Effects of ibudilast on oxycodone-induced analgesia and subjective effects in opioid-dependent volunteers.

Opioid-induced glial activation is hypothesized to contribute to the development of tolerance to opioid-induced analgesia. This inpatient, double-blind, placebo-controlled, within-subject and between-groups pilot study investigated the dose-dependent effects of ibudilast, a glial cell modulator, on oxycodone-induced analgesia. Opioid-dependent volunteers were maintained on morphine (30mg, PO, QID) for two weeks and received placebo ibudilast (0mg, PO, BID) during the 1st week (days 1-7). On day 8, participants (N=10/group) were randomized to receive ibudilast (20 or 40mg, PO, BID) or placebo for the remainder of the study. On days 4 (week 1) and 11 (week 2), the analgesic, subjective, and physiological effects of oxycodone (0, 25, 50mg/70kg, PO) were determined. Analgesia was measured using the cold pressor test; participants immersed their hand in cold water (4°C) and pain threshold and pain tolerability were recorded. Oxycodone decreased pain threshold and tolerability in all groups during week 1. During week 2, the placebo group exhibited a blunted analgesic response to oxycodone for pain threshold and subjective pain ratings, whereas the 40mg BID ibudilast group exhibited greater analgesia as measured by subjective pain ratings (p≤0.05). Oxycodone also increased subjective drug effect ratings associated with abuse liability in all groups during week 1 (p≤0.05); ibudilast did not consistently affect these ratings. These findings suggest that ibudilast may enhance opioid-induced analgesia. Investigating higher ibudilast doses may establish the utility of pharmacological modulation of glial activity to maximize the clinical use of opioids.

A novel CGRP-neutralizing Spiegelmer attenuates neurogenic plasma protein extravasation.

BACKGROUND AND PURPOSE: Calcitonin gene-related peptide (CGRP) plays an important role in the pathology of migraine, and recent clinical trials suggest the inhibition of CGRP-mediated processes as a new therapeutic option in migraine. In this study, we describe the generation of NOX-L41, a CGRP-neutralizing mirror-image (L-)aptamer (Spiegelmer) and investigate its in vitro and in vivo function. EXPERIMENTAL APPROACH: A CGRP-binding Spiegelmer was identified by in vitro selection. Binding studies were performed using surface plasmon resonance (SPR), and the inhibitory activity was determined in cell-based assays. The pharmacokinetic profile comparing i.v. and s.c. dosing was analysed in rats. Intravital two-photon microscopy was employed to follow extravasation from meningeal vessels. Finally, in vivo efficacy was tested in a model of electrically evoked meningeal plasma protein extravasation (PPE) in rats. KEY RESULTS: We identified NOX-L41, a novel CGRP-neutralizing Spiegelmer. SPR studies showed that NOX-L41 binds to human and rat/mouse CGRP with sub-nanomolar affinities and is highly selective against related peptides such as amylin. In vitro, NOX-L41 effectively inhibited CGRP-induced cAMP formation in SK-N-MC cells. In rats, NOX-L41 had a plasma half-life of 8 h. Pharmacodynamic studies showed that NOX-L41 extravasates from blood vessels in the dura mater and inhibits neurogenic meningeal PPE for at least 18 h after single dosing. CONCLUSIONS AND IMPLICATIONS: This is the first description of the CGRP-neutralizing Spiegelmer NOX-L41. Preclinical studies confirmed a role for CGRP in neurogenic PPE and provided proof-of-concept for the potential use of this new drug candidate for the treatment or prevention of migraine.

Activation of adult rat CNS endothelial cells by opioid-induced toll-like receptor 4 (TLR4) signaling induces proinflammatory, biochemical, morphological, and behavioral sequelae.

