Basic & Clinical Pharmacology of Anesthetics and Other Drugs

Updated 11/26/07

1. Modulation of Opioid Effects by Garlic Supplements

D. Shen, Ph.D.,G.W. Terman, M.D., Ph.D.

Its overall objective is to explore whether a CYP3A- and Pgp-dependent interaction exists between garlic supplements and a commonly used oral opioid analgesics–oxycodone.  The studies are designed to investigate the following hypotheses:

1. Garlic extract has the dual capability of inhibiting and inducing the activities of intestinal and hepatic CYP3A and intestinal Pgp, such that its effects on oxycodone pharmacokinetics vary over the course of garlic treatment (i.e., increased bioavailability and slowed clearance appear shortly after initiation of treatment with garlic supplement, and reduced bioavailability and accelerated clearance occur eventually at steady state during chronic treatment with garlic supplement).
2. Garlic-induced changes in oxycodone pharmacokinetics lead to significant changes in analgesic and side effects of oxycodone.  In particular, we will assess whether the same degree of change in analgesia and side effects will result; in other words, whether there is a change in the therapeutic index.  We will focus on the three most bothersome aspects of opioid side effects; i.e, the somatic, affective, and cognitive effects of oxycodone.
3. The magnitude and the time course of interaction differ between the two common types of garlic supplements, dried garlic powder and steam-distilled garlic oil, because of differences in their biologically active constituents.

These studies will allow us to assess the potential clinical significance of interactions between garlic and opioids and to elucidate the pharmacokinetic and pharmacodynamic basis of the observed interaction.  They may point to the need for a more systemic investigation of potentially adverse interactions between garlic supplements and other opioid analgesics in use.

2. Garlic Metabolism and Cytochrome P450 Modulation

D. Shen, Ph.D.,G.W. Terman, M.D., Ph.D.

There is growing concern over the quality, efficacy and safety of the many herbal products sold over the counter because of the increasing use of herbal medicine by Americans over the past decade and the current lack of stringent regulations governing the manufacturing and marketing of herbal products.  A major safety concern is the potential for adverse interactions between herbs and drugs.  At present, documentation of adverse herb-drug interactions relies mostly on clinical case reports, and studies in a small number of patients or healthy volunteers.  This has led to conflicting reports, and debates over the reliability and clinical significance of the purported herb-drug interactions.  Moreover, findings observed with one herbal product are often applied to all commercial products of that herb; such generalization warrants caution given the variation in the composition and strength of bioactive ingredients in many herbal medicines.  Hence, carefully controlled and systematic studies must follow to confirm and clarify the initial clinical reports of potentially significant and widespread herb-drug interactions.

Americans frequently use garlic supplements; in 1998, garlic was the fourth best selling herbal product in the U.S. with an annual sale of $84 million.  In a recently completed VITamins And Lifestyle (VITAL) Study of 77,438 older (50-79 years) adults conducted at FHCRC, garlic supplements were amongst the top ten most used herbal supplements; 7.3% and 6.8% of men and women, respectively, took garlic supplements at least once a week for a year.  In another earlier study from FHCRC, 27% of the cancer patients who admitted to using herbals were taking garlic supplements.  Epidemiological evidence and findings from animal and in vitro studies suggest that garlic may prevent or halt cancer through multiple biochemical and cellular mechanisms, including inhibition of tumor promotion and proliferation, antioxidant actions, as well as suppression of carcinogen activation through inhibition of bioactivating enzymes (e.g. CYP1A1, 2E1 and epoxide hydrolase) and increase in expression of detoxification enzymes (e.g. glutathione S-transferase) The claims of immune enhancement and anticancer effects probably explain the frequent use of garlic in cancer patients with active disease or in remission.

The overall objective of this proposed research is to investigate the modulating effects of garlic supplements on the activity of several major drug-metabolizing cytochrome P450 enzymes (CYPs) and the membrane efflux transporter P-glycoprotein (Pgp) in healthy subjects.  The studies are designed to investigate the pharmacokinetic mechanisms underlying several recently reported interactions between garlic supplements and drugs.

3. Subcellular Distribution & Regulation of α1 -Adrenoceptors

D.A. Schwinn, M.D., A.Oganesian, Ph.D.

