Ursofalk to fight NASH
"In many countries, nonalcoholic-fatty-liver disease (NAFLD) has become the most prevalent liver disease," said Dr. Gustav Paumgartner of University Hospital Munich, Germany. In the United States, for instance, it has a 31-percent prevalence rate. Among them, five percent will progress to nonalcoholic steatohepatitis (NASH) within a follow-up period of five to 17 years. He added that understanding the pathogenesis is essential in identifying targets for treatment. "The pathogenesis of NASH is multifactorial, with nonhepatic mechanisms being largely responsible for the development of insulin resistance and hepatic steatosis," he explained. Conventional treatment for insulin resistance involves metformin or thiazolidinediones. For example, a randomized, placebo-controlled study showed that pioglitazone and a hypocaloric diet could improve glucose control and decrease hepatic fat in patients with NASH and type 2 diabetes. Central obesity also plays a role in NASH's pathogenesis. This particular factor could be fought with lifestyle changes (diet and exercise), medication, or even surgery. Other factors that contribute to the progression of NAFL to NASH are increased free-fatty-acid oxidation, endoplasmic-reticulum stress, oxidative stress in the liver, and inflammatory cytokines. Factors related to lipid peroxidation and oxidative stress have been targeted by antioxidants, such as vitamin E. Hepatocellular injury and apoptosis are two other factors considered important in the pathogenesis of NASH. Ursodeoxycholic acid (Ursofalk) has been shown to effectively target these. An open-label study, for instance, shows that Ursofalk improves liver enzymes and the histological grade of steatosis in patients with NASH. Marketed by Pharmalink, Ursofalk is introduced as "the therapeutic bile acid" for fatty-liver and cholestatic liver diseases. It is known to prevent increased mitochondrial permeability, thereby inhibiting liver-cell injury and apoptosis by 50 to 100 percent. Aside from its cytoprotective, immunomodulatory, and antiapoptotic effects, it has been shown to displace toxic bile acids, making the bile-acid pool more hydrophilic and less cytotoxic. It is well tolerated by patients. Results of a recent randomized, placebo-controlled trial (Swiss Muticenter Study) showed improvements in liver enzymes (ALT and AST) levels, hepatic steatosis, and histological NASH activity index when Ursofalk (12-15 mg/kg/d) is combined with vitamin E. At present, a large study is being conducted in Germany to determine whether a high-dose (22-27 mg/kg/d) Ursofalk monotherapy has a more profound effect. M Mabelle Aban
Patients suffering from functional dyspepsia could experience relief of symptoms with the help of itopride, revealed a study published last year in the New England Journal of Medicine. The randomized, placebo-controlled, double-blind study showed that itopride, a dopamine D2 antagonist with acetylcholinesterase effects, yielded benefits in terms of overall symptom control, increased quality-of-life scores, and decreased symptoms of fullness and abdominal discomfort. Holtmann et al. recruited patients with functional dyspepsia (using the Rome II criteria), excluding those with predominant heartburn symptoms. A total of 524 patients were randomized into receiving placebo; and 50-mg, 100-mg; 200-mg itopride, three times daily, for eight weeks. The Leeds Dyspepsia Questionnaire (LDQ) was used to assess the overall response of the patients to the treatment. By the end of the eight-week trial period, it turned out that 59.9 percent of patients in the three treatment groups experienced a decrease in overall symptoms, compared with only 41.2 percent in the placebo group. In addition, the 100-mg and 200-mg groups had higher rates of relief from symptoms than the 50-mg group (50-mg group, 57 percent; 100-mg group, 59 percent; 200-mg group, 64 percent). Meanwhile, quality of life (using the Nepean Dyspepsia Index) was also assessed. The QOL of patients in itopride improved to 18 ± 22, compared with 13 ± 19 for the placebo group. In terms of relief from fullness and pain symptoms, the itopride group also showed higher scores than the placebo group (73 percent v. 63 percent; p = 0.04). Also, no major events were seen in the three treatment groups at the end of the trial. Since complaints regarding dyspepsia are a common reason patients consult with their doctors, the results of this trial show that there is a way to control the symptoms of functional dyspepsia better. Since very few therapeutic agents for functional dyspepsia have been introduced to the market over the past decade, it is good that itopride leads to improvements in terms of overall response and quality of life. Itopride (Ganaton) is marketed in the Philippines by Abbott Laboratories and Pharmalink. Aiming to restore natural gastric tone, Ganaton is not only indicated for patients with functional dyspepsia, but also those with reflux disorders, chronic gastritis, and diabetic gastroparesis. M Mabelle Aban
BASEL, Switzerland Novartis announced it suspending the marketing of tegaserod maleate (Zelnorm), a treatment for irritable-bowel syndrome (IBS) with constipation and chronic constipation, in the United States in compliance with a request from the Food and Drug Administration (FDA). Novartis said the action was taken after it notified the FDA about a retrospective analysis of data from more than 18,000 patients in the clinical-trial database, the result of an ongoing review involving a number of health authorities including the FDA. A small but not statistically significant imbalance in cases of angina pectoris was recorded and included in the US label when Zelnorm was approved in 2002. A recent analysis of the entire clinical database revealed a statistically significant imbalance in the incidence of cardiovascular ischemic events-myocardial infarction, stroke, and unstable angina pectoris-in patients taking Zelnorm as against those taking placebo, Novartis said. The data, reviewed by independent experts, showed that events occurred in 13 out of 11,614 patients treated with Zelnorm (0.11 percent), compared with one case in 7,031 placebo-treated patients (0.01 percent). All patients affected had preexisting cardiovascular disease or cardiovascular risk factors. The rate of cardiovascular ischemic events seen in Zelnorm-treated patients in controlled trials corresponds approximately with the expected rates for such events in the general population. "My review of the data suggested that a causal relationship is unlikely between tegaserod and the rare cardiovascular