, an outsider to both Merck and the drug industry, as Vagelos' successor in 1994. Gilmartin, trained in electrical engineering, not chemistry, has essentially mismanaged Merck's traditional balance between basic science and commercial viability — the principal challenge for the CEO of any firm that lives and dies by R&D. Tagged the "invisible man" by insiders who still miss the accessible and charismatic Vagelos, Gilmartin also lacks his predecessor's gut instinct about when to fold your cards. Far too many Merck projects have advanced to the most costly phases of development for Gilmartin's lack of discipline about when to shut them down. Last November, Merck finally axed an unprecedented four highly-touted drugs in their final development phase, losing precious credibility with the Street. The aborted projects and Gilmartin's accompanying seven per cent cut in the workforce — the biggest layoffs in Merck history — further eroded morale. Biotech giant Amgen Inc. is one of many competitors whose executive ranks are stocked with recent Merck defectors. In Merck's decade under Gilmartin, most of the 19 drugs launched by the company trace their origins to the Vagelos era. Innovations to which Gilmartin can claim credit have been underwhelming sales generators. Gilmartin has seemed intimidated by what the industry has always regarded as Merck's "scientific arrogance." (The company boasts four Nobel winners, and between 1996 and 2001 filed an astonishing 1,933 new chemical entities — about 500 more than its nearest competitor.) Lacking the discipline — and scientific credentials — to stare down managers of projects holding little promise, Gilmartin has deferred overly to Merck's research chiefs, including the current incumbent, Dr. Peter Kim. The CEO has suffered for not keeping that arrogance in check, as it was under previous Merck CEOs steeped in both chemistry and balance-sheet smarts. Merck's decline of recent years is easily attributed to "what management didn't do over the past five to 10 years," a Bear Stearns analyst complained in Fortune earlier this year. "Management is now playing a huge game of catch-up." In the context of mounting Wall Street pressure in recent years as Merck's shares lost about half their peak value it was tempting for Gilmartin to resolutely back one of his few remaining blockbusters that was not soon due to lose its patent protection. The first warnings about Vioxx came early, in a 2000 study published in the New England Journal of Medicine that showed an unusually high incidence of heart attacks in Vioxx users. A year later, cardiologists at the Cleveland Clinic, using Merck's own data from pre-launch clinical trials, concluded that Vioxx patients were at twice the normal rate of risk of strokes and heart attacks as people taking an older compound. And earlier this year, Kaiser Permanente, the huge California health provider, released a federally funded study that found triple the rate of heart attacks in Vioxx patients taking doses in excess of 25 milligrams per day than in members a control group. As if these warnings weren't sufficient, the first lawsuit against Merck over Vioxx's alleged roll in potentially fatal side-effects in 58 patients was filed back in 2001. And the lawsuits have multiplied even before the Vioxx recall. For more than three years, Merck responded to the alarming reports about Vioxx by questioning the methodology and other aspects of the warnings. In finally announcing the recall on Sept. 30, Dr. Kim expressed his astonishment at the results of the latest survey, "What we saw was stunning." That statement was itself stunning to outside critics like Dr. Daniel Solomon, a rheumatologist at Brigham and Women's Hospital in Boston. Solomon chortled at Dr. Kim's apparent bid to feign a lack of knowledge until now about the prodigious body of criticism regarding Vioxx. When he heard Dr. Kim's statement, Dr. Solomon said, "I was like, `Please. Really'." But Merck was deeply committed to Vioxx, and showed its commitment in a way that illustrates key problems with the industry as a whole. When Vioxx and the competing Pfizer Inc. product Celebrex were still in the pipeline, many medical experts were already doubting the efficacy of a $3 (U.S.) per pill treatment as a superior pain remedy to cheaper over-the counter products like ibuprofen (Advil, Motrin) and naproxen (Aleve, Naprosyn). They also questioned Vioxx's distinguishing virtue, an advertised lack of stomach discomfort and intestinal bleeding associated with traditional pain relievers. Of Vioxx and similar drugs, Dr. Solomon complained in the Wall Street Journal that "all are expensive and only should be used in patients at high risk for gastrointestinal bleeding. This is an example of how patients and doctors think that newer drugs are better than older and less expensive drugs." But Merck plunged ahead, backing the Vioxx launch with a massive ad campaign that sent patients rushing to their docs for the costly treatment. As late as the first half of this year, Merck was still supporting Vioxx with a startling $45 million (U.S.) in advertising — a practice abetted by Washington's decision in the 1990s to lift the ban on direct advertising of prescription drugs to the public. "These agents," says Dr. David Wofsy, president of the American College of Rheumatology, in reference to Vioxx, Celebrex and others of the class of so-called COX-2 inhibitors, "have been the subject of absolutely intensive, unrelenting marketing." The popularity of Vioxx and