Drugs Log

Merck, the manufacturer of the quadrivalent HPV vaccine Gardasil, already being administered in many countries to girls as young as 12 to help prevent cervical cancer, has announced findings of a trial that shows it is also effective for women as old as 45.

The drugmaker announced details of an investigational study where Gardasil reduced the rate of infection due to four strains of sexually transmitted human papillomavirus (HPV) in women up to the age of 45, at the 24th International Papillomavirus Conference (IPC) in Beijing, China, yesterday, Sunday November 4th.

Gardasil is a quadrivalent, recombinant vaccine designed to reduce infection due to HPV strains 6, 11, 16 and 18 and trials have already shown it be to effective for girls and women aged 9 to 26 years in the prevention of cervical cancer, precancerous or dysplastic lesions, and genital warts. In trials it was shown that by protecting against the four HPV strains that cause most of the diseases, it prevented 70 per cent of cervical cancer cases and 90 per cent of genital warts cases.

In the latest international, multi-center, trial involving more than 3,800 women, the three dose vaccine was also shown to prevent 91 per cent of persistent infection, low-grade cervical abnormalities and pre-cancers, as well as external genital lesions caused by the four strains of HPV in women aged 24 to 45.

The women in the trial had no history of genital warts; hysterectomy; LEEP (loop electrosurgical excision procedure) or biopsy-diagnosed cervical HPV disease in the five years previous to enrollment. They were also all free of infection from at least one of the four HPV strains when they were enrolled in the study and remained free of infection from the same strains when they finished the three doses of vaccine or placebo.

Dr Eliav Barr, executive director of Biologics Clinical Research and head of the HPV Vaccine Program, Merck Research Laboratories said in a press statement that:

“Women remain at significant risk for acquiring HPV infections and developing HPV-related diseases throughout their lifetime.”

“These data build on the clinical program for GARDASIL and will help us to understand the potential benefit that GARDASIL may have in women through age 45,” added Barr.

The drugmaker will be submitting the results of the trial with an application to the US Food and Drug Administration (FDA) before the end of the year to extend approved indication of the vaccine for women up to 45. The FDA approved Gardasil in June 2006 and the vaccine is recommended for use in the US for girls and women aged 11 to 26 by the Centers for Disease Control and Prevention (CDC).

Researchers tracked the incidence of persistent infection, cervical intraepithelial neoplasia (CIN) and external genital lesions caused by the four HPV strains (6, 11, 16 and 18) and diseases caused by HPV 16 and 18.

The results showed that:

• There were 4 cases of of persistent infection, CIN or external genital lesions (genital warts and vaginal and vulvar lesions) caused by HPV 6, 11, 16 or 18 in the vaccine group compared to 41 cases in the placebo group.
• This equated to a 91 percent reduction in incidence (at 95 per cent confidence interval, or CI) over an average follow up of 1.65 years.
• There were 4 cases of of persistent infection, low-grade cervical abnormalities and pre-cancers, and external genital lesions caused by HPV types 16 and 18 alone, in the vaccine group, and 23 cases in the placebo group.
• This equated to a 83 per cent prevention rate (at 95 per cent CI) for diseases caused by HPV types 16 and 18 alone.
• The vaccine prevented 100 per cent of persistent infections, external genital lesions, and low-grade cervical abnormalities and pre-cancers, caused by HPV strains 6 and 11.
• It also reduced abnormal Pap test results related to HPV 16 and 18 by 94 percent (at 95 per cent CI).
• The most common adverse events related to the injection site (redness, pain, pruritis, swelling, warmth) and were higher in the vaccine than the placebo group (76.4 versus 64.2 per cent).

Gardasil is widely available in the US, and all the country’s 55 immunization programs have adopted it. In addition to the US, the vaccine is approved in 85 countries throughout the world, including all of the European Union, Australia, Brazil, Canada, Mexico, New Zealand and Taiwan.

HPV is a common infection, and it is estimated that some 20 million people in the US have it and that 80 per cent of women will have acquired it by the age of 50. In most people HPV is self-limiting and disappears by itself. But for some women, the higher risk HPV strains can lead to cervical cancer if untreated.

Nearly half a million cases of cervical cancer are diagnosed worldwide every year, and 240,000 women die from it each year. It is the second most common cause of cancer death in women worldwide.

In June 2006, the Advisory Committee on Immunization Practices (ACIP) voted to recommend the first vaccine developed to prevent cervical cancer and other diseases in females caused by certain types of genital human papillomavirus (HPV). The vaccine, Gardasil®, protects against four HPV types, which together cause 70% of cervical cancers and 90% of genital warts.

The Food and Drug Administration (FDA) licensed this vaccine for use in girls/women, ages 9-26 years. The vaccine is given through a series of three shots over a six-month period.

Some general information about genital HPV & Cervical Cancer

Genital HPV is a common virus that is passed on through genital contact, most often during vaginal and anal sex. About 40 types of HPV can infect the genital areas of men and women. While most HPV types cause no symptoms and go away on their own, some types can cause cervical cancer in women. These types also have been linked to other less common genital cancers— including cancers of the anus, vagina, and vulva (area around the opening of the vagina). Other types of HPV can cause warts in the genital areas of men and women, called genital warts.

How is HPV related to cervical cancer?
Some types of HPV can infect a woman’s cervix (lower part of the womb) and cause the cells to change. Most of the time, HPV goes away on its own. When HPV is gone, the cervix cells go back to normal. But sometimes, HPV does not go away. Instead, it lingers (persists) and continues to change the cells on a woman’s cervix. These cell changes (or “precancers”) can lead to cancer over time, if they are not treated.

How common is HPV?
At least 50% of sexually active people will get HPV at some time in their lives. Every year in the United States (U.S.), about 6.2 million people get HPV. HPV is most common in young women and men who are in their late teens and early 20s.

Anyone who has ever had genital contact with another person can get HPV. Both men and women can get it – and pass it on to their sex partners- without even realizing it.

How common is cervical cancer in the U.S.? How many women die from it?
The American Cancer Society estimates that in 2006, over 9,700 women will be diagnosed with cervical cancer and 3,700 women will die from this cancer in the U.S.

How common are Genital Warts?
About 1% of sexually active adults in the U.S. (about 1 million people) have visible genital warts at any point in time.

Is HPV the same thing as HIV or Herpes?
HPV is NOT the same as HIV or Herpes (Herpes simplex virus or HSV). While these are all viruses that can be sexually transmitted— HIV and HSV do not cause the same symptoms or health problems as HPV.

Can HPV and its associated diseases be treated?
There is no treatment for HPV. But there are treatments for the health problems that HPV can cause, such as genital warts, cervical cell changes, and cancers of the cervix, vulva, vagina and anus.

Other ways to prevent HPV and Cervical Cancer

Another HPV vaccine is in the final stages of clinical testing, but it is not yet licensed. This vaccine would protect against the two types of HPV that cause most (70%) cervical cancers.

Are there other ways to prevent cervical cancer?
Regular Pap tests and follow-up can prevent most, but not all, cases of cervical cancer. Pap tests can detect cell changes in the cervix before they turn into cancer. Pap tests can also detect most, but not all, cervical cancers at an early, curable stage. Most women diagnosed with cervical cancer in the U.S. have either never had a Pap test, or have not had a Pap test in the last 5 years.

There is also an HPV DNA test available for use with the Pap test, as part of cervical cancer screening. This test is used for women over 30 or for women who get an unclear (borderline) Pap test result. While this test can tell if a woman has HPV on her cervix, it cannot tell which types of HPV she has.

Are there other ways to prevent HPV?
The only sure way to prevent HPV is to abstain from all sexual activity. Sexually active adults can reduce their risk by being in a mutually faithful relationship with someone who has had no other or few sex partners, or by limiting their number of sex partners. But even persons with only one lifetime sex partner can get HPV, if their partner has had previous partners.

It is not known how much protection condoms provide against HPV, since areas that are not covered by a condom can be exposed to the virus. However, condoms may reduce the risk of genital warts and cervical cancer. They can also reduce the risk of HIV and some other STIs, when used all the time and the right way.

A new blood thinner proved better than Plavix, one of the world’s top-selling drugs, at preventing heart problems after procedures to open clogged arteries, doctors reported Sunday. But the new drug also raised the risk of serious bleeding.

People given the experimental drug, prasugrel, were nearly 20 percent less likely to suffer one of the problems in a combined measure — heart attack, stroke or heart-related death — than those given Plavix, a drug that millions of Americans take to prevent blood clots that cause these events.

However, for each heart-related death that prasugrel (PRASS-uh-grell) prevented, compared to Plavix, almost one additional bleeding death occurred.

“There is a price to pay” for greater effectiveness, Dr. Deepak Bhatt, a Cleveland Clinic cardiologist, wrote in an editorial accompanying the results, which were published online by The New England Journal of Medicine and presented at an American Heart Association conference in Florida.

