FDA Withdraws Avastin Approval for Breast Cancer
Nov18

FDA Withdraws Avastin Approval for Breast Cancer

  As reported around the wires today, US FDA Commissioner Dr. Margaret A. Hamburg formally revoked the accelerated approval of the antiangiogenic drug Avastin (bevacizumab) for breast cancer treatment. Avastin is a humanized mouse antibody that binds and inactivates the vascular endothelial growth factor VEGF-A, a mediator of blood vessel growth. Andrew Pollack at The New York Times does a nice job condensing this episode for us. The highlights are that Avastin was approved based on the surrogate endpoint of progression-free survival in metastatic breast cancer, meaning that it appeared to increase the time from treatment to return of the growth of cancer metastases. However, the true endpoint is long-term patient survival. There, subsequent studies showed that Avastin had no benefit. Moreover, Avastin also use appears to increase the risk of hemorrhage and bowel perforation. These are potentially life-threatening side effects and are considered too great of a risk when no statistical benefit of survival or quality of life are apparent. Of course, there are cases of individual patients who have benefited from Avastin and many questions remain for them. In the 69-page ruling made available today (PDF), Dr. Hamburg includes a well-articulated Q&A for patients and their caregivers. I doubt seriously that the full text of this section will be published in the mainstream media, although Pollack does provide the hyperlink. I found this quite valuable as someone who cares about family and friends with breast cancer. But the text also provides an espeically close look at the rationale behind the US drug approval process. As this rich information is buried in a 69-page federal document, I wanted to provide this text here for ease of reading by those concerned about this ruling. This following statement is from US FDA Commissioner Dr. Margaret Hamburg. The full text is in the public domain and can be accessed here.   I. AN EXPLANATION FOR PATIENTS AND THOSE WHO SUPPORT THEM This document, which lays out the basis for my decision, has several purposes. It is an explanation, for physicians, scientists, patients and the public in general, of the data available on the metastatic breast cancer indication for Avastin and of FDA’s evaluation of those data. It also describes how FDA has applied the law and its regulations in making the decision to withdraw the approval for that indication. I know I speak on behalf of the many physicians that have been involved with this issue here at the Food and Drug Administration and elsewhere in saying that we encourage patients and those who support them, to ask hard questions and to demand explanations concerning the drugs that are recommended to...

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K2 Synthetic Marijuana: Heart Attacks, Suicides, and Surveillance
Nov14

K2 Synthetic Marijuana: Heart Attacks, Suicides, and Surveillance

Sixteen-year-old boys having heart attacks. Blog reports of deaths and suicides. And a little known chemistry and public health resource mobilized to identify “legal highs.” The chemical and biological phenomenon that is “synthetic marijuana” continued to develop over the last week as we learn more about these products from the medical and public health communities. Most notably, pediatric cardiologists reported in the journal Pediatrics on three cases of Texas teenagers who experienced myocardial infarctions – heart attacks – after using a synthetic marijuana product (DOI: 10.1542/peds.2010-3823). (Many thanks to Dr. Ivan Oransky, Executive Editor at Reuters Health, for providing us with primary information after their own excellent report by Frederik Joelving). Brief background Sold under names like K2 or Spice as “incense” or “potpourri” and labeled as “not intended for human consumption,” these products are laced with one or more synthetic psychoactive compounds that were published in 1990s work studying structure-activity relationships on cannabinoid receptors. The vast majority of the synthetic work was done in the laboratory of Dr. John W. Huffman, now professor emeritus of the Department of Chemistry at Clemson University, with his compounds know by “JWH-” nomenclature. The US Drug Enforcement Agency secured emergency prohibition of five of these compounds late last year, spurring “legal highs” manufacturers to reformulate second-generation Spice products containing related compounds not explicitly designated as illegal. Although the DEA does have the authority to prosecute sale and possession of these analogs, such action is rare. To learn more, we’ve put together a compilation of our synthetic marijuana posts for the reader’s further reference. Adolescent heart attacks In this week’s advance Pediatrics publication, the three cases – all in 16-year-old boys – were seen at the UT-Southwestern Medical Center in Dallas within three months of one another. The common presentation was a 3- to 7-day history of chest pain with myocardial infarction confirmed by electrocardiographic and biochemical endpoints (ST elevation in the inferolateral leads and substantial increases in cardiac troponin-I released into the bloodstream). As you might predict, heart attacks are extremely rare in otherwise healthy 16-year-olds. But marijuana itself is known to cause cardiac effects, with rare cases of myocardial infarction. In the discussion of the Pediatrics report, Dr. Arshid Mir and colleagues describe literature extending back to 1979 (DOI: 10.3109/15563657909010604) on the increased risk of cardiac disturbances, including myocardial infarction, within the first hour of marijuana use. Increased heart rate is a well-recognized effect of marijuana that is mediated by increased sympathetic nervous system outflow to the heart. This 1976 paper in Circulation describes how the majority of this tachycardia can be prevented by premedication with the non-selective beta-blocker, propranolol. But what about...