Celebrex, Dr. Jerry Avorn of Brigham and Women's Hospital told the New York Times recently, "is a terrifying testament to the power of marketing." Pfizer, maker of the only other COX-2 drugs on the market, Celebrex and Bextra, has wasted no time buying full-page newspaper ads encouraging Vioxx patients to promptly switch to its offerings. John Klippel, president of the non-profit Arthritis Foundation, despairs of that, telling the Wall Street Journal that osteoarthritis, for one, "is clearly associated with being overweight and paying less attention to exercise." Pfizer's COX-2 inhibitors have not been tested as thoroughly as Vioxx in post-launch studies, and in Dr. Klippel's estimation, should be avoided unless older and cheaper over-the-counter drugs prove ineffective. Merck and Pfizer targeted their COX-2 drugs to a wide audience, when most medical experts believe they should be prescribed narrowly to those suffering the most severe gastrointestinal problems, and should never have been aggressively marketed as a widely useful painkiller. That too, is a reality of the modern drug industry. Few blockbusters get more than a few years past their launch year without being "repositioned" to tap expanded patient populations — as with, for instance, the Prozac class of anti-depressants, which were soon marketed as remedies for pre-menstrual syndrome and other conditions. These repositionings not only expand the drug's revenue potential, but, with a bit of chemical tweaking, sometimes enable a drug maker to extend the patent life of a lucrative blockbuster if the U.S. Food and Drug Administration and Health Canada can be persuaded that it's a "new" drug. Modern drug marketing practices, a huge and growing contributor to the crisis of soaring health-care costs, are in desperate need of reform. So far, the U.S. — the pot of gold at the end of the rainbow for every global drugmaker — has resisted genuine reform. Last year, the U.S. Congress passed a drug-benefits bill now touted by George W. Bush on the campaign trail as the biggest enhancement of Medicare since the Great Society, but which merely asks American taxpayers to shoulder a greater portion of seniors' drug costs, and is a boon to Big Pharma. The Kerry camp, meanwhile, touts its wildly impractical promise to allow 290 million Americans to satisfy their drug needs by legally purchasing drugs in the comparatively tiny Canadian market. What's needed in the U.S. is price controls on drugs, an innovation, like metric measurement, that long ago won over the entire industrial world except the U.S. That seems unlikely to change anytime soon, given Big Pharma's status as one of the most active and deep-pocketed lobbies in Washington. Yet in the absence of realistic drug pricing, one of the world's traditionally most distinguished companies allowed itself to be held hostage to a handful of make-it-or-break-it blockbusters. While Merck's immediate future isn't threatened yet, its CEO is. Merck isn't alone. The whole industry has been struggling for years with a lack of new breakthrough drugs. "Ray is a very clear-thinking, straight-thinking person [who] really understands the business," one of Gilmartin's supporters on Merck's board told Fortune in February. "The board has never questioned that." Today the questions are flying as never before, of course. Gilmartin's ouster now, in a week when Office Depot Inc. calmly dumped its CEO merely for allowing his firm to slip behind archrival Staples Inc., and PeopleSoft Inc.'s CEO was dispatched simply for balking at a merger with Oracle Corp., would disconcert practically no one. Gilmartin would likely object to a mooted Merck combination with the struggling Schering-Plough Corp., which would bring on board its estimable CEO, Fred Hassan, one of the industry's most successful turnaround experts. Gilmartin's ouster might make him something of a scapegoat for the industry's wider problems — its weakness for so-called lifestyle drugs like baldness remedies and for "me-too" drugs that are only a slight improvement, if that, over existing products; and for pricing their remedies out of the reach of low-income patients whom, doctors complain, simply can't afford to fill the scripts their docs give them. But someone has to break the mould of drug company CEOs who try to get by on profit maximization and over-hyped drugs alone, in the absence of sufficient innovation in affordable drugs that really do save lives and make lives more livable — and Merck seems to be as good a place to start as any. We haven't yet seen the ruination of Merck, after all. Hard as it is to imagine these days, it's still possible for Merck and its peers to live up to their perception of themselves as being engaged in "a righteous cause."
'I would have died on the table'
By Teri Finneman,The Forum
Published Friday, October 08
Jack Keller sat alone in a doctor's lobby two years ago and absorbed the news of his life-threatening illness. Now 25, the Fargo man said there were two ways he could handle his rare diagnosis of primary pulmonary hypertension. He could get mad at God and wonder, "Why me?," or he could trust that God had a plan for his life. As he waits for a double lung transplant, Keller said Thursday he's glad the illness that affects one out of every 500,000 people per year happened to him. "I have no fears or anxieties. I don't cry or complain about it. I'm just so glad it's me that has it and not my brothers or my parents," said Keller, whose illness causes him to cough periodically.
