Bradly P. Jacobs

Milk thistle for the treatment of liver disease: A systematic review and meta-analysis

PURPOSE Milk thistle, an herbal compound, is the dietary supplement taken most frequently by patients with chronic liver disease. We performed a systematic review of the literature to determine the efficacy and safety of this herb for the treatment of liver disease. METHODS We searched English and non-English reports through July 1999 using thirteen databases and reference lists, and contacting manufacturers and technical experts. Reviewers independently screened all reports to identify randomized placebo-controlled trials that evaluated milk thistle for the treatment of liver disease. Outcomes of primary interest included mortality, histological findings on liver biopsy specimens, serum aminotransferase and albumin levels, and prothrombin times. RESULTS Fourteen trials met inclusion criteria. Four trials reported outcomes for mortality among 433 participants. The overall summary odds ratio for mortality in the milk thistle group compared with placebo was 0.8 (95% confidence interval [CI]: 0.5 to 1.5; P = 0.6). Three trials assessed histology on liver biopsy; study quality was inversely associated with the likelihood of histological benefit for milk thistle compared with placebo. There were no differences in serum alanine aminotransferase, aspartate aminotransferase, or albumin levels, or prothrombin times, among participants assigned to milk thistle compared with those assigned to placebo. The only statistically significant difference was a greater reduction in alanine aminotransferase levels among patients with chronic liver disease assigned to milk thistle (-9 IU/L, 95% CI: -18 to -1 IU/L; P = 0.05), but this reduction was of negligible clinical importance and no longer statistically significant after limiting analyses to studies of longer duration or of higher quality. The frequency of adverse effects was low and, in clinical trials, indistinguishable from placebo. CONCLUSION Treatment with milk thistle appears to be safe and well tolerated. We found no reduction in mortality, in improvements in histology at liver biopsy, or in biochemical markers of liver function among patients with chronic liver disease. Data are too limited to exclude a substantial benefit or harm of milk thistle on mortality, and also to support recommending this herbal compound for the treatment of liver disease.

MIND-BODY MEDICINE An Introduction and Review of the Literature

MBM is a well-established phenomenon in modern medicine. If one accepts a model of mind/body that is truly nondualistic, it could be said that the MBM phenomenon is inherent to medicine. Because of its popularity and efficacy for common chronic conditions, MBM may have its greatest presence in primary care medicine. The flourishing of MBM techniques resulting from the publics enthusiastic embrace of these therapies has created a great need for rigorous scientific examination. The MBM literature may be said to be in its adolescence, having grown out of its early years of enthusiastic case reports and small studies, but not yet fully grown into a broad catalogue of large controlled experimental trials. Nevertheless, clinical trials suggest that certain MBM therapies are effective in improving quality of life, anxiety, and pain intensity for a variety of conditions. There is moderate evidence to suggest these techniques improve chronic pain, headache, insomnia, and other common conditions. There is preliminary evidence to suggest these techniques may affect coronary artery disease and cancer. MBM techniques ultimately may prove to be most effective in combinations or in conjunction with traditional treatment.

Clinical studyMilk thistle for the treatment of liver disease: A systematic review and meta-analysis☆

PURPOSE Milk thistle, an herbal compound, is the dietary supplement taken most frequently by patients with chronic liver disease. We performed a systematic review of the literature to determine the efficacy and safety of this herb for the treatment of liver disease. METHODS We searched English and non-English reports through July 1999 using thirteen databases and reference lists, and contacting manufacturers and technical experts. Reviewers independently screened all reports to identify randomized placebo-controlled trials that evaluated milk thistle for the treatment of liver disease. Outcomes of primary interest included mortality, histological findings on liver biopsy specimens, serum aminotransferase and albumin levels, and prothrombin times. RESULTS Fourteen trials met inclusion criteria. Four trials reported outcomes for mortality among 433 participants. The overall summary odds ratio for mortality in the milk thistle group compared with placebo was 0.8 (95% confidence interval [CI]: 0.5 to 1.5; P = 0.6). Three trials assessed histology on liver biopsy; study quality was inversely associated with the likelihood of histological benefit for milk thistle compared with placebo. There were no differences in serum alanine aminotransferase, aspartate aminotransferase, or albumin levels, or prothrombin times, among participants assigned to milk thistle compared with those assigned to placebo. The only statistically significant difference was a greater reduction in alanine aminotransferase levels among patients with chronic liver disease assigned to milk thistle (-9 IU/L, 95% CI: -18 to -1 IU/L; P = 0.05), but this reduction was of negligible clinical importance and no longer statistically significant after limiting analyses to studies of longer duration or of higher quality. The frequency of adverse effects was low and, in clinical trials, indistinguishable from placebo. CONCLUSION Treatment with milk thistle appears to be safe and well tolerated. We found no reduction in mortality, in improvements in histology at liver biopsy, or in biochemical markers of liver function among patients with chronic liver disease. Data are too limited to exclude a substantial benefit or harm of milk thistle on mortality, and also to support recommending this herbal compound for the treatment of liver disease.

