Drugs Log

Schering-Plough said the results of a first prospective trial specifically designed to evaluate erectile function in erectile dysfunction (ED) patients with dyslipidemia showed that Levitra (vardenafil HCl), used in treating ED, significantly improves the ability of men with ED and dyslipidemia to achieve and maintain an erection for successful sexual intercourse.

The double-blind, placebo-controlled study is the first study to measure the safety and efficacy of a PDE 5 inhibitor in a cohort of men who all had ED and dyslipidemia. Results from the study of 395 men show that Levitra significantly increased rates of penetration (as measured by SEP2 scores) and the ability to maintain an erection (as measured by SEP3 scores) compared to placebo.

“ED is associated with high cholesterol, yet many physicians are not treating ED, a life-changing condition,” said Dr Martin Miner, clinical associate professor, Family Medicine, Brown University’s Warren Alpert School of Medicine. “This study provides further support that Levitra can successfully treat ED, even in men with a serious common condition like high cholesterol.”

Nearly 70 per cent of the estimated 30 million men in the United States who have ED also have other common conditions such as dyslipidemia (including high cholesterol), hypertension, or diabetes, which may lead to erectile dysfunction. Previous studies have demonstrated the efficacy and safety of Levitra in men with ED who also have high blood pressure or diabetes.

In the double-blind, placebo-controlled study, 395 men ages 18 to 64 that had ED and dyslipidemia were randomised to treatment with Levitra or placebo for 12 weeks.

Men treated with Levitra had statistically significant and clinically relevant improvements in SEP2 scores (a rating system that measures penetration) and SEP3 scores (a rating system that measures maintenance of erection) versus placebo (79.1 per cent and 66.7 per cent, respectively, for Levitra, vs. 51.9 per cent and 33.8 per cent, respectively, for placebo). IIEF-EF (International Index of Erectile Function) scores also were significantly higher for the Levitra group compared to the placebo group. These scores are evaluated based on a patient questionnaire and their daily diary response to specific questions about sexual performance.

Treatment-emergent adverse effects (occurring in = 5 per cent of patients) included headaches (9 per cent for Levitra, 1 per cent for placebo) and upper respiratory tract infections (5 per cent for Levitra, 3 per cent for placebo).

Erectile dysfunction (ED) is the consistent or recurrent inability of a man to attain and/or maintain a penile erection sufficient for sexual performance. ED can be a total inability to achieve an erection, an inconsistent ability to do so, or a tendency to sustain only brief erections. It is estimated that some degree of ED affects up to 30 million men in the United States.

Some of the most common treatments for ED include adjustments to lifestyle and better control of concomitant medical conditions as well as the use of oral medications or other forms of therapy. Treating related health conditions or reducing stress may help maintain erectile function.

Levitra (vardenafil HCl) is a prescription medicine that is indicated to treat erectile dysfunction (ED). Consistent with the effects of PDE5 inhibition, administration of Levitra with nitrates and nitric oxide donors is contraindicated.

In clinical trials, the most commonly reported adverse events with LEVITRA were headache, flushing, and rhinitis. Adverse events were generally transient.

Nonarteritic anterior ischemic optic neuropathy (NAION) has been reported rarely postmarketing in temporal relationship with the use of PDE5 inhibitors, including Levitra. Sudden loss of hearing, sometimes with tinnitus and dizziness, also has been reported rarely in temporal association with the use of PDE5 inhibitors, including Levitra. It is not possible to determine if these events are related to PDE5 inhibitors or to other factors. Physicians should advise patients to stop use of PDE5 inhibitors, including Levitra, and seek prompt medical attention in the event of sudden loss of vision or hearing.

The recommended starting dose of Levitra is 10 mg. Titrate up to 20 mg or down to 5 mg based on efficacy and side effects.

Consumer Information

Generic Name: vardenafil
Brand Names: Levitra
What is Levitra?

Levitra relaxes muscles and increases blood flow to particular areas of the body.

Levitra is used to treat erectile dysfunction (impotence).

Levitra may also be used for purposes other than those listed in this medication guide.

Important information about Levitra
Do not take Levitra if you are also using a nitrate drug for chest pain or heart problems. This includes nitroglycerin (Nitrostat, Nitrolingual, Nitro-Dur, Nitro-Bid, and others), isosorbide dinitrate (Dilatrate-SR, Isordil, Sorbitrate), and isosorbide mononitrate (Imdur, ISMO, Monoket). Nitrates are also found in some recreational drugs such as amyl nitrate or nitrite (”poppers”). Taking Levitra with a nitrate medicine can cause a serious decrease in blood pressure, leading to fainting, stroke, or heart attack. If you become dizzy or nauseated, or have pain, numbness, or tingling in your chest, arms, neck, or jaw during sexual activity, stop and call your doctor right away. You could be having a serious side effect of Levitra. Do not take this medication more than once a day. Allow 24 hours to pass between doses. Contact your doctor or seek emergency medical attention if your erection is painful or lasts longer than 4 hours. A prolonged erection (priapism) can damage the penis.

A small number of patients have had a sudden loss of eyesight after taking Levitra. This type of vision loss is caused by decreased blood flow to the optic nerve of the eye. It is not clear whether Levitra is the actual cause of such vision loss. Sudden vision loss with Levitra use has occurred most often in people with heart disease, diabetes, high blood pressure, high cholesterol, or certain pre-existing eye problems, and in those who smoke or are over 50 years old.

Stop using Levitra and get emergency medical help if you have sudden vision loss.

Before taking Levitra
Do not take Levitra if you are also using a nitrate drug for chest pain or heart problems. This includes nitroglycerin (Nitrostat, Nitrolingual, Nitro-Dur, Nitro-Bid, and others), isosorbide dinitrate (Dilatrate-SR, Isordil, Sorbitrate), and isosorbide mononitrate (Imdur, ISMO, Monoket). Nitrates are also found in some recreational drugs such as amyl nitrate or nitrite (”poppers”). Taking this medication with a nitrate medicine can cause a serious decrease in blood pressure, leading to fainting, stroke, or heart attack.

A small number of patients have had a sudden loss of eyesight after taking Levitra. This type of vision loss is caused by decreased blood flow to the optic nerve of the eye. It is not clear whether Levitra is the actual cause of such vision loss. Sudden vision loss with Levitra use has occurred most often in people with heart disease, diabetes, high blood pressure, high cholesterol, or certain pre-existing eye problems, and in those who smoke or are over 50 years old.

Before taking this medication, tell your doctor if you have:

• heart disease or heart rhythm problems;
• a recent history (in the past 6 months) of a heart attack, angina (chest pain), or congestive heart failure;
• a history of stroke or blood clots;
• a personal or family history of “Long QT syndrome”;
• high or low blood pressure;
• liver disease;
• kidney disease (or if you are on dialysis);
• a blood cell disorder such as sickle cell anemia, multiple myeloma, or leukemia;
• a bleeding disorder such as hemophilia;
• a stomach ulcer;
• retinitis pigmentosa (an inherited condition of the eye);
• a physical deformity of the penis (such as Peyronie’s disease); or
• if you have been told you should not have sexual intercourse for health reasons.

Levitra side effects

If you become dizzy or nauseated, or have pain, numbness, or tingling in your chest, arms, neck, or jaw during sexual activity, stop and call your doctor right away. You could be having a serious side effect of Levitra. Stop using Levitra and get emergency medical help if you have sudden vision loss. Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using Levitra and call your doctor at once if you have any of these serious side effects:

• chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling;
• irregular heartbeat;
• swelling in your hands, ankles, or feet;
• shortness of breath;
• vision changes;
• feeling light-headed, fainting; or
  penis erection that is painful or lasts 4 hours or longer.

Continue taking this medication and talk with your doctor if you have any of these less serious side effects:

• warmth or redness in your face, neck, or chest;
• stuffy nose;
• headache;
• upset stomach; or
• back pain.

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.

What other drugs will affect Levitra?