A Minot, N.D., native, Keller remembers struggling to keep pace with his teammates during high school athletics. One doctor attributed Keller's shortness of breath and lack of endurance to a possible hole in his heart. Keller was scheduled to have heart surgery in September 2002. Before operating, doctors measured his lung pressure, more than triple the reading considered safe to operate. "If they had operated on me, I would have died on the table," Keller said. Keller and his parents, Gary and Marlys Keller of Minot, went to the Mayo Clinic in Rochester, Minn., for further medical checkups. On Oct. 22, 2002, doctors diagnosed Keller with primary pulmonary hypertension. The illness occurs when the blood vessel that leads from the heart to the lungs rises above normal levels, according to the Pulmonary Hypertension Association's Web site. If the cause of the hypertension is unknown as it is in Keller's case, the disorder is referred to as primary. The illness forces the heart to work harder in order for an adequate amount of blood to flow through the lungs, enabling them to function. A cure is unknown. For Keller, the best treatment requires a double lung transplant and potentially a heart transplant. In mid-June, Keller began coughing up blood and was immediately flown to Rochester. Doctors concluded part of Keller's lung had died, which resulted in the blood. Since then, Keller's daily "equipment" load has increased. Wherever he goes, he carries his oxygen tank, as well as a backpack and cooler filled with medications. He added a Flolan unit a month ago that expands the veins and capillaries in his lungs to help his blood flow. A tube coming out of his chest connects his medication to his lungs. Marlys Keller said her son's positive attitude has helped the family handle his illness. She recently moved in with him as he adjusts to his new medication. "We've grown closer as a family through this," Marlys Keller said. "Our trust in the Lord sees us through." Keller's younger brother, Josh, is a youth pastor at Bethel Evangelical Free Church. Josh Keller said he respects his brother more than anyone else. "Jack is an inspiration, not only to the people he works with and comes in contact with every day, but he's also an inspiration to his family," Josh Keller said. Jack Keller works full-time as a computer technician at First International Bank and Trust in Fargo. Cory Thompson, the bank's assistant vice president, said Keller's attitude about his illness is "tremendous." "Jack is one of those guys that you want to know. He has a great outlook on life, especially with what he's dealing with," Thompson said. Bank president Dennis Schock said Keller "recognizes his illness is part of God's plan and that God continues to give him strength each and every day." Keller said he's waited since July 2003 for a lung transplant. He was told the typical wait is two to three years. If his condition deteriorates within the next three months, Keller will fly to Jacksonville, Fla., where he will move to the top of the transplant waiting list. The Midwest's small population and the limited number of donors are reasons for the long wait here, he said. Keller encourages people to become organ donors to save a life like his. In the meantime, he relies on God for strength. "I know God is in control and he's going to do what he sees fit," Keller said. Finneman is a reporter with the Dickinson (N.D.) Press, a Forum Communications newspaper
Woman pleads guilty in Fen-Phen case Lillie M. Walker of Fayette faces a maximum 20 years in prison and a $250,000 fine By Jimmie E. Gates
jgates@clarionledger.com
October 2, 2004
Lillie M. Walker, 63, of Fayette admitted Friday she lied when she initially told FBI agents she had purchased the prescription diet drug Fen-Phen over the counter. In fact, prosecutors say, Walker, one of 12 Fayette residents arrested in a federal fraud scheme, never took the drug blamed for causing heart valve problems. As a result of her false claim, Walker received a $250,000 settlement from the drug maker out of a $400 million settlement fund for individuals who suffered injuries from taking the drug, which was pulled off the market in 1997.
Walker pleaded guilty on Friday to one count of wire fraud conspiracy in U.S. District Court in Jackson. She is the fourth Mississippian to plead guilty to filing phony claims in the Fen-Phen settlement. When asked by District Judge William Barbour if she was guilty of the charge, Walker replied, "Yes sir, I'm guilty of receiving the money." She faces a maximum 20 years in prison and a $250,000 fine. Barbour set sentencing for Dec. 10, warning Walker not to be late for sentencing like she was Friday for her guilty plea. Three other individuals pleaded guilty last week and face sentencing Dec. 3. All 12 initially faced conspiracy charges in connection with the settlement from drug-maker American Home Products. All are accused of receiving at least $250,000 in settlement funds through false prescriptions, netting about $150,000 each after attorney fees and expenses. Assistant U.S. Attorney Richard Starrett said the government will recommend a lighter sentence for Walker for her cooperation in the ongoing federal investigation. Barbour allowed Walker to remain free on a personal recognizance bond. Walker and her attorney, Robert Smith Jr., had no comment after her guilty plea. Starrett said if the case would have gone to trial, testimony would have shown Walker initially gave a false statement about how she obtained the drug. "She knew she wasn't entitled to the settlement," Starrett said. Starrett said Walker was assisted in filing the false claim by another of the individuals charged in the case. A joint investigation by the FBI and IRS led to charges against the 12. Others also are expected to face charges, officials said.
List of pharmaceutical firms hit by product-liability suits adding up
Friday, October 01, 2004
BY KATE COSCARELLI
Star-Ledger Staff
Yesterday's news that drug giant Merck is pulling its arthritis drug Vioxx because it increases the risk of heart attack and stroke sent dozens of people looking to the product-liability firm for help. "This wave will be gigantic," said law firm partner Sam Davis. "We had no data on long-term effects. ... Now, there is a whole new pall cast." Even lawyers for the Whitehouse Station-based drug company acknowledged that the announcement meant Merck is likely to join a small but growing number of pharmaceutical companies hit with lawsuits after revelations their drugs have potentially dangerous side effects.