Still, many doctors said that on balance, the new drug comes out ahead, and offers great promise as a more potent alternative to Plavix, which costs $4 a day and does not work for many patients.

“I’m encouraged by the results” and think prasugrel should win Food and Drug Administration approval because it so dramatically cuts non-fatal heart attacks, said the Cleveland Clinic’s Dr. Steven Nissen, a frequent government adviser.

Doctors can sort out who might most benefit from it, such as diabetics, and who might face too much bleeding risk to use it, like the elderly, people who previously had strokes and those with kidney problems, he said. (The Cleveland doctors give to charity or the clinic the consulting and research fees they earn from drugmakers.)

Doctors also were waiting for prasugrel’s makers to clarify why they stopped two small studies of it a week ago. They said it was due to dosing problems but did not explain.

Prasugrel is being developed by Indianapolis-based Eli Lilly and Co. and a Japanese firm, Daiichi Sankyo Co. It could be a hugely important drug, and the study has been one of the most-watched tests of a novel heart medication in recent years.

Like Plavix, prasugrel prevents blood components called platelets from sticking together and forming a clot. Anti-platelet drugs are advised for most people with stents — tiny mesh tubes that keep arteries open after balloon angioplasty, an artery-clearing procedure that more than a million Americans have each year.

Plavix, sold by Sanofi-Aventis SA and Bristol-Myers Squibb Co., has been the most effective drug of this type. More than 70 million people have taken it since it went on sale a decade ago.

Plavix had 18.6 million prescriptions and nearly $3 billion in U.S. sales last year, according to IMS Health, a healthcare information firm. Worldwide sales were nearly $6 billion.

The study comparing it to prasugrel involved 13,608 patients from 30 countries and was led by Dr. Elliott Antman at Harvard Medical School and Brigham and Women’s Hospital in Boston. Prasugrel’s makers paid for the study; many of the researchers work or consult for them.

Study participants were having angioplasty due to heart attacks or blockages causing sudden or worsening chest pain, and were randomly assigned to one drug or the other for six to 15 months.

The results: about 12 percent of people taking Plavix but only 10 percent on prasugrel suffered heart attacks, strokes or heart-related deaths — a 20 percent reduction in risk. Only 1.1 percent on the new drug developed blood clots in stents versus 2.4 percent on Plavix — a 52 percent lower risk. Prasugrel also worked faster than Plavix and showed more effectiveness at the first checkpoint — three days.

However, major bleeding occurred in 2.4 percent of those on prasugrel versus 1.8 percent of those on Plavix. This included brain or gastrointestinal bleeding, or after falls. Fatal bleeding was uncommon, but four times more frequent with the new drug.

Results hinted that some people might be in greater danger — those who had a previous stroke, were elderly, or weighed less than 132 pounds.

These signs are why prasugrel’s makers suspended two small studies a week ago to see whether such patients should be included in the study or should get a lower dose, said Dr. Anthony Ware of Eli Lilly.

“It was a precaution … because of a risk of a safety problem rather than an actual one,” he said.

Lilly will conduct another big study of prasugrel in people not having angioplasty but on medications because they are at risk of having a heart attack, Ware said.

That 10,000-person study will be led by Dr. E. Magnus Ohman at Duke University Medical Center.

In the study reported on Sunday, “the benefit clearly outweighs the risk” for most patients, Ohman said.

Bhatt of Cleveland Clinic noted that even aspirin — which is widely recommended to prevent clots and was prescribed to all patients in this study — carries a risk of bleeding.

Dr. Spencer King, a heart specialist at Piedmont Hospital in Atlanta and spokesman for the American College of Cardiology, was on the safety monitoring committee for the study. He said prasugrel would be “a little bit of a tough sell” to doctors who are comfortable with using Plavix, but that competition could give patients drugs more closely matched to their needs.

“We’ve had one size fits all … now we’ll have two choices,” King said.

Dr. Harlan Krumholz, a Yale University cardiologist with no role in the study, noted that “in absolute numbers, for every 1,000 people you treat, you’d save a lot more heart events than you’d cause bleeds,” because heart problems are more common.

Cost also keeps many people from taking Plavix now. Prasugrel’s makers have not said what it would cost, but “if they start competing on price, it could be a boon for the health care system,” Krumholz said.

Lilly’s Prasugrel Reduces Heart Risks But Has Higher Bleeding Rate

An experimental Eli Lilly & Co. blooding-thinning drug, prasugrel, was effective at reducing the number heart attacks, strokes and cardiovascular deaths, but carries a risk of serious bleeding, according to a new study released Sunday.

The study compared prasugrel and a similar anti-clotting drug, Plavix, by Bristol-Myers Squibb Co. and Sanofi-Aventis SA in 13,608 patients set to undergo a procedure to open blocked coronary arteries. Most patients then received a stent to keep the arteries open.

Overall, the study showed prasugrel was better than Plavix at reducing the number of heart attacks, strokes and cardiovascular deaths, but prasugrel had a higher rate of bleeding including fatal bleeding.

One of the study’s researchers, Elliott Antman, the director of the Brigham and Women’s Hospital’s cardiac unit, said patients on Prasugrel were 19% less likely to have a stroke, heart attack or death from a cardiovascular cause compared with patients on Plavix, but were 32% more likely to suffer a serious bleeding event. Patients on prasugrel were 24% less likely to suffer a heart attack compared with those on Plavix, Dr. Antman said.

Both drugs are designed to keep blood platelets from sticking together to form dangerous blood clots that can cause heart attacks and strokes. But they also carry a risk of bleeding if the drugs go too far at inhibiting platelets. Aspirin is also an anti-clotting agent and is commonly prescribed with Plavix.

The study, known as Triton, was presented Sunday at the American Heart Association’s annual meeting in Orlando and is also being published online in the New England Journal of Medicine.

Researchers, led by Harvard Medical School and Brigham and Women’s Hospital in Boston, said the net clinical benefit, which takes into account the benefits and risks of a drug, favors prasugrel. Dr. Antman said that for every 1,000 patients treated with prasugrel compared with Plavix, prasugrel would prevent an additional 23 heart attacks, but would likely cause six additional cases of serious bleeding.

Lilly, which is developing prasugrel with Daiichi Sankyo Co. of Japan, said Oct. 24 it halted two smaller studies of prasugrel amid concerns about the dosage used in certain patient groups, rattling investors and in turn, putting an even greater focus on the Triton data. Both Lilly and Daiichi funded the study.

Specifically, the Triton study showed that 12.1% of patients on Plavix had a heart attack, stroke or death from a cardiovascular cause during the study, compared with 9.9% of patients receiving prasugrel, which translates into an overall difference of 19%. Patients in the study were either given a one-time “loading” dose of prasugrel at 60 milligrams and maintenance doses of 10 milligrams, or a 300 milligram loading dose of Plavix followed by 75 milligram maintenance doses. Patients were treated for six to 15 months.

The rate of major bleeding among patients receiving prasugrel was 2.4% compared with 1.8% receiving Plavix. The study showed the rate of life-threatening bleeding was 1.4% for patients on prasugrel and 0.9% for patients on Plavix. That included fatal bleeding, which occurred among 0.4% of patients receiving prasugrel and 0.1% of patients on Plavix, along with non-fatal bleeding, which was 1.1% in the prasugrel group and 0.9% in the Plavix group.

Lilly has said it plans to submit an application for Food and Drug Administration approval of prasugrel by the end of this year.

“We are very pleased with the trial’s outcome and are excited by the potential for these results to help us further tailor prasugrel therapy to assure the greatest benefit from this novel treatment,” said J. Anthony Ware, Lilly’s cardiovascular platform leader for prasugrel.

Researchers said there were “significant reductions” in stent thrombosis and repeat procedures to reopen clogged arteries among patients on prasugrel compared with those on Plavix. The stent thrombosis rate, or blood clots attributed to the stent, was 1.1% for those receiving prasugrel and 2.4% for the Plavix patients, or a 52% reduction in the stent thrombosis rate for patients on Plavix. Urgent target vessel revascularization among prasugrel patients was 2.5% compared with 3.7% for those on Plavix, a 34% reduction.

In an accompanying editorial in the New England Journal of Medicine, Dr. Deepak Bhatt of The Cleveland Clinic, said for each additional cardiovascular death prevented by the use of prasugrel compared with Plavix, “approximately one additional episode of fatal bleeding was caused by prasugrel.” He wrote that prasugrel would probably benefit patients who are at high risk of additional heart problems such as a heart attack and at low risk of bleeding, while patients with a high risk of bleeding and at lower risk for heart attacks or strokes “may be better served by” Plavix.

Indeed, researchers wrote that an analysis of subgroups of patients in the study suggested those with a history of smoking, stroke, those age 75 and older as well as those who weighed less than 60 kilograms (132 pounds) had “less clinical efficacy and greater absolute levels of bleeding than the overall cohort.”