Before taking Levitra, tell your doctor if you are using any of the following medications:

• cimetidine (Tagamet, Tagamet HB);
• erythromycin (E-Mycin, Eryc, Ery-Tab) or clarithromycin (Biaxin);
• doxazosin (Cardura), prazosin (Minipress), terazosin (Hytrin);
• HIV medicines such as amprenavir (Agenerase), tipranavir (Aptivus), darunavir (Prezista), efavirenz (Sustiva), nevirapine (Viramune), indinavir (Crixivan), saquinavir (Invirase, Fortovase), lopinavir/ritonavir (Kaletra), fosamprenavir (Lexiva), ritonavir (Norvir), atazanavir (Reyataz), or nelfinavir (Viracept);
• itraconazole (Sporanox) or ketoconazole (Nizoral);
• heart rhythm medicine such as amiodarone (Cordarone, Pacerone), quinidine(Quinidex, Quinaglute), procainamide (Procan, Pronestyl), or sotalol (Betapace);
• carbamazepine (Tegretol), phenobarbital (Luminal), or phenytoin (Dilantin); or
• rifampin (Rifadin, Rimactane).

If you are using any of these drugs, you may not be able to take Levitra, or you may need dosage adjustments or special tests during treatment.

There may be other drugs not listed that can affect Levitra. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

Merck & Co., Inc. said it voluntarily recalled 13 lots of its Hib vaccine given to ankle-biters to prevent meningitis and pneumonia as quality control found production equipment may not have been properly sterilised.

Merck recalled 11 lots of Pedvaxhib [Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)], and two lots of its combination Haemophilus influenzae type B/ hepatitis B vaccine, Comvax [Haemophilus b Conjugate (Meningococcal Protein Conjugate)]. The recall is specific to these 13 lots and does not affect any other vaccines manufactured by Merck. The affected doses of Pedvaxhib and Comvax were distributed starting in April 2007.

The company said the recall is because it can not assure sterility of these specific vaccine lots. The potential contamination of these specific lots was identified as part of the company’s standard evaluation of its manufacturing processes. Sterility tests of the vaccine lots that are the subject of this recall have not found any contamination in the vaccine.

The potential for contamination of any individual vaccine is low, and, if present, the level of contamination would be low. However, because the company cannot assure the sterility of these specific lots of vaccine, it is conducting this recall.

Merck is working closely with the US Food and Drug Administration (FDA) and the US Centres for Disease Control and Prevention (CDC) to inform affected healthcare providers of this recall. The company is also communicating with public health authorities and healthcare providers in the US and in other countries where these lots were distributed, as appropriate.

“We are taking this action because we are committed to ensuring the quality of our vaccines,” said Mark Feinberg, MD, Ph.D., vice president, medical and policy affairs, Merck vaccines and infectious diseases. “We know that our vaccines can play an important role in the nation’s public health system, and we are committed to resolving this issue as quickly as possible to ensure that our vaccines are readily available.”

Physicians are advised not to administer any vaccine from the vaccine lots being recalled. Individuals who received vaccine from these lots should complete their immunization series with a Haemophilus b conjugate-containing vaccine not affected by this recall, but do not need to be revaccinated to replace a dose they received from a recalled lot. The efficacy of the vaccine was not affected, the company officials said in a press statement.

Pedvaxhib is indicated for routine vaccination against invasive disease caused by Haemophilius influenzae type b in infants and children two to 71 months of age. As with any vaccine, the use of Pedvaxhib may not result in a protective antibody response in all vaccines; Pedvaxhib may not induce protective antibody levels immediately following vaccination.

Comvax [Haemophilus b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) Vaccine] is indicated for vaccination against invasive disease caused by Haemophilus influenzae type b and against infection caused by all known subtypes of hepatitis B virus in infants six weeks to 15 months of age born to HBsAg-negative mothers.

Comvax is contraindicated in patients with hypersensitivity to yeast or any component of the vaccine. Comvax included injection-site reactions, somnolence, irritability, crying, and fever.

As with other vaccines, Comvax may not induce protective antibody levels immediately following vaccination and may not result in a protective antibody response in all individuals given the vaccine.

General information about Haemophilus b Conjugate Vaccine

Some commonly used brand names in the U.S. and Canada are:

• Act-Hib
• Hibtiter
• Pedvaxhib
• Prohibit

Category: Immunizing agent, active

Description

Read the rest of this entry »

Telmisartan, a drug widely used to help control blood pressure, may have uniquely potent activity in preventing stroke, according to a new study conducted in an animal model.

Whether they used the drug alone or in combination with a different type of antihypertensive medication, ramipril, Weill Cornell Medical College researchers found that rats fed a high-salt, stroke-inducing diet were completely protected from the brain attacks while on telmisartan.

“No other study has ever shown complete protection against stroke in this rat model using normal human drug doses” notes study senior author Dr. Daniel F. Catanzaro, professor of physiology and biophysics and professor of physiology in cardiothoracic surgery at Weill Cornell Medical College.

The study, which was funded by telmisartan’s German maker, Boehringer Ingelheim Pharma GmbH & Co., is published online in the Journal of the American Society of Hypertension.

Telmisartan (brand name Micardis) is one of a class of widely used antihypertensive drugs known as angiotensin receptor blockers (ARBs). “These drugs primarily act on the vasculature to relax the small blood vessels,” Dr. Catanzaro explains.

Telmisartan stands out from other ARBs in that its molecular structure allows it to more easily pass through the blood-brain barrier and enter the brain — something many drugs cannot do.

The new animal study was not constructed to specifically look at telmisartan’s effect on stroke. “Because blood pressure is closely related to stroke risk, we really just wanted to look and see if combinations of antihypertensive drugs were better at lowering blood pressure and stroke compared to the use of single agents,” Dr. Catanzaro explains.

In this case, his team tested two drugs — telmisartan and an ACE inhibitor, ramipril (Altace) — in a rat model long favored by stroke researchers. In this approach, rats are fed what’s known as a “stroke-prone diet,” meaning they get lots of salt in both their food and water.

“This rat model has been great at showing us the neuroprotective properties of different drugs in the past, and the results usually correlate with results in humans,” Dr. Catanzaro says.

In the study, 25 rats were fed the stroke-prone diet for 8 weeks and received either no medication, telmisartan alone, ramipril alone, or the two drugs together at either full- or half-doses.

“A main finding was that combination therapy did reduce blood pressure the best of any treatment, and it also was best at cutting damage to the rats’ hearts and kidneys,” Dr. Catanzaro says. “But what was really surprising to us was that any regimen involving telmisartan at doses that would normally be given to humans completely prevented stroke in this model. Most studies with other drugs have used much higher doses and have found only partial protection.”

Specifically, 83 percent of rats given no medication showed signs of stroke, as did 56 percent of rats given ramipril alone. However, no strokes were noted in the telmisartan-only or the telmisartan/ramipril combo groups.

Telmisartan’s ability to easily pass through the blood-brain barrier (something ramipril cannot do) is likely behind the neuroprotective effect noted in the study, the researchers say.

“Going forward, that’s something that we would really like to test out in head-to-head trials pitting telmisartan against other ARBs, for example,” Dr. Catanzaro said. “At the same time, we’d like to examine whether telmisartan is actually getting into the brain, or if more peripheral effects — a lowering of blood pressure, for instance — are behind the reduction in stroke.”

In the meantime, Boehringer Ingelheim is nearing the end of a major clinical trial looking at the effectiveness of combining telmisartan with ramipril to lower patients’ blood pressures and reduce their odds for heart attack and stroke. Dr. Catanzaro’s team is not involved in that study.

Co-authors on this study include lead researcher Dr. Ying Zhou, as well as Dr. Fangmin Yu and Dr. Ada R. Ene — all of Weill Cornell Medical College in New York City.

Telmisartan information.

GENERIC NAME: Telmisartan
BRAND NAME: Micardis

DRUG CLASS AND MECHANISM: Telmisartan is a member of a family of drugs called angiotensin receptor blockers (ARBs), which includes losartan (Cozaar), valsartan (Diovan), irbesartan (Avapro), and candesartan (Atacand). ARBs block the ability of the chemical angiotensin II to constrict or squeeze arteries and veins. As a result, the arteries and veins enlarge and blood pressure falls. The reduced pressure in the arteries also makes it easier for the heart to pump blood. Telmisartan was approved by the FDA in November of 2000.