CNS immune signaling contributes to deleterious opioid effects including hyperalgesia, tolerance, reward, and dependence/withdrawal. Such effects are mediated by opioid signaling at toll-like receptor 4 (TLR4), presumptively of glial origin. Whether CNS endothelial cells express TLR4 is controversial. If so, they would be well positioned for activation by blood-borne opioids, contributing to opioid-induced pro-inflammatory responses. These studies examined adult primary rat CNS endothelial cell responses to (-)-morphine or its mu opioid receptor (MOR)-inactive metabolite morphine-3-glucuronide (M3G), both known TLR4 agonists. We demonstrate that adult rat CNS endothelial cells express functional TLR4. M3G activated nuclear factor kappaB (NF-κB), increased tumor necrosis factor-α (TNFα) and cyclooxygenase-2 (COX2) mRNAs, and released prostaglandin E2 (PGE2) from these cells. (-)-Morphine-induced upregulation of TNFα mRNA and PGE2 release were unmasked by pre-treatment with nalmefene, a MOR antagonist without TLR4 activity (unlike CTAP, shown to have both MOR- and TLR4-activity), suggestive of an interplay between MOR and TLR4 co-activation by (-)-morphine. In support, MOR-dependent Protein Kinase A (PKA) opposed TLR4 signaling, as PKA inhibition (H-89) also unmasked (-)-morphine-induced TNFα and COX2 mRNA upregulation. Intrathecal injection of CNS endothelial cells, stimulated in vitro with M3G, produced TLR4-dependent tactile allodynia. Further, cortical suffusion with M3G in vivo induced TLR4-dependent vasodilation. Finally, endothelial cell TLR4 activation by lipopolysaccharide and/or M3G was blocked by the glial inhibitors AV1013 and propentofylline, demonstrating endothelial cells as a new target of such drugs. These data indicate that (-)-morphine and M3G can activate CNS endothelial cells via TLR4, inducing proinflammatory, biochemical, morphological, and behavioral sequelae. CNS endothelial cells may have previously unanticipated roles in opioid-induced effects, in phenomena blocked by presumptive glial inhibitors, as well as TLR4-mediated phenomena more broadly.

Development of a novel antibody to calcitonin gene-related peptide for the treatment of osteoarthritis-related pain.

OBJECTIVE: Investigate a role for calcitonin gene-related peptide (CGRP) in osteoarthritis (OA)-related pain. DESIGN: Neutralizing antibodies to CGRP were generated de novo. One of these antibodies, LY2951742, was characterized in vitro and tested in pre-clinical in vivo models of OA pain. RESULTS: LY2951742 exhibited high affinity to both human and rat CGRP (KD of 31 and 246 pM, respectively). The antibody neutralized CGRP-mediated induction of cAMP in SK-N-MC cells in vitro and capsaicin-induced dermal blood flow in the rat. Neutralization of CGRP significantly reduced pain behavior as measured by weight bearing differential in the rat monoiodoacetate model of OA pain in a dose-dependent manner. Moreover, pain reduction with neutralization of CGRP occurred independently of prostaglandins, since LY2951742 and NSAIDs worked additively in the NSAID-responsive version of the model and CGRP neutralization remained effective in the NSAID non-responsive version of the model. Neutralization of CGRP also provided dose-dependent and prolonged (>60 days) pain reduction in the rat meniscal tear model of OA after only a single injection of LY2951742. CONCLUSIONS: LY2951742 is a high affinity, neutralizing antibody to CGRP. Neutralization of CGRP is efficacious in several OA pain models and works independently of NSAID mechanisms of action. LY2951742 holds promise for the treatment of pain in OA patients.

Southern Appalachian peatlands support high archaeal diversity.

Mid-latitude peatlands with a temperate climate are sparsely studied and as such represent a gap in the current knowledge base regarding archaeal populations present and their roles in these environments. Phylogenetic analysis of the archaeal populations among three peatlands in the Southern Appalachians reveal not only methanogenic species but also significant populations of thaumarchaeal and crenarchaeal-related organisms of the uncultured miscellaneous crenarchaeotal group (MCG) and the terrestrial group 1.1c, as well as deep-branching Euryarchaeota primarily within the Lake Dagow sediment and rice cluster V lineages. The Thaum/Crenarchaea and deep-branching Euryarchaea represented approximately 24-83% and 2-18%, respectively, of the total SSU rRNA clones retrieved in each library, and methanogens represented approximately 14-72% of the clones retrieved. Several taxa that are either rare or novel to acidic peatlands were detected including the euryarchaeal SM1K20 cluster and thaumarchaeal/crenarchaeal-related clusters 1.1a, C3, SAGMCG-1, pSL12, and AK59. All three major groups (methanogens, Thaumarchaea/Crenarchaea, and deep-branching Euryarchaea) were detected in the RNA library, suggesting at least a minimum level of maintenance activity. Compared to their northern counterparts, Southern Appalachian peatlands appear to harbor a relatively high diversity of Archaea and exhibit a high level of intra-site heterogeneity.

The murine long-term multi-lineage renewal marrow stem cell is a cycling cell.