Dr. Antman said most of the excess bleeding and fatal bleeding occurred in patients who’ve suffered a previous stroke and said if approved, the drug shouldn’t be used in that group.

Plavix, which generated almost $6 billion in global sales last year, is among the world’s top-selling drugs. Lilly is hoping prasugrel, which some researchers said might work more consistently than Plavix, could take market share away from Plavix if it’s approved later next year.

In a statement, Bristol-Myers said “with the wealth of safety and efficacy data on Plavix, this drug is well understood by phsyicians in a real-world setting. The bleeding rate observed with prasugrel in Triton raises important questions.”

Lilly’s best selling drug Zyprexa loses U.S. patent protection in 2011 and prasugrel is widely viewed as the company’s most promising drug in its pipeline. Zyprexa treats schizophrenia and bipolar disorder.

Other companies also are developing anti-clotting drugs, including AstraZeneca PLC and Schering-Plough Corp. along with Bayer AG and Johnson & Johnson, which are jointly working on a product.

Bayer HealthCare AG announced today the submission of a Marketing Authorization Application to the European Agency for the Evaluation of Medicinal Products (EMEA) for approval to market rivaroxaban (Xarelto®) for the prevention of venous thromboembolism (VTE) after major orthopedic surgery of the lower limbs. Rivaroxaban is an investigational, oral, once-daily direct Factor Xa inhibitor. Data from one of the pivotal studies (RECORD3) was presented prior to the EMEA submission and revealed that rivaroxaban significantly reduces the risk of VTE in patients undergoing total knee replacement surgery compared with enoxaparin, the current standard of care therapy. Rivaroxaban is being jointly developed by Bayer HealthCare and Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

“The submission of the data for VTE prevention to the EMEA is an important milestone in the development of this new treatment for the prevention of life-threatening blood clots,” said Dr. Kemal Malik, Head of Global Development and member of the Bayer HealthCare Executive Committee. “As an effective and convenient, once-daily oral treatment with a reassuring safety profile, we feel confident that rivaroxaban has the potential to set a new standard of care in the preventative treatment of thrombosis in patients undergoing major orthopedic surgery.”

VTE is a type of thromboembolic disease that is caused by the obstruction of a blood vessel by a blood clot. In the EU it is estimated that there are 543,000 deaths due to VTE each year. People undergoing major surgery, in particular total knee or hip replacement, are prone to developing VTE due to a combination of factors such as prolonged bed rest, damage to blood vessels and an increased tendency of the blood to clot. It is estimated that up to 50% of patients undergoing lower limb surgery develop VTE if they do not receive preventative care.

The Marketing Authorization Application is based on data from three Phase III studies of rivaroxaban involving nearly 10,000 patients in total, and an extensive Phase I and Phase II program. One of the Phase III studies was in patients undergoing total knee replacement surgery, the results of which were presented at the International Society on Thrombosis and Hemostasis (ISTH) in July 2007 (RECORD3). The results of the other two studies in patients undergoing hip replacement surgery (RECORD1 and RECORD2) will be presented at the upcoming 49th Annual Meeting of the American Society of Hematology (ASH) meeting, 8–11 December 2007.

About RECORD3
The results of this study in 2,531 patients undergoing knee replacement surgery revealed that once-daily oral rivaroxaban 10 mg was superior in preventing VTE to once-daily subcutaneous enoxaparin 40 mg, the current standard of care therapy. Specifically, patients in this RECORD3 study (REgulation of Coagulation in major Orthopedic surgery reducing the Risk of DVT and PE) who were treated with rivaroxaban demonstrated a 49% relative risk reduction (p<0.001) in the composite primary endpoint of deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE) and all-cause mortality compared to those treated with enoxaparin. Patients treated with rivaroxaban also had a 62% reduced risk (p=0.01) of developing major VTE (the composite of proximal DVT, non-fatal PE and VTE-related death), the main secondary endpoint of the trial. Importantly, there was a similar low rate of major bleeding for patients being treated with rivaroxaban and enoxaparin (0.6% and 0.5%, respectively).

About Rivaroxaban (Xarelto®)
To date, rivaroxaban is the most studied oral direct Factor Xa inhibitor in development. More than 20,000 patients have been evaluated in the completed Phase II programs and enrolled thus far in the Phase III programs. More than 40,000 patients are expected to be evaluated in total.

Upon regulatory approval, rivaroxaban will be commercialized in Europe by Bayer Schering Pharma. A filing for rivaroxaban for a similar indication in the United States is planned in 2008, where if approved, it will be will commercialized by Scios Inc. and Ortho-McNeil, Inc., both of which are Johnson & Johnson companies.

The trade name of rivaroxaban is expected to be Xarelto®, pending health authority approval.

CLINICAL PHARMACOLOGY: Rivaroxaban directly inhibits factor Xa therefore prolonging clotting times and reducing the formation of thrombin, an essential component to the development of thrombus formation. The L-shaped structure of rivaroxaban allows it to be highly selective for factor Xa.1, 3 This high selectivity allows the drug to inhibit free factor Xa, prothrombinase activity, and clot-associated factor Xa, giving it the ability to not only prevent clots from forming, but to also possibly break down clots already present. This drug does not have significant direct effects on thrombin or antithrombin activity.1, 3, 8 The mechanism of action of rivaroxaban is beneficial in the prevention and treatment of thromboembolic diseases.

PHARMACOKINETICS:

Absorption:

Peak plasma concentrations are reached 2 to 4 hours after oral administration, and the bioavailability of rivaroxaban ranges from 60-80%. The presence of food increased maximum concentration, time to maximum concentration, and AUC. Prothrombin time was also affected depending on if a patient was in a fed or fasting state. Maximum PT was increased by 53% (10mg) and 83% (20mg) if patients were fed compared to 44% (10mg) and 53% (20mg) in the fasting state. Maximum inhibition of factor Xa occurred within 1 to 4 hours after administration and ranged from 20-61% for the 5-80mg doses.

Distribution:

After multiple doses of rivaroxaban, dose-proportional increases in AUC were observed. It was also noted that once the drug reached steady state, there were no significant accumulations of the drug.1 It appears that body weight influences the volume of distribution, but this change has not been found to be significant.

A study by Kubitza et al. looked at the effects of extreme body weights (>= 120 kg and <= 50 kg) and gender on the PK and PD of rivaroxaban 10mg. Results showed no effects on Cmax in subjects >= 120 kg and up to a 24% increase in Cmax in subjects <= 50 kg. This increase in Cmax caused a slight increase in prothrombin time, but the investigators concluded that this was not clinically significant. No significant differences were seen between males and females as well. These results suggest that dose adjustments are not needed in patients with extreme body weights or between the different genders.

Metabolism:

It is unknown whether rivaroxaban is metabolized hepatically or renally. Other direct factor Xa inhibitors are metabolized by the liver, so there is a high probability that rivaroxaban is also metabolized through this route.

Elimination:

Rivaroxaban goes through both renal (66%) and biliary (28%) excretion, and 36% is excreted as unchanged drug in the urine. In young, healthy subjects, rivaroxaban has a half-life of around 9 hrs, but this number increases in elderly subjects (12 hrs) and patients with renal impairment. It has not been determined if dose-adjustments are needed in the elderly or renal impairment because of this increased half-life. In Phase III trials, patients with renal impairment received reduced doses of rivaroxaban. Most trials have excluded patients with creatinine clearances below 30 ml/min, but it has not been officially determined if this level of renal impairment required dosage adjustments.

PK parameters correlated closely with the inhibition of factor Xa activity and PT prolongation.

Because of its predictable pharmacokinetics, this drug does not require the routine monitoring like warfarin does.

DRUG INTERACTIONS: No significant drug interactions have been found with rivaroxaban, including with aspirin, NSAIDs, antacids, H2 antagonists and digoxin.

The interaction between rivaroxaban and aspirin was studied in a phase I trial to determine if aspirin influenced the effectiveness and safety of rivaroxaban. This combination was well tolerated in the healthy, male subjects studied. Aspirin did not affect the inhibition of factor Xa activity or prolongation of PT/aPTT by rivaroxaban. In addition, rivaroxaban did not interfere with the inhibitory effects of aspirin on platelet aggregation.

A phase II study in 2007 looked at the effects of the combination of naproxen and rivaroxaban on safety, tolerability, PK and PD. Patients were given naproxen alone, rivaroxaban alone, or a combination of the two drugs. This study showed no mechanistic interaction between rivaroxaban and naproxen, and the addition of naproxen did not effect the prothrombin time, pTT or platelet aggregation. There was a significant increase in bleeding seen with the combination group, however, this increase was less than that seen with naproxen alone. Further phase III studies are being conducted to confirm the safety of this combination.

DOSING: There have been several studies that have looked at various dosing ranges of rivaroxaban, from 2.5mg to 40mg, given either twice-daily or once-daily. Most strengths of rivaroxaban have proven to be effective, and no dose-efficacy response has been established. However, twice daily dosing has resulted in significantly more bleeding than once-daily dosing suggesting that dose frequency might influence bleeding risk independently of dose intensity.