The first lawsuit in response to the Vioxx news was filed yesterday in Oklahoma, and it is possible Merck could eventually face billions in punitive damages. "We continue to believe we have a substantial and vigorous defense to mount," said Kenneth Frazier, Merck's general counsel. Recent years have brought a number of similar cases. Wyeth, based in Madison, has struggled with lawsuits that its drug Pondimin and chemical cousin Redux -- half of the weight-loss cocktail "fen-phen" -- caused severe health problems, and that its hormone-replacement therapy Prempro did more harm than good. Merck was already facing hundreds of existing claims regarding the arthritis drug, including more 150 claims in the New Jersey courts. The New Jersey cases, filed by people who suffered heart attacks, stroke and kidney problems, were designated a mass tort and are being overseen by a state judge in Atlantic County. The first batch of 15 cases is scheduled for trial next spring, said Fred Gerson, a Florham Park lawyer representing about 30 people in the case. Until yesterday, Merck had asserted that the drug was not defective and there was no increased health risk when using Vioxx. Anthony Sabino, associate professor of law at St. John's University in New York, said Merck is likely to set aside a huge reserve fund to pay for legal costs. Bayer's recall of the cholesterol drug Baycol in 2001 has cost the German drug maker more than $1 billion so far, while Wyeth has taken more than $16 billion in charges to pay for fen-phen medical claims and legal expenses. The central issue in any cases generated by yesterday's news will be what the drug company knew and when it knew it. By holding a conference to detail findings and pull the drug, many lawyers said Merck was already preparing a defense. Lawyers will also have to duel over whether Merck's modifications to the label information were sufficient to warn people of risks in taking the drug, said Kenneth Labbate, a Rutherford attorney who defends companies in product liability cases. Merck also has to worry about where the cases will be filed, he added. Because it was so widely prescribed, lawyers can choose to file suits in jurisdictions such as Texas or Mississippi where jurors routinely give huge verdicts to plaintiffs. The cases won't be a slam-dunk for plaintiffs. Such suits can be a challenge, and lawyers must overcome the fact clients already had health problems that led them to take the drug. And some in the legal community cautioned that Merck's liability won't necessarily be widespread. Though the drug has been used by 84 million people, the number who had serious problems could be a small fraction, said Howard Gutman, a Parsippany lawyer. Merck faces other potential liability outside the personal-injury realm. Many lawyers said it is likely the company will also face claims from shareholders hurt financially from dropping stock prices. There is already a securities case pending against the company in federal court in New Orleans alleging the company's stock price was artificially inflated. "It just got a lot worse, about $30 billion worse," said Christopher Seeger, a New York lawyer in the case. "The damages incurred by shareholders today are going to be added to this suit. They're in a world of hurt." Staff writer Ed Silverman contributed to this report.
Merck's Legal Nightmare
Robert Langreth, 09.30.04
NEW YORK - Merck's recall of its popular painkiller Vioxx after a big study found it increased the risk of heart attacks and strokes could set off the next big class-action feeding frenzy. Virtually every time a drug has been recalled because of side-effect problems in recent years, the companies have faced legal liability. The question for Merck (nyse: MRK - news - people ) and its investors now is, How big will its legal bill be? The answer is unknown but could potentially be huge, because Vioxx was a popular drug used by millions of consumers. Overall, 84 million people worldwide have taken Vioxx worldwide since it was approved in 1999. "This is going to be a nightmare of unbelievable proportions in terms of legal liability" for Merck, says independent analyst Hemant Shah of Warren, N.J., who was one of the first to predict that Wyeth (nyse: WYE - news - people ) would face enormous legal liability from its recall of the diet drugs fenfluramine (part of the fen-phen combo) and Redux in 1997. Shah says that the extent of the liability will depend on whether plaintiffs' lawyers are able to find "smoking gun" e-mails or internal memos from Merck officials privately acknowledging the possibility for heart risk in the years before the recall. If such documents exist, "the liability potentially could be greater than for fen-phen" and Redux, Shah says. If there are no embarrassing documents, then the liability would be much more manageable. Shah says the rise and fall of Vioxx "is one more example of how analysts and the media jumped on the bandwagon and hyped a drug." When Merck started selling Vioxx in 1999, the new drug was often dubbed a "super-aspirin" in the media, even though there was never any evidence that it was more effective than older, non-steroidal anti-inflammatory drugs such as ibuprofen. But the potential for Vioxx-related heart problems first surfaced in a big Merck study published in The New England Journal of Medicine in 2000. But it was largely ignored until 2001, when two cardiologists at the Cleveland Clinic, Steven Nissen and Eric Topol, stuck their necks out and wrote a big article in The Journal of the American Medical Association warning of the potential for heart side effects. Merck said that prior to the recall, two lawsuits alleging cardiovascular side effects from Vioxx and seeking class-action status had been filed, in addition to numerous other individual lawsuits. The first of those lawsuits could go to trial as soon as next year. "We anticipate that additional lawsuits alleging personal injury from Vioxx may be filed," says Tony Plohoros, a Merck spokesman. Until now, some plaintiffs' lawyers have shied away from bringing Vioxx-related lawsuits, seeing the issue of whether Vioxx might cause heart attacks as murky. The recall should open the floodgates. "One of the first questions a judge asks is, Is the drug still on the market?" says New York attorney Jerrold Parker of Parker & Waichman. His firm, which has been investigating the Vioxx-heart attack connection for three years, has over ten ongoing Vioxx patient-injury cases and hundreds more in the works. In the few hours since the recall was announced, the firm had already received over 100 calls and e-mails from patients alleging harm from Vioxx, he says. Some experts said it is far too soon to assume that Merck will face a giant legal bill. Because Merck moved quickly to withdraw the drug after getting conclusive evidence that Vioxx raised the risk of heart attacks, "this will be an uphill battle" for plaintiffs' lawyers to win huge settlements, says Anthony Sabino, a business law professor at St. John's University, who adds that he owns a small amount of Merck stock. "This is not a death knell for Merck."
