Interactive Columns

MI This Month: The Case for Clinical Trials of Therapeutic Cancer Vaccines in the Prophylactic Setting

2010-08-31T14:54:00Z

Tumor cells frequently express antigens that allow them to be specifically targeted and destroyed by the immune system. Many tumor immunotherapy clinical trials have been conducted, directed at several types of cancer using myriad antigens and multiple immunization strategies. Despite this, only one therapeutic cancer vaccine, sipuleucel-T, has been approved. A groundbreaking study by Jaini et al. recently demonstrated that prophylactic immunization against a breast cancer associated antigen can prevent tumor development, and is far more effective than therapeutic vaccination. This study highlights the urgent need to rethink the clinical testing of tumor immunotherapies; it is time to consider clinical trials of cancer vaccines in the prophylactic setting. See article at Mol. Interv. 2010, 10:197-203.

JPET Highlight: Preventing Doxorubicin Cardiotoxicity through the Selective Inhibition of Phosphodiesterase 5

2010-08-26T14:54:00Z

Antineoplastic anthracycline therapy is limited by the cardiotoxicity of this class of compounds, and there is a continuing need to investigate and develop effective therapeutic agents to reduce cardiac damage induced by the anthracyclines. Inhibition of phosphodiesterase 5 has been shown to have protective effects in cardiac ischemia/reperfusion injury in rats; therefore, Koka et al. investigated the cardioprotective effects of the selective phosphodiesterase 5 inhibitor tadalafil on doxorubicin-induced cardiac damage and sought to delineate the cellular and molecular mechanisms underlying its cardioprotective effects. In an acute model of doxorubicin-induced cardiac damage, tadalafil significantly improved cardiac contractile function, attenuated doxorubicin-induced apoptosis and depletion of prosurvival proteins (including Bcl-2 and GATA-4 in the myocardium), attenuated cardiac oxidative stress through the up-regulation of mitochondrial superoxide dismutase, and increased cGMP levels and PGK activity in the myocardium; all of this was observed without a significant effect on the efficacy of doxorubicin. These results suggest that prophylactic treatment with tadalafil might be a promising therapy for doxorubicin-induced cardiotoxicity. See article at: J Pharmacol Exp Ther 2010, 334:1023-1030.

Neuropharmacology Division Blog & Facebook Page

2010-08-16T14:54:00Z

Thanks to efforts by Hibah Awwad and Badr Mostafa, the ASPET Neuropharmacology Division now has its own blog and a presence on Facebook. Check out the initial blog post: "Do postdoctoral fellowships need better structured programs?"

JPET Highlight: Dopamine D2 or D3 Antagonism for Treating Cocaine Addiction?

2010-07-26T14:54:00Z

At present, there are no effective therapies to treat cocaine addiction or relapse. The role of specific dopamine (DA) receptors has been hampered by the lack of selective agents for D2 and D3 receptors, and the restricted distribution of D3 receptors has led to speculation that selective D3 antagonists may be therapeutic without extrapyramidal side effects of nonselective antagonists. Achat-Mendes et al. investigated the role of D2 and D3 receptors in abuse-related effects of cocaine with selective agonists and antagonists in squirrel monkeys. The authors demonstrated that selective D3 antagonism with PG01037 [N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2- enyl}-4-pyridine-2-yl-benzamide HCl] does not inhibit cocaine self-administration, similar to findings with other D3 antagonists; therefore, selective D3 antagonists would not decrease cocaine use in active drug users. However, D3-selective antagonists may blunt some aspects of the subjective effects of cocaine and forestall relapse in abstinent cocaine abusers. These results demonstrate novel, important evidence in non–human primates, supporting the discovery of novel D2- and D3-preferring ligands for in vivo investigations that could help guide the development of effective therapies for cocaine addiction and relapse. See article at: J Pharmacol Exp Ther 2010, 334:556-565.