Rivaroxaban 20mg once-daily is the strength that is being used in Phase III trials looking at treatment of VTE and prevention of stroke in A. fib. During the RECORD3 study, a phase III trial, it was determined that 10mg of rivaroxaban given once daily was the most effective and safest dose at preventing VTE after orthopedic surgery. This strength is currently being evaluated further in this population.

CONCLUSION: There is a need for a new anticoagulant that is just as effective as warfarin, but without the rigorous monitoring schedule. Once-daily dosing of rivaroxaban has been shown to produce 24 hours of inhibition of factor Xa and thrombin generation, allowing for convenient dosing. Rivaroxaban offers once-daily dosing, and there may be the potential for no monitoring with this drug. Unlike warfarin that has several different strengths and may need to be taken differently each day, rivaroxaban will be much easier to manage and may increase patient compliance as well.

Related drugs

Ximelagatran, a direct thrombin inhibitor, was not marketed further due to its potential side-effects; the related compound dabigatran is undergoing studies. Together with rivaroxaban, the related factor Xa-inhibitor apixaban (Bristol-Myers-Squibb) andLY517717 (Lilly) are under development as non-monitored antithrombotic drugs.

Two-thirds of the foreign drug manufacturers subject to inspection by the Food and Drug Administration may never have been visited by agency inspectors, a government watchdog reported to Congress Thursday.

The FDA this year listed 3,249 foreign pharmaceutical manufacturers subject to its inspection — yet the agency cannot determine whether it has ever inspected 2,133 of them, according to a Government Accountability Office report released during a House subcommittee hearing.

While some of the more than 3,000 firms may never have exported prescription drugs or drug ingredients to the United States, others likely have.

Who are those firms and what are they shipping? asked Rep. Bart Stupak, D-Mich., during Thursday’s hearing of the House Energy and Commerce subcommittee on oversight and investigations.

“We don’t know and we are not certain the FDA knows,” Marcia Crosse, director of health care at the GAO, replied.

The few foreign inspections the FDA does conduct in any given year hit just 7 percent of the foreign drug makers exporting to the U.S., the GAO estimates. That means more than 13 years can pass before a foreign manufacturer is visited even once, Crosse said.

In the case of China, which with 714 drug firms boasts the largest number subject to FDA scrutiny of any country, the record is far worse. The FDA is slated to inspect just 13 Chinese establishments this year, meaning just 1.8 percent will see an FDA inspector, according to the GAO report.

In India, the No. 2 country, the record is far better. There, 65 of its 410 firms, or 15.8 percent, are slated for inspection this year, according to the GAO. That’s in line with the 16.8 percent of Swiss drug firms the FDA likely will inspect in 2007.

The GAO and Congress have long warned of the FDA’s shortcomings in its foreign drug inspection program. The GAO findings released Thursday largely reprise many of the same warnings outlined in a 1998 report.

“It’s deja vu all over again,” said Rep. John Dingell, D-Mich.

Nearly all U.S. drug makers are inspected at least once every two years, as mandated by a law drawn up long before imports seized a sizable chunk of the drug market. There is no such requirement that the FDA conduct foreign inspections with any regularity, even as imports of all kinds grow in volume. Concerns about the safety of imported drugs, food, toys and other consumer products have been at the fore for months.

“We’re finding ourselves again on the brink of one more problem dealing with imports into our country,” said Rep. Michael Burgess, R-Texas, adding that current FDA laws and regulations were never intended to handle the increasing volume of imports.

An estimated 80 percent of the active pharmaceutical ingredients used to make drugs sold in the U.S. are imported. Among finished drugs, an estimated 40 percent are made abroad.

The FDA plans to inspect just 300 foreign drug firms this year, announcing in advance its intent to do so each time. That can hinder the FDA’s ability to view normal, day-to-day operations, the GAO found. Further, FDA inspectors aren’t provided with translators, leaving them to rely on English-speaking firm employees.

Of those foreign inspections, 88 percent are of firms that make drugs awaiting FDA approval, according to the GAO. The balance are of the type of periodic assessment meant to ensure a company’s products remain safe in the years following FDA approval. Within the U.S., the proportion is flipped, with 78 percent of FDA drug inspections of the routine, surveillance variety.

The head of the FDA, meanwhile, said the issue is larger than just one of inspection numbers.

“The solution to ensuring the quality of imports does not rely solely on increasing the number of inspections we conduct abroad — or even at the border,” Dr. Andrew von Eschenbach said, adding that the FDA seeks to revamp its whole import strategy to focus on ensuring quality is built into agency-regulated products from the start. He also proposed posting FDA employees abroad, where they could help build up the agency’s foreign counterparts.

When FDA does visit foreign plants, its inspectors can make sometimes harrowing findings. A warning letter released Thursday by the FDA cited a Chinese manufacturer of pharmaceutical ingredients for a litany of problems, including rust, flaking paint and holes in the ceiling of the production area for an unnamed product.

Much of the uncertainty in the FDA’s handling of foreign drug makers stems from its outdated computer systems, which rely on multiple databases that contain sometimes conflicting information that can be compared only manually, the GAO found. Those databases, for instance, contain tallies of foreign drug firms subject to FDA inspection that range from roughly 3,000 to about 6,800, the GAO found.

“How can we have any confidence FDA is truly managing the risk that may come from foreign-made drug products if the FDA doesn’t know the exact number or location of foreign drug manufacturers,” Stupak said.

Some clarity should be forthcoming: The FDA is soliciting bids to have its worldwide registration database verified, said Margaret Glavin, the FDA’s associate commissioner for regulatory affairs.

Von Eschenbach acknowledged his agency’s computer infrastructure remains a problem. Still, he said the U.S. drug supply is among the world’s safest.

“We shouldn’t leave people with the impression the drug supply is unsafe — ” said William Hubbard, a former FDA associate commissioner.

“It’s vulnerable,” interjected Rep. Greg Walden, R-Ore., finishing his sentence.

FDA’s Scrutiny Of Drug Makers Abroad Faulted

The Food and Drug Administration only has inspection records for about one-third of the foreign manufacturers that may be making drugs for U.S. consumers, congressional investigators found.

The Government Accountability Office, an investigative arm of Congress, found that the FDA “could not identify a previous inspection” for 2,133 facilities out of 3,249 on a list the agency used to set its inspection priorities. The agency said some of those may not be exporting products to the U.S. At its typical pace of 241 annual examinations, the agency would only check on 7% of the manufacturers each year — taking more than 13 years to give each one a single inspection, the GAO said in a preliminary report.

The report said the FDA also is struggling to calculate precisely how many foreign drug makers it oversees; different agency databases provided varying estimates.

The report was released during a hearing of the House Energy and Commerce investigations subcommittee, chaired by Michigan Democrat Bart Stupak. The hearing turned the congressional spotlight, previously trained on the safety of imported consumer goods and foods, on the rapidly growing flow of pharmaceutical ingredients and drugs from China and India.

The GAO found that in fiscal 2007, the FDA inspected just 13 of China’s 714 drug makers who were potentially supplying the U.S. India had 410 facilities and 65 inspections for the year ended Sept. 30. Even when foreign manufacturers are inspected, the GAO found, FDA inspectors must rely on the companies for translators.

FDA Commissioner Andrew von Eschenbach said the agency is moving to improve its monitoring of foreign drug makers and upgrading the technology it uses to track them. The FDA “must revamp our entire strategy, our entire game plan,” he said. Former FDA officials said the agency has struggled with budget constraints on its inspection force.

Bruce Downey, chief executive of Barr Pharmaceuticals Inc., a generic and branded-drug maker, testified that U.S. drug companies do their own extensive checks on suppliers and consumers shouldn’t be alarmed about the quality of the U.S. drug supply. But, he said, there “isn’t a justification for” the disparity between the FDA’s inspections of domestic manufacturers — which by law must be checked every two years — and foreign ones, which don’t have a similar requirement.

Republicans on the committee questioned whether the concerns about oversight of foreign-made drug products had implications for efforts to allow freer importing of cheaper medicines from Canada and some other countries. Drug makers have argued that such a move would expose Americans to counterfeits and other risky medicines; backers of liberalized import policies say their bills would add new safety protections.

A phase II trial on axitinib, a new experimental drug for treating patients with cytokine-refractory, metastatic kidney cancer who have a poor response to more traditional drugs has shown promising results according to a new study published in the The Lancet Oncology.

Professor Olivier Rixe of the University of Paris, France, and colleagues assessed the activity and safety of axitinib in a group of patients with metastatic renal-cell cancer who had failed to respond to cytokine-based treatments.

The researchers enrolled 52 patients between October 2003 and April 2004. Each patient had at least one measurable lesion that could be targeted and was given an oral dose of axitinib starting at 5 mg twice a day.