Like many in U.S., Utahns struggling to overcome obesity
By Carey Hamilton
The Salt Lake Tribune
10/25/2004
Marsha Christiansen watched her husband die from cancer this year and fears it won't be long until she has to bury her beloved son, Mark.
Mark has been overweight since childhood, but now, at 30, he is tipping the scales at nearly 600 pounds.
With an injured knee, he finds it difficult to stand. He has had to take a leave of absence from his job as a quality assurance technician at Abbott Laboratories in Salt Lake City and mostly sits day after day hooked up to oxygen.
Although Mark's situation is extreme and potentially dire, it underscores the country's growing weight epidemic.
Americans are the fattest they've ever been, with 60 percent of adults considered overweight or obese. Experts blame a culture of sedentary lifestyles, processed and fast foods and years of apathy.
In Utah, 55 percent of adults are overweight or obese. The obesity rates have increased from 10.7 percent in 1989 to 19 percent in 2002, according to the Utah Department of Health.
"Every day in Utah, 65 people cross the line from overweight to obese," said LaDene Larsen, director of the health department's bureau of health promotion.
The days of describing overweight people as fat and jolly are history. Obesity, defined as 100 or more pounds over a healthy weight, is the second preventable leading cause of death in the United States, behind smoking, and is a major risk factor for diabetes, heart disease and stroke.
Lifelong struggle: Mark has struggled with his weight - and slurs like fat and lazy - all his life. He believes he inherited a slow metabolism; other family members are overweight, and his dad hit 1,100 pounds at his heaviest.
Lezlee Jones, of Bountiful, says she lost weight the old-fashioned way - by eating right and exercising. In 12 weeks in 1999, she dropped from 171 pounds to 115 pounds. She has kept the weight off ever since. (Courtesy of Lezlee Jones)
His parents fed him vegetables, fruits and meats and limited his candy and soda intake as a child because he was husky as early as age 5. As an adult, Mark has tried the low-carbohydrate Atkins diet and prescription diet pills but says nothing has worked.
Now he is caught in a quandary. Before undergoing the knee surgery doctors say will allow him to return to a more normal life, he needs to lose weight. But moving enough to shed the necessary pounds is a problem, because the bad knee buckles underneath him.
"I want to go back to work," Mark said. "I had a doctor who told me I would die in two years and that was four years ago. But I really don't know what will happen to me if I don't get help."
Mark's doctor, Warren Stack in West Valley City, says Mark needs gastric bypass surgery. But his insurance company won't cover the procedure, which costs about $17,000 to $25,000.
"It's critical to have his knee fracture repaired, but the surgeon won't do the surgery until his weight is down," Stack said. "He can't lose the weight because he is immobilized. It's kind of a vicious cycle. His insurance company ought to keep in mind if they get him productive again they will gain another taxpayer. He's a hard-working guy, well-liked at his work and wants to get back to work."
In the past, Mark's dilemma was viewed as a personal, rather than a medical, problem. But attitudes are starting to change. Medicare recently redefined obesity as an illness, a move expected to pave the way for Medicare eventually to cover gastric bypass surgery. Private insurers may feel pressured to follow Medicare's lead.
Mark Christiansen, 30, of West Valley City, has always been heavy but now is nearly 600 pounds. His insurance refuses to pay for gastric bypass surgery. (Francisco Kjolseth/The Salt Lake Tribune)
In the meantime, help is elusive for Mark. And he's certainly not alone in his battle.
Half of Utahns heavy: Utah's rate of overweight and obese residents is below the national average, officials believe, because they get more regular physical activity. In fact, only two states - Montana and Alaska - reported higher levels of physical activity in 2003.
Even so, that leaves more than half of Utah's population heavier than it should be.
"As a society, we've reduced our amount of physical activity while food is more readily available," Larsen said.
While lifestyle plays a large role in the epidemic, research indicates genetics also contribute.
Ted Adams and Steven Hunt began studying the genetics of obesity in 1988 at the University of Utah Cardiovascular Genetics Department of Internal Medicine. They tracked 7,000 people from 400 Utah families with at least two family members who were 75 pounds or more overweight.
"We've done a lot of genotyping of these people," Hunt said. "We found that very few families had only one person who is obese. Ninety percent of the families we've studied have one or more of the genes that contribute to obesity."