USES: This drug is used to treat high blood pressure (hypertension). This drug works by blocking the hormone angiotensin thereby relaxing blood vessels, causing them to widen. High blood pressure reduction helps prevent strokes, heart attacks, and kidney problems.

OTHER USES: This drug may also be used to treat congestive heart failure and to help protect the kidneys from damage due to diabetes.

HOW TO USE: Take this medication by mouth, usually once daily or as directed by your doctor. You may take this drug with or without food. Use this medication regularly in order to get the most benefit from it. To help you remember, use it at the same time each day. Do not take potassium supplements or salt substitutes containing potassium without talking to your doctor or pharmacist first. This medicine can raise your potassium levels, which rarely can cause serious side effects such as muscle weakness or very slow heartbeats. Tell your doctor immediately if these effects occur. The dosage is based on your medical condition and response to therapy. For the treatment of high blood pressure, it may take 4 weeks before the full benefit of this drug occurs. It is important to continue taking this medication even if you feel well. Most people with high blood pressure do not feel sick.

SIDE EFFECTS: You may experience dizziness, lightheadedness, blurred vision, or back pain as your body adjusts to the medication. If any of these effects persist or worsen, notify your doctor or pharmacist promptly. Tell your doctor immediately if any of these unlikely but serious side effects occur: fainting, decreased sexual ability. Tell your doctor immediately if any of these highly unlikely but very serious side effects occur: change in the amount of urine. An allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of an allergic reaction include: rash, itching, swelling (especially of the face, lips, tongue, or throat), severe dizziness, trouble breathing. If you notice other effects not listed above, contact your doctor or pharmacist.

WARNING: This drug can cause serious fetal harm (possibly death) if used during the last six months of pregnancy. If you become pregnant or think you may be pregnant, contact your doctor immediately.

The findings of clinical trials have linked the use of thiazolidinediones, a class of diabetes drugs, with congestive heart failure and possibly heart attacks. Now, new research indicates that these associations, at least with Avandia, also apply to individuals in the community, and not just clinical trials.

Dr. Lorraine L. Lipscombe, from the Institute for Clinical Evaluative Sciences in Toronto, and colleagues analyzed data for 159,026 older adults who were treated with at least one oral diabetes drug between 2002 and 2005 and were entered in an Ontario healthcare database. The subjects were followed through March 2006.

During an average follow-up period of 3.8 years, 7.9 percent of the patients were hospitalized for congestive heart failure, 7.9 percent were hospitalized for a heart attack, and 19 percent died, according to the researchers’ report in Journal of the American Medical Association.

Current thiazolidinediones use increased the risks of heart failure, heart attack and death by 60 percent, 40 percent, and 29 percent, respectively, compared with the use of other types of oral diabetes drugs.

Further analysis revealed that the risks were largely confined to patients who were using Avandia, known generically as rosiglitazone.

“These findings provide evidence from a real-world setting and support data from clinical trials that the harms of thiazolidinediones may outweigh their benefits, even in patients without obvious…cardiovascular disease,” the authors write.

More studies are needed to better define the risk-benefit ratio and the trade-offs associated with thiazolidinedione therapy and to explore if the treatment risks are confined specifically to rosiglitazone.

Avandia risks highlighted

Canadian researchers furnished the strongest evidence to date linking the popular diabetes drug Avandia to an increased risk of heart attack in a scientific study released yesterday.

Compared with other diabetes pills, Avandia’s use was associated with a 60 percent higher risk of heart failure, 40 percent higher risk of heart attack and 30 percent higher risk of death in patients 65 and older, the researchers found.

“The risks associated with these drugs may outweigh the benefits, at least for older populations,” said Dr. Lorraine L. Lipscombe, the lead author of the study and a researcher at a health research agency funded by the Ontario government.

The findings, published in the influential Journal of the American Medical Association, will probably intensify pressure on the government to restrict sales of the oral diabetes medicine.

“It should come off the market,” said Dr. Sidney M. Wolfe, director of health research at Public Citizen, a liberal interest group preparing to petition the Food and Drug Administration to pull the drug.

Sales of Avandia have plummeted since Dr. Steven Nissen, a prominent cardiologist, reported in May that it raised the risk of heart attack. His report prompted congressional hearings and demands to stop sales.

The FDA decided against that last month, instead adding a label warning that urges users to consult a doctor if they have serious heart problems.

The decision divided agency staff. Ultimately, FDA officials decided the scientific evidence wasn’t conclusive, and they asked Avandia’s manufacturer to conduct a long-term study.

In a statement, the FDA said it would review the results from the Canadian study, but it needs more evidence before taking any further action. “This new study we have just seen today does not change FDA’s recommendations,” the agency said.

GlaxoSmithKline, Avandia’s maker, dismissed the Canadians’ findings as limited and misleading because the elderly studied might have been at higher risk of heart problems.

The Philadelphia company, which is conducting a long-term study of Avandia’s side effects, said in a statement that many other studies show Avandia is safe and effective.

The new study is the first to review side effects in real patients, rather than test subjects, according to Lipscombe, a researcher at the Institute for Clinical Evaluative Sciences in Toronto.

Beginning in March, Lipscombe and her colleagues analyzed health care records for all elderly Ontario residents who took an oral diabetes medicine between 2002 and 2006.

Lipscombe said they focused on the elderly because 40 percent of diabetes patients in Ontario are 65 and older, but the elderly tend to be underrepresented in scientific drug studies.

The researchers didn’t find a higher heart risk among users of Actos, an Avandia competitor that belongs to the same class of diabetes drugs, but Lipscombe said there weren’t enough Actos users to draw a firm conclusion.

Older Diabetics Using Avandia Face Increased Death Risk

Older patients using the diabetes drug Avandia faced an increased risk of heart attack, heart failure and even death, new research shows.

According to the Canadian authors of the study, which is published in the Dec. 12 issue of the Journal of the American Medical Association, this is the first population-based look at the class of drugs to which Avandia belongs and the first report to find an increase in mortality rates.

“Our study looked at an older population in the real world who tend to be underrepresented in research trials and are at higher risk,” said study author Dr. Lorraine L. Lipscombe, a researcher with the Institute for Clinical Evaluative Sciences in Toronto. “While the overall risk versus benefit is difficult to interpret in all people, in older people, the risks may outweigh the benefit.”

“This is very striking data,” added Dr. Steven Nissen, chairman of the department of cardiovascular medicine at the Cleveland Clinic Foundation. “This and other studies are going to put tremendous pressure on the FDA [U.S. Food and Drug Administration] to act more forcefully with regard to Avandia.”

But the maker of Avandia (rosiglitazone), GlaxoSmithKline, took issue with the findings.

In a prepared statement, the company said the Canadian study “has significant limitations and generates misleading conclusions regarding acute myocardial infarction and death. These conclusions are inconsistent with a more robust body of evidence from large, long-term, prospective, well-designed clinical studies, including ADOPT and RECORD. These long-term trials in diabetic patients comparing rosiglitazone to other oral anti-diabetic medicines show no increased risk for cardiovascular events compared to other commonly used medications, other than the well-known risk of congestive heart failure with thiazolidinedione (TZDs).”

Nissen was the first scientist to publish concerns about Avandia and increased heart risks in a study last May.

After that and other research was released, the FDA added a “black box” warning to all drugs in the class. An FDA advisory panel voted against removing the drug from the market, citing inconclusive evidence.

The Canadian label for Avandia carries a stronger message: The drug is not to be used as the sole medication for type 2 diabetes unless the patient cannot take another drug to lower blood sugar and that the drug should not be used by any patient with heart failure.

People with type 2 diabetes are already at heightened risk for cardiovascular disease.

Thiazolidinediones including Avandia and Actos (pioglitazone) heighten the body’s sensitivity to insulin. Some 3.5 million U.S. patients take Avandia, which has also been linked to bone loss in some patients.

