UA Pharmacy Researcher To Study the Adverse Effects of Street Drug 'Ecstasy'

[Source : Karin Lorentzen, UA School of Pharmacy] - The National Institute on Drug Abuse has awarded a researcher at The University of Arizona College of Pharmacy $1.7 million for a nearly five-year study of the long-term adverse effects of the street drug ecstasy, also known as the “hug drug.

Terrence J. Monks, PhD, head of the college’s Department of Pharmacology and Toxicology and a BIO5 member, is a specialist in the study of drug toxicology, or the “bad” effects of drugs. He will be the principal investigator on the ecstasy project.

“Most research on ecstasy focuses on the pharmacological, or nontoxic effects of the drug,” says Monks. “My interest lies in learning how the drug negatively affects the brain.”

Classified as a Schedule I substance, ecstasy has been controlled in the United States since 1985. Ecstasy (also known as MDMA, or methylenedioxymethamphetamine) is a synthetic, psychoactive drug that is chemically similar to the stimulant methamphetamine. It produces an energizing effect as well as feelings of euphoria, emotional warmth, and distortions in time perception and tactile experiences.

These effects of MDMA have contributed to its popularity as a “party drug” among adolescents and young adults who frequent weekend-long “raves” or “techo-parties.” However, the drug has a serious down side.

“A number of adverse effects are associated with the use of MDMA,” says Monks. “MDMA use and abuse therefore has the potential to give rise to a major public health problem.”

According to the U.S. Department of State, the short-term negative effects of ecstasy can be nausea, dilated pupils, dry mouth and throat, and lower jaw tension. Use of the drug often leads to dramatic increases in body temperature exceeding 100 degrees Fahrenheit, which in turn can lead to muscle breakdown and kidney and cardiovascular system failure. This hyperthermic response can therefore result in fatal blood clotting, heart attacks and strokes.

Scientific studies have found that ecstasy use also produces long-term damage to the brain’s ability to release serotonin, which regulates mood, body temperature and memory.

“Ecstasy may be the only amphetamine-based drug that attacks the serotonin system,” says Monks. “There is little doubt that it has the potential to be toxic to the human nervous system. The question is how.”

Monks’ research will focus on the process by which ecstasy is metabolized by the body. When the drug enters the body orally in pill form (the manner in which it is usually taken), enzymes in the body convert it either to harmless metabolites or into toxic metabolites. Predicting which people process ecstasy into toxic metabolites more readily than other people is the challenge.

“Individuals metabolize ecstasy differently,” says Monks. “If 100 people take ecstasy, perhaps five will metabolize the drug very efficiently, whereas five others will metabolize the drug poorly. Since metabolism of ecstasy is required for it to produce neurotoxicity, the individual who efficiently metabolizes the drug will likely be more susceptible to the long-term adverse effects.”

The UA professor is believed to be the only researcher in the U.S. studying the role of metabolism in the neurotoxicity of the drug.

The results of Monks’ research will help people understand which individuals are more likely to suffer long-term negative effects of ecstasy.

“The multitude of adverse effects resulting from the misuse of ecstasy necessitates a complete understanding of the neuropharmacology and neurotoxicology of this unusual amphetamine derivative,” says Monks. “We hope to help define important factors that contribute to individual susceptibility to the long-term adverse effects of this drug.”

Answering the Question: ‘Which Drug Therapy Is Right for Me?’

[Source: Karin Lorentzen, AHSC Office of Public Affairs] - In the world of pharmaceutical science, the question of why two very similar individuals can react differently to a drug is the subject of intense interest.

At The University of Arizona College of Pharmacy, researchers are striving to find answers to seemingly simple questions asked by patients, such as, "Why did I have to try three different high blood pressure medications before my doctor found one that worked for me?" and "Why did my cancer stay in remission with drug treatment, but my friend who had the same treatment was not so fortunate?"

At the basis of the answers to these questions is a field of study called pharmacogenomics, the analysis of how the expression of the human genome, the DNA code that instructs the making of the machinery of a cell, is key to the body's response to drugs.

"Importantly," said Walt Klimecki, assistant professor at UA College of Pharmacy, "pharmacogenomics helps us understand why two apparently similar individuals could have very different responses to the same drug. It holds the promise that drugs might one day be tailor-made for individuals and adapted to each person's own particular makeup."

In his lab at the UA's BIO5 Institute, Klimecki and Alicia Bolt, a graduate student in pharmacology and toxicology, are conducting pharmacogenomic research on a collection of white blood cells taken from about 200 healthy individuals from diverse global populations in the United States, China and Africa. The cells have been manipulated experimentally so that they can easily be grown in a plastic flask with growth media. Klimecki stores stocks of these individuals' cells in a lab freezer at the BIO5 Institute – a "town in a tube," he said.

This system allows Klimecki and Bolt to explore the diversity of individual variation in drug response in a much more controlled way than could be possible with the short-lived samples taken directly from human study participants.

In the lab, Klimecki and Bolt expose the white blood cells to arsenic trioxide, a relatively recent addition to the cancer-treatment arsenal in the United States, to measure how different expression patterns of the genome can predict response to this anti-cancer drug.

To measure differences in drug response, they use a technology called microarrays, a highly miniaturized analysis technology that allows scientists to measure the levels of each and every product contained in the master recipe book that is the human genome. For example, on one typical microscope slide, 44,000 such products can be measured four separate times.

Bolt reported he results of the research this month at the Mountain West Society of Toxicology meeting. In her abstract, Bolt states that a frequent observation in humans is the scenario of a relatively uniform toxicant exposure that is associated with a variable response. "The results are exciting," said Bolt. "Our observations suggest that this cell line model reproduces the inter-individual variation seen in arsenic-induced cell-killing observed in humans."