The long-term objective of this research is to understand the role of stress (acute and chronic) on perioperative outcome in humans. Within this context, our laboratory has focused on examining mechanisms underlying regulation of one of the stress hormone (catecholamine) binding receptor families, the alpha1-adrenergic receptors (alpha1 ARs). Our previous studies characterized subtype specific regulation of alpha1a AR transcription, desensitization, and internalization. One key finding that emerged was that alpha1a ARs have the unique ability to continuously signal in the presence of agonist in situations where alpha1b and alpha1dARs (and indeed many G protein-coupled receptors [GPCRs]) concurrently dampen (desensitize and/or downregulate) signaling. Indeed, our recent indicate that alpha1a AR trafficking mechanisms are distinct from other alpha1 AR subtypes since alpha1a AR displays a unique ability to constitutively recycle, independent of agonist stimulation. Underlying mechanisms remain unknown, but it is becoming increasingly clear that GPCRs are able to interact directly with an array of cytosolic that directly modulate receptor dimerization, trafficking, and transcription. The focus of this competitive renewal is to elucidate these processes with the overall hypothesis that alpha1a ARs couple to regulatory pathways distinct from other ARs. We propose two specific aims designed to identify novel alpha1a AR coupling (including clathrin, Gq-independent, and caveolin associated pathways). In the first aim we will investigate the ability of alpha1a ARs to interact directly with specific proteins in these pathways (e.g., beta-arrestins) using quantitative immunoprecipitation approaches in classic cellular models of both stably transfected rat-1 fibroblasts and neonatal cardiomyocytes. We will utilize novel soluble competitors that target intracellular loops to determine distinct alpha1a AR intracellular regions involved in alpha1a AR signaling and identify the proteins to which they bind using targeted proteomics. In a parallel second aim, we will examine mechanisms underlying both constitutive and agonistinduced alpha1a AR cycling using highly characterized functional and subcellular localization assays. Perturbation of model systems using engineered mutants for both alpha1a AR, as well as targeted factors within relevant pathways, be used to independently confirm results. Mutation of putative phosphorylation sites will be used to further mechanisms underlying alpha1a AR trafficking. Identification of alpha1a AR-responsive pathways is an important in understanding the role of catecholamines in stress responses with the ultimate goal of identifying novel designed to improve therapeutic strategies for acute and chronic disease.

4. Bladder Function During Thoracic Epidural Anesthesia and Analgesia(C)

D. J. Pavlin, M.D.

The purpose of this study is to investigate the effects of thoracic epidural anesthesia and analgesia on urinary bladder function, and determine the potential utility of ultrasound monitoring of bladder volume intra- and postoperatively in such patients, to diminish the incidence of painless urinary retention, bladder dysfunction, and urinary tract infection after surgery.  Thoracic epidural analgesia is a method of pain control commonly used after thoracic or upper abdominal surgery.  It is particularly advantageous for these types of operations (i.e. lung operations, gall bladder surgery, upper gastrointestinal surgery, colon surgery) because it has been shown to improve postoperative lung function when compared to use of pain medications without epidural analgesia.

We are proposing to study bladder function in patients who have a functioning thoracic epidural placed for management of postoperative pain.  It will be studied in two groups of patients.  Group 1 will have bladder volume monitored by ultrasound with intermittent sporadic catheterization if indicated for urinary retention during surgery and in the first 5 days after surgery.  Group 2 will have continuous catheter drainage of the bladder for 24-48 hours after surgery, followed by non-invasive monitoring by ultrasound on day 3-5 with intermittent catheterization as required for retention. 

Our expectation is that this study will allow us to (1) determine the need for continuous bladder catheter drainage or ultrasound monitoring in future in patients with a functioning thoracic epidural, (2) compare the risks/complications of continuous catheter drainage versus non-invasive monitoring with intermittent catheterization as required for retention, (3) identify risk factors for retention in patients with a functioning thoracic epidural.  We will also evaluate the ability of patients and/or nurses to assess/estimate or guess bladder volume with and without the aid of an ultrasound scanner.

* (C) denotes clinical investigation.