Genes influence appetite and metabolism. Adams and Hunt theorize that our genes remained the same as our lifestyles became increasingly inactive. When food was scarce and we had to hunt and forage, our genes conserved energy.
Now food is plentiful and the population is less mobile, but our bodies continue to store the energy that we aren't expending, leading to weight gain.
And some people's bodies cling to the fuel more strongly than others.
"Two people could eat the same thing, and one would burn the food much faster," Adams explained. "Some people can eat whatever they want and not gain weight. Others eat a restricted diet and remain obese."
Adams likens obesity to smoking. While people in some families can puff away their entire lives without getting lung cancer, others die from the disease, he said.
Adams and Hunt say more work is needed to pinpoint genes that predispose people to obesity. Once that is done, pharmaceutical companies could design drugs to alter the genes' activity, much in the same way researchers created drugs to lower cholesterol.
No magic: For now there is no magic pill - and there may never be.
The fen-phen debacle showed the dangers of relying on pills to lose weight. The drugs were pulled from the market in the late 1990s due to concern that they caused leaky heart valves, stranding many people who had thrived on the medication and then gained back even more weight than they lost.
Exercise, diet - and surgery in drastic cases - are the best tools, experts say.
Lezlee Jones, 44, of Bountiful says she is an example of how to lose weight the old-fashioned way - by altering her diet and amping up her physical activity.
The mother of three slimmed down from 171 pounds and a size 14 to 115 pounds and a size 2 in 1999. She has kept the pounds off ever since.
How did she do it?
By eating six small meals a day and working out six days a week, she maintains. Each day, she typically eats three small cooked meals, mainly lean meats and vegetables, and drinks three protein shakes. She alternates
Fat and Digestion
three days of weight training for 45 minutes with three days of cardiovascular training for 20 minutes - usually speed walking up the hills in her neighborhood. She takes the seventh day off.
"If you're a busy person, eating six times a day is no small task," she said. "I was hesitant to do that at first because I thought I would gain weight. But the more frequently I ate, the more quickly I lost."
The reason is that eating small portions of healthy food throughout the day boosts some people's metabolism, said Shawn Talbott, associate clinical professor in the Division of Nutrition at the University of Utah.
"It's something that athletes have been doing for a long time, and it also works well for people who want to lose weight," he said. "If you're eating several times throughout the day, you generally don't get very hungry between meals, so you don't overeat. It's a very effective way of regulating caloric intake. And, metabolically speaking, your body handles smaller doses of calories better than large doses."
Jones said she was motivated to stick to her new eating and exercising patterns in part by a $100,000 prize sponsored by Body for Life, which she won in 2000 for transforming her physique in 12 weeks.
"The biggest mistake people make is they starve themselves and then they overeat," Jones said. "Changing your body takes planning. It's not always convenient, but it's doable."
Prevention also is key, said Larsen of the health department.
"We need to address the cultural and environmental factors that promote obesity," Larsen said. "We need support at schools, worksites and communities or this huge problem will get worse."
A Transition Study From Flolan® to Remodulin® in Patients with Pulmonary Arterial Hypertension This study is currently recruiting patients. Sponsored by: United Therapeutics
Information provided by: United Therapeutics Purpose This trial is a study of Remodulin in patients with pulmonary arterial hypertension who have been transitioned from Flolan therapy. The study consists of Screening, Baseline and Treatment Phases. Patients meeting all inclusion/exclusion criteria during the Screening Phase will enter the Baseline Phase, during which baseline exercise capacity, vital signs, and clinical signs and symptoms of the disease will be assessed. After confirmation of all inclusion/exclusion criteria, patients will be assigned to study drug (Remodulin or placebo) and will enter the Treatment Phase. The Treatment Phase begins with a Dose Transition Period, during which patients will begin receiving subcutaneous study drug at a low dose determined by the patient’s current dose of Flolan. The study drug dose will be increased gradually while the Flolan dose is decreased gradually over a period of up to 14 days. The dose changes will continue until Flolan therapy has been discontinued and the patient is stable on study drug. Patients who are transitioned off Flolan, who are stable on study drug will be discharged from the clinic, and will continue to receive study drug on an outpatient basis. The patient will return to the clinic at Weeks 4 and 8 for assessments. Patients will remain on study drug for 8 weeks from the first dose of study drug. At Week 8, final assessments will be conducted and the patient will be dismissed from the study. Patients who successfully complete Week 8 assessments may be offered Remodulin therapy or other therapy, at the investigator’s discretion. Condition Treatment or Intervention Phase
Pulmonary Arterial Hypertension
Pulmonary Hypertension
Drug: treprostinil sodium
Phase IV
MedlinePlus related topics: Pulmonary Hypertension Study Type: Interventional
Study Design: Treatment, Randomized, Double-Blind, Placebo Control, Parallel Assignment, Safety/Efficacy Study Official Title: A Multicenter, Randomized, Parallel Placebo-Controlled Study of the Safety and Efficacy of Subcutaneous Remodulin® Therapy After Transition From Flolan® in Patients with Pulmonary Arterial Hypertension Further Study Details: Expected Total Enrollment: 100 Study start: October 2002 This trial is a multicenter, randomized, parallel placebo-controlled study of Remodulin in patients with pulmonary arterial hypertension with WHO Functional Class II or III clinical status who have been transitioned from Flolan therapy. The study consists of Screening, Baseline and Treatment Phases. Patients meeting all inclusion/exclusion criteria during the Screening Phase will enter the Baseline Phase, during which baseline exercise capacity, vital signs, and clinical signs and symptoms of the disease will be assessed. After confirmation of all inclusion/exclusion criteria, patients will be randomized to study drug (1:1 Remodulin:placebo) and will enter the Treatment Phase. The Treatment Phase begins with a Dose Transition Period, during which patients will begin receiving subcutaneous study drug at a low dose determined by the patient’s current dose of Flolan. The study drug dose will be increased gradually while the Flolan dose is decreased gradually over a period of up to 14 days. The dose changes will be done according to a recommended schedule, which may be modified if necessary according to the patient’s clinical status. The dose changes will continue until Flolan therapy has been discontinued and the patient is stable on study drug, or until the patient has met the primary endpoint criteria. Patients who are transitioned off Flolan, who are stable on study drug, and who have demonstrated the ability to properly self-administer study drug will be discharged from the clinic, and will continue to receive study drug on an outpatient basis.