The current study involved an older (66 and over), “real-world” population consisting of more than 159,000 residents of Ontario in this age group who were treated with at least one oral diabetic medication. The patients were followed for about four years.

Compared to individuals taking more than one oral hypoglycemic agent, people using Avandia on its own had a 60 percent increased risk of congestive heart failure, a 40 percent increased risk of heart attack, and a 29 percent increased risk of dying.

The increased risks were associated with Avandia only, but fewer people in the study took Actos, so the results could be skewed, the researchers noted.

“It looks like the results were limited to Avandia, but 50 percent fewer people were on Actos, so you can’t rule out an increased or decreased risk with Actos,” Lipscombe said. “We need more studies.”

“It’s an observational study and, like all observational studies, this has strengths and weaknesses. These studies do not provide the strength of evidence of a prospective, randomized trial,” Nissen pointed out. “But as observational studies go, this one is very helpful, because it is quite large, and it is independent, not sponsored by any company. Remarkably, with Avandia, the increased risk of heart attack is very similar to what we reported in our meta-analysis last May.”

In related research appearing in the same issue of JAMA, a review of 25 studies found that current smokers have a 44 percent increased risk of developing type 2 diabetes compared with nonsmokers.

The degree of risk was linked to the level of smoking — there was a 61 percent increased risk for those smoking 20 or more cigarettes a day and a 29 percent increased risk for those who smoked less, said the Swiss researchers. Former smokers had a 23 percent increased risk.

Herbal sex-pill alternatives pose a hidden danger for men on common heart and blood-pressure drugs: popping one could lead to a stroke, or even death.

Many of the “all-natural” products with names such as Stamina-RX and Vigor-25 work because they contain unregulated versions of the drugs they are supposed to replace.

An Associated Press investigation found that spiked herbal impotency pills are emerging as a major public-health concern.

Herbal Sex Pills May Pose Hidden Dangers

Many of the pills marketed as safe herbal alternatives to Viagra and other prescription sex medications pose a hidden danger: For men on common heart and blood-pressure drugs, popping one could lead to a stroke, or even death.

“All-natural” products with names like Stamina-RX and Vigor-25 promise an apothecary’s delight of rare Asian ingredients, but many work because they contain unregulated versions of the very pharmaceuticals they are supposed to replace.

That dirty secret represents a special danger for the millions of men who take nitrates — drugs prescribed to lower blood pressure and regulate heart disease. When mixed, nitrates and impotency pharmaceuticals can slow blood flow catastrophically, leading to a heart attack or stroke.

An Associated Press investigation shows that spiked herbal impotency pills are emerging as a major public health concern that officials haven’t figured out how to track, much less tame.

Emergency rooms and poison control hot lines are starting to log more incidents of the long-ignored phenomenon. Sales of “natural sexual enhancers” are booming — rising to nearly $400 million last year. And dangerous knockoffs abound.

At greatest risk are the estimated 5.5 million American men who take nitrates — generally older and more likely to need help with erectile dysfunction.

The all-natural message can be appealing to such men, warned by their doctors and ubiquitous TV commercials not to take Viagra, Cialis or Levitra.

James Neal-Kababick, director of Oregon-based Flora Research Laboratories, said about 90 percent of the hundreds of samples he has analyzed contained forms of patented pharmaceuticals — some with doses more than twice that of prescription erectile dysfunction medicine. Other testers report similar results, particularly among pills that promise immediate results.

While no deaths have been reported, the AP found records of emergency room visits attributed to all-natural sex pills in Georgia, Chicago, Philadelphia, San Diego and elsewhere.

An elderly man in a retirement community north of Los Angeles took an in-the-mail sample and landed in the hospital for four days. A Michigan man sued the maker of Spontane-ES, blaming it for the stroke he suffered 20 minutes after taking a freebie that was advertised as “extremely safe.” Tim Fulmer, a lawyer representing Spontane-ES, said the pill did not contain any pharmaceutical and was not responsible for the stroke.

Mark B. Mycyk, a Chicago emergency room doctor who directs Northwestern University’s clinical toxicology research program, said he is seeing increasing numbers of patients who unwittingly took prescription-strength doses of the alternatives, a trend he attributes to ease of purchase on the Internet and the desperation of vulnerable men. He said he wouldn’t be surprised if there’d been undetected deaths from bad herbal pills.

Some herbal labels warn off users with heart or blood-pressure problems if they have taken their medicine within six hours; some doctors say 24 hours or more would be safer.

The AP often couldn’t determine from records whether incidents reported to tracking systems of the federal Food and Drug Administration and state poison control centers involved mixing herbal alternatives with nitrates.

Some men in their 30s who went to emergency rooms after taking herbal sex pills were presumably otherwise healthy, but they showed the transitory side effects of the active ingredients in regulated impotency pharmaceuticals, such as difficulty seeing clearly or severe headaches, records show.

While public health officials don’t know the extent of the problem, they agree that incidents are vastly underreported, with national tracking systems capturing perhaps as little as 1 percent of them. Victims may be embarrassed, and doctors rarely ask about supplements.

Since 2001, sales of supplements marketed as natural sexual enhancers have risen $100 million, to $398 million last year, including herbal mixtures, according to estimates by Nutrition Business Journal. Some legitimate herbal mixtures claim to work gradually over weeks; it’s the herbals marketed for immediate trysts that often are the problem.

Tight budgets, weak regulations and other priorities limit the FDA’s ability to police the products, often promoted via blasts of e-mail spam and fly-by-night Web sites.

“The Internet poses many enforcement challenges,” said Dr. Linda Silvers, who leads an FDA team that targets fraudulent health products sold online. “A Web site can look sophisticated and legitimate, but actually be an illegal operation.”

In many cases, the ingredients used to alter herbal pills come from Asia, particularly China, where the sexual enhancers are cooked up in labs at the beginning of a winding supply chain. The FDA has placed pills by two manufacturers in China and one from Malaysia on an import watch list.

Pills like Cialis generally retail at pharmacies for between $13 and $20, while herbals can cost less than $1, up to about $5.

Many health insurance plans provide limited coverage for prescription sex pills, especially for those with health-related difficulties. Few over-the-counter treatments are covered, and herbals aren’t likely to be among them, in part because they’re classified as foods not pharmaceuticals, said Mohit M. Ghose, spokesman for America’s Health Insurance Plans, which represents major health insurers.

Spiked pills have turned up in Thailand, Taiwan, Canada, Australia, New Zealand, Hong Kong, Malaysia, the United Kingdom and the United States, according to testing done by Pfizer Inc., the New York-based pharmaceutical giant that developed Viagra. The company said that 69 percent of 3,400 supplements it purchased in China contained sildenafil citrate, the main ingredient in Viagra. Pfizer didn’t check for the patented ingredients of its rivals.

Under U.S. law, because such pills are “dietary supplements,” they’re far less regulated than pharmaceuticals and face few barriers to market. Viagra, by contrast, underwent years of testing before it was publicly available.

While herbal alternatives often contain exact copies of the patented drugs, some makers tweak the molecules to keep the effect of the original pharmaceutical while avoiding the scrutiny of the FDA and outside testing labs.

Federal officials have only recently stepped up investigations and prosecutions, and in any case, the FDA’s recall power is limited. Last week, in response to safety concerns about imported toothpaste, dog food and toys, President Bush recommended that the FDA be authorized to order mandatory recalls of dangerous products.

Currently, recalls are voluntary, and even if the agency determines that a product poses a “significant health risk,” a firm may refuse to cooperate. Plus, recalled products are widely offered on the Internet and pills are hard to round up.

Before a product called Nasutra was recalled a year ago by its manufacturer, the FDA had received a 30-year-old man’s report of a raging headache and an erection that wouldn’t go down. Following the recall, a 32-year-old man reported having spontaneous nose bleeds after taking the pill, records show.

E-mails requesting comment from Nasutra LLC, the company that voluntarily recalled the product in September 2006, were not returned. The FDA says the firm is located in Los Angeles; there is no listed phone number in the region.

