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Biomedical subjects

William J Martin

Publications and source records attributed to William J Martin.

At least 19 recordsLinked to original sources
PubMed2006

Sodium channel blockade may contribute to the analgesic efficacy of antidepressants.

UNLABELLED: Sodium channel blockers such as lidocaine, lamotrigine, and carbamazepine can be effective in the treatment of neuropathic pain. Though not approved for neuropathic pain indications, tricyclic antidepressants are often considered first-line treatment for conditions such as post-herpetic neuralgia and diabetic neuropathy. Several tricyclic antidepressants have been shown to block peripheral nerve sodium channels, which may contribute to their antihyperalgesic efficacy. In this study, we compared the sodium channel-blocking potency of a number of antidepressants, including tricyclic antidepressants and selective serotonin reuptake inhibitors. All compounds tested inhibited Na(V)1.7 in a state- and use-dependent manner, with affinities for the inactivated state ranging from 0.24 micromol/L for amitriptyline to 11.6 micromol/L for zimelidine. The tricyclic antidepressants were more potent blockers of Na(V)1.7. Moreover, IC(50)s for block of the inactivated state for amitriptyline, nortriptyline, imipramine, desipramine, and maprotiline were in the range of therapeutic plasma concentrations for both the treatment of depression as well as neuropathic pain. By contrast, fluoxetine, paroxetine, mianserine, and zimelidine had IC(50)s for Na(V)1.7 outside their therapeutic concentration ranges and generally were not efficacious against post-herpetic neuralgia or diabetic neuropathy. These results suggest that block of peripheral nerve sodium channels may contribute to the antihyperalgesic efficacy of certain antidepressants. PERSPECTIVE: Tricyclic antidepressants are often considered first-line treatment for neuropathic pain. Some tricyclic antidepressants block sodium channels, which may contribute to their antihyperalgesic efficacy. In the current study, we compared the potency of peripheral sodium channel blockade for several tricyclic antidepressants and selective serotonin reuptake inhibitors with their therapeutic efficacy.

Analgesics↗
PubMed2006

Relationship between the firing frequency of injured peripheral neurons and inhibition of firing by sodium channel blockers.

UNLABELLED: Animal models of neuropathic pain in which a peripheral nerve is damaged result in spontaneous activity in primary afferents that can be inhibited by intravenous administration of sodium channel blockers. Many of these compounds exhibit use-dependent block of sodium current, leading to the prediction that they should more readily inhibit neurons that fire at higher frequencies. This prediction was tested in 2 rat models of nerve injury, L5 spinal nerve section and sciatic nerve section. Sciatic nerve section produced average firing frequencies that were higher than spinal nerve section and often manifested as high-frequency bursting. Inhibition of firing by intravenous sodium channel blockers was longer lasting in this model. Within each model, higher frequency of firing did not translate into more effective block. In the spinal nerve section model, there was a robust inverse correlation between frequency and inhibition. Within the sciatic section model, only neurons that fired in rhythmic bursts were inhibited, and again, those firing at lower mean frequencies were more effectively inhibited. These results indicate that the efficacy of sodium channel blockers depends on the nature of the injury and the pattern of the resulting activity rather than simply the frequency of action potentials generated. PERSPECTIVE: This study examines the ability of frequency-dependent sodium channel blockers to inhibit spontaneous firing of injured peripheral nerves in vivo. It outlines the conditions under which inhibition is more and less effective and will provide insight into conditions under which sodium channel blockers are likely to be therapeutically useful.

Anesthetics, Local↗
PubMed2006

Selection of stem cells by using antibodies that target different CD34 epitopes yields different patterns of T-cell differentiation.

The objective of this study was to compare the patterns of T-cell differentiation from CD34(+) human stem cells selected with different classes of antibody targeting the CD34 molecule. We compared signal-joint T-cell receptor excision circle (sjTREC) production in thymocytes selected with different classes of anti-CD34 antibody. Based on these results, we studied immune reconstitution in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice using human stem cells selected with the same antibodies that yielded variation in the thymocytes. Human CD34(+) stem cells were immunomagnetically selected using the class II QBEnd antibody (prevalent in clinical graft engineering) and the class III 8G12 antibody (common in diagnostic tests). Engraftment and T-cell reconstitution were examined after transplantation. Thymocytes selected with the 8G12 class III antibody have a higher TREC production than those selected with the QBEnd class II antibody. Of mice transplanted with cells selected using the 8G12 antibody, 50% had sjTREC production, compared with 14% of mice transplanted with cells selected using the clinically common antibody QBEnd. 8G12 thymic progenitors are characterized by higher quality in thymic distribution and higher activity in T-cell differentiation. Using class III antibody targeting the CD34 molecule resulted in increased T-cell reconstitution in the NOD/SCID mouse. Use of a single antibody epitope targeting the CD34 molecule may lead to loss of cells that might provide richer T-cell reconstitution. Use of different or multiple epitopes, targeting of alternate stem cell markers, or use of cell-depletion strategies might prevent this loss.

