The anticonvulsant gabapentin (GBP) has been shown effective for the treatment of neuropathic pain, although its mechanism of action remains unclear. A recent report has suggested that binding to the ␣ 2 ␦ subunit of voltage-gated calcium channels contributes to its antinociceptive effect, based on the stereoselective efficacy of two analogs: (1S,3R)3-methylgabapentin (3-MeGBP) (IC 50 ϭ 42 nM), which is effective in neuropathic pain models; and (1R,3R)3-MeGBP (IC 50 Ͼ 10,000 nM), which is ineffective (Field et al., 2000). The present study was designed to further examine the profiles of GBP and 3-MeGBP in rat models of acute and persistent pain. Systemic administration of GBP or (1S,3R)3-MeGBP inhibited tactile allodynia in the spinal nerve ligation model of neuropathic pain, whereas (1R,3R)3-MeGBP was ineffective. The antiallodynic effect of GBP, but not (1S,3R)3-MeGBP, was blocked by i.t. injection of the GABA B receptor antagonist [3-[[(3,4-Systemic GBP or (1S,3R)3-MeGBP also inhibited the second phase of formalin-evoked nociceptive behaviors, whereas (1R,3R)3-MeGBP was ineffective. However, both (1S,3R)3-MeGBP and (1R,3R)3-MeGBP, but not GBP, inhibited first phase behaviors. In the carrageenan model of inflammatory pain, systemic GBP or (1R,3R)3-MeGBP failed to inhibit thermal hyperalgesia, whereas (1S,3R)3-MeGBP had a significant, albeit transient, effect. Systemic (1S,3R)3-MeGBP, but not GBP or (1R,3R)3-MeGBP, also produced an antinociceptive effect in the warm water tail withdrawal test of acute pain. These data demonstrate that GBP and 3-MeGBP display different antinociceptive profiles, suggesting dissimilar mechanisms of antinociceptive action. Thus, the stereoselective efficacy of 3-MeGBP, presumably related to ␣ 2 ␦ binding, likely does not completely account for the mechanism of action of GBP.Gabapentin (GBP; Neurontin) is an anticonvulsant that has found increased utility for the treatment of clinical neuropathic pain. Although originally developed for the treatment of spasticity and epilepsy, recent attention has focused on the utility of GBP for the treatment of neuropathic pain based on its efficacy and minimal side-effect profile in clinical trials (Rice and Maton, 2001). In rodent neuropathic pain models, GBP effectively attenuates thermal and mechanical hypersensitivity following peripheral nerve ligation (Xiao and Bennett, 1996;Hunter et al., 1997;Hwang and Yaksh, 1997). GBP has also been shown to inhibit thermal and mechanical hyperalgesia following carrageenan-induced inflammation (Field et al., 1997b;Lu and Westlund, 1999); however, other studies have reported limited effectiveness of GBP for inflammatory pain (Gould et al., 1997;Patel et al., 2001). Additionally, GBP inhibits spontaneous nociceptive behaviors and mechanical hyperalgesia produced by intraplantar formalin or surgical incision, respectively (Field et al., 1997a,b). The antinociceptive effects of GBP in models of neuropathic, inflammatory, and surgical pain appear to be selective for injury-induced hypersensitivity, ...

A novel class of 6-aryl-6H-pyrrolo[3,4-d]pyridazine ligands for the alpha2delta subunit of voltage-gated calcium channels has been described. Substitutions in the aryl ring of the molecule were generally not tolerated, and resulted in diminished binding to the alpha2delta subunit. Modifications to the pyridazine ring revealed numerous permissive substitutions, and detailed SAR studies were carried out in this portion of the molecule. Replacement of the pyridazine ring methyl group with an aminomethyl functionality provided greatly improved potency over the initial lead. The initial lead compound displayed good rat pharmacokinetic properties, and was shown to be efficacious in the Chung model for neuropathic pain in rats.

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<p><strong>Objective</strong>: The aim of our study was to investigate whether current eGFR equations in clinical use might systematically overestimate the kidney function, and thus misclassify CKD status, of Black Americans with HIV. Specifically, we evaluated the impact of removing the race coefficient from the MDRD and CKD-EPI equations on comparisons between Black and White HIV-infected veterans related to: 1) the prevalence of reduced eGFR; 2) the distribution of eGFR values; and 3) the relationship between eGFR and all-cause mortality.</p><p><strong>Design:</strong> Retrospective cohort study.</p><p><strong>Setting:</strong> The Department of Veterans Affairs (VA) HIV Clinical Case Registry (CCR), which actively monitors all HIV-infected persons receiving care in the VA nationally.</p><p><strong>Patients/Participants:</strong> 21,905 treatmentnaïve HIV-infected veterans.</p><p><strong>Main Outcome Measures:</strong> Estimated glomerular filtration rate (eGFR) using the abbreviated Modification of Diet in Renal Disease (MDRD) formula with and without (MDRD-RCR) the race coefficient and allcause mortality.</p><p><strong>Results:</strong> Persons with eGFR &lt;45 mL/ min/1.73m2 had a higher risk of death compared with those with eGFR &gt;80 mL/ min/1.73m2 among both Blacks (HR=2.8, 95%CI: 2.4-3.3) and Whites (HR=1.9, 95%CI: 1.4-2.6), but the association appeared to be stronger in Blacks (P=.038, test for interaction). Blacks with eGFR 45- 60 mL/min/1.73m2 also had a higher risk of death (HR=1.7, 95%CI: 1.4-2.1) but Whites did not (HR=0.86, 95%CI: .67- 1.10; test for interaction: P&lt;.0001). Racial differences were substantially attenuated when eGFR was re-calculated without the race coefficient.</p><p><strong>Conclusions:</strong> Our findings suggest that clinicians may want to consider estimating glomerular filtration rate without the race coefficient in Blacks with HIV. <em>Ethn Dis.</em> 2016;26(2):213-220; doi:10.18865/ ed.26.2.213</p>