During the past year, the FDA has orchestrated eight recalls of “herbal” pills that contained the ingredients found in Viagra, Cialis or Levitra, or their unregulated chemical cousins. Many of the firms were based around Los Angeles, their offices ranging from an unsigned door in a grungy hall on the fringe of downtown to a gated complex near Beverly Hills.

One recall involved a pill called Liviro3.

The current owner of the drug’s marketing and distributing firm said that after he tried the product, he quit his job at a car dealership and bought the brand name and stock of several thousand pills in 2004 for $450,000. In January, he said, FDA agents seized his stockpile after an agency lab found that Liviro3 contained tadalafil, the main ingredient in Cialis. The man told the AP he’d had no idea the pills were drug-laced.

One prosecution involved V. Vigor Corp., the Long Island-based maker of Vigor-25. While the product was advertised as containing Asian ginseng, lycium fruit and Chinese yam rhizome, FDA testing indicated that the pills contained Viagra.

Company executive Michael Peng had agreed to stop selling Vigor-25 following an FDA agent’s visit in late 2004, according to an arrest warrant affidavit. But between then and his arrest in September, at least 4.5 million pills were packaged for distribution, the affidavit said. According to prosecutors, Peng thought he could evade tests simply by switching from the sildenafil citrate he imported from China to Levitra’s active ingredient, vardenafil — a shipment of which U.S. Customs intercepted from Thailand.

Peng, who said through his attorney that he was “unaware that there was anything other than natural supplements” in Vigor-25, faces a charge of misbranding — in this instance, claiming that a pharmaceutical is a dietary supplement.

Two other pills, Spontane-ES and Stamina-RX, were made by companies run by Jared Wheat, who’s facing federal charges in Atlanta that he peddled knockoff pharmaceuticals cooked in a Central American lab. Prosecutors tried to keep Wheat from posting bail by asserting that he contemplated killing an FDA investigator and bribing a prosecutor.

Fulmer rejected those assertions, which did not lead to charges, saying Wheat is hardworking and nonviolent. Fulmer said Wheat’s two businesses are legitimate and continue to be successful.

Wheat was granted bond after pledging approximately $7.5 million in cash and property; he’s free under home confinement.

A drug used for high blood pressure, enlargement of the prostate and as an antipsychotic may protect the brain from stress, U.S. researchers say.

Researchers at Oregon Health & Science University and Portland Veterans Affairs Medical Center say Prozosin (brand name Minipress) appears to block the increase of steroid hormones known as glucocorticoids. Elevated levels of these hormones are linked to atrophy of nerve branches and nerve cell death.

“It’s known, from human studies, that corticosteroids are not good for you cognitively,” study co-author, Dr. S. Paul Berger, said in a statement. “We think prazosin protects the brain from being damaged by excessive levels of corticosteroid stress hormones.”

The researchers said high levels of glucocorticoids in blood serum are associated with such psychiatric conditions as schizophrenia, depression, post-traumatic stress syndrome and Alzheimer’s disease and are linked to decreases in cognitive performance in older people not suffering from clinical dementia.

The study was presented at the annual Society for Neuroscience conference in San Diego.

Prazosin drug helps posttraumatic stress disorder nightmares

A generic drug already used by millions of Americans for high blood pressure and prostate problems has been found to improve sleep and lessen trauma nightmares in veterans with posttraumatic stress disorder (PTSD).

“This is the first drug that has been demonstrated effective for PTSD nightmares and sleep disruption,” said Murray A. Raskind, MD, executive director of the mental health service at the Veterans Affairs Puget Sound Health Care System and lead author of a study appearing April 15 in Biological Psychiatry.

The randomized trial of 40 veterans compared a nightly dose of prazosin (PRAISE-oh-sin) with placebo over eight weeks. Participants continued to take other prescribed medications over the course of the trial.

At the end of the study, veterans randomized to prazosin reported significantly improved sleep quality, reduced trauma nightmares, a better overall sense of well being, and an improved ability to function.

“These nighttime symptoms are heavily troublesome to veterans,” said Raskind, who also is director of VA’s VISN 20 (Veterans Integrated Service Network #20) Mental Illness Research, Education and Clinical Centers program (MIRECC). “If you get the nighttime symptoms under control, veterans feel better all around.”

Raskind, also a professor of psychiatry and behavioral sciences at the University of Washington, estimates that of the 10 million U.S. veterans and civilians with PTSD, about half have trauma-related nightmares that could be helped with the drug.

Participants were given 1 mg of prazosin per day for the first three days. The dose was gradually increased over the first four weeks to a maximum of 15 mg at bedtime. The average dose of prazosin in the trial was 13.3 mg. By comparison, typical prazosin doses for controlling blood pressure or treating prostate problems range from 3 mg to 30 mg per day in divided doses.

The drug did not affect blood pressure compared to placebo, though some participants reported transient dizziness when standing from a sitting position during the first weeks of prazosin titration. Other occasional side effects included nasal congestion, headache, and dry mouth, but these were all minor, according to the authors.

“This drug has been taken by many people for decades,” said Raskind. “If there were serious long-term adverse side effects, it is likely we would know about them by now.”

The relatively small size of the study was due to the easy availability of this generic drug, Raskind said. “If you are doing a study with a new drug, the only way people can get it is to be in the study. With prazosin, we have approximately 5,000 veterans with a PTSD diagnosis taking it already in the Northwest alone. So we had to find veterans with PTSD who were not [taking it].”

For treating PTSD, prazosin costs 10 to 30 cents a day at VA contract prices. It is not a sedating sleeping pill, emphasized Raskind. “It does not induce sleep. But once you are asleep, you sleep longer and better.”

And better sleep can make a big difference. “This drug changes lives,” Raskind said. “Nothing else works like prazosin.”

Trauma nightmares appear to arise during light sleep or disruption in REM sleep, whereas normal dreams ,both pleasant and unpleasant, occur during normal REM sleep. Prazosin works by blocking the brain’s response to the adrenaline-like neurotransmitter norepinephrine. Blocking norepinephrine normalizes and increases REM sleep. In this study, veterans taking prazosin reported that they resumed normal dreaming.

One dose of prazosin works for 6 to 8 hours. Unlike similar drugs, prazosin does not induce tolerance; people can take it for years without increasing the dose. But when veterans stop taking it, Raskind said, the trauma nightmares usually return.

Aside from the VA-funded study he just published, Raskind is working on three larger studies of prazosin. One, a VA cooperative study slated to start this month, will enroll about 300 veterans at 12 VA facilities. The second, a collaborative study with Walter Reed Army Medical Center and Madigan Army Medical Center, will enroll active-duty soldiers who have trauma nightmares. The third study, funded by the National Institute of Mental Health, will look at prazosin in the treatment of civilian trauma PTSD.

Why is this medication prescribed?

Prazosin is used alone or in combination with other medications to treat high blood pressure. Prazosin is in a class of medications called alpha-blockers. It works by relaxing the blood vessels so that blood can flow more easily through the body.

How should this medicine be used?

Prazosin comes as a capsule to take by mouth. It usually is taken two or three times a day at evenly spaced intervals. The first time taking prazosin, you should take it before you go to bed. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take prazosin exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Your doctor will probably start you on a low dose of prazosin and gradually increase your dose.

Prazosin controls high blood pressure but does not cure it. Continue to take prazosin even if you feel well. Do not stop taking prazosin without talking to your doctor.

Other uses for this medicine

Prazosin is also used to treat benign prostatic hyperplasia (BPH, noncancerous enlargement of the prostate), congestive heart failure, pheochromocytoma (adrenal gland tumor), and Raynaud’s disease (condition where the fingers and toes change skin color from white to blue to red when exposed to hot or cold temperatures). Talk to your doctor about the possible risks of using this medication for your condition.