Animals↗
PubMed2006

Reversal of neuropathic pain by alpha-hydroxyphenylamide: a novel sodium channel antagonist.

Sodium (Na) channel blockers are known to possess antihyperalgesic properties. We have designed and synthesized a novel Na channel antagonist, alpha-hydroxyphenylamide, and determined its ability to inhibit both TTX-sensitive (TTX-s) and TTX-resistant (TTX-r) Na currents from small dorsal root ganglion (DRG) neurons. alpha-Hydroxyphenylamide tonically inhibited both TTX-s and TTX-r Na currents yielding an IC(50) of 8.2+/-2.2 microM (n=7) and 28.9+/-1.8 microM (n=8), respectively. In comparison, phenytoin was less potent inhibiting TTX-s and TTX-r currents by 26.2+/-4.0% (n=8) and 25.5+/-2.0%, respectively, at 100 microM. alpha-Hydroxyphenylamide (10 microM) also shifted equilibrium gating parameters of TTX-s Na channels to greater hyperpolarized potentials, slowed recovery from inactivation, accelerated the development of inactivation and exhibited use-dependent block. In the chronic constriction injury (CCI) rat model of neuropathic pain, intraperitoneal administration of alpha-hydroxyphenylamide attenuated the hyperalgesia by 53% at 100mg/kg, without affecting motor coordination in the Rotorod test. By contrast, the reduction in pain behavior produced by phenytoin (73%; 100mg/kg) was associated with significant motor impairment. In summary, we report that alpha-hydroxyphenylamide, a sodium channel antagonist, exhibits antihyperalgesic properties in a rat model of neuropathic pain, with favorable sedative and ataxic side effects compared with phenytoin.

Action Potentials↗
PubMed2005

Synthesis and SAR of 1,2-trans-(1-hydroxy-3-phenylprop-1-yl)cyclopentane carboxamide derivatives, a new class of sodium channel blockers.

Novel cyclopentane-based 3-phenyl-1-hydroxypropyl compounds were evaluated for inhibitory activity against the peripheral nerve sodium channel Na(V)1.7 and off-target activity against the cardiac potassium channel hERG. The stereochemistry of the hydroxyl group and substitution on the phenyl rings with either fluorinated O-alkyl or alkyl groups were found to be critical for conferring potency against Na(V)1.7. A benchmark compound from this series displayed efficacy in rat models of inflammatory and neuropathic pain.

Animals↗
PubMed2005

Combination immunotherapy with clinical-scale enriched human gammadelta T cells, hu14.18 antibody, and the immunocytokine Fc-IL7 in disseminated neuroblastoma.

PURPOSE: To evaluate a combined cellular and humoral immunotherapy regimen in a mouse model of disseminated human neuroblastoma. We tested combinations of clinical-grade, isolated human gammadelta T cells with the humanized anti-GD2 antibody hu14.18 and a novel fusion cytokine, Fc-IL7. EXPERIMENTAL DESIGN: gammadelta T cells were large-scale enriched from leukapheresis product obtained from granulocyte colony-stimulating factor-mobilized donors. gammadelta T cell cytotoxicity was tested in a europium-TDA release assay. The effect of Fc-IL7 on gammadelta T-cell survival in vitro was assessed by flow cytometry. NOD.CB17-Prkdc(scid)/J mice received 1 x 10(6) NB-1691 neuroblastoma cells via the tail vein 5 to 6 days before therapy began. Treatment, for five consecutive weeks, consisted of injections of 1 x 10(6) gammadelta T cells weekly, 1 x 10(6) gammadelta T cells weekly, and 20 microg hu14.18 antibody four times per week, or 1 x 10(6) gammadelta T cells weekly with 20 microg hu14.18 antibody four times per week, and 20 mug Fc-IL7 once weekly. RESULTS: The natural cytotoxicity of gammadelta T cells to NB-1691 cells in vitro was dramatically enhanced by hu14.18 antibody. Fc-IL7 effectively kept cultured gammadelta T cells viable. Combination therapy with gammadelta T cells and hu14.18 antibody significantly enhanced survival (P = 0.001), as did treatment with gammadelta T cells, hu14.18 antibody, and Fc-IL7 (P = 0.005). Inclusion of Fc-IL7 offered an additional survival benefit (P=0.04). CONCLUSIONS: We have shown a new and promising immunotherapy regimen for neuroblastoma that requires clinical evaluation. Our approach might also serve as a therapeutic model for other malignancies.