Prevailing wisdom holds that hematopoietic stem cells (HSCs) are predominantly quiescent. Although HSC cycle status has long been the subject of scrutiny, virtually all marrow stem cell research has been based on studies of highly purified HSCs. Here we explored the cell cycle status of marrow stem cells in un-separated whole bone marrow (WBM). We show that a large number of long-term multi-lineage engraftable stem cells within WBM are in S/G2/M phase. Using bromodeoxyuridine, we show rapid transit through the cell cycle of a previously defined relatively dormant purified stem cell, the long-term HSC (LT-HSC; Lineage(-)/c-kit(+)/Sca-1(+)/Flk-2(-)). Actively cycling marrow stem cells have continually changing phenotype with cell cycle transit, likely rendering them difficult to purify to homogeneity. Indeed, as WBM contains actively cycling stem cells, and highly purified stem cells engraft predominantly while quiescent, it follows that the population of cycling marrow stem cells within WBM are lost during purification. Our studies indicate that both the discarded lineage-positive and lineage-negative marrow cells in a stem cell separation contain cycling stem cells. We propose that future work should encompass this larger population of cycling stem cells that is poorly represented in current studies solely focused on purified stem cell populations.

A community prevention model to prevent children from inhaling and ingesting harmful legal products.

Children's misuse of harmful legal products (HLPs), including inhaling or ingesting everyday household products, prescription drugs, and over-the-counter drugs, constitutes a serious health problem for American society. This article presents a community prevention model (CPM) focusing on this problem among pre and early adolescents. The model, consisting of a community mobilization strategy and environmental strategies targeting homes, schools, and retail outlets, is designed to increase community readiness and reduce the availability of HLPs, which is hypothesized to reduce HLPs use among children. The CPM is being tested in Alaskan rural communities as part of an inprogress eight-year National Institute on Drug Abuse randomized-controlled trial. This paper presents the CPM conceptual framework, describes the model, and highlights community participation, challenges, and lessons learned from implementation of the model over a 21-month period.

Cross-species comparisons of the pharmacokinetics of ibudilast.

To enable clinical development of ibudilast for new indications, its pharmacokinetics were characterized in mice, rats, rabbits, dogs, cynomolgus monkeys, and minipigs. Animal pharmacokinetics were compared with a separate study in healthy volunteers. Following oral dosing, the dose-normalized area under the curve (AUC) (DN-AUC(24h)) in humans is 896 ((ng*h ml(-1))/(mg kg(-1))), and in animals ranges from 0.3 to 87. The variability among species cannot be explained by intrinsic clearance, which in intravenous dosing experiments shows only moderate interspecies variation (13-41 l h(-1) m(-2)). A portal vein rat pharmacokinetics model suggested that differences in first-pass gut clearance may explain some of the interspecies variation in oral bioavailability. Ibudilast shows auto-induction of metabolism in some animals, but not in humans. Plasma protein binding in humans and some animals is greater than or equal to 95%. The primary metabolite 6,7-dihyrdodiol-ibudilast is measurable and has been quantitated in plasma from animals and humans. Finally, biodistribution studies show that ibudilast distributes rapidly, extensively, and reversibly to the central nervous system.

Anti-inflammatory cytokine gene therapy decreases sensory and motor dysfunction in experimental Multiple Sclerosis: MOG-EAE behavioral and anatomical symptom treatment with cytokine gene therapy.

Multiple Sclerosis (MS) is an autoimmune inflammatory disease that presents clinically with a range of symptoms including motor, sensory, and cognitive dysfunction as well as demyelination and lesion formation in brain and spinal cord. A variety of animal models of MS have been developed that share many of the pathological hallmarks of MS including motor deficits (ascending paralysis), demyelination and axonal damage of central nervous system (CNS) tissue. In recent years, neuropathic pain has been recognized as a prevalent symptom of MS in a majority of patients. To date, there have been very few investigations into sensory disturbances in animal models of MS. The current work contains the first assessment of hind paw mechanical allodynia (von Frey test) over the course of a relapsing-remitting myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis (MOG-EAE) rat model of MS and establishes the utility of this model in examining autoimmune induced sensory dysfunction. We demonstrate periods of both decreased responsiveness to touch that precedes the onset of hind limb paralysis, and increased responsiveness (allodynia) that occurs during the period of motor deficit amelioration traditionally referred to as symptom remission. Furthermore, we tested the ability of our recently characterized anti-inflammatory IL-10 gene therapy to treat the autoimmune inflammation induced behavioral symptoms and tissue histopathological changes. This therapy is shown here to reverse inflammation induced paralysis, to reduce disease associated reduction in sensitivity to touch, to prevent the onset of allodynia, to reverse disease associated loss of body weight, and to suppress CNS glial activation associated with disease progression in this model.