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

What side effects can this medication cause? Return to top

Prazosin may cause side effects. Tell your doctor if any of these symptoms or those listed in the SPECIAL PRECAUTIONS section are severe or do not go away:

• weakness
• tiredness
• headache
• nausea

Some side effects can be serious. If you experience any of the following symptoms, call your doctor immediately:

• hives
• rash
• itching
• difficulty breathing
• fast, pounding, or irregular heartbeat
• chest pain
• painful erection of the penis that lasts for hours

Brand name - Minipress®

AIDS vaccine researchers are worried about the future of their field after learning an experimental HIV vaccine not only does not work, but just might make recipients more susceptible to infection with the AIDS virus!

They are worried about their volunteers and the future of AIDS vaccines in general. And they are worried because they cannot understand how a vaccine would make a person more vulnerable.

Researchers from Merck & Co., which makes the vaccine, and the National Institute of Allergy and Infectious Diseases, which is helping develop it, said on Wednesday they believe a type of common cold virus used as the basis of the vaccine may somehow have made their volunteers more susceptible to HIV.

They are meeting this week in Seattle to hash through the data and figure out what happened.

This is what they know: Out of 1,500 people vaccinated, 82 became infected with the AIDS virus. Of these, 49 got the vaccine and 33 got a placebo shot.

While they are counseling volunteers that they may have raised their own risk of becoming infected, they are also trying to figure out what happened.

“The data are disappointing and puzzling but we don’t have definitive answers,” Dr. Lawrence Corey of Fred Hutchinson Cancer Research Center in Seattle, who was organizing the trial, told reporters.

Only one woman in the trial became infected with HIV. The rest were men having sex with other men, and it was the men who started out with the highest immune response to the adenovirus 5 common cold bug used to make the vaccine who were the most likely to become infected with the AIDS virus.

But the infected men were also less likely to have been circumcised — circumcision can also prevent HIV infection — and may have engaged in more risky behavior. So did the vaccine actually do something, or were the results a fluke?

“I don’t think we really do know,” Dr. Keith Gottesdiener of Merck Research Laboratories told Reuters.

FUTURE OF THE FIELD

Nearly 30 potential AIDS vaccines are being tested in people around the world.

“It is very important for the future of the field,” said Margaret Johnston, director of the AIDS vaccine research program at the NIAID.

“It makes us rethink some of the candidates that are in trial,” said Dr. Seth Berkley, president of the International AIDS Vaccine Initiative.

Even vaccine advocates are calling it a setback.

“These data are deeply disappointing and troubling, and raise more questions than answers for the field of AIDS vaccine,” said AIDS Vaccine Advocacy Coalition executive director Mitchell Warren.

“This setback should not and can not diminish our commitment to developing an effective HIV vaccine,” said NIAID director Dr. Anthony Fauci. “Every day, another 12,000 people become infected with HIV, most of whom live in resource-poor countries,” he added.

The researchers agree the finding could at the very least scare people off from taking part in AIDS vaccine trials. And because HIV only infects people, having human volunteers is key to finding a way to prevent an infection that has killed 25 million people and affects 40 million more.

“That is why we are being completely transparent, as open as possible,” Fauci said in a recent interview.

Berkley agreed. “I am only worried if there is a lot of buzz, misinformation around,” he said.

But the fact that vaccine volunteers even became infected drives home the need for a vaccine, said Berkley. All the volunteers were counseled about ways to avoid HIV infection, and given condoms. “If those behavioral change interventions worked, we wouldn’t need a vaccine,” Berkley said.

“People will get infected despite the best counseling possible.”

Experimental aids vaccine increased risk

New data on an experimental AIDS vaccine that failed to work shows volunteers who got the shots were far more likely to get infected with the virus through sex or other risky behavior than those who got dummy shots.

The new details, released Wednesday by drugmaker Merck & Co., don’t answer the crucial question of whether failure of the vaccine also spells doom for many similar AIDS vaccines now in testing.

And researchers weren’t sure why more of the vaccinated volunteers wound up getting HIV than those who got dummy shots.

Some 3,000 people, mostly gay men and female sex workers, had volunteered to get the vaccine or dummy shots. All were warned to protect themselves from AIDS exposure.

At the time the study was halted in September, Merck said 24 of 741 volunteers who got the vaccine in one segment of testing later developed HIV; 21 of 762 participants who got dummy shots also were infected.

New data released Wednesday showed that to date, 49 of 914 vaccinated men had become infected with HIV, compared with 33 of the 922 men who got dummy shots.

AIDS vaccine may raise infection risk

More than 3,000 people who volunteered to receive an experimental Merck and Co. AIDS vaccine are being told to come back and get extra tests because the jab may itself raise the risk of infection.

Researchers stress that they do not yet have enough information to say whether those who got the shot indeed are more susceptible to infection with HIV. But they said initial information from the trial, which was stopped suddenly last month, is worrisome.

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Pharmion Corporation (Nasdaq: PHRM) released interim findings from its Phase 2 trial of Amrubicin in second-line chemo-sensitive small cell lung cancer (SCLC). Amrubicin, the company’s third-generation synthetic anthracycline, is a potent topoisomerase II inhibitor currently in development for the treatment of SCLC. These findings indicate favorable interim results in terms of response rate and survival for Amrubicin in second-line treatment of small-cell lung cancer patients with extensive disease (ED) SCLC. The early results of this study were presented at the 2007 Chemotherapy Foundation Symposium in New York City.

“Treatment options for second-line SCLC are limited and preliminary data from the US-based Phase 2 sensitive SCLC trial indicate that Amrubicin may provide a new option for SCLC patients who desperately need more treatment choices,” said principal investigator Robert M. Jotte, MD, PhD, Medical Director of the Lung Cancer Clinic of the Rockies, Developmental Co-Chair USON Lung Committee. “As we near completion of the Phase 2 trial, we hope that accrual to the Phase 3 trial will be rapid and confirm the results of the US Phase 2 trial and similar trials in Japan.”

The trial presented today compares Amrubicin and topotecan in patients with ED-SCLC that initially responded to first-line platinum-based therapy but whose disease recurred or progressed at least 90 days after completion of first-line treatment (sensitive SCLC). Study participants are randomized in a 2:1 ratio to receive either IV Amrubicin (40mg/m2 daily for 3 days) or topotecan (1.5 mg/m2 daily for 5 days), both starting on Day 1 of a 21-day cycle.

Response data from 42 patients have been analyzed, 28 treated with Amrubicin and 14 with topotecan. Eleven of 28 (39 percent) patients who received one or more cycles of Amrubicin have demonstrated a response, including two complete responses (CR) and nine partial responses (PR). Eight of the responses are confirmed and three are pending follow-up scans. Two of 14 (14 percent) patients who received one or more cycles of topotecan had a response (both PRs). One is confirmed and one is pending a follow-up scan.

Survival times are not yet mature, however, at this time preliminary data already show an observed difference of 2.4 months in overall survival, which translates to a hazard ratio of 0.67, favoring Amrubicin.

The most common adverse events were hematological and were generally equal between the two arms. No classical anthracycline cardiotoxicity has been observed to date, supporting data from earlier Japanese studies that suggest Amrubicin may be devoid of this anthracycline-associated adverse event.

A second Amrubicin Phase 2 trial is also underway evaluating single-agent Amrubicin in patients with ED SCLC that are chemo-refractory or progressive within 90 days of completion of first-line platinum-based chemotherapy (refractory SCLC). Study participants receive Amrubicin (40 mg/m2 via 5-minute infusion daily for 3 days) on Day 1 of a 21-day cycle.

Enrollment in both second-line Phase 2 studies of Amrubicin is expected to complete by the end of 2007.

Pharmion has an additional ongoing Phase 2 study of Amrubicin in first line SCLC patients in association with the European Organization for the Research and Treatment of Cancer (EORTC). This study evaluates Amrubicin as single-agent or combination therapy with cisplatin versus cisplatin plus etoposide in previously untreated ED-SCLC patients. Preliminary data from this study are expected in the second half of 2008.