Animals↗
PubMed2005

Block of peripheral nerve sodium channels selectively inhibits features of neuropathic pain in rats.

Several sodium channel blockers are used clinically to treat neuropathic pain. However, many patients fail to achieve adequate pain relief from these highly brain-penetrant drugs because of dose-limiting central nervous system side effects. Here, we describe the functional properties of trans-N-{[2'-(aminosulfonyl)biphenyl-4-yl]methyl}-N-methyl-N'-[4-(trifluoromethoxy)benzyl]cyclopentane-1,2-dicarboxamide (CDA54), a peripherally acting sodium channel blocker. In whole-cell electrophysiological assays, CDA54 blocked the inactivated states of hNa(V)1.7 and hNa(V)1.8, two channels of the peripheral nervous system implicated in nociceptive transmission, with affinities of 0.25 and 0.18 microM, respectively. CDA54 displayed similar affinities for the tetrodotoxin-resistant Na+ current in small-diameter mouse dorsal root ganglion neurons. Peripheral nerve injury causes spontaneous electrical activity in normally silent sensory neurons. CDA54 inhibited these injury-induced spontaneous action potentials at concentrations 10-fold lower than those required to block normal A- and C-fiber conduction. Consistent with the selective inhibition of injury-induced firing, CDA54 (10 mg/kg p.o.) significantly reduced behavioral signs of neuropathic pain in two nerve injury models, whereas the same dose of CDA54 did not affect acute nociception or motor coordination. In anesthetized dogs, CDA54, at plasma concentrations of 6.7 microM, had no effect on cardiac electrophysiological parameters including conduction. Thus, the peripheral nerve sodium channel blocker CDA54 selectively inhibits sensory nerve signaling associated with neuropathic pain.

Administration, Oral↗
PubMed2005

Genetic mapping of expressed sequences in onion and in silico comparisons with rice show scant colinearity.

The Poales (which include the grasses) and Asparagales [which include onion (Allium cepa L.) and other Allium species] are the two most economically important monocot orders. Enormous genomic resources have been developed for the grasses; however, their applicability to other major monocot groups, such as the Asparagales, is unclear. Expressed sequence tags (ESTs) from onion that showed significant similarities (80% similarity over at least 70% of the sequence) to single positions in the rice genome were selected. One hundred new genetic markers developed from these ESTs were added to the intraspecific map derived from the BYG15-23xAC43 segregating family, producing 14 linkage groups encompassing 1,907 cM at LOD 4. Onion linkage groups were assigned to chromosomes using alien addition lines of Allium fistulosum L. carrying single onion chromosomes. Visual comparisons of genetic linkage in onion with physical linkage in rice revealed scant colinearity; however, short regions of colinearity could be identified. Our results demonstrate that the grasses may not be appropriate genomic models for other major monocot groups such as the Asparagales; this will make it necessary to develop genomic resources for these important plants.

Base Sequence↗
PubMed2005

Varicella zoster virus induces neuropathic changes in rat dorsal root ganglia and behavioral reflex sensitisation that is attenuated by gabapentin or sodium channel blocking drugs.

Reactivation of latent varicella zoster virus (VZV) within sensory trigeminal and dorsal root ganglia (DRG) neurons produces shingles (zoster), often accompanied by a chronic neuropathic pain state, post-herpetic neuralgia (PHN). PHN persists despite latency of the virus within human sensory ganglia and is often unresponsive to current analgesic or antiviral agents. To study the basis of varicella zoster-induced pain, we have utilised a recently developed model of chronic VZV infection in rodents. Immunohistochemical analysis of DRG following VZV infection showed the presence of a viral immediate early gene protein (IE62) co-expressed with markers of A- (neurofilament-200; NF-200) and C- (peripherin) afferent sensory neurons. There was increased expression of neuropeptide Y (NPY) in neurons co-expressing NF-200. In addition, there was an increased expression of alpha2delta1 calcium channel, Na(v)1.3 and Na(v)1.8 sodium channels, the neuropeptide galanin and the nerve injury marker, Activating Transcription Factor-3 (ATF-3) as determined by Western blotting in DRG of VZV-infected rats. VZV infection induced increased behavioral reflex responsiveness to both noxious thermal and mechanical stimuli ipsilateral to injection (lasting up to 10 weeks post-infection) that is mediated by spinal NMDA receptors. These changes were reversed by systemic administration of gabapentin or the sodium channel blockers, mexiletine and lamotrigine, but not by the non-steroidal anti-inflammatory agent, diclofenac. This is the first time that the profile of VZV infection-induced phenotypic changes in DRG has been shown in rodents and reveals that this profile appears to be broadly similar (but not identical) to changes in other neuropathic pain models.