Fluorescence activated cell sorting: a window on the stem cell.

Fluorescence activated cell sorting (FACS) in the field of stem cell biology has become an indispensable tool for defining and separating rare cell populations with a high degree of purity. Steady progress has been made in this regard, but the intrinsic lability of the stem cell phenotype presents a different challenge and there are many technical caveats. FACS remains, however, the technology of choice for reporting and characterizing rare cell populations such as stem cells.

PDF inhibitors: an emerging class of antibacterial drugs.

The metalloenzyme peptide deformylase (PDF) represents one of the most promising bacterial targets in the search for novel mode of action antibiotics that lack cross-resistance to existing drugs. Initial research and clinical development has focused on anti-pneumococcal applications. During optimization, peptide analogs were developed containing either a hydroxamate or formyl-hydroxylamine as metal interacting group, yielding inhibitors with in vitro activity against a broad spectrum of organisms. Preclinical studies revealed potent antibacterial activity in vivo that is paired with good pharmacokinetic properties and excellent tolerability in different species. BB-83698, a potent PDF inhibitor with i.v. and oral efficacy in preclinical animal models, represents the first class-representative compound evaluated in man. The inhibitor was administered by i.v. infusion and was shown to exhibit generally dose-proportional pharmacokinetics. It was well tolerated up to doses providing predicted therapeutic exposures. These human results, combined with the preclinical information, clearly support the potential of PDF inhibitors for development as a novel class of antibacterial therapeutics.

LY293558, a novel AMPA/GluR5 antagonist, is efficacious and well-tolerated in acute migraine.

Glutamatergic hyperactivity is implicated migraine pathogenesis. Also, LY293558, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate (KA) receptor antagonist, is effective in preclinical models of migraine. We therefore tested LY293558 in acute migraine. We conducted a randomized, triple-blind, parallel-group, double-dummy, multicentre trial of 1.2 mg/kg intravenous (IV) LY293558, 6 mg subcutaneous (SC) sumatriptan, or placebo in the treatment of acute migraine. The primary efficacy variable was the headache response rate, i.e. headache score improvement from moderate/severe at baseline to mild/none at 2 h. Of 45 enrolled patients, 44 patients (20M:24F; mean age +/- SD = 40 +/- 9 years) completed the study. Response rates were 69% for LY293558 (P = 0.017 vs. placebo), 86% for sumatriptan (P < 0.01 vs. placebo) and 25% for placebo. LY293558 and sumatriptan were superior to placebo (P < 0.01 for all comparisons) on all other measures of improvement in pain and migraine associated symptoms. Fifteen percent of patients who took LY293558 reported adverse events (AEs) (n = 2; one mild, one severe). Fifty-three percent of patients who took sumatriptan (n = 8; seven mild, one moderate) and 31% of those who received placebo reported AEs (n = 5; four mild, one severe). The efficacy and safety results of LY293558 in this small migraine proof of concept trial, together with supportive preclinical data, provide evidence for a potential role of nonvasoactive AMPA/KA antagonists in treating migraine. Larger trials are needed to further test the hypothesis.

Oral anti-pneumococcal activity and pharmacokinetic profiling of a novel peptide deformylase inhibitor.

OBJECTIVE: BB-81384, a novel peptide deformylase (PDF) inhibitor, was characterized in terms of enzyme inhibition profile, antibacterial activity, rodent pharmacokinetics and oral efficacy in murine infection models. METHODS: MICs were determined by standard NCCLS broth microdilution. Selectivity of metalloenzyme inhibition was determined with a limited panel of enzymes via standard biochemical assays. Profiling of the pharmacokinetics and select tissue disposition in mice was determined and compared with that of the macrolide, azithromycin. In vivo murine efficacy studies using Streptococcus pneumoniae were conducted using a peritonitis model, as well as lung and thigh burden models of infection. RESULTS: BB-81384 selectively inhibited PDF with an IC(50) approximately 10 nM and with MICs < 0.5 mg/L against most S. pneumoniae pathogens. Pharmacokinetic analysis revealed good oral bioavailability and moderate clearance and volume of distribution. BB-81384 partitioning to lung tissue was similar in terms of magnitude and kinetics to that of the plasma compartment. Single-administration oral efficacy in a mouse peritonitis model was evident with an ED(50) of 30 mg/kg. BB-81384 reduced the bacterial load by approximately 5 and 3 log units in organ-burden models of lung and thigh infection, respectively. CONCLUSION: BB-81384, a novel PDF inhibitor with good activity against S. pneumoniae in vitro, was the first compound of this class to be profiled for oral pharmacokinetics and tissue disposition and to demonstrate oral anti-pneumococcal efficacy in mice.

