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Imaging drugs with and without clinical analgesic efficacy.

ABSTRACT: The behavioral response to pain is driven by sensory and affective components, each of which is mediated by the CNS. Subjective pain ratings are used as readouts when appraising potential analgesics; however, pain ratings alone cannot enable a characterization of CNS pain circuitry during pain processing or how this circuitry is modulated pharmacologically. Having a more objective readout of potential analgesic effects may allow improved understanding and detection of pharmacological efficacy for pain. The pharmacological/functional magnetic resonance imaging (phMRI/fMRI) methodology can be used to objectively evaluate drug action on the CNS. In this context, we aimed to evaluate two drugs that had been developed as analgesics: one that is efficacious for pain (buprenorphine (BUP)) and one that failed as an analgesic in clinical trials aprepitant (APREP). Using phMRI, we observed that activation induced solely by BUP was present in regions with ?-opioid receptors, whereas APREP-induced activation was seen in regions expressing NK(1) receptors. However, significant pharmacological modulation of functional connectivity in pain-processing pathways was only observed following BUP administration. By implementing an evoked pain fMRI paradigm, these drugs could also be differentiated by comparing the respective fMRI signals in CNS circuits mediating sensory and affective components of pain. We report a correlation of functional connectivity and evoked pain fMRI measures with pain ratings as well as peak drug concentration. This investigation demonstrates how CNS-acting drugs can be compared, and how the phMRI/fMRI methodology may be used with conventional measures to better evaluate candidate analgesics in small subject cohorts.

SUBMITTER: Upadhyay J

PROVIDER: S-EPMC3230490 | biostudies-other | 2011 Dec

REPOSITORIES: biostudies-other

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Imaging drugs with and without clinical analgesic efficacy.

Upadhyay Jaymin J Anderson Julie J Schwarz Adam J AJ Coimbra Alexandre A Baumgartner Richard R Pendse G G George Edward E Nutile Lauren L Wallin Diana D Bishop James J Neni Saujanya S Maier Gary G Iyengar Smriti S Evelhoch Jeffery L JL Bleakman David D Hargreaves Richard R Becerra Lino L Borsook David D

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20110817 13

The behavioral response to pain is driven by sensory and affective components, each of which is mediated by the CNS. Subjective pain ratings are used as readouts when appraising potential analgesics; however, pain ratings alone cannot enable a characterization of CNS pain circuitry during pain processing or how this circuitry is modulated pharmacologically. Having a more objective readout of potential analgesic effects may allow improved understanding and detection of pharmacological efficacy fo ...[more]

PMID: 21849979

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Project description:IntroductionThere is a wide variety of drugs for the clinical treatment of immunoglobulin A (IgA) nephropathy; however, previous studies have failed to clarify the quantitative differences in the efficacy of various drugs. In this study, we aimed to quantitatively compare the clinical efficacy of 6 classes of drugs with different pharmacological mechanisms for the treatment of IgA nephropathy and to identify relevant influencing factors.MethodsClinical trials of drugs for the treatment of IgA nephropathy were obtained from public databases. The change in daily urinary protein excretion from baseline was used as the efficacy index, and the time-effect model was established using a model-based meta-analysis method. Based on the final model, the typical efficacy was simulated, and the differences in efficacy were compared.ResultsA total of 40 studies with 2288 subjects were included in this study. The results showed that the time-effect relationship of the placebo and 6 classes of drugs was consistent with the Emax model. The placebo reduced urinary protein excretion by up to 0.44 g/day, and it took more than 27 months to reach half of its maximum effect. The onset of the 6 classes of drugs were the same; they all reached half of their maximum effect after 5.59 months. More importantly, we found a significant influence of urinary protein baseline on drug efficacy, as indicated by an increase of 0.63 g/day in the theoretical maximum effect of drugs for every 1 g/day increase in urinary protein baseline. After correcting for the urinary protein baseline, the order of efficacy of the 6 classes of drugs was as follows: corticosteroids > immunosuppressants > other drugs > renin-angiotensin system blockers > antiplatelet agents > N-3 fatty acids.ConclusionThis study provides the first comprehensive quantitative analysis of the differences in the efficacy of 6 classes of drugs with different pharmacological mechanisms for treating IgA nephropathy. The results of this study provide an important reference for the rational clinical use of drugs for IgA nephropathy, and also provide a reliable efficacy standard for the development of new drugs for IgA nephropathy.

Dataset Information

Imaging drugs with and without clinical analgesic efficacy.

Publications

Imaging drugs with and without clinical analgesic efficacy.

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