Amines↗
PubMed2005

Discovery and activity of (1R,4S,6R)-N-[(1R)-2-[4-cyclohexyl-4-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperidinyl]-1-[(4-fluorophenyl)methyl]-2-oxoethyl]-2-methyl-2-azabicyclo[2.2.2]octane-6-carboxamide (3, RY764), a potent and selective melanocortin subtype-4 receptor agonist.

A novel isoquinuclidine containing selective melanocortin subtype-4 receptor small molecule agonist, 3 (RY764), is reported. Its in vivo characterization revealed mechanism-based food intake reduction and erectile activity augmentation in rodents.

Animals↗
PubMed2005

Contribution of the tetrodotoxin-resistant voltage-gated sodium channel NaV1.9 to sensory transmission and nociceptive behavior.

The transmission of pain signals after injury or inflammation depends in part on increased excitability of primary sensory neurons. Nociceptive neurons express multiple subtypes of voltage-gated sodium channels (NaV1s), each of which possesses unique features that may influence primary afferent excitability. Here, we examined the contribution of NaV1.9 to nociceptive signaling by studying the electrophysiological and behavioral phenotypes of mice with a disruption of the SCN11A gene, which encodes NaV1.9. Our results confirm that NaV1.9 underlies the persistent tetrodotoxin-resistant current in small-diameter dorsal root ganglion neurons but suggest that this current contributes little to mechanical thermal responsiveness in the absence of injury or to mechanical hypersensitivity after nerve injury or inflammation. However, the expression of NaV1.9 contributes to the persistent thermal hypersensitivity and spontaneous pain behavior after peripheral inflammation. These results suggest that inflammatory mediators modify the function of NaV1.9 to maintain inflammation-induced hyperalgesia.

Anesthetics, Local↗
PubMed2005

Discovery of potent and use-dependent sodium channel blockers for treatment of chronic pain.

A new series of voltage-gated sodium channel blockers with potential for treatment of chronic pain is reported. Systematic structure-activity relationship studies, starting with compound 1, led to identification of potent analogs that displayed use-dependent block of sodium channels, were efficacious in pain models in vivo, and most importantly, were devoid of activity against the cardiac potassium channel hERG.

Chronic Disease↗
PubMed2005

Relationship between sodium channel NaV1.3 expression and neuropathic pain behavior in rats.

A multitude of voltage-gated sodium channel subtypes (NaV1) are expressed in primary sensory neurons where they influence excitability via their role in the generation and propagation of action potentials. Peripheral nerve injury alters the expression of several NaV1subtypes, but among these only NaV1.3 is up-regulated in dorsal root ganglia (DRG) neurons. The increased expression of NaV1.3 implicates this subtype in the development and maintenance of neuropathic pain, but its contribution to neuropathic pain behavior has not been examined. Using the spared nerve injury (SNI) model, we found that peripheral nerve lesion increased NaV1.3-like immunoreactivity (-LI) in DRG neurons and that mechanical allodynia was partially alleviated following oral administration of two NaV1 blockers, mexiletine (30 and 100 mg/kg, p.o.) and lamotrigine (30 and 100 mg/kg, p.o.). Intrathecal administration of antisense oligonucleotides (4 days) selective for NaV1.3 decreased NaV1.3 immunostaining in the DRG by 50% in the SNI model, but did not attenuate mechanical or cold allodynia. Moreover, we found that only 18% of NaV1.3 positive neurons also expressed activated transcription factor-3 (ATF3), a marker of injured neurons. We then selectively axotomized a cutaneous nerve (sural) and a muscle nerve (gastrocnemius) in order to identify if NaV1.3 up-regulation is dependent on cutaneous and/or muscle afferent activation and found that the numbers of neurons expressing NaV1.3 was proportional to the magnitude of the injury, but independent of the nature of innervation. These results suggest that NaV1.3 increases in primary sensory neurons that are not directly damaged in response to injury. Thus, although NaV1.3 is up-regulated in a subpopulation of DRG neurons after injury, reduction in the expression of NaV1.3 subtype alone is not sufficient to influence the NaV1-dependent behavioral hypersensitivity associated with nerve injury.

Analgesics↗