"Our research to date is encouraging," Klimecki said, "but these are complicated problems to solve. We need to study the effects of both genetics and the environment. The long-term solutions to these complex problems are going to involve multidisciplinary teams that include pharmacist-scientists, pharmacologists, toxicologists, chemists and computational/statistical scientists. But the results will be worth the work. These approaches and tools are an important part of the movement away from ‘trial-and-error' drug selection to the more individually targeted drug choices that are on the horizon."

Madeira Therapeutics Names J. Lyle Bootman to Board of Directors

[Source: Business Wire] - Madeira Therapeutics, a new drug-development company specializing in pediatric pharmaceuticals, has announced the addition of a notable pharmaceutical industry veteran to its Board of Directors. According to Madeira CEO Peter S. Joiner, J. Lyle Bootman, PhD, ScD, Dean of the University of Arizona College of Pharmacy will take an active role in the direction of the company.

Dr. J. Lyle Bootman is professor of pharmacy, medicine and public health, and a Fellow of several professional associations including the American Pharmacists Association, American Association of Pharmaceutical Scientists and the American College of Apothecaries. He is the author of Principles of Pharmacoeconomics and the founding and executive director of the University of Arizona Center for Health Outcomes and PharmacoEconomic (HOPE) Research, one of the first such centers in the world. He is former president of the American Pharmacists Association and President Emeritus of the Pharmacy Therapeutics Society.

Dr. Bootman recently received the 2008 Remington Honor Medal, widely considered the profession's highest honor.

"This is a significant step in the growth and development of Madeira," stated Pete Joiner, CEO, Madeira Therapeutics. "Our strategy focuses on the reformulation of pediatric pharmaceuticals for appropriate dosage levels in children. Dr. Bootman is a renowned expert--his knowledge and guidance will serve us well. It is an honor to have him join our Board of Directors."

Madeira Therapeutics is a new drug-development company specializing in pediatric pharmaceuticals. The Madeira strategy focuses on reformulating approved adult drugs for better dosage control in children. A cholesterol drug is already in the development pipeline and the company has plans to develop formulations for acute pain management and diabetes. Madeira intends to utilize the FDA's 505(b)(2) approval method, which relies in part on the FDA's findings for a previously approved drug, thereby shortcutting IND approval by years and tens of millions of dollars. For more information, contact Peter Joiner, (913) 661-1962, or via email at pjoiner@madeiratherapeutics.com.

ClinXus joins international Critical Path Institute Consortium

[Source: Sarah Lamb, Van Andel Institute] - ClinXus, a Grand Rapids-based, life-sciences alliance, recently became the first non-profit organization to join the Critical Path Institute’s Predictive Safety Testing Consortium (PSTC). Critical Path Institute supports the U.S. Food and Drug Administration (FDA) with collaborative research and education programs that enable the safe acceleration of medical product development. The PSTC brings pharmaceutical companies together to share and validate each other’s safety testing methods under advisement of the FDA and its equivalent in Europe, the European Medicines Agency (EMEA). “The PSTC has been described as a model for modernizing the development of medicinal products,” said ClinXus Board President Craig P. Webb, Ph.D., Van Andel Institute scientific investigator and director of translational medicine. “It allows pharmaceutical companies and partners to share knowledge and resources to bring life-saving drugs to the FDA more quickly and safely.”

The FDA launched the Critical Path Initiative in March 2004, to identify medical product development problems and opportunities for improvement. The study identified the process for preclinical and clinical testing of drugs as a major contributor to delays in drug development. Critical Path Institute was established in 2005 as an independent nonprofit research and education institute to facilitate collaboration between scientists in government, industry and academia. In March 2006, Department of Health and Human Services Secretary Mike Leavitt, announced the formation of the PSTC involving scientists from the FDA, Critical Path Institute and several of the United States’ largest pharmaceutical companies to share internally developed laboratory methods to predict the safety of new treatments before they are tested in humans.

The initial PSTC members include Bristol-Myers Squibb Company, GlaxoSmithKline, Johnson & Johnson Pharmaceutical Research & Development, LLC, Merck and Co., Inc., Novartis Pharmaceutical Corporation, Pfizer, Inc., Roche Palo Alto, LLC, and Schering Plough Research Institute. Since that time, the PSTC has added seven additional pharmaceutical industry members and invited EMEA to serve in an advisory role similar to that of the FDA.
William Mattes, Ph. D., director of the PSTC noted, “The PSTC has made rapid progress since its inception last year and this is a testimony to the commitment and willingness of the member companies to share their testing methods and data. We have already found a number of improved tests for drug safety that can be used in the early stages of drug development. ClinXus will greatly facilitate the next phase that includes clinical evaluation of these new tests.”

ClinXus, a life-sciences alliance dedicated to introducing molecular biomarkers into the clinical trial process, a fundamental component of personalized medicine, becomes the first non-profit organization to join the consortium. ClinXus was formed in July 2006, with the assistance of a $1.5 million grant from the Michigan 21st Century Jobs Fund in addition to funding and in-kind donations from each of the six member institutions. The alliance uses the expertise and services of each member institution to provide a single point of contact for clinical research clients, as well as patients and physicians that participate in clinical studies. Its focus is to develop innovative clinical trials that are primarily biomarker driven, involving new medicines, devices and diagnostics in all stages of testing. ClinXus’ members include Van Andel Institute (VAI), Spectrum Health, Saint Mary’s Health Care, Jasper Clinical Research & Development, Grand Valley State University (GVSU) and Grand Valley Medical Specialists. For more information, contact Joe Gavan, (616) 234-5390.