Dr. Steven Brody, Ethel Brody, Dr. Paul Hollenberg & Dr. J.R. Haywood

Hollenberg Awarded 2011 Theodore M. Brody Lectureship

Paul F. Hollenberg, PhD, Professor and Chair of the Department of Pharmacology at the University of Michigan Medical School Ann Arbor, MI was awarded the 2011 Theodore M. Brody Lectureship on November 14, 2011.

The topic of his seminar was:

MECHANISM-BASED INACTIVATORS OF CYTOCHROME P450:PROBES OF STRUCTURE AND FUNCTION

Dr. Kenneth E. Moore & Dr. Nancy Kanagy

Nan Kanagy: 2011 Kenneth E. Moore Distinguished Alumna Awardee and Recipient of the “Golden Sovereign”

Nancy Kanagy, PhD, Professor, Dept of Physiology & Cell Biology

Sparkenbaugh Earns PhD, Accepts Post-Doc Position at UNC

Congratulations to Erica Sparkenbaugh on completing the requirements for a PhD and the successful defense of her dissertation.

Dr. Sparkenbaugh conducted her PhD research in Dr. Robert Roth’s laboratory.  She will be moving to the University of North Carolina in Chapel Hill to start a postdoctoral fellowship in the McAllister Heart Institute.

“I don’t need help because if I can’t help myself I can’t be helped.” --Amy Winehouse

“Amy Winehouse found dead at her London flat…autopsy inconclusive…toxicology results expected in two to four weeks.” 

by Jane Maddox, Ph.D., Assistant Professor
Department of Pharmacology and Toxicology

Why do forensic toxicology results take so long? There are several reasons:

Multiple samples must be tested: blood, stomach contents, and urine are commonly first taken, but other tissues such as liver, brain, kidney, and vitreous humor of the eye may also be sampled.

If there are no obvious signs or symptoms linked to specific drugs or toxins observed at the time of death, testing for many different toxic substances must occur.

The tests must identify and quantify a wide repertoire of both legally prescribed drugs and illicit substances to determine if either any single drug or combination of drugs could have been the cause of death.

The initial tests would likely be immunoassays to screen for a wide variety of drugs suspected as the cause of death. These tests use antibodies to detect known drugs, but they can only measure a predetermined set of substances; therefore, if a new or unknown drug has been taken, it can be missed. Other analyses, such as mass spectrometry (that can identify unknown toxic substances) must also be performed.  Mass spectrometry is very sensitive and specific, but it also takes more time to complete.

Once potentially toxic substances have been detected, the concentrations in the sample must be compared with clinical data to determine if the dose, or combination of doses, was high enough to be lethal. In addition, samples may be retested in the same laboratory or sent to a second laboratory for confirmation. Again, these tests take more time. Confirmatory tests are important for several reasons: 1) to ensure scientific integrity of the data, 2) to defend against potential legal issues involved in cause of death, particularly in the case of a celebrity death.

As for the death of Amy Winehouse, it is complicated.

She was alone at the time of death, so no symptoms were observed, and it was reported that no drugs or paraphernalia were found on the premises. Therefore, important clues to direct the toxicology testing were lacking and the search could take some time to complete.

by James J. Galligan, Ph.D., Associate Chair,

Chantix (Varenicline) is one of the most popular smoking cessation drugs available by prescription.  However, a number of problems with this drug have been identified and this has led to many restrictions on its use.  These problems include an increased incidence of depression, suicidal thoughts, lightheadedness and fainting.

Results of a recent study published in the Canadian Medical Association Journal add another potential problem for Chantix.  These investigators conducted a meta-analysis of 14 published papers describing the beneficial and negative effects associated with Chantix when used to treat nicotine addiction.  The investigators included only double-blind randomized controlled trials in their analysis.  This means that subjects and investigators did not know who was receiving Chantix vs. placebo (simply a sugar pill with no active ingredients) and subjects were assigned to the Chantix or placebo group randomly.  This reduces the chance that subjects at risk for cardiovascular problems were assigned more frequently to the Chantix group.  The investigators analyzed data from 8,216 subjects.  Their study revealed a small but statistically significant increase in the risk for cardiovascular problems such as heart attacks or strokes in the subjects taking Chantix.  Although there was a difference, it was small.  In the Chantix group 52 of 4908 (1.06%) subjects experiences a so called adverse cardiovascular event while in the placebo group 27 of 3308 (0.82%) subjects experienced the same kind of event.