ischemic events observed in clinical trials," said Dr. Jeffrey Anderson, associate chief of cardiology division at LDS Hospital in Salt Lake City and an independent cardiologist who reviewed the data. "Furthermore, the data did not show any consistent pattern of event type, time to event, or dose relationship in tegaserod-treated patients." Multiple studies do not suggest any constrictive effects of Zelnorm on coronary arteries. "Zelnorm provides unique benefits to patients by treating the multiple symptoms of abdominal pain, bloating, and constipation that are associated with IBS with constipation," said Dr. James Shannon, global head of development at Novartis Pharma AG. "Although we have complied with the FDA's request and are collaborating with the agency, we continue to believe that Zelnorm provides important benefits for appropriate patients." Nevertheless, Novartis has suspended the marketing of Zelnorm in response to the FDA's request so that public discussion and an advisory-committee meeting can take place to weigh the risks and benefits. Novartis said it is also in discussion with health authorities in other countries where Zelnorm is available to determine next steps. M
Initial studies made by GlaxoSmithKline (GSK) Biologicals with its candidate human-papillomavirus (HPV) vaccine for the prevention of cervical cancer showed positive results against precancerous lesions caused by HPV16 and HPV 18. The candidate vaccine, which is formulated with the proprietary AS04 adjuvant system, demonstrated strong and sustained immune response for at least four years after vaccination. This latest study published in Vaccine was conducted to directly compare GSK's proprietary AS04 adjuvant system against another GSK vaccine formulated with conventional aluminum salt only. The AS04 is composed of aluminum salt and monophosphoryl lipid A (MPL). In this study, human subjects were given three doses each of either of the two types of vaccines at zero, one, and six months. Results revealed that the vaccine with AS04 adjuvant system produced antibody levels 1.5 to 2.1 times higher for HPV 16 and 18 than the vaccine formulated with conventional aluminum-salt adjuvant. Antibodies are proteins produced by the body's immune system once foreign substances like viruses enter the body. These antibodies go after the viruses to destroy them. The adjuvant in a vaccine helps trigger the production of more antibodies, enhancing the body's immune response against viruses. Previous studies conducted using GSK's candidate vaccine also produced positive results with 100-percent protection against precancerous lesions over four years. According to Dr. Philippe Monteyne, head of global vaccine deve-lopment at GSK Biologicals, a cervical-cancer vaccine must induce a strong immune response and provide lasting protection for it to be effective. "These new data demonstrate a genuine immunological effect of the AS04 adjuvant system by contributing to a strong and sustained vaccine-induced immune response of high quality. Formulating our candidate vaccine with this proprietary adjuvant system further supports GSK's ambition to developing the best possible vaccine for the prevention of cervical cancer in women of all ages," he said. HPV16 and 18 are two of the most common types of HPV that can cause precancerous lesions on the cervical area. Cervical cancer among all women develops due to persistent infection by these oncogenic types of HPV. The other most prevalent cancer-causing types are HPV 45 and 31 which, along with types 16 and 18, collectively account for 80 percent of cervical cancers worldwide. The study, published in The Lancet, provided preliminary evidence that GSK's candidate vaccine demonstrated protection against these four types. Cervical cancer is the second most common cancer among women worldwide. A simple Pap smear test can detect the presence of the common HPV. However, the coverage is very low in the Philippines. M
BASEL, Switzerland Patients with hepatitis C who respond quickly to treatment have an excellent chance of being cured of the disease, according to data presented at the 42nd annual meeting of the European Association for the Study of the Liver (EASL) in April. Patients with genotype 1 hepatitis C (HCV) who clear the virus within a month of starting treatment with Roche peginterferon alfa-2a (40KD) (Pegasys) plus ribavirin have up to a 91-percent chance of achieving a sustained virological response (SVR), considered a cure by researchers. "Now we can tell earlier than ever-at just week four of treatment-whether a patient has a good chance to be cured or not," said Prof. Patrick Marcellin of Hôpital Beaujon, Clichy, France. "Knowing their virus levels in the first and third months of treatment helps patients take ownership of beating the disease and helps motivate them to stay on treatment. This information should be made available for everyone starting therapy." An analysis of six different clinical trials highlights the value of checking how well patients with genotype 1 HCV have responded to treatment at weeks four and 12 of therapy. The results of the analysis showed that of those patients treated with peginterferon alfa-2a 180 mcg weekly plus ribavirin 1,000 to 1,200 mg daily: o Up to one in five cleared the virus by week four of therapy (called rapid viral response); o 83 to 91 percent who had a rapid viral response went on to be cured of their hepatitis C; and o About 40 percent who did not achieve a rapid viral response managed to clear the virus by week 12 of therapy (called complete early virological response); 65 percent of them were cured. A large real-life study involving 4,377 patients conducted by the Association of German Independent Gastroenterologists also confirmed that these results can be replicated in clinical practice. One quarter of patients with "difficult-to-cure" genotype 1 or 4 HCV who had their viral levels tested at week four of treatment achieved a rapid viral response. While the study is not yet complete, over 70 percent of those who have finished their six-month posttreatment follow-up period were cured. "These are really important results," said German hepatologist Elmar Zehnter, one of the researchers in the study. "This study confirms that the high cure rates reported for rapid viral responders in clinical trials translate into clinical practice and are relevant to the patients we see every day. At the moment, testing viral levels at four weeks of treatment is not standard practice. Based on these results, however, testing viral levels at four weeks of therapy should become a routine test." M |