Rixe and colleagues assessed the percentage of patients who responded either completely or partially using the Response Evaluation Criteria In Solid Tumors (RECIST) method, as well as how long they took to respond, the time to progression, overall survival, safety and other measures.

In an intention to treat analysis, the study produced the following results:

• Of the 52 patients, 2 responded completely and 21 partially.
• This equated to an objective response rate of 44.2 per cent.
• The median response rate was 23.0 months (range 4.2 to 29.8 months).
• But 12 of 23 initial responders progressed with response durations of 4.2 to 26.5 months.
• Also, 22 patients showed stable disease for more than 8 weeks, with 13 of them for 24 weeks or more.
• 4 patients had early disease progression, 3 had missing response data.
• Median time to progression was 15.7 months (range 0.03 to 31.5 months).
• Median overall survival was 29·9 months (range 2·4 to 35·8 months).
• Adverse events linked to treatment included diarrhoea, hypertension, fatigue, nausea, and hoarseness.
• High blood pressure was found in 30 patients.
• Of these, all but 8 responded to blood pressure treatment. 7 of the 8 had a history of high blood pressure at enrollment.

The researchers concluded that:

“Axitinib shows clinical activity in patients with cytokine-refractory metastatic renal-cell cancer. Although 28 patients had grade 3 or grade 4 treatment-related adverse events, these adverse events were generally manageable and controlled by dose modification or supportive care, or both. Further studies are needed to confirm these findings.”

Kidney cancer is the sixth leading cause of cancer deaths in the US, and thought to be responsible for nearly 13,000 deaths a year. Kidney cancer is actually a range of cancers, each with a different histology or tissue characteristics. Each type of kidney cancer also develops differently and needs different kinds of treatment.

The most common type of kidney cancer is clear-cell renal cancer, found in 75 per cent of kidney cancer patients.

There are few treatment options for kidney cancer and most patients die. Even with chemotherapy, hormone or biological therapy with the latest targeted drugs, the survival rate is rarely more than 10 per cent.

Axitinib is a selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. By selectively targeting a single growth factor receptor pathway, treatments with this drug could provide a way to adjust dosage and combine with other drugs aimed at specific parts of the pathway. This would potentially minimise toxicity as well as optimise therapeutic outcomes suggested the researchers.

Rixie said that although a randomized controlled trial was now needed:

“The objective response and time to progression in our study suggest that axitinib might be a promising drug in the treatment of patients with metastatic renal-cell cancer.”

In an accompanying article in the same issue of the journal, Dr W Marston Linehan of the US National Cancer Institute, said that these findings “suggest that a drug such as axitinib has promise as a second-line treatment in cytokine-refractory metastatic renal-cell carcinoma, and might have potential as first-line treatment or in combination with other agents targeting the Von Hippel-Lindau pathway (or both).”

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Use of cholesterol and blood pressure medicines by young adults appears to be rising rapidly — at a faster pace than among senior citizens, according to an industry report being released Tuesday.

Experts point to higher rates of obesity, high blood pressure and high cholesterol problems among young people. Also, doctors are getting more aggressive with preventive treatments.

“This is good news, that more people in this age range are taking these medicines,” said Dr. Daniel W. Jones, president of the American Heart Association.

Still, he said many more people should be on the drugs that lower cholesterol or blood pressure and which have been shown to reduce risks for heart attack and stroke.

The new data, from prescription benefit manager Medco Health Solutions Inc., indicate use of cholesterol-lowering drugs among people aged 20 to 44, while still low, jumped 68 percent over a six-year period.

The rate rose from 2.5 percent in 2001 to just over 4 percent in 2006 among Medco customers. That means roughly 4.2 million Americans in that age group are now taking cholesterol medicines.

Meanwhile, use of blood pressure medicines increased 21 percent, from about 7 percent of 20- to 44-year-olds in 2001 to over 8 percent in 2006. That translates into about 8.5 million Americans in that age group taking drugs to lower their blood pressure.

“It was a surprise to us,” said Dr. Robert Epstein, chief medical officer at Franklin Lakes, N.J.-based Medco. “Maybe the fact that we’re seeing more young people with high cholesterol and blood pressure is indicative of the epidemic of obesity and overweight that we’re seeing in this country.”

Among people 65 and older, use of blood pressure drugs increased only 9.5 percent and use of cholesterol drugs by 52 percent. That’s because half the seniors were already taking blood pressure drugs and more than one in four were taking cholesterol drugs in 2001.

Jones, dean of the University of Mississippi School of Medicine, said he has seen some increase in young adults with blood pressure or cholesterol problems, but not of the magnitude suggested by Medco’s data.

Dr. Howard Weintraub, the heart disease prevention expert at the American College of Cardiology, said he’s “thrilled” by the dramatic increase, which he says is tied to requests from patients with “a brand new sense of urgency” and referrals from other doctors to his private practice.

“If you wait until a heart attack or stroke, it’s a little bit late,” Weintraub said.

He and Epstein both said patients with problems should first work with their doctors on lifestyle changes — more exercise, a better diet and weight loss. But Weintraub said many people need medication to achieve and maintain the ever-lower levels of blood pressure and cholesterol that experts now recommend.

However, Dr. John LaRosa, president of SUNY Downstate Medical Center, said, “particularly for young people, lifestyle change is worth a try.”

Once patients start taking these medicines, they usually stay with them and there are some side effects, LaRosa said.

“It’s amazing what (losing) five or 10 pounds will do” to reduce blood pressure and cholesterol levels, he said.

Federal health statistics show that while the percentage of people with high cholesterol has dropped overall in recent years, it has risen among younger people, especially those 20 to 34 years old.

Meanwhile, the prevalence of high blood pressure was flat or up slightly among those age groups; among women in the 35 to 44 age group, the rate of high blood pressure rose significantly.

Medco processes prescription claims for about 60 million insured Americans. The report’s findings are based on a representative sample of data from 2.5 million members.

Increase in use of cholesterol and hypertension medications largest among people ages 20 to 44Drop in the age of women using heart disease medications greater than men

Heart disease, high blood pressure and hardening of the arteries - conditions that are usually associated with the senior population - are creeping into young adulthood. According to new research conducted by Medco Health Solutions, Inc. , prescription drug use by younger adults for heart disease- related conditions is increasing at a rapid rate, far outpacing older adults and offering a glimpse into the forthcoming clinical and financial challenges facing the nation’s health care system.

The analysis shows that between 2001 and 2006, the number of 20-44 year olds taking prescription medications to treat high cholesterol increased 68 percent, and use of antihypertensives jumped 21 percent.

Based on this new analysis, the estimated number of 20-44 year olds nationwide on lipid-lowering drugs surged from 2.5 million in 2001 to 4.2 million in 2006, while the number of people of that age taking antihypertensives spiked from 7 million to 8.5 million in the six-year period.

“This may be both a good news, bad news story,” said Dr. Robert Epstein, Medco’s chief medical officer. “The good news is that younger patients are taking medications that control conditions that, if left untreated, could lead to heart attacks and strokes - indicating that physicians are screening patients more regularly and treating these precursors more aggressively than in the past. The bad news is that these conditions are showing up in patients at younger ages, which could be the result of the growing obesity epidemic and various lifestyle factors.”

Not only were the increases among 20-44 year olds significant, but so too were the rates of increase when compared to age groups more traditionally associated with these categories of medications. The increase in the number of 20-44 year-olds on lipid-lowering medications was 37 percent higher than it was for 45 to 64 year olds; the growth in prevalence of those on antihypertensives was 52 percent greater. When compared with patients 65 years or older, the increase in usage of lipid-lowering medications was 31 percent higher in the 20-44 group, and among those on antihypertensives it was more than double.

Decline Seen in Age of Patients on Drug Treatment

The analysis also found a significant shift downward in the age of patients using these drug treatments. In 2006, half of all patients on lipid- lowering drugs were 61 years old or younger; the median age of women fell more sharply than men, dropping from 67 to 62 in the six-year span, as compared to 62 to 59 for men.

The median age of those using antihypertensives declined four years over the six-year period, with half of all patients on these drugs being 60 years or younger in 2006; again women had the greatest decline, dropping from 65 to 60 versus men whose median age fell from 63 to 60.

“There is a history of women being under-diagnosed and under-treated for heart conditions,” said Epstein. “The fact that more women at a younger age are receiving medication treatment for high cholesterol and hypertension is a sign that the medical community is recognizing that heart disease is a serious threat to women as well as men.”

Heart Disease Risks

High cholesterol and high blood pressure are two of the leading risk factors for heart disease, heart attack and stroke. High LDL cholesterol can cause atherosclerosis, a narrowing and hardening of the arteries that feed the heart and brain. High blood pressure, or hypertension, can weaken the arterial walls and make them more prone to atherosclerosis. Both conditions can lead to blood clots that can block blood flow and result in a heart attack or stroke.

