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Aim To examine community pharmacists’ attitudes towards pharmacogenetic (PGx) testing, including their views of the clinical utility of PGx and the ethical, social, legal and practical implications of PGx testing. Methods A web-based survey administered to 5600 licensed community pharmacists in the states of Ohio and Pennsylvania (USA). Results Of 580 respondents, 78% had a Bachelor of Science degree in pharmacy and 58% worked in a chain drug store. Doctors of pharmacy-trained pharmacists had a significantly higher knowledge score than those with a Bachelor of Science in pharmacy (3.2 ± 0.9 vs 2.6 ± 0.6; p < 0.0001). All pharmacists had positive attitudes towards PGx and most (87%) felt it would decrease the number of adverse events, and optimize drug dosing. More than half (57%) of pharmacists felt that it was their role to counsel patients regarding PGx information. Many (65%) were concerned that PGx test results may be used to deny health insurance. Conclusion Regardless of the type of education, all pharmacists had positive attitudes towards PGx. There is still a concern among pharmacists that PGx test results may be used to deny health insurance and, thus, there is a need to educate pharmacists about legal protections prohibiting certain forms of unfair discrimination based on genotype.

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These data show that alpha1 and beta3-adrenergic receptors may contribute to the mediation of MDMA-induced hyperthermia and that drugs targeting these receptors, such as carvedilol, warrant further investigation as novel therapies for the treatment of psychostimulant-induced hyperthermia and its sequelae.

An acute and potentially life-threatening complication associated with the recreational use of the 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) is hyperthermia. In the present study, Sprague-Dawley rats treated with MDMA (40 mg/kg s.c.) responded with a significant increase (maximal at 1 h) in rectal and skeletal muscle temperatures that lasted for at least 3 h post-treatment. Hypophysectomized (HYPO) and thyroparathyroidectomized (TX) animals treated with MDMA (40 mg/kg s.c.) did not become hyperthermic and in fact displayed a significant hypothermia. The HYPO and TX animals were also resistant to the serotonergic neurotoxic effects of MDMA assessed by serotonin measurements 4 to 7 days later in the striatum and hippocampus. MDMA (40 mg/kg s.c.) induced a significant increase in thyroxine levels 1 h post-treatment. Thyroid hormone replacement in TX animals returned the hyperthermic response seen after MDMA. Prazosin, an ␣ 1 -antagonist (0.2 mg/kg i.p.), administered 30 min before MDMA significantly attenuated the MDMA-induced increase in rectal temperature, but had no effect on skeletal muscle temperature. Cyanopindolol, a ␤ 3 -antagonist (4 mg/kg s.c.), administered 30 min before MDMA (40 mg/kg s.c.) significantly attenuated the increase in skeletal muscle temperature, but had no effect on the rise in rectal temperature. The combination of prazosin and cyanopindolol resulted in an abolishment of MDMA-induced hyperthermia. The mechanisms of thermogenesis induced by MDMA seem to result from an interaction between the hypothalamicpituitary-thyroid axis and the sympathetic nervous system, wherein mechanisms leading to core and skeletal muscle hyperthermia after MDMA exposure seem to be differentially regulated by ␣ 1 -and ␤ 3 -adrenergic receptors.