DMD Highlight: Methadone is an Inactivating Substrate for Aromatase

2010-07-25T14:54:00Z

Aromatase is a steroid-metabolizing enzyme, once thought to only catalyze the conversion of androgens to estradiol and estrone. However, results reported by Lu et al in the August, 2010, issue of Drug Metabolism and Disposition demonstrate that aromatase may also play a role in metabolizing methadone. In addition, the metabolism of methadone by aromatase results in destruction of the enzyme’s activity. It follows that the use of methadone may cause changes in endogenous steroid metabolism, as well as resulting in unanticipated drug-drug interactions. This work is the first known connection between methadone and steroid metabolism, suggesting the possibility that that inhibition of aromatase may contribute to the “endocrine” side effects experienced by patients taking methadone. See article at Drug Metab. Dispos. 2010, 38:1308-1313

Poll Results: Things I Wish I Learned in Graduate School

2010-07-12T14:54:00Z

We asked you to tell us which things you feel are lacking in current Pharmacology Graduate education, by ranking five topics. The chart below shows the distribution of priorities among the choices provided (note: many people did not include all listed items in their ranking):

(click for larger image)

We also provided a place to fill in an "Other" item, so that you could vote for things not in that list. Most of the 175 "Other" items could be grouped into these categories:

Business/Leadership Skills	28
Career Development	25
Grantsmanship	16
Drug Discovery/Development	13
Presentation Skills	10
Medical/Clinical Pharmacology	9
Broad Pharmacology Knowledge	8
Critical Thinking/Data Analysis	8
Pharmacokinetics/Pharmacodynamics	7
Pathology/Physiology	6
Pharmacogenomics	5

Although it is difficult to concisely do justice to all of the responses, at least two clear themes seemed to emerge. First, we sensed broad agreement that there is an urgent need for better training in aspects of being a successful scientist that are not related specifically to pharmacological sciences, including scientific writing & presentation, planning & preparing grant applications, gaining business & political skills needed to survive in competitive environments, and career development in general. These sentiments were reflected in many of the comments received:

"Writing is one of the most important and universal areas of research regardless of the setting or career level. However, it is unfortunately miniaturized during graduate school. It should be taught as a core class along with the other science courses." (Postdoctoral Trainee - Academia)

"...Very few programs, if any, provide THE most important information...'what are my career options?!'..." (Senior Faculty/Investigator - Industry)

"It is also very important for trainees to understand all of the various career options that are available to them with Biomedical training. This is something that is rarely covered in graduate & post graduate training yet something that is critical for planning one's career." (Junior Faculty/Investigator - Academia)

The other prevalent theme was strong support for more thorough coverage of applied topics, especially medical pharmacology, drug discovery/development, pharmacokinetics/pharmacodynamics and other areas with translational impact:

"As a pharmacology professor, I [am] teaching many health professionals (Medical, dental, nursing, physician assistants, etc). I think it is very important that the new graduates get exposed to clinical pharmacology (it should be a MUST for all those going into academia, not an option)..." (Senior Faulty/Investigator - Academia)

"Unfortunately, most graduating pharmacologists do not have the tools to address drug design/PK studies that are used routinely by our desired employers (pharm companies)..." (Postdoctoral Trainee - Academia)

"Like other related graduate programs, Pharmacology training is focused on training researchers for academia, with little or no emphasis on industry." (Graduate Student - Academia)

Although many insightful comments were made, perhaps the most important came from this Graduate Student:

"Many similar surveys and discussions have taken place about the subject matter addressed here. The problem is that no one is doing anything about it. How is ASPET moving toward a solution to this constant void in graduate education and training?"

Does your program/department address these areas well?

If so, how?

What do YOU think that ASPET should do?

Please join the conversation by making a comment below...

[ASPET members can subscribe to this post (i.e., follow comments via Email) by logging in and then clicking the envelope icon that will be shown below the title]

MI This Month: Getting down to the bone...

