Pharmacological reviews
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Pharmacological reviews · Oct 2015
ReviewThe Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential.
Voltage-gated calcium channels are required for many key functions in the body. In this review, the different subtypes of voltage-gated calcium channels are described and their physiologic roles and pharmacology are outlined. We describe the current uses of drugs interacting with the different calcium channel subtypes and subunits, as well as specific areas in which there is strong potential for future drug development. ⋯ In addition, selective or nonselective T-type channel blockers are considered potential therapeutic targets in epilepsy, pain, obesity, sleep, and anxiety. Use-dependent N-type calcium channel blockers are likely to be of therapeutic use in chronic pain conditions. Thus, more selective calcium channel blockers hold promise for therapeutic intervention.
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Pharmacological reviews · Jul 2015
ReviewNeuro-Bio-Behavioral Mechanisms of Placebo and Nocebo Responses: Implications for Clinical Trials and Clinical Practice.
The placebo effect has often been considered a nuisance in basic and particularly clinical research. This view has gradually changed in recent years due to deeper insight into the neuro-bio-behavioral mechanisms steering both the placebo and nocebo responses, the evil twin of placebo. For the neuroscientist, placebo and nocebo responses have evolved as indispensable tools to understand brain mechanisms that link cognitive and emotional factors with symptom perception as well as peripheral physiologic systems and end organ functioning. ⋯ Finally, in the clinical context, the systematic exploitation of these mechanisms will help to maximize placebo responses and minimize nocebo responses for the patient's benefit. In this review, we summarize and critically examine the neuro-bio-behavioral mechanisms underlying placebo and nocebo responses that are currently known in terms of different diseases and physiologic systems. We subsequently elaborate on the consequences of this knowledge for pharmacological treatments of patients and the implications for pharmacological research, the training of healthcare professionals, and for the health care system and future research strategies on placebo and nocebo responses.
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Pharmacological reviews · Oct 2014
ReviewInteraction of risk factors, comorbidities, and comedications with ischemia/reperfusion injury and cardioprotection by preconditioning, postconditioning, and remote conditioning.
Pre-, post-, and remote conditioning of the myocardium are well described adaptive responses that markedly enhance the ability of the heart to withstand a prolonged ischemia/reperfusion insult and provide therapeutic paradigms for cardioprotection. Nevertheless, more than 25 years after the discovery of ischemic preconditioning, we still do not have established cardioprotective drugs on the market. Most experimental studies on cardioprotection are still undertaken in animal models, in which ischemia/reperfusion is imposed in the absence of cardiovascular risk factors. ⋯ The aim of this article is to review the recent evidence that cardiovascular risk factors and their medication may modify the response to cardioprotective interventions. We emphasize the critical need to take into account the presence of cardiovascular risk factors and concomitant medications when designing preclinical studies for the identification and validation of cardioprotective drug targets and clinical studies. This will hopefully maximize the success rate of developing rational approaches to effective cardioprotective therapies for the majority of patients with multiple risk factors.
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Pharmacological reviews · Jul 2013
ReviewPharmacogenetics and cardiovascular disease--implications for personalized medicine.
The past decade has seen tremendous advances in our understanding of the genetic factors influencing response to a variety of drugs, including those targeted at treatment of cardiovascular diseases. In the case of clopidogrel, warfarin, and statins, the literature has become sufficiently strong that guidelines are now available describing the use of genetic information to guide treatment with these therapies, and some health centers are using this information in the care of their patients. There are many challenges in moving from research data to translation to practice; we discuss some of these barriers and the approaches some health systems are taking to overcome them. ⋯ Finally, we comment briefly on pharmacogenetics of other cardiovascular drugs and highlight β-blockers as the drug class with strong data that has not yet seen clinical implementation. It is anticipated that genetic information will increasingly be available on patients, and it is important to identify those examples where the evidence is sufficiently robust and predictive to use genetic information to guide clinical decisions. The review herein provides several examples of the accumulation of evidence and eventual clinical translation in cardiovascular pharmacogenetics.
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Pharmacological reviews · Jan 2013
ReviewCofactoring and dimerization of proteinase-activated receptors.
Proteinase-activated receptors (PARs) are G protein-coupled receptors that transmit cellular responses to extracellular proteases and have important functions in vascular physiology, development, inflammation, and cancer progression. The established paradigm for PAR activation involves proteolytic cleavage of the extracellular N terminus, which reveals a new N terminus that functions as a tethered ligand by binding intramolecularly to the receptor to trigger transmembrane signaling. Most cells express more than one PAR, which can influence the mode of PAR activation and signaling. ⋯ Thus, PARs can regulate each other's activity by localizing thrombin when in complex with PAR3 and PAR4 or by cleaved PAR1, providing its tethered ligand domain for PAR2 activation. The ability of PARs to cofactor or transactivate other PARs would necessitate that the two receptors be in close proximity, likely in the form of a heterodimer. Here, we discuss the cofactoring and dimerization of PARs and the functional consequences on signaling.