The patient will return to the clinic at Weeks 4 and 8 for assessments. At weeks other than Weeks 1, 4, and 8, the site staff will contact the patient to assess progress and adjust the study drug dose if necessary. Patients will remain on study drug for 8 weeks from the first dose of study drug. At Week 8, final assessments will be conducted and the patient will be dismissed from the study. Patients who successfully complete Week 8 assessments may be offered Remodulin therapy or other therapy, at the investigator’s discretion. Eligibility Ages Eligible for Study: 18 Years - 75 Years, Genders Eligible for Study: Both Criteria Inclusion Criteria Patients must: Be between 18 years and 75 years of age.
If female, be physiologically incapable of childbearing or practicing an acceptable method of birth control.
Have a current confirmed diagnosis of WHO Functional Class II or III pulmonary arterial hypertension (either PPH or PAH associated with the scleroderma spectrum of diseases).
Have been clinically stable with regard to signs and symptoms of PAH for at least the last 30 days.
Have a baseline six-minute walk distance of at least 250 meters.
Have been receiving Flolan therapy for at least 6 months, and have documented clinical benefit from Flolan therapy on an exercise assessment.
Be receiving Flolan at a dose of at least 15 ng/kg/min, but not more than 75 ng/kg/min, and have maintained the current dose of Flolan unchanged for at least 30 days at screening.
Unless contraindicated, be able to receive one of the following anticoagulants: warfarin to achieve an INR between 2.0 and 3.0 or heparin to produce an aPTT between 1.3 to 1.5 times control, unless higher levels are clinically indicated.
Be mentally and physically capable of learning to administer study drug using an subcutaneous infusion pump.
Exclusion Criteria Patients must not: Be a nursing or pregnant woman (women of childbearing potential must have a negative serum pregnancy test).
Have had a new type of chronic therapy (including but not limited to oxygen, a different category of vasodilator, a diuretic, digoxin) for pulmonary hypertension added within the last month.
Have any pulmonary hypertension medication except for anticoagulants discontinued within the week prior to study entry.
Have ever received Remodulin or any other prostaglandin/prostacyclin analog other than Flolan or Beraprost; or have received Bosentan or any other endothelin receptor antagonist within the past 30 days.
Have evidence of significant parenchymal lung disease as evidenced by pulmonary function tests within the last six months as follows (any one of the following): a)Total Lung Capacity < 60% (predicted), or b)If Total Lung Capacity is between 60% and 70% (predicted), a High Resolution CT scan must be performed to document diffuse interstitial fibrosis or alveolitis, or c)FEV/FVC ratio < 50%, or *All Scleroderma patients must have Pulmonary Function Test performed within six weeks prior to study entry.
Be positive for HIV.
Have Portal Hypertension.
Have a history of uncontrolled Sleep Apnea within the past three months.
Have a history of left-sided heart disease including: a)Aortic or mitral valve disease or, b)Pericardial constriction or, c)Restrictive or congestive cardiomyopathy.
Have evidence of current left-sided heart disease as defined by: a)PCWPm or left ventricular end diastolic pressure > 15 mmHg or b)LVEF < 40% by MUGA or Angiography or echocardiography or c)LV Shortening Fraction < 22% by echocardiography or d)Symptomatic coronary disease (demonstrable ischemia).
Have any other disease that is associated with pulmonary hypertension (e.g. congenital systemic to pulmonary shunt, sickle cell anemia, schistosomiasis).
Have a musculoskeletal disorder (e.g. arthritis, artificial leg, etc.) or any other disease, which is thought to limit ambulation, or be connected to a machine, which is not portable.
Have uncontrolled systemic hypertension as evidenced by systolic blood pressure greater than 160 mmHg or diastolic blood pressure greater than 100 mmHg.
Have used prescription appetite suppressants within 3 months of study entry.
Have chronic renal insufficiency as defined by creatinine greater than 3.5 mg/dL or the requirement for dialysis.
