Co-administration of morphine and gabapentin leads to dose dependent synergistic effects in a rat model of postoperative pain.

Despite much evidence that combination of morphine and gabapentin can be beneficial for managing postoperative pain, the nature of the pharmacological interaction of the two drugs remains unclear. The aim of this study was to assess the interaction of morphine and gabapentin in range of different dose combinations and investigate whether co-administration leads to synergistic effects in a preclinical model of postoperative pain. The pharmacodynamic effects of morphine (1, 3 and 7mg/kg), gabapentin (10, 30 and 100mg/kg) or their combination (9 combinations in total) were evaluated in the rat plantar incision model using an electronic von Frey device. The percentage of maximum possible effect (%MPE) and the area under the response curve (AUC) were used for evaluation of the antihyperalgesic effects of the drugs. Identification of synergistic interactions was based on Loewe additivity response surface analyses. The combination of morphine and gabapentin resulted in synergistic antihyperalgesic effects in a preclinical model of postoperative pain. The synergistic interactions were found to be dose dependent and the increase in observed response compared to the theoretical additive response ranged between 26 and 58% for the synergistic doses. The finding of dose-dependent synergistic effects highlights that choosing the right dose-dose combination is of importance in postoperative pain therapy. Our results indicate benefit of high doses of gabapentin as adjuvant to morphine. If these findings translate to humans, they might have important implications for the treatment of pain in postoperative patients.

Effect of mushroom diet on pharmacokinetics of gabapentin in healthy Chinese subjects.

AIMS: This study evaluated the pharmacokinetics of gabapentin in Chinese subjects who received a diet rich in shiitake mushrooms. Shiitake mushrooms have been shown to contain high amount of ergothioneine. In vitro studies have shown that OCTN1-mediated secretion of gabapentin is trans-stimulated by ergothioneine. This study also investigated the concentrations of ergothioneine in plasma at baseline and following mushroom consumption. METHODS: Ten healthy male subjects were recruited and received a diet containing no mushrooms (treatment A) or a high mushroom diet (treatment B; after at least a 7 day washout period) 1 day prior to administration of a single oral dose of gabapentin 600 mg. RESULTS: Ingestion of shiitake mushrooms produced significant increases in plasma ergothioneine concentrations that were sustained for more than 48 h. A statistically significant but modest increase in the renal clearance (CLR ) of gabapentin occurred after intake of the mushroom diet (91.1 ± 25.1 vs. 76.9 ± 20.6 ml min(-1) , P = 0.031). No significant changes in AUC(0,tlast ) of gabapentin were observed (P = 0.726). Creatinine clearance did not correlate with CLR of gabapentin at baseline (treatment A). After ingestion of the mushroom diet, creatinine clearance accounted for 65.3% of the variance in CLR of gabapentin. CONCLUSIONS: These data suggest that diet-drug pharmacokinetic interactions may occur during co-exposure to gabapentin and mushroom constituents. However, as it does not affect the AUC(0,tlast ) of gabapentin, it may not have clinically important consequences. Shiitake mushrooms can also be used as a source of ergothioneine for future clinical studies.

A novel, potent, and orally active VLA-4 antagonist with good aqueous solubility: trans-4-[1-[[2-(5-Fluoro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl]acetyl]-(5S)-[methoxy(methyl)amino]methyl-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid.

We have carried out the optimization of substituents at the C-3 or the C-5 position on the pyrrolidine ring of VLA-4 antagonist 3 with 2-(phenylamino)-7-fluorobenzoxazolyl moiety for the purpose of improving in vivo efficacy while maintaining good aqueous solubility. As a result, we successfully increased in vitro activity in the presence of 3% human serum albumin and achieved an exquisite lipophilic and hydrophilic balance of compounds suitable for oral administrative regimen. The modification resulted in the identification of zwitterionic compound 7n with (5S)-[methoxy(methyl)amino]methylpyrrolidine, which significantly alleviated bronchial hyper-responsiveness to acetylcholine chloride at 12.5mg/kg, p.o. in a murine asthma model and showed favorable aqueous solubility (JP1, 89 µg/mL; JP2, 462 µg/mL). Furthermore, this compound showed good oral bioavailability (F=54%) in monkeys.

Optimised protocol design for the screening of analgesic compounds in neuropathic pain.

We have previously shown how screening experiments for neuropathic pain can be optimised taking into account parameter and model uncertainty. Here we demonstrate how optimised protocols can be used to screen and rank candidate molecules. The concept is illustrated by pregabalin as a new chemical entity and gabapentin as a reference compound. ED-optimality was applied to a logistic regression model describing the relationship between drug exposure and response to evoked pain in the complete Freund's adjuvant (CFA) model in rats. Design variables for optimisation of the experimental protocol included dose levels and sampling times. Prior information from the reference compound was used in conjunction with relative in vitro potency as priors. Results from simulated scenarios were then combined with fitting of experimental data to estimate precision and bias of model parameters for the empirical and optimised designs. The pharmacokinetics of pregabalin was described by a two-compartment model. The expected value of EC(50) of pregabalin was 637.5 ng ml(-1). Model-based analysis of the data yielded median (range) of EC(50) values of 1,125 (898-2412) ng ml(-1) for the empirical protocol and 755 (189-756) ng ml(-1) for the optimised design. In contrast to current practice, optimal design entails different sampling schedule across dose levels. ED-optimised designs should become standard practice in the screening of candidate molecules. It ensures lower bias when estimating the drug potency, facilitating accurate ranking and selection of compounds for further development.