Pharmacology of novel heteroaromatic polycycle antibacterials.

Heteroaromatic polycycle (HARP) compounds are a novel class of small (M(w), 600 to 650) DNA-binding antibacterials. HARP compounds exhibit a novel mechanism of action by preferentially binding to AT-rich sites commonly found in bacterial promoters and replication origins. Noncovalent binding in the minor groove of DNA results in inhibition of DNA replication and DNA-dependent RNA transcription and subsequent bacterial growth. HARP compounds have previously been shown to have potent in vitro activities against a broad spectrum of gram-positive organisms. The present report describes the extensive profiling of the in vitro and in vivo pharmacology of HARP antibacterials. The efficacies of representative compounds (GSQ-2287, GSQ-10547, and GSQ-11203), which exhibited good MIC activity, were tested in murine lethal peritonitis and neutropenic thigh infection models following intravenous (i.v.) administration. All compounds were efficacious in vivo, with potencies generally correlating with MICs. GSQ-10547 was the most potent compound in vitro and in vivo, with a 50% effective dose in the murine lethal peritonitis model of 7 mg/kg of body weight against methicillin-sensitive Staphylococcus aureus (MSSA) and 13 mg/kg against methicillin-resistant S. aureus (MRSA). In the neutropenic mouse thigh infection model, GSQ-11203 reduced the bacterial load (MRSA and MSSA) 2 log units following administration of a 25-mg/kg i.v. dose. In a murine lung infection model, treatment with GSQ-10547 at a dose of 50 mg/kg resulted in 100% survival. In addition to determination of efficacy in animals, the pharmacokinetic and tissue disposition profiles in animals following administration of an i.v. dose were determined. The compounds were advanced into broad safety screening studies, including screening for safety pharmacology, genotoxicity, and rodent toxicity. The results support further development of this novel class of antibiotics.

5-HT1F receptor agonists in acute migraine treatment: a hypothesis.

Serotonin-1F receptor (5-HT1F) agonists may relieve acute migraine without vasoconstriction. We conducted a review of preclinical and clinical data that assessed the potential link between migraine and 5-HT1F activation. (i) A high correlation exists between the potency of various 5-HT1 receptor agonists in the guinea pig dural plasma protein extravasation assay and their 5-HT1F receptor binding affinity. (ii) 5-HT1F receptors are on the trigeminal system, and may participate in blocking migraine pain transmission through the trigeminal ganglion and nucleus caudalis. (iii) 5-HT1F receptors are located on glutamate-containing neurones and their activation might inhibit glutamate release; glutamate excess may play a role in migraine. (iv) Selective 5-HT1F receptor agonists (LY334370; LY344864) are effective in preclinical migraine models and are non-vasoconstrictive. (v) LY334370 is effective in acute migraine, and does not cause any symptoms/signs of coronary vasoconstriction. Preclinical experiments and clinical observations argue for a role of selective 5-HT1F agonists in migraine.

Neurogenic dural protein extravasation induced by meta-chlorophenylpiperazine (mCPP) involves nitric oxide and 5-HT2B receptor activation.

The compound m-chlorophenylpiperazine (mCPP), which is known to trigger migraine-like head pain in some subjects, was evaluated for its ability to induce dural plasma protein extravasation (PPE) in guinea pigs. Intravenous mCPP dose-dependently increased PPE. This effect was inhibited by non-selective 5-HT2 receptor antagonists (methysergide, LY53857, LY215840), by a peripherally restricted 5-HT2 receptor antagonist (xylamidine) and by a 5-HT2B selective receptor antagonist (LY202146). These data suggests that peripheral 5-HT2B receptors mediate mCPP-induced PPE. The nitric oxide synthase inhibitor L-NAME and 5-HT1 agonist sumatriptan also blocked mCPP-induced PPE, suggesting a role for nitric oxide (NO) and the trigeminal system, respectively. NO release has been linked to activation of the 5-HT2B receptor on the vascular endothelium. However, LY202146 did not block PPE induced by electrical stimulation of the trigeminal ganglion. These data are consistent with activation of peripheral 5-HT2B receptors initiating PPE and the theory that selective 5-HT2B antagonists might be effective prophylactic therapies for migraine.