Ginkgo biloba: a living fossil

In 1998, Americans spent about 4 billion dollars on botanical medicines (1, 2) and Ginkgo biloba ranked first among herbal medications sold in health food stores (3). Ginkgo biloba, whose medicinal uses were described in the Chinese Materia Medica more than 2,000 years ago, is used most frequently to treat memory and cognitive impairment, for which it has moderate efficacy with minimal side effects (4 –9). Some patients also use ginkgo to treat symptoms of claudication, a condition for which the German Federal Health Agency considers it to be effective (10). Ginkgo biloba comes from the leaves of the ginkgo tree, one of the oldest living plant species. Dating back more than 200 million years, it is often referred to as “a living fossil.” Because its leaves resemble the maidenhair fern, it is also known as the maidenhair tree. Unrelated to any other living plant species, it grows throughout China, Korea, Japan, Europe, and the United States. Ginkgo trees can be up to 100 feet tall, 50 feet in circumference, and can live for as long as 1000 years. After the nuclear bomb was detonated in Hiroshima, they were the first plants to re-grow and were free of signs of genetic mutation. Partly because of their hardiness, the trees are frequently planted in large cities such as New York and Tokyo. The ginkgo leaf contains many active ingredients, including flavonol and flavone glycosides, diterpene lactones, ginkgolides, sesquiterpenes, iron-based superoxide dismutase, p-hydroxybenzoic acid, ascorbic acid, and catechin. The crude drug formulation of ginkgo is obtained from the dried green leaves. An acetone-water mixture is used to extract and concentrate the active constituents and remove toxic compounds such as ginkgolic acids. The German government has approved a standardized form of ginkgo leaf extract (Egb761) which contains 22% to 27% flavonoid glycosides, 5% to 7% terpene lactones, and , 5 parts per million of ginkgolic acids. The flavonoid glycosides are considered to be a major active ingredient in the extract, and manufacturers commonly standardize their product to a flavonoid glycosides content of 24%. Ginkgolic acids are potentially allergenic and toxic; they share similar properties to the urushiols that are found in mango rind, cashew nut shells, and the sumac-poison ivy family. How might this living fossil help patients with dementia or peripheral arterial disease? A common pathway for both diseases may be improved tissue perfusion and increased tolerance of hypoxia. The flavonoid glycosides seem to have antioxidant activity, and they may reduce endothelial cell injury due to free radical oxidation, thereby reducing the progression of atherosclerosis (11, 12). Flavonoids may also protect hypoxic tissue. In the early phases of brain ischemia, massive release of free fatty acids and the accumulation of platelet activating factor result in the production of free radicals that are extremely neurotoxic. Ginkgolide B, a terpene, is a platelet-activating factor antagonist and may provide some of the neuroprotective and antithrombotic properties attributed to ginkgo (13–15). Additional suggested mechanisms include reduced capillary fragility and decreased erythrocyte aggregation activity (13,16). Finally, the flavonoid glycosides and ginkgolide B may inhibit other events, which include platelet aggregation, platelet adherence, and oxidized lipoprotein formation, that lead to atherosclerosis and vascular injury. In this issue of The Green Journal, Pittler and Ernst report the results of their meta-analysis of the use of Ginkgo biloba extract for patients with intermittent claudication (17). Peripheral arterial disease affects about 1 in 8 elderly patients (18), although not all have intermittent claudication (19). While the majority of nondiabetic patients with this condition remain stable, approximately 10% to 15% have progressive disease, and some require amputation. Therapeutic interventions are targeted at reducing cardiovascular risk factors, especially tobacco smoking, and promoting regular exercise with the goal of increasing exercise tolerance. Pharmacologic treatment has been less successful; in particular, vasodilators have not proven effective. Current options approved by the Food and Drug Administration (FDA) include pentoxifylline and cilostazol. It can be difficult to determine the efficacy of therapies for intermittent claudication. Proper evaluation requires using objective measures such as exercise performance and hemodynamic measurements, as well as subjective measures that include questions about walking impairment, physical activity, and general health status (20). In the meta-analysis reported in this issue of The Green Journal, Pittler and Ernst used pain-free and maximal walking distance as their primary outcomes. There is controversy about which of these two measurements provides a better assessment of clinical status. Recently, Muller-Beuhl and colleagues evaluated a cohort of 150 patients to determine which of these two parameters was more closely associated with angiographic findings and Am J Med 2000;108:341–342. From the Osher Center for Integrative Medicine (BPJ) and Department of Medicine (BPJ, WSB), University of California at San Francisco, San Francisco, California. Correspondence should be addressed to Bradly P. Jacobs, MD, Senior Clinical Research Fellow, Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, California 94121.