For some people with high cholesterol and hypertension, lifestyle changes such as weight loss, dietary changes and exercise can control the conditions. For others, medications may be needed. The most common medications used to treat high cholesterol are statins. To treat hypertension, diuretics, beta- blockers and ACE inhibitors are often prescribed.

Your brain is supposed to fire a “hold your horses” signal when faced with a tough choice. But a brain implant that stops the tremors of Parkinson’s disease may block that signal — a new explanation for why some Parkinson’s patients become hugely impulsive.

Scientists have long known that anti-Parkinson medications occasionally spark compulsions like pathological gambling.

Research published Thursday found another treatment, a pacemaker-like brain implant, can trigger a completely different kind of impulsiveness. How different? The drugs leave a subset of patients unlikely to learn from bad experiences, like a losing poker hand.

The brain implant doesn’t hinder learning. In contrast, those patients can make hasty decisions as the brain loses its automatic tendency to hesitate when faced with conflict, University of Arizona researchers reported online in the journal Science.

In fact, the first patient they studied displayed an alarming example when he saw something across the room he wanted and tried to dash over without his wheelchair. Neuroscientist Michael Frank had to catch the man before he fell.

“Deep brain stimulation,” or DBS, involves placing electrodes into a small region called the subthalamic nucleus, an area important for controlling movement. But it also is where scientists believe the brain yells: “Stop, weigh your options!”

Frank’s theory: When electrodes fire to disrupt excessive movement, they also may block that signal.

“It makes a lot of sense,” said Dr. Valerie Voon, a psychiatrist with the National Institutes of Health’s neurology center, after reviewing the research.

The study doesn’t offer easy solutions. But it could affect how neurologists counsel Parkinson’s patients after DBS surgery.

“Because they don’t have those brakes in place, you need to teach someone to slow down” when faced with certain decisions, Voon said.

At least 1 million Americans have Parkinson’s, suffering increasingly severe tremors and periodically stiff or frozen limbs as brain cells quit producing dopamine, a chemical crucial for movement. There is no cure. Standard treatments include medications to stimulate dopamine and, once those fail, DBS surgery to control tremors.

Doctors have long noticed varying degrees of impulsiveness in Parkinson’s patients, from making uncensored remarks to rare cases of extreme behavior such as compulsive gambling, shopping, eating or sex. Changing medications or doses often solves extreme symptoms — if patients or their families report the worrisome behavior.

Frank wondered what role the brain implant plays.

His team used specialized computer games to probe decision-making in 15 Parkinson’s patients taking dopamine drugs, 17 others who received DBS, and 14 healthy older adults.

First, participants were shown pairs of Japanese characters and told to pick the “correct” one. It was baffling — what makes one symbol better, especially if you don’t know Japanese? But as the computer screen beamed back “Correct!” or “Incorrect!” their brains learned to prefer some characters over others.

Then Frank paired the symbols differently: “Correct” ones together to simulate “win-win” decisions; “incorrect” pairings to model choosing the lesser of two evils; and easy “right-wrong” pairs.

Healthy people and Parkinson’s patients on dopamine drugs hesitated briefly when faced with win-win or lose-lose choices, allowing time to weigh options. But DBS patients didn’t hesitate with lose-lose choices — and actually sped up win-win decisions.

Remarkably, switch off the brain implant and DBS patients quit rushing the close calls.

As in previous research, medicated patients were less likely to learn which “wrong” symbols to avoid, backing the theory that dopamine drugs can hinder learning from negative feedback.

But do the DBS patients’ hasty choices really matter in a win-win situation, where there’s no clearly wrong answer?

In the real world, definitely, said Arizona’s Frank. Say your job offers a range of 401K options. Sure, any one is better than no investment, but just grabbing the first one might not be the most lucrative.

It hasn’t been obvious that different treatments cause different impulsive behaviors, said Dr. Kathleen Shannon of Chicago’s Rush University Hospital.

“They all seem to make bad decisions and have trouble making decisions,” she said. Now, “I’ll start to look at my patients differently.”

What is Parkinson’s Disease?

Parkinson’s disease (PD) belongs to a group of conditions called motor system disorders, which are the result of the loss of dopamine-producing brain cells. The four primary symptoms of PD are tremor, or trembling in hands, arms, legs, jaw, and face; rigidity, or stiffness of the limbs and trunk; bradykinesia, or slowness of movement; and postural instability, or impaired balance and coordination. As these symptoms become more pronounced, patients may have difficulty walking, talking, or completing other simple tasks. PD usually affects people over the age of 50. Early symptoms of PD are subtle and occur gradually. In some people the disease progresses more quickly than in others. As the disease progresses, the shaking, or tremor, which affects the majority of PD patients may begin to interfere with daily activities. Other symptoms may include depression and other emotional changes; difficulty in swallowing, chewing, and speaking; urinary problems or constipation; skin problems; and sleep disruptions. There are currently no blood or laboratory tests that have been proven to help in diagnosing sporadic PD. Therefore the diagnosis is based on medical history and a neurological examination. The disease can be difficult to diagnose accurately. Doctors may sometimes request brain scans or laboratory tests in order to rule out other diseases.

Is there any treatment?

At present, there is no cure for PD, but a variety of medications provide dramatic relief from the symptoms. Usually, patients are given levodopa combined with carbidopa. Carbidopa delays the conversion of levodopa into dopamine until it reaches the brain. Nerve cells can use levodopa to make dopamine and replenish the brain’s dwindling supply. Although levodopa helps at least three-quarters of parkinsonian cases, not all symptoms respond equally to the drug. Bradykinesia and rigidity respond best, while tremor may be only marginally reduced. Problems with balance and other symptoms may not be alleviated at all. Anticholinergics may help control tremor and rigidity. Other drugs, such as bromocriptine, pramipexole, and ropinirole, mimic the role of dopamine in the brain, causing the neurons to react as they would to dopamine. An antiviral drug, amantadine, also appears to reduce symptoms. In May 2006, the FDA approved rasagiline to be used along with levodopa for patients with advanced PD or as a single-drug treatment for early PD.

In some cases, surgery may be appropriate if the disease doesn’t respond to drugs. A therapy called deep brain stimulation (DBS) has now been approved by the U.S. Food and Drug Administration. In DBS, electrodes are implanted into the brain and connected to a small electrical device called a pulse generator that can be externally programmed. DBS can reduce the need for levodopa and related drugs, which in turn decreases the involuntary movements called dyskinesias that are a common side effect of levodopa. It also helps to alleviate fluctuations of symptoms and to reduce tremors, slowness of movements, and gait problems. DBS requires careful programming of the stimulator device in order to work correctly.

What is the prognosis?

PD is both chronic, meaning it persists over a long period of time, and progressive, meaning its symptoms grow worse over time. Although some people become severely disabled, others experience only minor motor disruptions. Tremor is the major symptom for some patients, while for others tremor is only a minor complaint and other symptoms are more troublesome. No one can predict which symptoms will affect an individual patient, and the intensity of the symptoms also varies from person to person.

What research is being done?

The National Institute of Neurological Disorders and Stroke (NINDS) conducts PD research in laboratories at the National Institutes of Health (NIH) and also supports additional research through grants to major medical institutions across the country. Current research programs funded by the NINDS are using animal models to study how the disease progresses and to develop new drug therapies. Scientists looking for the cause of PD continue to search for possible environmental factors, such as toxins, that may trigger the disorder, and study genetic factors to determine how defective genes play a role. Other scientists are working to develop new protective drugs that can delay, prevent, or reverse the disease.

The US Food and Drug Administration has decided to put more prominent warnings of potential hearing loss on impotence drugs Viagra, Cialis and Levitra.

An FDA statement said the goal was “to display more prominently the potential risk of sudden hearing loss, and to guide consumers on what to do if they experience sudden problems with their hearing.”

Revatio, used to treat pulmonary hypertension, also will get the same labelling changes, the FDA said.

The warnings followed what the administration called “a very small number” of patients reporting hearing loss and at times ringing in the ears and dizziness.

“Because some level of hearing loss is usually associated with the aging process, patients on these drugs may not think to talk to their doctor about it,” said Janet Woodcock, MD, FDA deputy commissioner for scientific and medical programs, chief medical officer, and acting director of its Center for Drug Evaluation and Research.

Anti-impotence drugs linked to hearing loss

The U.S. Food and Drug Administration has approved labelling changes for three kinds of erectile dysfunction drugs to display more prominently the potential risk of sudden hearing loss.

The FDA on Thursday asked manufacturers of Viagra, Cialis and Levitra to revise product labelling after a very small number of patients taking the drugs reported sudden hearing loss, sometimes accompanied by ringing in the ears and dizziness.

It’s not clear if the drugs actually trigger hearing loss, but the agency decided to act after counting 29 reports of hearing problems since 1996 among users.

Dr. Robert Boucher, an agency ear, nose and throat specialist, said in reviewing the reports he noticed that the hearing loss occurred within hours to two days of taking one of the drugs.