N-[3-(2-Dimethylaminoethyl)-2-methyl-1H- indol-5-yl]-4-fluorobenzamide: a potent, selective, and orally active 5-HT(1F) receptor agonist potentially useful for migraine therapy.

Recent studies have demonstrated that selective 5-HT(1F) receptor agonists inhibit neurogenic dural inflammation, a model of migraine headache, indicating that these compounds may be effective therapies for the treatment of migraine pain. This communication describes the synthesis and discovery of a novel compound, N-[3-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl]-4-fluorobenzamide (4), which possesses high binding affinity and selectivity at the 5-HT(1F) receptor relative to more than 40 other serotonergic and nonserotonergic receptors examined.

Selective seratonin 1F (5-HT(1F)) receptor agonist LY334370 for acute migraine: a randomised controlled trial.

BACKGROUND: Triptans (5-HT(1B/1D) receptor agonists) are effective drugs for acute migraine, but the side-effect of coronary vasoconstriction restricts their use in patients who are at risk of coronary artery disease. We have studied the efficacy of LY334370, a selective serotonin 1F (5-HT(1F)) receptor agonist with preclinical efficacy and no vasoconstriction, for migraine relief. METHODS: We gave LY334370 (20, 60, or 200 mg) or placebo to 99 outpatients with moderate or severe migraine headaches in a double blind, parallel group study. We measured efficacy by sustained response, response at 2 h, pain free at 2 h, and sustained pain free. FINDINGS: The proportions of patients with defined endpoints for placebo and LY334370 20, 60, and 200 mg, respectively, were: sustained response, two of 26 (8%), three of 22 (14%), 11 of 30 (37%), and 11 of 21 (52%) (dose response p<0.001); response, five of 26 (19%), four of 22 (18%), 15 of 30 (50%), and 15 of 21 (71%) (p<0.001); pain free, one of 26 (4%), none of 22, eight of 30 (27%), and eight of 21 (38%) (p=0.001); sustained pain free, one of 26 (4%), none of 22, seven of 30 (23%), and seven of 21 (33%) (p=0.002); recurrence rates, one of five (20%), none of four, four of 15 (27%), and three of 15 (20%). More patients given LY334370 than placebo reported asthenia, somnolence, and dizziness. INTERPRETATION: Our findings show that LY334370 is effective in treatment of acute migraine through selective trigeminovascular neuronal inhibition.

Lanepitant, an NK-1 antagonist, in migraine prevention.

Lanepitant, a potent non-peptide neurokinin-1 receptor antagonist, inhibits neurogenic dural inflammation, and may have a role in migraine therapy. This study evaluated the effect of lanepitant taken daily for migraine prevention. Patients with migraine headaches with and without aura by International Headache Society classification criteria were enrolled in a 12-week double-blind, parallel design study comparing the effect of 200 mg qd lanepitant (n = 42) and placebo (n = 42) on reduction of migraine frequency. The primary outcome measure was response rate, i.e. the proportion of patients with a 50% reduction in days of headache. Of the 84 patients enrolled, 90.5% were female. The endpoint response rate for lanepitant-treated patients (41.0%) was not statistically significantly (P = 0.065) greater than that for placebo-treated patients (22.0%). No efficacy variables differed significantly between treatments, except for response rates at month 3 (P = 0.045). Higher plasma concentrations were no more effective than lower concentrations. In this study lanepitant was not effective in preventing migraine, but was well tolerated. These results do not support a role for NK-1 antagonism in migraine prevention.

Dural inflammation model of migraine pain.

The cause of migraine pain is controversial. One recently proposed theory is that migraine pain may originate from inflammation of the meninges, particularly the dural membranes that surround the brain. This theory proposes that, during a migraine, there is an idiopathic activation of trigeminal sensory afferents, resulting in nociceptive transmission to the CNS as well as the release of pro-inflammatory substances in the periphery, particularly the dura. Dural inflammation is thought to lower the nociceptive threshold of dural afferents and facilitate nociceptive transmission to the central nervous system. In the procedure described in this unit, trigeminal sensory afferents are activated by electrically stimulating the trigeminal ganglion. This stimulation causes trigeminal peripheral sensory afferents to depolarize, inflammatory substances to be released from these afferents, and dural inflammation to appear. Dural inflammation is quantified by measuring plasma protein extravasation. The basic protocol describes this model in rats, and the alternate protocol describes the analogous procedure in guinea pigs.