Pharmion recently initiated an international pivotal Phase 3 trial of Amrubicin versus topotecan as second-line treatment of small cell lung cancer (sensitive or refractory and limited or extensive disease). The randomized, controlled, multi-center study will compare Amrubicin to topotecan, the only approved chemotherapy for second-line treatment of SCLC in the US and EU. The primary endpoint of the study is overall survival. Enrollment in the study of 480 patients is underway. Pharmion has completed the Scientific Advice (SA) process with the European Medicines Agency (EMEA) and has reached Special Protocol Assessment (SPA) agreement with the US Food and Drug Administration (FDA) for the Amrubicin Phase 3 SCLC study.

New Synthetic Anthracycline, Amrubicin, Shows Promise for the Treatment of Small Cell Lung Cancer

Researchers from Japan have determined that a new synthetic anthracycline in combination with cisplatin (Platinol®) has significant activity in newly diagnosed extensive small cell lung cancer (SCLC). The details of this phase I/II study appeared in the March 2005 issue of the Annals of Oncology .

Small cell lung cancer is very sensitive to a variety of chemotherapy agents, including anthracyclines such as doxorubicin (Adriamycin®). However, anthracyclines are associated with early and late cardiac damage, limiting their use. Amrubicin is a totally synthetic anthracycline developed by the Japanese and is currently in phase I testing. In animal testing, this synthetic agent has few, if any, heart toxicities.

In this phase I/II study, the goal was to determine the maximum tolerated doses of the drug combination amrubicin and cisplatin and to ensure the safety of the recommended doses. Study participants were diagnosed with extensive SCLC and had not been previously treated with any type of chemotherapy. All patients received their amrubicin doses on days 1-3 and cisplatin on day 1 only, every 3 weeks. Results of the study defined safe and potentially effective doses. The overall response rate was 87.8% among both groups. The average survival time was 13.6 months and the 1-year survival rate was 56.1%. The most common side effects that were observed included a drop in the white blood count. Researchers concluded that the combination of amrubicin and cisplatin demonstrated a promising response rate and survival period for patients who were previously untreated for extensive SCLC.

Comments: This is an important study, as it shows significant activity for a totally synthetic drug that was engineered to eliminate cardiac. Unfortunately, this drug will not be on the market for quite some time. However, when there is concern about cardiac toxicity, there are currently FDA-approved drugs such as Doxil®, that are less cardio-toxic than doxorubicin.

About Amrubicin

Pharmion acquired the rights to Amrubicin in November 2006 through its acquisition of Cabrellis Pharmaceuticals. In 2002, Amrubicin was approved and launched for sale in Japan based on Phase 2 efficacy data in both SCLC and NSCLC. Since January 2005, Amrubicin has been marketed by Nippon Kayaku, a Japanese pharmaceutical firm focused on oncology, which licensed Japanese marketing rights from Dainippon Sumitomo, the original developer of Amrubicin.

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Merck & Co. said it will pay $4.85 billion to end thousands of lawsuits over its painkiller Vioxx in what is believed to be the largest drug settlement ever.

Merck faced personal injury lawsuits representing 47,000 plaintiffs, and about 265 potential class action cases, filed by people or family members who claimed the drug proved fatal or injured its users. The agreement covers cases filed in both federal and state courts.

Negotiating teams met more than 50 times in eight states and spoke hundreds of times over the telephone to hammer out the deal, according to attorneys.

“I’m very happy with it,” Chris Seeger, one of the six plaintiff lawyers who helped negotiate the settlement, said Friday. “It’s a tremendous way to resolve this litigation.”

Merck pulled Vioxx from the market Sept. 30, 2004 after its researchers determined the then-blockbuster painkiller doubled risk of heart attacks and strokes.

To qualify for a settlement, plaintiffs must have filed claims by Thursday and meet several criteria, including medical proof that they suffered a heart attack or stroke, that they received at least 30 Vioxx pills and that they received enough pills to support a presumption that they were ingested within two weeks before injury.

That is a big concession by Merck, which has long claimed that Vioxx caused harm only after 18 months of use.

Those claims were dismissed by independent scientists and plaintiffs lawyers.

Merck stressed that the agreement is not a class action settlement and that it is not admitting fault.

Company executives and attorneys said as recently as last month that every case would be fought individually.

Analyst Steve Brozak of WBB Securities called Merck’s’ handling of the litigation “a Harvard casebook study of how to deal with a problematic product.”

Investors seemed to agree, as Merck shares jumped 4.6 percent, or $12.50, to $57.27 Friday.

Analysts predicted early on that liability could reach $50 billion, but after losing its first case in a $253 million verdict, Merck has won a string of civil cases.

Merck may now have put the uncertainty of millions of dollars in legal costs behind it, though it has been fairly successful fighting cases individually, winning 10 of 15 court verdicts to date.

The company said last month it had added $70 million to its reserves for defending lawsuits. As of Sept. 30, Merck had reserved a total of $1.92 billion for legal expenses and spent a total of $1.2 billion.

The deal becomes binding only if 85 percent of the plaintiffs in about 26,600 lawsuits agree to drop their cases. It was finalized in the early morning hours after attorneys for Merck and the plaintiffs met with three of the four judges overseeing nearly all Vioxx claims.

Seeger said the deal was put in motion last December when three key judges pushed the parties to open out-of-court talks.

“Every claimant is going to be compensated” once their claim is validated, he said.

Seeger believes it is the largest settlement ever in the industry and said he will recommend that his 2,000 clients accept the deal.

Payments would vary, depending on severity of injuries and the length of time that Vioxx was used.

“The agreement is structured to provide a significant degree of certainty toward resolving the majority of the outstanding VIOXX product liability claims in the United States for a fixed amount,” Richard T. Clark, chairman, president and chief executive officer of Merck, said in a statement.

Attorneys for both sides were to present the deal Friday morning to U.S. District Judge Eldon E. Fallon in New Orleans.

“In light of significant costs and delay that would result in protracted litigation, the settlement program will ensure that those who suffered injuries as a result of Vioxx are compensated fairly and efficiently,” according to a statement from one of the lead plaintiffs law firms in the case, Beasley, Allen, Crow, Methvin, Portis & Miles of Montgomery, Ala.

Merck agrees to pay $4.85 bln in Vioxx settlement

Merck & Co has agreed to pay $4.85 billion to settle claims that its painkiller Vioxx caused heart attacks and strokes in thousands of users, the drugmaker said on Friday.

The agreement covers lawsuits filed against the company in U.S. courts, resolving a major legal battle that has dogged the drugmaker since it pulled Vioxx off the market three years ago.

Merck recalled the popular painkiller, which had $2.5 billion in annual sales, in September 2004 after a study showed it doubled the risk of heart attack and stroke in patients taking it for more than 18 months.

In the settlement, reached with representatives of plaintiffs in federal and state courts, Merck did not admit Vioxx caused patient injury and did not admit fault.

The drugmaker, whose shares rose nearly 2 percent in pre-market trade on news of the deal, said it would take a charge of $4.85 billion to cover costs of the agreement.

The settlement marks a shift in strategy for Merck, which previously said it intended to fight Vioxx litigation on a case-by-base basis rather than consider a broad settlement.

“The agreement is structured to provide a significant degree of certainty toward resolving the majority of the outstanding Vioxx product-liability claims in the United States for a fixed amount,” said Richard Clark, chairman, president and chief executive officer of Merck.

The drugmaker said it would still defend all claims not included in the settlement. Since the withdrawal of Vioxx, Merck has won 11 court cases over the drug and lost five.

While it is appealing those cases that it lost, analysts said the settlement will solidify Merck’s future.

“They’re trying to reduce the uncertainty surrounding the costs related to Vioxx,” said Damien Conover, an analyst at Morningstar. “While it will probably bring a little more clarity, I think there are still going to be a lot of cases that won’t settle within this agreement.”

Conover said the cases included in the settlement are likely the weakest cases.

“What you’re going to be left with is a significant number of plaintiffs who will want to address Merck on an individual basis, which means they will likely seek higher compensation,” he said.

Conover said that while it is difficult to gauge how many people will try to fight Merck alone, he estimates the company could be facing 1,000 to 2,000 outstanding claims and could face more than $1 billion in additional costs.