Web-based trial to evaluate the efficacy and safety of tolterodine ER 4 mg in participants with overactive bladder: REMOTE trial

INTRODUCTION Participatory patient-centered, web-based methods could streamline and improve the convenience of clinical trial participation. We used an entirely web-based approach to conduct a randomized, placebo-controlled, Phase 4 (REMOTE) trial under an Investigational New Drug (IND) application to evaluate tolterodine extended release (ER) 4 mg for overactive bladder. METHODS The trial was designed to replicate previous clinic-based trials of tolterodine ER but was conducted via the web from one clinical site overseen by physicians. Participants were recruited via the web, screened for eligibility using web-based questionnaires, had laboratory testing in their community, and entered a run-in phase requiring bladder e-diaries. Informed consent was obtained using an interactive web-based method with physician countersignature. Study medication was shipped directly to participants. RESULTS With a goal of 283 randomized participants, 5157 registered on the trial website. Of 456 who passed initial screening, identification verification, and signed consent, 237 passed additional medical screening and were countersigned by the investigator. After laboratory testing, 118 entered the placebo run-in; only 18 passed e-diary assessments and were randomized to treatment. At week 12, the mean change from the baseline in micturitions/24 hours (primary endpoint) was -2.4 for tolterodine ER versus -0.8 for placebo [treatment difference (95% CI): -1.6 (-3.9, 0.6)]. CONCLUSION The REMOTE trial is the first entirely web-based trial conducted under an IND application. The efficacy observed was consistent with results from conventional trials. With simplification of multi-step screening and testing, web-based trials or their component parts should provide a participant-friendly approach to many clinical trials.

Integrative Tumor Board: Recurrent Breast Cancer or New Primary?

History of present illness: 1994 – Bilateral mammogram revealed bilateral benign calcifications confirmed by ultrasound. 1995 – increase in calcifications in the left breast. Excisional biopsy – 2.5 × 2 × 2 cm tumor positive for welldifferentiated intraductal and infiltrating ductal carcinoma, grade I. Borderline high S-phase. Estrogen and progesterone receptors positive. Her-2/ neu is negative. 1996 – Left axillary dissection, which revealed 1/17 positive lymph nodes. 1996 – Patient received cytoxan, methotrexate, 5-FU (6 cycles) with radiation sandwiched in between at 6,640 cGy over 36 fractions. Patient was then on tamoxifen for 5 years. Patient did well with routine physical exams, mammograms, and occasional ultrasounds until spring 2002 when a mammogram revealed a cluster of calcifications in the left breast. Left breast lumpectomy revealed an infiltrating ductal carcinoma with clear margins. Estrogen receptor positive. Progesterone receptor negative. Her-2/neu negative. Within 1 month, the patient was started on Arimidex. Whole body PET/CT scan was negative for metastatic disease. BRCA-1 and 2 = negative.