Be receiving an investigational drug, have in place an investigational device, or have participated in an investigational drug study within the past 30 days.
Have had an atrial septostomy.
Have anemia (hemoglobin <10 g/dL), active infection or any other ongoing condition that would interfere with the interpretation of study assessments.
Have any serious or life-threatening disease other than conditions associated with PAH (e.g. malignancy requiring aggressive chemotherapy, renal dialysis, etc.).
Have unstable psychiatric status or be mentally incapable of understanding the objectives, nature or consequences of the trial, or any condition which in the investigator’s opinion would constitute an unacceptable risk to the patient’s safety. Location and Contact Information California
Harbor-UCLA Medical Center, Torrance, California, 90502, United States; Recruiting
Joy Beckmann 310-222-3560 beckmann@humc.edu
Ronald Oudiz, MD, Principal Investigator University of Southern California, Los Angeles, California, 90033, United States; Recruiting
Wendy Hill 323-442-5483 whill@hsc.usc.edu
Shelley Shapiro, MD, Principal Investigator Illinois
The Rush Heart Institute Center for Pulmonary Heart Disease, Chicago, Illinois, 60612, United States; Recruiting
Christine List 312-563-2297 clist@rush.edu
Vallerie McLaughlin, MD, Principal Investigator Massachusetts
Massachusetts General Hospital, Boston, Massachusetts, 02114, United States; Recruiting
Margaret Hegarty 617-726-6564
Aaron Waxman, MD, Principal Investigator Michigan
University of Michigan, Ann Arbor, Michigan, 48106, United States; Recruiting
Raquel Casarez 734-647-5748 rcasarez@med.umich.edu
Melvin Rubenfire, MD, Principal Investigator Ohio
University Hospitals of Cleveland, Cleveland, Ohio, 44106, United States; Recruiting
Kathy Hague 216-844-2629 kathleen.hague@uhhs.com
Robert Schilz, DO, PhD, Principal Investigator Texas
Baylor College of Medicine, Houston, Texas, 77030, United States; Recruiting
Helena Purl 713-790-2076 hpurl@bcm.tmc.edu
Adaani Frost, MD, Principal Investigator Utah
LDS Hospital, Salt Lake City, Utah, 84143, United States; Recruiting
Natalie Kitterman 801-408-3500 ldnkitte@ihc.com
Greg Elliott, MD, Principal Investigator More Information Study ID Numbers: P01:13
Record last reviewed: April 2003
Record first received: April 14, 2003
ClinicalTrials.gov Identifier: NCT00058929
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2004-10-29
Merck turns to a nasal spray to help in weight reduction fight
BY ED SILVERMAN AND SUSAN TODD
Star-Ledger Staff
A little spritz in the nose may help you lose weight.
At least, that's what Merck is hoping. September 28, 2004
Yesterday, the world's fourth-largest drug maker licensed an unusual obesity medication that is still being developed -- a nasal spray that would discourage overeating by giving a patient a full feeling. Known in the lab as PYY, the spray is supposed to deliver an appetite-regulating hormone directly into the bloodstream. The hormone is produced by special endocrine cells in the gut after a person eats, and triggers a full feeling. For Merck, the deal with Nastech Pharmaceutical is the latest in a growing number of alliances the Whitehouse Station-based drug maker is striking with small biotechnology companies. Merck needs to bolster its pipeline, thanks to generic competition and setbacks in the lab. More significantly, the pact reflects an intensifying race for a new fat fighter. As many as 52 companies are believed to be conducting some level of research in the field, which suffered a resounding setback with the 1997 recall of two widely used diet pills. The market, nonetheless, remains large and lucrative. Approximately 60 million adults in the United States are considered obese, including 9 million who are severely obese, according to the American Obesity Association. The drug maker considered to be leading the race, Sanofi-Aventis, has said it expects peak sales of $3.7 billion for its own medicine -- Acomplia, which is still about two years from reaching pharmacies. "This is one of the most hotly pursued areas in the entire pharmaceutical and health-care industry," said George Yancopoulos, chief scientific officer of Regeneron Research Laboratories, a New York biotech developing an obesity drug. The market for diet pills soared in the mid-1990s with fen-phen, and the subsequent introduction of Redux, a chemical cousin of Pondimin, one of the fen-phen pills. Pondimin and Redux were recalled in 1997 after being linked to serious heart and lung damage. There are two older obesity drugs on the market -- Xenical, marketed by Hoffmann-La Roche, and Meridia, sold by Abbott Pharmaceuticals. Neither is a big seller, though, partly because only modest weight reduction is possible. As part of the latest deal, Merck will initially give $5 million to Nastech Pharmaceutical, which is based in Bothell, Wash. Another $340 million will be paid if various development milestones and sales targets are met. PYY is currently in the early stages of development. Merck will jointly develop the medicine, and will lead and fund all marketing activities. Nastech CEO Steven Quay said the medicine could reduce patients' daily calorie intake 30 percent, pending additional tests. That would results in a weight loss of about 50 pounds a year, based on the 2,800 calories a day the average American eats, he said. | 
