Alleviation of Chronic Pain Following Rat Spinal Cord Compression Injury With Multimodal Actions of Huperzine A.

Alleviation of chronic pain following rat spinal cord compression injury with multimodal actions of huperzine A.

Filed under: Drug and Alcohol Rehabilitation

Proc Natl Acad Sci U S A. 2013 Feb 5;
Yu D, Thakor DK, Han I, Ropper AE, Haragopal H, Sidman RL, Zafonte R, Schachter SC, Teng YD

Diverse mechanisms including activation of NMDA receptors, microglial activation, reactive astrogliosis, loss of descending inhibition, and spasticity are responsible for ?40% of cases of intractable neuropathic pain after spinal cord injury (SCI). Because conventional treatments blocking individual mechanisms elicit only short-term effectiveness, a multimodal approach with simultaneous actions against major pain-related pathways may have value for clinical management of chronic pain. We hypothesize that [-]-huperzine A (HUP-A), an alkaloid isolated from the club moss Huperzia serrata, that is a potent reversible inhibitor of acetylcholinesterase and NMDA receptors, could mitigate pain without invoking drug tolerance or dependence by stimulating cholinergic interneurons to impede pain signaling, inhibiting inflammation via microglial cholinergic activation, and blocking NMDA-mediated central hypersensitization. We tested our hypothesis by administering HUP-A i.p. or intrathecally to female Sprague-Dawley rats (200-235 g body weight) after moderate static compression (35 g for 5 min) of T10 spinal cord. Compared with controls, HUP-A treatment demonstrates significant analgesic effects in both regimens. SCI rats manifested no drug tolerance following repeated bolus i.p. or chronic intrathecal HUP-A dosing. The pain-ameliorating effect of HUP-A is cholinergic dependent. Relative to vehicle treatment, HUP-A administration also reduced neural inflammation, retained higher numbers of calcium-impermeable GluR2-containing AMPA receptors, and prevented Homer1a up-regulation in dorsal horn sensory neurons. Therefore, HUP-A may provide safe and effective management for chronic postneurotrauma pain by reestablishing homeostasis of sensory circuits.
HubMed – drug

Serum Levels of 25-hydroxyvitamin D and the CYP3A Biomarker 4?-hydroxycholesterol in a High-dose Vitamin D Supplementation Study.

Filed under: Drug and Alcohol Rehabilitation

Drug Metab Dispos. 2013 Feb 5;
Bjorkhem-Bergman L, Nylen H, Norlin AC, Lindh JD, Ekstrom L, Eliasson E, Bergman P, Diczfalusy U

The primary aim was to study the relationship between individual serum levels of 25-hydroxyvitamin D and 4?-hydroxycholesterol, which is an endogenous biomarker of the drug-metabolising CYP3A enzymes. In addition, the relationship between this biomarker and inflammation, measured as C-reactive protein (CRP), was investigated. Serum samples were used from a recently performed clinical trial in patients with antibody deficiency or increased susceptibility to respiratory tract infections that were randomised to either placebo or high dose (4000 IU/day) vitamin D for 12 months. 116 patients were included in the final analyses and serum samples collected 6 months after study start were analysed. At this time point, 25-hydroxyvitamin D levels were found to range between 10-284 nmol/ L. Individual levels of 25-hydroxyvitamin D as well as CRP were compared with 4?-hydroxycholesterol levels. In addition, all participants were genotyped for two polymorphisms (Taq1 and Foq1) in the vitamin D receptor gene (VDR). There was no significant correlation between individual serum levels of 25-hydroxyvitamin D and 4?-hydroxycholesterol. However, a moderate, but statistically significant, negative correlation between CRP and 4?-hydroxycholesterol levels was observed. This study in patients with highly variable serum levels of 25-hydroxyvitamin D could not reveal any relationship between vitamin D and 4?-hydroxycholesterol, an endogenous biomarker of CYP3A activity. However, the negative correlation between CRP and 4?-hydroxycholesterol supports earlier experimental results that inflammation may suppress hepatic CYP3A activity, a finding of potentially high clinical relevance that warrants further exploration.
HubMed – drug

Investigating the Enteroenteric Recirculation of Apixaban, a Factor Xa Inhibitor: Administration of Activated Charcoal to Bile Duct-Cannulated Rats and Dogs Receiving an Intravenous Dose and Use of Drug Transporter Knockout Rats.

Filed under: Drug and Alcohol Rehabilitation

Drug Metab Dispos. 2013 Feb 5;
Zhang D, Frost CE, He K, Rodrigues AD, Wang X, Wang L, Goosen TC, Humphreys WG

Abstract The study described here investigated the impact of intestinal excretion (IE, excretion of drug directly from circulation to intestinal lumen), enteroenteric recirculation (EER), and renal tubule recirculation (RTR) on apixaban pharmacokinetics and disposition. The experimental approaches involve integrating apixaban elimination pathways with pharmacokinetic profiles obtained from bile duct-cannulated (BDC) rats and dogs receiving intravenous (IV) doses together with orally administration of activated charcoal (AC). Additionally, the role of P-gp and BCRP in apixaban disposition was evaluated in experiments using transporter inhibitors and transporter knockout (KO) rats. Approximately 20-50% of an apixaban IV dose was found in feces of BDC rats and dogs, suggesting IE leading to fecal elimination and intestinal clearance (IC). The fecal elimination, IC, and systemic clearance of apixaban were increased upon AC administration in both BDC rats and dogs, and were decreased in BDC rats dosed with GF-120918 (a BCRP and P-gp inhibitor). BCRP appeared to play a more important role for absorption, intestinal and renal elimination of apixaban than P-gp in transporter-KO rats after oral and IV dosing, which led to a higher level of active renal excretion in rat than other species. These data demonstrate that apixaban undergoes IE, EER, and RTR that are facilitated by efflux transporters. Intestinal re-absorption of apixaban could be interrupted by AC even at 3 h post drug dose in dogs (late charcoal effect). This study demonstrates that the intestine is an organ for direct clearance and redistribution of apixaban. The IE, EER, and RTR contribute to overall pharmacokinetic profiles of apixaban. IE as a clearance pathway, balanced with metabolism and renal excretion, helps decrease the impacts of intrinsic (renal or hepatic impairment) and extrinsic (drug-drug interactions) factors on apixaban disposition.
HubMed – drug

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