2010-06-17T14:54:00Z

In the June 2010 issue of Molecular Interventions, Drake and Cremers discuss the use of biphosphonates to treat bone disease while Schmidt et al review mechanisms and treatment of bone (and other) pain in cancer patients... See full Table of Contents

JPET Highlight: Amiodarone is a Selective Allosteric Modulator of the M5-Muscarinic Receptor

2010-06-16T14:54:00Z

Muscarinic orthosteric site modulators that have excellent affinity for mucscarinic receptors are usually without high receptor subtype selectivity, which is necessary to reduce muscarinic side effects and has limited their usefulness as therapeutics. Stahl and Ellis investigated the binding of the antiarrythmic drug, amiodarone, to muscarinic receptors and demonstrate a novel allosteric interaction of amiodarone with the M₁ and M₅ receptors. Amiodarone does not interact at the “common” obidoxime binding site and [³H]N-methylscopalamine (NMS) was able to bind simultaneous with amiodarone, suggesting a novel allosteric mode of binding that alters the rate of NMS dissociation from M1 and M5 receptors. Functionally, amiodarone allosterically enhanced the efficacy but not the potency of acetylcholine at the M₅ receptor; however, amiodarone did not enhance M₁ receptor activation. These results are the first to demonstrate an allosteric enhancement of efficacy but not potency at any muscarinic receptor, and that amiodarone is a novel M5-selective positive allosteric modulator of muscarinic receptors. See article at J Pharmacol Exp Ther 2010, 334:214-222.

Let it flow!

2009-08-18T14:54:00Z

Posted by Jon Maybaum, ASPET Web Editor

Several months ago, ASPET leadership undertook a major project to overhaul the society's website. Now, thanks to the efforts of Executive Officer Christie Carrico and her staff, the first phase of this transformation is complete. In August 2009 the new site went live, bringing with it many updates and improvements, including:

Reorganization of material, to find things more easily
More attractive and functional user interface
RSS feeds for selected pages
PharmTalk - The President's Blog (a place for direct interaction between the ASPET President and society members)
Discussion Groups capability, to facilitate interaction among members, and between members and society leadership
Improved use of online forms for symposia submissions, copyright permissions and awards (coming soon)
Interactive advocacy resources

While these changes already represent a substantial enhancement from the previous website, we believe that having better technology available will provide opportunities to make the site even more valuable for ASPET members, as well as for a broader audience. My most important task as Web Editor will be to bring these opportunities to fruition, by engaging people who want to participate as both consumers and producers of information, and by developing effective ways to use the new website as a communications tool. I hope to use this column as the "pipeline" for a continuing dialog about how accomplish this task.

Even though we are just settling into the initial form of the new website, there has already been a lot of discussion about new ideas and initiatives to extend it. Here are a few things that we are thinking about...

Micro-Communities

Websites can be great tools for knitting together people who are physically far apart, and allowing them to function as communities. Because some investment in effort and technology is needed to create and sustain such communities, it often takes hundreds or thousands of participants to form a critical mass that makes the investment worthwhile. But in the diverse and specialized world of research, there are many potential "micro-communities", each comprising perhaps a handful of labs, that would benefit from being able to communicate effectively about finicky experimental techniques, scarce reagents, etc. We would like to explore the possibilities of fostering such micro-communities using the ASPET website.

ASPET Expert Views

The combined expertise of ASPET's membership is an enormous asset that could be leveraged to benefit both its individual members and the society as a whole. We envision an interactive column (in a blog format) where ASPET members are commissioned to write concise articles about pharmacology-related topics with a short turnaround time, while the topic is generating a significant amount of public interest. The purpose would be to provide for general audiences a timely analysis of each subject that is more in-depth and insightful than pieces produced by writers without a background in pharmacology. The author would also respond to questions or comments posted by readers, for a limited period of time. We anticipate that this column would become known as a place for scientists, science writers, policy-makers and sophisticated lay readers to go for thoughtful, reliable information and discussion about issues with pharmacotherapeutic implications.

Mentoring Resources

The future of any family rests in the success of its younger members, and this is certainly true of ASPET. One of the highest priorities for ASPET leadership is to develop ways to help students, trainees and junior faculty advance in their careers and their lives. The ASPET website has the potential to facilitate mentoring in a number of different ways, including compilation of mentoring resources and maintenance of peer-to-peer discussion and support groups.

These examples are just a few among many possibilities, to give some flavor of what you might see on the ASPET website soon. An ASPET Web Advisory Committee is being formed to help prioritize our web initiatives...but they and I can only know what is really valuable and important to you if we hear your feedback. That's what the "Comments" link is for :-)