The therapeutic potential of nicotinic acetylcholine receptor agonists for pain control.
ABSTRACT Due to the limitations of currently available analgesics, a number of novel alternatives are currently under investigation, including neuronal nicotinic acetylcholine receptor (nAChR) agonists. During the 1990s, the discovery of the antinociceptive properties of the potent nAChR agonist epibatidine in rodents sparked interest in the analgesic potential of this class of compounds. Although epibatidine also has several mechanism-related toxicities, the identification of considerable nAChR diversity suggested that the toxicities and therapeutic actions of the compound might be mediated by distinct receptor subtypes. Consistent with this view, a number of novel nAChR agonists with antinociceptive activity and improved safety profiles in preclinical models have now been identified, including A-85380, ABT-594, DBO-83, SIB-1663 and RJR-2403. Of these, ABT-594 is the most advanced and is currently in Phase II clinical evaluation. Nicotinically-mediated antinociception has been demonstrated in a variety of rodent pain models and is likely mediated by the activation of descending inhibitory pathways originating in the brainstem with the predominant high-affinity nicotine site in brain, the alpha4beta2 subtype, playing a critical role. Thus, preclinical findings suggest that nAChR agonists have the potential to be highly efficacious treatments in a variety of pain states. However, clinical proof-of-principle studies will be required to determine if nAChR agonists are active in pathological pain.
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ABSTRACT: Snake and insect venoms have been demonstrated to have beneficial effects in the treatment of certain diseases including drug resistant human immunodeficiency virus (HIV) infection. We evaluated and hypothesized the probable mechanisms of venoms against HIV. Previous literatures published over a period of 30 years (1979-2009) were searched using the key words snake venom, insect venom, mechanisms and HIV. Mechanisms were identified and discussed. With reference to mechanisms of action, properties and components of snake venom such as sequence homology and enzymes (protease or L-amino acid oxidase) may have an effect on membrane protein and/or act against HIV at multiple levels or cells carrying HIV virus resulting in enhanced effect of anti-retroviral therapy (ART). This may cause a decrease in viral load and improvement in clinical as well as immunological status. Insect venom and human Phospholipase A2 (PLA2) have potential anti-viral activity through inhibition of virion entry into the cells. However, all these require further evaluation in order to establish its role against HIV as an independent one or as a supplement.AIDS Research and Therapy 11/2009; 6:25. · 2.54 Impact Factor
Article: Newer antiepileptic drugs: possible uses in the treatment of neuropathic pain and migraine.[show abstract] [hide abstract]
ABSTRACT: Both neuropathic pain and migraine are now being treated with a variety of newer antiepileptic drugs (AEDs). The proven efficacy of gabapentin in postherpetic neuralgia (PHN) and painful diabetic neuropathy (PDN), and of divalproex sodium in the prevention of migraine has led to increased clinical investigation of the newer AEDs for these conditions. While basic and clinical research are expanding the knowledge base concerning the fundamental mechanisms of neuropathic pain and migraine, growing recognition of the similarities in the pathophysiology of epilepsy, migraine, and various chronic pain disorders has further heightened interest in exploring the newer AEDs in the treatment of these conditions. The goals of this article were to review the empiric basis and scientific rationale for the use of AEDs in the treatment of neuropathic pain and migraine; summarize available clinical research on the use of 5 newer AEDs (gabapentin, lamotrigine, oxcarbazepine, topiramate, and zonisamide) in these conditions; and provide a summary comparison of the dosing, tolerability, and drug-interaction potential of these agents. Relevant English-language articles were identified through searches of MEDLINE (1990-March 2003), American Academy of Neurology abstracts (1999-2003), and American Epilepsy Society abstracts (2000-2002). The search terms were antiepileptic medication or drug, migraine headache, neuropathic pain, pathophysiology, treatment, mechanism of action, gabapentin, lamotrigine, oxcarbazepine, topiramate, and zonisamide. The newer AEDs possess the potential advantages of better tolerability and fewer drug-drug interactions compared with standard treatments such as tricyclic antidepressants or established AEDs. However, with the exception of data supporting the efficacy of gabapentin in PHS and PDN, there is currently insufficient evidence to determine whether the newer AEDs have equal or superior efficacy relative to proven pharmacotherapies.Clinical Therapeutics 11/2003; 25(10):2506-38. · 2.32 Impact Factor