Robert Raffa

..Intracerebroventricular infusion of opioid analgesics thus appears to be a safe and effective therapy for the palliative treatment of refractory pain...

..It is generally assumed that these compounds are CB₁ 'selective' and produce their effects exclusively via CB₁ receptors...

..Of those for which there is a lot of data, only methadone, oxycodone, and LAAM (levo--acetylmethadol) appear to have a known and accepted level of effect on the QT interval...

..The optimal efficacy and side-effect ratio must be determined in a scientifically rigorous manner...

..Our objective is to briefly summarize the basic science and clinical evidence about OIH as background to consider the possible benefit of using a multi-mechanistic analgesic approach...

..Our objective was to trace the evolution of the understanding of flupirtine's mechanism of analgesic action to its current status...

..01) of certain ratios of this combination was possible. This synergy, here analyzed with the latest (nonlinear) isobolographic methodology, is now quantitatively established for the first time...

..We report excellent fit of the data (R(2)=0.96) by adding: (1) a transient early phase, and (2) a delay in the buildup of protein...

..The concept that certain combinations of drugs leads to attenuated withdrawal might generalize to humans...

..This chapter introduces the reader to the fascinating and complex challenges-to patients, healthcare providers, basic scientists, employers, insurers and others-inherent in this topic and the current state of knowledge about it...

..The deficits are reported to persist. The magnitude of the negative impact on quality of life depends, as does the condition itself, on multiple and varied factors. This chapter relates the experience of one patient...

..The results provide further evidence of a kappa-opioid-like receptor in planarians...

..This review examines the multiple basic science, clinical and pharmacoeconomic issues relating to analgesic combinations and the methodologies available for assessing these issues...

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..The technique results in analogs that retain the folding of the native peptides, are more potent, and have the same or greater biological activity...

..These results provide evidence that the withdrawal from cocaine and amphetamine, but not cannabinoids, in planarians is mediated through a common nor-BNI-sensitive (kappa-opioid receptor-like) pathway...

..No synergistic effect on seizure induction was observed between concomitant tramadol and codeine or morphine...

..There is nothing unique about tramadol in this regard, but its multimodal mechanism of action, pharmacologically active enantiomers, and active metabolite make it a particularly instructive and relevant example...

..As with all combinations, the profile of adverse effects must also be determined in order to provide the clinician with the overall benefit/risk assessment...

..Such measure can help clinicians who seek to maximize therapeutic effect while simultaneously minimizing adverse effects...

..The relatively few such studies, and fewer electrophysiological studies, offer an alternative way to evaluate changes that might be related to cognitive deficits in patients treated with cancer chemotherapeutic regimens...

..Neuroimaging techniques might offer additional insight. This chapter is a succinct summary of a more expanded review of the relatively few such studies...

..Nevertheless, these formulations are important innovations and warrant further study to assess their appropriate role as analgesics...

..Our objective is to review and to comment on the basic science and clinical evidence of potential pharmacologic targets for managing this emerging concern...

..These data provide pharmacologic evidence of a kappa-opioid receptor-mediated withdrawal phenomenon and neuroadaptation to a pharmacologic stimulus (adaptations in transduction mechanisms) in this model...

..Therefore, the elucidation of the mechanism(s) of action of natural products is important, but presents significant challenges. This article examines this issue using peroxide oil (essential oxygen oil) as an illustrative example...

..05) by UV light (366 nm and 254 nm). The results demonstrate alteration of a relatively complex choice behavior by UV light...

..e., it often originates from multiple causes and is transmitted by multiple mediators). Therefore, the choice of the analgesics for the patient who has OA should be based upon the most appropriate mechanisms of action...

..The results demonstrate the importance of protonation in measures of affinity...

..Our objective is to comment on a proposed mechanism for 'chemo-fog'...

..These findings further implicate endogenous opioids (viz., endorphins, enkephalins, and dynorphins) and their pathways as contributors to the central antinociceptive action of acetaminophen...

..Such drugs would have novel mechanisms of action and might therefore be more effective against antibiotic-resistant strains of bacteria...