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NCCU Dinner with Discoverers: Chemist, Dr. Mansukh Wani
Nov05

NCCU Dinner with Discoverers: Chemist, Dr. Mansukh Wani

The NCCU Eagles RISE program is a NIH/NIGMS research education program for which I serve as principal investigator at North Carolina Central University in Durham. When I moved to the Research Triangle area, I had the opportunity to work as a pharmacologist with the late Dr. Monroe Wall and Dr. Mansukh Wani, scientists who with colleagues discovered the anticancer compounds, taxol and camptothecin. I first came to know of Dr. Wani while I was a graduate student in 1987 while attending a DNA topoisomerase chemotherapy conference at NYU in Manhattan. To be honest, I was too nervous to even introduce myself to this legend of natural products chemistry. Almost 25 years later, I am now blessed to call him a family friend. One of the other joys I have is sharing the now 86-year-old Dr. Wani and his story with my students. Here’s a recap of our visit with him as posted on our NCCU Eagles RISE blog:   On the evening of October 26th, we had the remarkable pleasure to have dinner with Dr. Mansukh Wani, Chemist Emeritus of RTI International (formerly Research Triangle Institute). Together with his longtime collaborator, the late Dr. Monroe Wall, Dr. Wani and colleagues isolated and determined the structures of the anticancer drugs Taxol and camptothecin. Taxol has been a mainstay in the treatment of breast and ovarian cancer while camptothecin gave rise to two, semi-synthetic FDA-approved drugs: topotecan (Hycamtin) and irinotecan (Camptosar). For these discoveries they received numerous awards culminating in the naming of the RTI Natural Products Laboratory as a National Historic Chemical Landmark of the American Chemical Society in 2003. The landmark application was led by Dr. Nick Oberlies, now in the Department of Chemistry and Biochemistry at the University of North Carolina at Greensboro; Nick and I reformulated the application and supplementary historical information into a 2004 review article in the Journal of Natural Products (DOI: 10.1021/np030498t) In this interview for an Indian publication in the Research Triangle, Dr. Wani shares what it was like to move to North Carolina in 1962. He graciously accepted our invitation to tell these and other stories to us at Sitar Indian restaurant, a Durham favorite. Rather than recap his discussion of his career, we thought it would be more valuable to share with you student insights from their evening with this remarkable, warm, and humble man. From Adama Secka, M.S. Candidate, Pharmaceutical Sciences: Wednesday, October 26th 2011 will be a day that I will always remember for the rest of my life; I met the most incredible man in our science world. He was most genuine, kind, patient, and supportive – I mean he is...

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Intravenous Milk Thistle for Mushroom Poisoning
Nov03

Intravenous Milk Thistle for Mushroom Poisoning

Apologies to readers for the radio silence – a heavier-than-usual load at the day job has been compounded by what I hope is not a prelude to a similar, serious bout of pneumonia I had almost two years ago. In the meantime, I wanted to share with you a chemistry-relevant post I wrote for my monthly gig at Science-Based Medicine on 28 October 2011. The comments there evolved into a mouth-watering discussion of culinary mushrooms. Enjoy! If you’ve been fortunate to live in the parts of the US that were soggier than usually as of late – or unfortunate enough to have had flooding from hurricanes and tropical storms – then you’ve be noticing a tremendous burst of mushrooms. For mycologists – mushroom enthusiasts – there are two classic chestnuts: “There are old mushroom collectors and bold mushrooms collectors, but there are no old, bold mushroom collectors.” Or, in a more concise Croatian proverb, “All mushrooms are edible, but some only once.” As such, this is the time of year that emergency rooms and regional poison centers begin to see a burst in poisonings from mushroom ingestion, due primarily to amateur misidentification of the fruiting bodies. Just this past week, Jason McClure at Medscape Oncology News (free reg req’d) wrote about the unusual bloom of mushrooms in the northeastern US and the concomitant bloom of mushroom poisonings this fall. But “mushroom poisoning” is an imprecise diagnosis for the ER physician. The constellation of symptoms caused by toxic mushrooms is as diverse as the colors and shapes of these wonders of nature. From another Medscape article on emergency management of mushroom poisoning by Dr. Rania Habal from the Emergency Medicine department of NYU: Mushrooms are best classified by the physiologic and clinical effects of their poisons. The traditional time-based classification of mushrooms into an early/low toxicity group and a delayed/high toxicity group may be inadequate. Additionally, many mushroom syndromes develop soon after ingestion. For example, most of the neurotoxic syndromes, the Coprinus syndrome (ie, concomitant ingestion of alcohol and coprine), the immunoallergic and immunohemolytic syndromes, and most of the GI intoxications occur within the first 6 hours after ingestion. Ingestions most likely to require intensive medical care involve mushrooms that contain cytotoxic substances such as amatoxin, gyromitrin, and orellanine. Mushrooms that contain involutin may cause a life-threatening immune-mediated hemolysis with hemoglobinuria and renal failure. Inhalation of spores of Lycoperdon species may result in bronchoalveolitis and respiratory failure that requires mechanical ventilation. Mushrooms that contain the GI irritants psilocybin, ibotenic acid, muscimol, and muscarine may cause critical illness in specific groups of people (eg, young persons, elderly persons). Hallucinogenic mushrooms may...

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