Thyroid hormone (TH) plays a fundamental role in thermoregulation, yet the molecular mediators of its effects are not fully defined. Recently, skeletal muscle (SKM) uncoupling protein (UCP) 3 was shown to be an important mediator of the thermogenic effects of the widely abused sympathomimetic agents 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) and methamphetamine. Expression of UCP3 is regulated by TH. Activation of UCP3 is indirectly regulated by norepinephrine (NE) and is dependent upon the availability of free fatty acids (FFAs). We hypothesized that UCP3 may be a molecular link between TH and hyperthermia, requiring increased levels of both NE and FFAs to accomplish the thermogenic effect. Here, we demonstrate that MDMA (40 mg/kg s.c.) significantly increases plasma FFA levels 30 min after treatment. Pharmacologically increasing NE levels through the inhibition of phenylethanolamine N-methyltransferase with Ϯ2,3-dichloro-␣-methylbenzylamine potentiated the hyperthermic effects of a 20 mg/kg dose of MDMA. Using Western blots and regression analysis, we further illustrated that chronic hyperthyroidism in rats potentiates the hyperthermic effects of MDMA and increases levels of SKM UCP3 protein in a linear fashion according to levels of circulating plasma TH. Conversely, chronic hypothyroidism results in a hypothermic response to MDMA that is directly proportionate to decreased UCP3 expression. Acute TH supplementation did not change the skeletal muscle UCP3 expression levels or temperature responses to MDMA. These findings suggest that, although MDMA-induced hyperthermia appears to result from increased NE and FFA levels, susceptibility is ultimately determined by TH regulation of UCP3-dependent thermogenesis.Hyperthermia results from a severe, unregulated rise in core body temperature induced by high ambient temperature, strenuous exercise, endocrinopathy, or drug exposure. To our knowledge, no drug treatment has been established through controlled trials as an efficacious therapy for conditions that involve severe hyperthermia, with the exception of malignant hyperthermia, which is effectively reversed with dantrolene (Blank and Boggs, 1993). The lack of therapeutic options for the management of hyperthermia probably results from an inadequate understanding of the basic molecular mechanisms of thermogenesis.The principal active thyroid hormone (TH) 3,5,3Ј-triiodo-Lthyronine is formed from the precursor 3,5,3Ј,5Ј-tetraiodothyronine (T 4 , thyroxine) by deiodinases present in various tissues (Bianco and Larsen, 2005). Although TH has been established as the primary endocrinologic regulator of body temperature (Silva, 2005) and facultative thermogenesis (FT) (for review see Lowell and Spiegelman, 2000), the mechanisms involved are complex and incompletely characterized. One family of genes regulated by TH (Gong et al., 1997) and believed to play a significant role in FT encodes for the mitochondrial uncoupling proteins (UCPs).UCPs "uncouple" free energy stored in the mitochondrial electrochemical p...

Background Synthetic cathinones are popularly referred to in the media as “bath salts.” Through the direct and indirect activation of the sympathetic nervous system, smoking, snorting, or injecting synthetic cathinones can result in tachycardia, hypertension, hyperthermia, myocardial infarction and death. Objectives The chemical structures and names of bath salts identified by the State of Ohio Bureau of Criminal Identification and Investigation Laboratory are presented. Based on their common pharmacophores the authors review the history, pharmacology, toxicology, detection methods and clinical implications of synthetic cathinones. Through the integration of this information, the pharmacological basis for the management of patients using synthetic cathinones is presented. Discussion Synthetic cathinones activate central serotonergic and dopaminergic systems contributing to acute psychosis and the peripheral activation of the sympathetic nervous system. The over stimulation of the sympathetic nervous system contributes to the many toxicities reported with bath salt use. The pharmacological basis for managing these patients is targeted at attenuating the activation of these systems. Conclusions Treatment of patients presenting after using bath salts should be focused on reducing agitation and psychosis, and supporting renal perfusion. The majority of successfully treated synthetic cathinones cases have used benzodiazepines and antipsychotics along with general supportive care.

Uncoupling protein 1 (UCP1) is the established mediator of brown adipose tissue-dependent thermogenesis. In contrast, the role of UCP3, expressed in both skeletal muscle and brown adipose tissue, in thermoregulatory physiology is less well understood. Here, we show that mice lacking UCP3 (UCP3KO) have impaired sympathomimetic (methamphetamine) and completely abrogated lipopolysaccharide (LPS) thermogenesis, but a normal response to noradrenaline. By comparison, UCP1 knockout (UCP1KO) mice exhibit blunted methamphetamine and fully inhibited noradrenaline thermogenesis, but an increased febrile response to LPS. We further establish that mice lacking both UCP1 and 3 (UCPDK) fail to show methamphetamine-induced hyperthermia, and have a markedly accelerated loss of body temperature and survival after cold exposure compared to UCP1KO mice. Finally, we show that skeletal muscle-specific human UCP3 expression is able to significantly rescue LPS, but not sympathomimetic thermogenesis blunted in UCP3KO mice. These studies identify UCP3 as an important mediator of physiological thermogenesis and support a renewed focus on targeting UCP3 in metabolic physiology.