Trends in pharmacological sciences
-
Trends Pharmacol. Sci. · Apr 2013
ReviewDoes the pharmacology of oxycodone justify its increasing use as an analgesic?
Oxycodone is a semisynthetic opioid analgesic that is increasingly used for the treatment of acute, cancer, and chronic non-malignant pain. Oxycodone was synthesized in 1917 but its pharmacological properties were not thoroughly studied until recently. Oxycodone is a fairly selective μ-opioid receptor agonist, but there is a striking discrepancy between the relatively low binding potential and G protein activation by oxycodone and its analgesic efficacy. ⋯ We critically review studies on the basic pharmacology of oxycodone and on its pharmacokinetics and pharmacodynamics in humans. In particular, the role of pharmacogenomics and population pharmacokinetics in understanding the properties of oxycodone is discussed in detail. We compare oxycodone with morphine, the standard opioid in clinical use.
-
Cloning of the transient receptor potential vanilloid type 1 (TRPV1), the heat-gated cation channel/capsaicin receptor expressed by sensory neurons, has opened the door for development of new types of analgesics that selectively act on nociceptors. Here we summarize mutagenetic evidence for selective loss of responsiveness to vanilloids, protons, and heat stimuli to provide clues for avoiding on-target side effects of hyperthermia and burn risk. ⋯ Several endogenous lipid ligands activate and inhibit TRPV1 and its gating initiates sensory transducer and mediator-releasing functions. Second generation TRPV1 antagonists that do not induce hyperthermia are under development, and a dermal capsaicin patch is already on the market for long-term treatment of neuropathic pain.
-
The current gap between basic science research and the development of new analgesics presents a serious challenge for the future of pain medicine. This challenge is particularly difficult in the search for better treatment for comorbid chronic pain conditions because: (i) animal 'pain' models do not simulate multidimensional clinical pain conditions; (ii) animal behavioral testing does not assess subjective pain experience; (iii) preclinical data provide little assurance regarding the direction of new analgesic development; and (iv) clinical trials routinely use over-sanitized study populations and fail to capture the multidisciplinary consequences of comorbid chronic pain. Therefore, a paradigm shift in translational pain research is necessary to transform the current strategy from focusing on molecular switches of nociception to studying pain as a system-based integral response that includes psychosocial comorbidities. Several key issues of translational pain research are discussed in this review.
-
Trends Pharmacol. Sci. · Jun 2012
ReviewAt the heart of the matter: the endocannabinoid system in cardiovascular function and dysfunction.
Starting from the well-documented effects of marijuana smoking on heart rate and blood pressure, the cardiovascular effects of Δ⁹-tetrahydrocannabinol (THC, the main psychotropic ingredient of Cannabis) and endocannabinoids [THC endogenous counterparts that activate cannabinoid receptor type 1 (CB₁) and 2 (CB₂)] have been thoroughly investigated. These studies were mostly aimed at establishing the molecular bases of the hypotensive actions of THC, endocannabinoids and related molecules, but also evaluated their therapeutic potential in cardiac injury protection, metabolic cardiovascular risk factors and atherosclerotic plaque vulnerability. The results of these investigations, reviewed here, also served to highlight some of the most peculiar aspects of endocannabinoid signaling, such as redundancy in endocannabinoid targets and the often dualistic role of CB₁ and CB₂ receptors during pathological conditions.
-
Lower operational costs, recent regulatory reforms and several logistic advantages make India an attractive destination for conducting clinical trials. Efforts for maintaining stringent ethical standards and the launch of Pharmacovigilance Program of India are expected to maximize the potential of the country for clinical research.