There are some points worth discussion here.  Firstly, it is not surprising that Chantix might be associated with cardiovascular complications.  Chantix is a nicotine replacement therapy.  Therefore, Chantix shares many of the same pharmacological actions of nicotine.  Cigarette smoking does increase the risk of cardiovascular disease partly because cigarette smoke contains nicotine (cigarette smoke also contains carbon monoxide and other toxins which are not present with Chantix).  Nicotine increases blood pressure and increase blood clots which can cause heart attacks and strokes and Chantix may do this as well.  Secondly, although the increased risk for adverse events in the Chantix group was small, the overall sample size was also small (<5,000 subjects).  Worldwide, there are millions of people using Chantix to help kick the smoking habit and therefor a much larger number of patients might be at risk worldwide.

Finally, it is important to remember that all drugs cause side effects (some worse than others).  When deciding whether or not a drug should be used, the doctor and patient must consider the risk vs. the benefit.  Chantix might produce a small increase in the risk for a heart attack or stroke in a patient trying to kick the nicotine habit.  But, what is the heart attack/stroke risk for that patient if he/she continues to smoke?  Many smokers become former smokers without the need for drugs like Chantix but there are also many smokers who have quit hundreds of times.  This is the subset of people who are most likely to benefit from nicotine replacement treatments.  Larger studies will likely reveal the real risk/benefit ratio of Chantix when used to treat nicotine addiction.

In the meantime, the wise person will discuss these issues with their doctor before using Chantix to help kick the smoking habit.

Additional information available can be found at:

• Nature News Blog
• CNN
• “Pfizer questions findings of new report on smoking-cessation treatment Chantix” – mlive.com

Nicotine is a highly addictive drug and kicking the smoking habit has proven to be extremely difficult for many cigarette smokers.

Several smoking cessation strategies work reasonably well in the short term (3 months or so) but relapse rates are greater than 80% after 1 year.  There are a variety of reasons why smokers relapse but a strong relapse predictor is body weight gain, particularly in women.

Nicotine does decrease body weight and it does so by several mechanisms.  Nicotine acts in the brain to inhibit the brain regions that regulate appetite.  Nicotine also acts on fat cells to stimulate fat breakdown and it also stimulates energy expenditure (metabolism) by cells throughout the body.  Without nicotine onboard, appetite increases, fat breakdown and metabolism decrease and before you know it, the ex-smoker has put on 10 or more pounds.  After a peak in the mirror, the ex-smoker becomes a former ex-smoker.  If there was some way to prevent the weight gain, smoking relapse rates would likely fall and this would be beneficial for the individual smoker and for the overall health profile of the U.S population.

A new study published in Science magazine may provide some hope that the appetite and body weight gain can becontrolled in the abstinent smoker.  These studies were done in mice where food intake and body weight were monitored after treatments which stimulated or blocked receptors for nicotine were tested.

Nicotine does have specific targets (receptors) in the brain where it produces its addictive actions.  The nicotinic receptors are found on neurons in the ventral tegmental area that use dopamine as a neurotransmitter and these neurons are in the reward pathways in the brain.  However, receptors for nicotine are also found in a region of the brain called the hypothalamus which is responsible for regulating appetite (among other things).  The study in Science revealed that the nicotinic receptors were found on a subset of neurons called POMC neurons and nicotine and a related drug activated these neurons.  POMC is an abbreviation for a protein known as pro-opiomelanacortin.  This in an interesting protein because it breaks down into three important smaller proteins: endorphin (the body’s natural opiate), melanocortin and adrenoccorticotrophin (which stimulates the adrenal gland).  The connection between endorphin and adrenocorticotrophin and nicotine induced appetite regulation was not investigated in this study.  However, it looks like melanocortin may be a key player here because when receptors for melanocortin were “knocked down” nicotine was no longer able to suppress feeding in these mice.

These studies were done in mice and there is a long way to go before these results can be translated into safe and effective treatments for nicotine addiction in human smokers.

These studies were also done in nicotine naïve mice; they were not nicotine addicted.  It is known that nicotine changes the nervous system in nicotine-addicted mice and humans so the role of melanocortin in appetite regulation needs to be studied in nicotine addicted mice.  However, these studies do provide new and important data about the complex mechanisms that regulate appetite and feeding behaviors and how these mechanisms may overlap with the reward pathways in the brain.  This could eventually lead to effective suppression of appetite in nicotine abstinent smokers leading to more appealing reflections in the mirror.