“We don’t know enough to say that it’s ironclad caused by the drugs, but we see enough to say we can’t ignore it either,” he said.

The reports involved hearing loss in one ear, which in a third of cases was temporary.

The FDA has urged patients who experience any hearing problems, loss or ringing in the ears to promptly call their doctors and stop taking the impotence drugs.

Because some level of hearing loss is usually associated with the aging process, patients taking these drugs (phosphodiesterase type 5 inhibitors) may not think to talk to their doctor about it, said Dr. Janet Woodcock, the FDA’s chief medical officer.

An emerging “superbug” that causes ear infections in children and is resistant to multiple antibiotics can only be treated with an adult medication, researchers report.

Two Rochester, N.Y., pediatricians report finding a multiple antibiotic-resistant strain of Streptococcus pneumoniae that caused ear infections in nine children in their practice over three years. The only antibiotic that was effective in treating these infections was levofloxacin, which isn’t approved by the U.S. Food and Drug Administration for use in children.

“We found a superbug causing ear infections in Rochester — the Legacy strain — that’s resistant to all antibiotics approved by the FDA for use in children,” said the study’s lead author, Dr. Michael Pichichero, a professor of microbiology, immunology and pediatrics at the University of Rochester Medical Center, and a private practice pediatrician with the Legacy Pediatric Group.

The resistant infections accounted for only 1.5 percent of the ear infections in their practice, Pichichero noted.

The findings are published in the Oct. 17 issue of the Journal of the American Medical Association.

Pneumococcal infections are caused by S. pneumoniae, and can include ear infections, sinus infections, pneumonia, meningitis and bloodstream infections. Some of these infections can be life-threatening. Young children are most susceptible to pneumococcal infections, according to the U.S. Centers for Disease Control and Prevention. Fortunately, the serious forms of the disease are rare, causing about 4,500 illnesses each year. However, pneumococcal infections cause more than 3 million ear infections each year, according to the CDC.

While a vaccine (brand name Prevnar) is available that covers seven strains of pneumococcal disease, a strain dubbed serotype 19A isn’t currently one of them. However, the vaccine’s manufacturer, Wyeth Pharmaceuticals, reports that it’s currently in phase III trials of the next generation vaccine, which does include serotype 19A.

“Prevnar is a fantastic vaccine that is taking care of the top seven strains of pneumococcal disease, but after you’ve knocked down the other strains, of course others will become more prominent,” Pichichero explained.

Dr. Peter Paradiso is vice president of scientific affairs for Wyeth Pharmaceuticals. He said, “When we developed Prevnar, we had hoped that the response to serotype 19F would provide some cross-protection against 19A.” When it became clear that there was no cross-protection, and other strains needed to be addressed, Wyeth added six more strains to the next generation vaccine. The company plans to begin the regulatory filings needed for FDA approval sometime in 2009, after the phase III trials are completed, he said.

In the meantime, Pichichero said physicians need to do more ear tap procedures to identify which bacteria are causing antibiotic-resistant ear infections. Doing so, he said, would help avoid the unnecessary use of antibiotics and allow for a more targeted approach to treating ear infections.

From 2003 until 2006, Pichichero and his colleagues saw just over 1,800 youngsters with ear infections, according to the study. Of those children, 212 had ear taps, known as tympanocentesis, a procedure that draws fluid out from behind the ear drum. Much like when a tooth cavity is filled, children are given local anesthetic to make the procedure pain-free.

Using this procedure, the doctors found that 59 of the ear infections were caused by S. pneumoniae. One particular strain of the bacterium — serotype 19A — had developed a new genotype that was resistant to all of the antibiotics approved for use in children. Pichichero and his colleague, Dr. Janet Casey, dubbed this the Legacy strain. Nine children were found to be infected with this strain.

The only antibiotic effective against this superbug is levofloxacin (brand name, Levaquin). But, levofloxacin has never been approved for use in children. Pichichero said that because previous studies on young animals have suggested that the drug might cause irreversible damage to growing cartilage, the “FDA has put significant barriers for the use of the antibiotics in children.” No such effects have been found in adults, and it’s a commonly used antibiotic in adults.

However, in these nine pediatric cases, no other treatments were effective, and the children were at risk of losing their hearing. Since Pichichero had been involved in previous research on levofloxacin’s use in children, he knew the correct dose to administer, and it was effective.

But, he cautioned, because the drug hasn’t been well studied in children, “I would not allow a child to receive levofloxacin unless I knew for sure [that it was the Legacy strain].”

Dr. Katherine Poehling, a pediatrician at Brenner Children’s Hospital at Wake Forest University Baptist Medical Center, said the new findings are worrisome, but “nine cases out of 1,800 doesn’t make me panic. We’ve always had some ear infections that are very hard to treat, but they usually aren’t serotyped to figure out what they are.”

Poehling, who’s been involved in research on the current pneumococcal vaccine, added that the “pneumococcal conjugate vaccine has been extraordinarily successful, and children continue to benefit from this vaccine.”

Paradiso agreed, adding that the current vaccine has caused a dramatic — 99 percent — reduction in infections in the serotypes that are covered by the vaccine.

The CDC recommends that the current vaccine be given to all infants younger than 24 months of age at 2, 4, and 6 months of age, followed by a booster dose at 12-15 months of age.

What is pneumococcal disease?

Pneumococcal disease is defined as infections that are caused by the bacteria Streptococcus pneumoniae, also known as pneumococcus. The most common types of infections caused by this bacteria include middle ear infections, pneumonia, blood stream infections (bacteremia), sinus infections, and meningitis.

Which children are most likely to get pneumococcal disease?

Young children are much more likely than older children and adults to get pneumococcal disease. Children under 2, children in group child care, and children who have certain illnesses (for example sickle cell disease, HIV infection, chronic heart or lung conditions) are at higher risk than other children to get pneumococcal disease. In addition, pneumococcal disease is more common among children of certain racial or ethnic groups, such as Alaska Natives, Native Americans, and African-Americans, than among other groups.

How prevalent is pneumococcal disease?

Each year in the U.S. Streptococcus pneumoniae causes approximately 480 cases of meningitis, 4,000 cases of bacteremia or other invasive disease in children under the age of 5. Children under 2 average more than 1 middle ear infection each year, many of which are caused by pneumococcal infections. Streptococcus pneumoniae is the most common cause of bacteremia, pneumonia, meningitis and otitis media in young children.

Who is at most serious risk?

Children at increased risk of pneumococcal infections include those with anatomic or functional asplenia (including sickle cell disease), patients taking immunosuppressive chemotherapy, those with congenital and acquired immune deficiency (including HIV infections), those with chronic renal disease and healthy Native American, Alaskan Native, and African American children. Children less than 60 months of age in out-of-home day care are at 2-3 fold higher risk of experiencing invasive pneumococcal infections than children in home care.

What are the symptoms of pneumococcal disease?

Meningitis:
High fever, headache, and stiff neck are common symptoms of meningitis in anyone over the age of 2 years. These symptoms can develop over several hours, or they may take 1 to 2 days. Other symptoms may include nausea, vomiting, discomfort looking into bright lights, confusion, and sleepiness. In newborns and small infants, the classic symptoms of fever, headache, and neck stiffness may be absent or difficult to detect, and the infant may only appear slow or inactive, or be irritable, have vomiting, or be feeding poorly.

Pneumonia:
In adults, pneumococcal pneumonia is often characterized by sudden onset of illness with symptoms including shaking chills, fever, shortness of breath or rapid breathing, pain in the chest that is worsened by breathing deeply, and a productive cough. In infants and young children, signs and symptoms may not be specific, and may include fever, cough, rapid breathing or grunting.

Otitis media:
Children who have otitis media (middle ear infection) typically have a painful ear, and the eardrum is often red and swollen. Other symptoms that may accompany otitis media include sleeplessness, fever and irritability.

Blood stream infections:
Infants and young children with blood stream infections-also known as bacteremia-typically have non-specific symptoms including fevers and irritability.

How serious is pneumococcal disease?

Pneumococcal disease is a very serious illness in young children. Pneumococcal infections are now the most common cause of invasive bacterial infection in U. S. children. In the United States it is estimated that pneumococcal infections cause 100 deaths, 450 cases of meningitis, 4,000 cases of bacteremia or other invasive disease, and 3.1 million cases of otitis media (ear infections) annually in children under 5 years of age.

Meningitis is the most severe type of pneumococcal disease. Of children less than 5 years of age with pneumococcal meningitis, about 5% will die of their infection and others may have long-term problems such as hearing loss. Many children with pneumococcal pneumonia or blood stream infections will be ill enough to be hospitalized; about 1% of children with blood stream infections or pneumonia with a blood stream infection will die of their illness. Nearly all children with ear infections recover, although children with recurrent infections can suffer hearing loss.
How is pneumococcal disease spread?