..3-3 mM) inhibited L-glutamate-induced paroxysms. These results provide further evidence of a topiramate-sensitive glutamate receptor-mediated activity in this model...

..These findings strengthen the hypothesis that the effects of dopaminergic ligands and UV light on pLMV relate to interaction with neurotransmitter transduction process(es)...

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..The chapters of this book summarize much of what has been done and reported regarding cancer chemotherapy-related cognitive impairment. In this chapter, we point out some future directions for investigation...

..This chapter is a succint summary of a more expanded review...

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..Buprenorphine displays attributes of opioids, but also some features distinct from them. We examined spinal and supraspinal signal transduction of buprenorphine-induced anti-nociception in mice compared with morphine and fentanyl...

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..Laboratory studies have demonstrated that these agents interact to produce synergistic analgesia with a desirable safety/efficacy profile...

..The present results suggest that the magnitude of withdrawal-like behavior in planarians is dependent on both the duration and type of drug exposure, and that planarians do not display withdrawal to caffeine...

..These data should be useful for molecular modeling and suggest that inhibitor activity will be a function of cellular conditions (normal or pathological)...

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..Isothermal titration calorimetry (ITC) and progress curve analysis was used to measure the enzyme kinetic parameters (KM and kcat) of the hydrolysis of cCMP by RNase-A, a reaction that includes end-product competitive inhibition by 3'-CMP...

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..Compared to the cocaine/cocaine group, the cocaine/water group displayed a significant number of atypical behaviors, providing direct evidence of a 'withdrawal phenomenon' in planarians...

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..The harmonic mean was found to be a good estimator when applied to the published data from 14 alanine-scan studies. This result is consonant with the present understanding of ligand-receptor interactions...

..These results suggest a common NO-dependent pathway of withdrawal from cocaine and WIN 55212-2 in Planaria...

..90 kcal/mol; DeltaH degrees =-15.7 kcal/mol; and DeltaS degrees =-0.028 kcal/mol-K ('enthalpy-driven' interaction). These data should assist drug design of small-molecule inhibitors of homologous RNase catalytic domains...

..The present results reveal that NMDA receptor activation mediates the development of cannabinoid physical dependence and the expression of cannabinoid withdrawal in planarians...

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..This is the first demonstration of a TRPM8/TRPA1 channel subtype agonist-induced differential pharmacological effect in invertebrates and provides a novel sensitive, quantifiable end-point for studying TRP channel pharmacology...

..This suggests that a change in agmatine signaling is a common mechanism in the withdrawal caused by these drugs, at least in planarians...

..The present results provide pharmacologic evidence of a functional inhibitory action of topiramate on glutamate receptor activity in invertebrates and provide a sensitive, quantifiable end-point for studying anti-seizure pharmacology...

..This novel technique offers possible insight into the dual low-dose (analgesic), high-dose (addiction medication) uses of buprenorphine...

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..The concern that adjuvant cancer chemotherapy agents cause cognitive impairment in a significant number of patients has been expressed by patients and healthcare providers, but clinical studies have yielded conflicting results to date...

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..Assay accuracy and precision of back-calculated standards were within +/-15%. DISCUSSION: This method will be useful for investigation of buprenorphine's mechanism of action and clinical profile...

..New formulas derived to assess the statistical variance for additive combinations are included, and the more detailed mathematical topics are included in the Appendix...

..The role of genetic variability in clinical opioid therapy is examined, and relevant clinical trials cited. The present status of opioid pharmacogenetics, promises and challenges and future directions are discussed...

..These results suggest compensatory mechanisms in receptor number and abnormalities in 2nd messenger transduction and can help direct efforts for improving antihypertensive or other pharmacological therapy for diabetic patients...

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..These findings provide in vivo evidence for a possible link between RHS and a LiCl-sensitive, possibly phosphoinositide-related, effector pathway...

..g., electrophysiologic or molecular biology techniques. An improved understanding of how withdrawal is influenced by poly-drug abuse could lead to development of enhanced clinical treatment. ..