Mike Ward of Nomura Securities in London said a settlement value of less than $5 billion likely would be taken positively by the market, noting that litigation over Wyeth’s Phen-Fen diet drug was only now coming slowly to a close after 10 years in the courts and over $21 billion in settlement costs.

Merck shares tumbled on news of the withdrawal of Vioxx in 2004, losing more than a third of their market value. But with Merck’s Vioxx victories in court, and a string of successful new medicines, the shares have recouped those losses.

The stock, even with the major litigation drag, has outperformed its peers on the American Stock Exchange pharmaceutical index this year, rising 25 percent, compared with little change in the index.

Merck shares rose to $55.70 in pre-market trade from a Thursday close at $54.77 on the New York Stock Exchange. The stock is trading just below a four-year high of $58.36, reached earlier this month.

!Vioxx was withdrawn from the U.S. market in 2004!

The manufacturer of Vioxx has announced a voluntary withdrawal of the drug from the U.S. and worldwide market. This withdrawal is due to safety concerns of an increased risk of cardiovascular events (including heart attack and stroke) in patients taking Vioxx.

Notify your doctor immediately if you develop abdominal pain, tenderness, or discomfort; nausea; blood in your vomit; bloody, black, or tarry stools; unexplained weight gain; swelling or water retention; fatigue or lethargy; a skin rash; itching; yellowing of your skin or eyes;”flu-like” symptoms; or unusual bruising or bleeding. These symptoms could be early signs of dangerous side effects.

What is Vioxx?

!Vioxx was withdrawn from the U.S. market in 2004!

Vioxx is in a class of drugs called nonsteroidal anti-inflammatory drugs (NSAIDs). Vioxx works by reducing substances that cause inflammation, pain, and fever in the body.

Vioxx is used to reduce pain, inflammation, and stiffness caused by osteoarthritis, rheumatoid arthritis and certain forms of juvenile rheumatoid arthritis; to manage acute pain in adults; to treat migraines; and to treat menstrual pain.

Merck announced that the extended-release niacin/laropiprant (cordaptive) co administered with simvastatin had significant additive effects on reducing LDL-cholesterol (LDL-C), increasing HDL-cholesterol (HDL-C) and reducing triglyceride levels in a phase III study with patients with primary hypercholesterolemia or mixed dyslipidemia. The results were presented by Merck & Co, Inc. at the American Heart Association 2007 Scientific Sessions in Orlando, Fla.

In the study, 2 g (two 1-gram tablets) of Cordaptive co administered with simvastatin (pooled across 20 mg or 40 mg doses) reduced LDL-C by 48 per cent, increased HDL-C by 28 per cent, and reduced triglyceride levels by 33 per cent following 12 weeks of treatment. The primary study endpoint was LDL-C reduction; secondary endpoints included increased HDL-C, triglyceride reduction and effects on other lipoproteins. A 1 g tablet of cordaptive contains 1 g of Merck-developed extended-release niacin and 20 mg of laropiprant - a novel flushing pathway inhibitor that is designed to reduce the flushing associated with niacin. All of the comparative lipid efficacy results were measured as mean per cent change from baseline and were statistically significant, p < 0.001.

“The results in this study suggest that, if approved, cordaptive used with a statin could offer another approach to treat patients with dyslipidemia,” said Christie M. Ballantyne, associate chief and professor of medicine, Baylor College of Medicine, and co-author of the study.

The double-blind, parallel, 12-week study with seven treatment arms in almost 1400 patients evaluated 1 g of cordaptive (1 g extended-release niacin/20 mg laropiprant) coadministered with simvastatin 10 mg to 40 mg in weeks one through four and 2 g of cordaptive (two 1-gram tablets each containing 1 g extended-release niacin/20 mg of laropiprant) co administered with simvastatin 20 mg to 40 mg in weeks five through 12 (n = 590). Tolerability and the safety profile of Cordaptive co administered with simvastatin were also evaluated.

Reported lipid results in other treatment arms included a 17 per cent decrease in LDL-C, 23 per cent increase in HDL-C, and 22 per cent decrease in triglycerides with Cordaptive alone (n = 192); and a 37 per cent reduction in LDL-C, six per cent increase in HDL-C and 15 per cent reduction in triglycerides with simvastatin alone (pooled) (n = 585).

Reported side effects of interest included: liver enzyme elevations >3x ULN in ALT and/or AST (0.3 per cent with cordaptive co administered with simvastatin, 0.5 per cent with Cordaptive alone, and 1.0 per cent with simvastatin alone), and increased median fasting plasma glucose values (4.0 mg/dL with Cordaptive plus simvastatin, 4.0 mg/dL with Cordaptive alone, and 1.0 mg/dL with simvastatin alone). There were no cases of creatine kinase (CK) levels >10x ULN in the group treated with Cordaptive coadministered with simvastatin, which was not significantly different than that of the group treated with Cordaptive or simvastatin alone (0.5 per cent and 0.3 per cent, respectively). All elevations were asymptomatic and resolved with discontinuation of treatment. There were no cases of myopathy, rhabdomyolysis or drug-related hepatitis.

Discontinuations due to flushing were 4.8 per cent in the group treated with cordaptive co administered with simvastatin, 8.7 per cent with Cordaptive alone and 0.3 per cent with simvastatin alone.

Niacin-induced flushing is primarily caused by a prostaglandin, PGD2, a chemical that causes vasodilatation in the skin and flushing symptoms, acting through the DP1 flushing pathway. Laropiprant selectively blocks the binding of PGD2 to its receptor, DP1. Research has shown blocking DP1 reduces flushing associated with niacin.

“It has been shown that niacin-based therapies reduce the risk of cardiovascular events. But even though niacin has broad lipid effects, the flushing side effect has been a barrier to many patients reaching the maximum 2 g dose,” said John Paolini, MD, Clinical Research, Cardiovascular Disease, Merck Research Laboratories.

Cordaptive is in development by Merck for the treatment of elevated LDL-C, low HDL-C and elevated triglycerides. Merck has previously announced that the NDA for cordaptive has been accepted by the US FDA and the regulatory action is anticipated in the second quarter of 2008. Merck is also on track to file an NDA in 2008 for the company’s investigational compound MK 0524B.

Dyslipidemia is the elevation of LDL-C and/or triglycerides or a low HDL-C level that contributes to the development of atherosclerosis, the number one cause of death among men and women and the primary reason for loss of quality of life in Western countries. Major modifiable risk factors for atherosclerotic disease include hypertension, diabetes, obesity, smoking and high levels of total cholesterol or LDL-C. Low levels of HDL-C also increase a person’s chances of developing atherosclerosis. In fact, epidemiologic studies have shown that for every 1 mg/dL rise in HDL-C, the risk of developing cardiovascular disease decreases by two per cent to three per cent.

Simvastatin, a cholesterol-modifying medicine from Merck, and marketed under the brand name Zocor, is used in addition to diet to modify cholesterol levels after diet and other non-drug measures have failed to achieve target levels.

Researchers have said that patients were able to safely use Merck & Co.’s experimental Cordaptive drug to raise good HDL cholesterol alongside the company’s older Zocor cholesterol medicine.

Results of the Phase III trial involved about 1,400 patients and lasted 12 weeks. Cordaptive is a combination of an extended release form of niacin, a nutrient that raises heart-protective HDL, and an experimental drug called laropiprant that reduces the uncomfortable facial flushing which is a side effect of niacin.

Merck aims to seek approval next year for a separate product called MK-524B. It would combine Cordaptive in the same tablet with simvastatin, the active ingredient of Zocor which works by cutting the body’s production of LDL.

In the trial, levels of LDL fell 48 percent among patients receiving simvastatin as well as Cordaptive containing the full recommended two gram dose of niacin. That effectiveness against LDL, the primary goal of the trial, was deemed highly statistically significant.

Patients taking Cordaptive by itself in the trial experienced favorable, but less-impressive results: a 17 percent decrease in LDL, a 23 percent boost in HDL and a 22 percent drop in triglycerides.

Cordaptive is now awaiting U.S. marketing approval.