The bacteria are spread through contact between persons who are ill or who carry the bacteria in their throat. Transmission is mostly through the spread of respiratory droplets from the nose or mouth of a person with a pneumococcal infection. It is common for people, especially children, to carry the bacteria in their throats without being ill from it.

How is pneumococcal disease treated/cured?

Pneumococcal disease is treated with antibiotics. Over the last decade, many pneumococci have become resistant to some of the antibiotics used to treat pneumococcal infections; high levels of resistance to penicillin are common.

Can pneumococcal disease in children be prevented?

In late 2000, the FDA licensed a new vaccine for the prevention of pneumococcal disease in children. The new pneumococcal vaccine, Prevnar® (manufactured by Wyeth-Lederle Vaccines), is a vaccine in which the serotypes are conjugated (or linked) to a protein. This new pneumococcal conjugate vaccine has been shown to be highly effective in preventing invasive pneumococcal disease (such as in young children. In a study of the new vaccine among 37,000 infants in California, the vaccine was over 90% effective in preventing invasive disease among the children studied. The children who received the new vaccine also had 7% fewer episodes of otitis media and a 20% decrease in the number of tympanostomy tubes (ear tubes) placed. The vaccine was also shown to decrease the number of episodes of pneumonia.

CDC conducted a study soon after a vaccine was licensed and found that the vaccine was highly effective in preventing disease in children under 5 years of age. The investigators found that the vaccine was 96% effective against pneumococcal disease in healthy children who received one dose or more and 81% effective in children with medical conditions that put them at risk of pneumococcal disease. The vaccine was also highly effective at preventing pneumococcal disease caused by antibiotic-resistant strains.

Prevnar® is indicated for use in infants and toddlers. The vaccine should be given to all infants younger than 24 months of age at 2, 4, and 6 months of age, followed by a booster dose at 12-15 months of age. Children who are unvaccinated and are 7 to 11 months of age should be given a total of 3 doses (2 months apart) and children age 12 to 23 months should be given a total of 2 doses at least two months apart. Most children who are 24 months of age or older only need one dose of the vaccine.

The Advisory Committee on Immunization Practices (ACIP) also recommends the new pneumococcal childhood vaccine be given to children age 24 to 59 months at highest risk of infection, including those with certain illness (sickle cell anemia, HIV infection, chronic lung or heart disease). Vaccine should be considered for all children aged 24-35 months and other children through 59 months of age with a priority for those at higher risk which includes Alaska Natives, American Indians, or African Americans and those children who attend out-of-home day day care for more than 4 hours per week.

The recently licensed pneumococcal conjugate vaccine, Prevnar®, is the first pneumococcal vaccine that can be used in children under the age of 2 years. However, pneumococcal vaccines for the prevention of disease among children and adults who are 2 years and older have been in use since 1977. Pneumovax® and Pnu-Immune® are 23-valent polysaccharide vaccines that are currently recommended for use in all adults who are older than 65 years of age and for persons who are 2 years and older and at high risk for disease such as persons with sickle cell disease, HIV infection, or other immunocompromising condition.

Campaigns for judicious use of antibiotics may also slow or reverse emerging drug resistance found among pneumococcal infection.

Makers of OTC Cough and Cold Medicines Announce Voluntary Withdrawal of Oral Infant Medicines

• Potential misuse of these infant medicines, not product safety, is driving the voluntary withdrawal
• This withdrawal does not affect cough and cold medicines for children age 2 and older
• Further evaluation of these oral cough and cold medicines for infants and children will occur at the October 18 and 19 FDA advisory committee meeting

The Consumer Healthcare Products Association (CHPA) on behalf of the leading makers of over-the-counter cough and cold medicines today announced voluntary market withdrawals of oral cough and cold medicines that refer to “infants.” The voluntary withdrawal affects only these “infant” oral medicines, not those intended and labeled for use in children age two and older.

“It’s important to point out that these medicines are safe and effective when used as directed, and most parents are using them appropriately,” said Linda A. Suydam, D.P.A, president of CHPA. “The reason the makers of over-the-counter, oral cough and cold medicines for infants are voluntarily withdrawing these medicines is that there have been rare patterns of misuse leading to overdose recently identified, particularly in infants, and safety is our top priority.”

The branded cough and cold medicines that are being voluntarily withdrawn are:
Dimetapp® Decongestant Plus Cough Infant Drops
Dimetapp® Decongestant Infant Drops
Little Colds® Decongestant Plus Cough
Little Colds® Multi-Symptom Cold Formula
PEDIACARE® Infant Drops Decongestant (containing pseudoephedrine)
PEDIACARE® Infant Drops Decongestant & Cough (containing pseudoephedrine)
PEDIACARE® Infant Dropper Decongestant (containing phenylephrine)
PEDIACARE® Infant Dropper Long-Acting Cough
PEDIACARE® Infant Dropper Decongestant & Cough (containing phenylephrine)
Robitussin® Infant Cough DM Drops
Triaminic® Infant & Toddler Thin Strips® Decongestant
Triaminic® Infant & Toddler Thin Strips® Decongestant Plus Cough
TYLENOL® Concentrated Infants’ Drops Plus Cold
TYLENOL® Concentrated Infants’ Drops Plus Cold & Cough

This voluntary withdrawal does not affect medicines intended for children age two and older. CHPA and its member companies have put forth recommendations to the U.S. Food and Drug Administration (FDA) to strengthen the labels on all oral OTC children’s cough and cold medicines from “ask a doctor” before using to “do not use” in children under two years.

CHPA made these recommendations to the FDA in preparation for a joint FDA advisory committee meeting on October 18 and 19. These recommendations, as well as several additional recommendations, including those proposed by FDA review staff, will be explored further at this meeting.

“These medicines are—and always have been—safe at recommended doses,” Suydam said.

“These voluntary actions are being taken out of an abundance of caution. The vast majority of parents and caregivers safely use these medicines to help relieve their children’s symptoms. But as with all medicines, it’s important that parents read over-the-counter medicine labels carefully, use these medicines only as directed, and store them safely out of the reach of children.”

CHPA will be launching a major, multi-year national campaign to educate parents and healthcare providers about the safe use of over-the-counter medicines in children, partnering with major physician, nurse, and pharmacist organizations.

What Parents and Caregivers Need to Know: OTC Cough and Cold Medicines and Children

On October 11, the Consumer Healthcare Products Association (CHPA), on behalf of the leading makers of over-the-counter (OTC) cough and cold medicines, announced the voluntary withdrawal of oral infant medications from store shelves. Here are the facts:

• The voluntary withdrawal of OTC oral infant cough and cold medicines was initiated by the makers of those medications out of an abundance of caution. This is not a mandatory recall or a safety issue.
• Kids’ OTC cough and cold medicines are both safe and effective when used correctly. Rare cases of overdose from misuse, however, have occurred—particularly in infants less than two years of age.
• Infants under the age of two are the most vulnerable to the consequences of this misuse.
• The voluntary withdrawal only affects oral infant cough and cold medications. It does not affect any other children’s medicines.
• OTC pediatric cough and cold medicines affected by this voluntary withdrawal are listed above.

Parents can continue to trust and rely on over-the-counter cough and cold medicines for their children, as they have for generations, because these medicines are safe at recommended doses.

• As with any medicine, it is important for parents to read the labels carefully, use these medicines only as directed, and make sure to safely store them out of the reach of children.
• Labels currently direct parents and caregivers to “ask a doctor” before giving these medicines to children under two. In September 2007, the makers of these medicines recommended to the U.S. Food and Drug Administration that medicine labels have stronger language instructing that parents “do not use” for children under two to prevent incidents of misuse.

Harm from OTC cough and cold medicines is rare and, when it does occur, is almost always the result of misuse (significant overdose or accidental swallowing due to medicine not being properly stored and secured).

• As with all medicines, dosing instructions for all over-the-counter remedies must be read and followed carefully. It is important to remember that any medicine can cause harm if taken or used improperly.
• Safe use and safekeeping are extremely important. Giving medicine according to label directions is part of the solution; storing it out of the sight and reach of children is part of it, as well.

Because children under age two are the most vulnerable to the harm caused by the misuse of oral, over-the-counter cough and cold medicines, the makers of these medicines have recommended strengthening their labels to state “Do Not Use” for children under two.

• This recommendation, as well as others, will be discussed before a U.S. Food and Drug Administration advisory committee on October 18 and 19. FDA asked for the meeting of outside experts to bring the best science to bear on this important issue.
• FDA requested analyses and recommendations from its staff of reviewers, but the agency has not and will not take an official position until after it has the opportunity to discuss and examine all the information.
• FDA has not called for a “ban” on or “recall” of these medicines.

The makers of over-the-counter cough and cold medicines want to ensure that parents and caregivers understand when and how to use these medicines safely.

The safe use of these medicines is our highest priority. We will soon launch a major national educational program to build awareness among parents and other caregivers about how to safely use over-the-counter medicines in children, and, as importantly, when not to use them.