Application of ED-optimality to screening experiments for analgesic compounds in an experimental model of neuropathic pain.

In spite of the evidence regarding high variability in the response to evoked pain, little attention has been paid to its impact on the screening of drugs for inflammatory and neuropathic pain. In this study, we explore the feasibility of introducing optimality concepts to experimental protocols, enabling estimation of parameter and model uncertainty. Pharmacokinetic (PK) and pharmacodynamic data from different experiments in rats were pooled and modelled using nonlinear mixed effects modelling. Pain data on gabapentin and placebo-treated animals were generated in the complete Freund's adjuvant model of neuropathic pain. A logistic regression model was applied to optimise sampling times and dose levels to be used in an experimental protocol. Drug potency (EC(50)) and interindividual variability (IIV) were considered the parameters of interest. Different experimental designs were tested and validated by SSE (stochastic simulation and estimation) taking into account relevant exposure ranges. The pharmacokinetics of gabapentin was described by a two-compartment PK model with first order absorption (CL = 0.159 l h(-1), V(2) = 0.118 l, V(3) = 0.253 l, Ka = 0.26 h(-1), Q = 1.22 l h(-1)). Drug potency (EC(50)) for the anti-allodynic effects was estimated to be 1400 ng ml(-1). Protocol optimisation improved bias and precision of the EC50 by 6 and 11.9. %, respectively, whilst IIV estimates showed improvement of 31.89 and 14.91 %, respectively. Our results show that variability in behavioural models of evoked pain response leads to uncertainty in drug potency estimates, with potential impact on the ranking of compounds during screening. As illustrated for gabapentin, ED-optimality concepts enable analysis of discrete data taking into account experimental constraints.

Discovery of a novel melanin concentrating hormone receptor 1 (MCHR1) antagonist with reduced hERG inhibition.

An initial SAR study resulted in the identification of the novel, potent MCHR1 antagonist 2. After further profiling, compound 2 was discovered to be a potent inhibitor of the hERG potassium channel, which prevented its further development. Additional optimization of this structure resulted in the discovery of the potent MCHR1 antagonist 11 with a dramatically reduced hERG liability. The decrease in hERG activity was confirmed by several in vivo preclinical cardiovascular studies examining QT prolongation. This compound demonstrated good selectivity for MCHR1 and possessed good pharmacokinetic properties across preclinical species. Compound 11 was also efficacious in reducing body weight in two in vivo mouse models. This compound was selected for clinical evaluation and was given the code AMG 076.

Discovery of a biaryl cyclohexene carboxylic acid (MK-6892): a potent and selective high affinity niacin receptor full agonist with reduced flushing profiles in animals as a preclinical candidate.

Biaryl cyclohexene carboxylic acids were discovered as full and potent niacin receptor (GPR109A) agonists. Compound 1e (MK-6892) displayed excellent receptor activity, good PK across species, remarkably clean off-target profiles, good ancillary pharmacology, and superior therapeutic window over niacin regarding the FFA reduction versus vasodilation in rats and dogs.

New antiepileptic drugs that are second generation to existing antiepileptic drugs.

In the last decade, 10 new antiepileptic drugs (AEDs) have been introduced that offer appreciable advantages in terms of their favourable pharmacokinetics, improved tolerability and lower potential for drug interactions. However, despite the large therapeutic range of old and new AEDs, approximately 30% of the patients with epilepsy are still not seizure free and, consequently, there is a substantial need to develop new AEDs. The new AEDs currently in development can be divided into two categories: drugs with completely new chemical structures such as lacosamide (formally harkoseride), retigabine, rufinamide and talampanel; and drugs that are derivatives or analogues of existing AEDs that can be regarded as second-generation or follow-up compounds of established AEDs. This article focuses on the second category and thus critically reviews the following second-generation compounds: eslicarbazepine acetate or BIA-2-093 and 10-hydroxy carbazepine (carbamazepine derivatives); valrocemide and NPS 1776 (isovaleramide; valproic acid derivatives); pregabalin and XP13512 (gabapentin derivatives); brivaracetam (ucb 34714) and seletracetam (ucb 44212; levetiracetam derivatives); and fluorofelbamate (a felbamate derivative). In addition, a series of valproic acid derivatives that are currently in preclinical stage has also been evaluated because some lead compounds of this series have a promising potential to become new antiepileptics and CNS drugs. For any of these follow-up compounds to become a successful second generation to an existing AED, it has to be more potent, safer and possess favourable pharmacokinetics, including low potential for pharmacokinetic and pharmacodynamic drug interactions.