Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new neurontin research articles will be listed here shortly after becoming available to us.
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Medical research on neurontin
Eur J Pharm Biopharm. 2008 Jun 12;
Carcaboso AM, Chiappetta DA, Höcht C, Blake MG, Boccia MM, Baratti CM, Sosnik A
Gabapentin (GBP) is a water soluble low molecular weight drug with anticonvulsivant and antinociceptive activity. In animal models, systemic administration regimes resembling chronic exposure to this drug (50mg/kg, twice a day during one week), induce memory impairment. Aiming to gain further insight on the mechanisms involved in this process, a monolithic implant that releases constant plasma levels during one-week was designed. GBP-loaded poly(epsilon-caprolactone) matrices were produced by means of a simple and reproducible melt-molding/compression procedure. In vitro release studies firstly comprised uncoated implants that displayed release profiles according to a pseudo-first order model. In order to further regulate the release, two-sided coated implants where drug-free layers would perform as membranes controlling the delivery rate were prepared. A more moderated burst effect and a relatively linear (zero-order) release between days 1 and 7 were apparent. Implants were investigated in vivo and the plasma levels monitored during 10 days. Findings indicated that after a more pronounced release during day 1 and the achievement of the levels in blood comparable to a twice-a-day intraperitoneal management, relatively constant levels were attained until day 7. Overall results support the usefulness of this manufacturing method for the production of implants to attain more prolonged GBP release profiles in memory animal studies.
Curr Neurol Neurosci Rep. 2008 Jul; 8(4): 345-52
Rogawski MA, Bazil CW
Many currently prescribed antiepileptic drugs (AEDs) act via voltage-gated sodium channels, through effects on gamma-aminobutyric acid-mediated inhibition, or via voltage-gated calcium channels. Some newer AEDs do not act via these traditional mechanisms. The molecular targets for several of these nontraditional AEDs have been defined using cellular electrophysiology and molecular approaches. Here, we describe three of these targets: alpha(2)delta, auxiliary subunits of voltage-gated calcium channels through which the gabapentinoids gabapentin and pregabalin exert their anticonvulsant and analgesic actions; SV2A, a ubiquitous synaptic vesicle glycoprotein that may prepare vesicles for fusion and serves as the target for levetiracetam and its analog brivaracetam (which is currently in late-stage clinical development); and K(v)7/KCNQ/M potassium channels that mediate the M-current, which acts a brake on repetitive firing and burst generation and serves as the target for the investigational AEDs retigabine and ICA-105665. Functionally, all of the new targets modulate neurotransmitter output at synapses, focusing attention on presynaptic terminals as critical sites of action for AEDs.
Use of second-generation antiepileptic drugs in the pediatric population.
Paediatr Drugs. 2008; 10(4): 217-54
Chung AM, Eiland LS
Epilepsy is common in the pediatric population. Nine second-generation antiepileptic drugs have been approved in the US for use in epilepsy over the past 15 years: felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, zonisamide, and pregabalin. Their use in pediatric patients is fairly widespread, despite most of these agents not having US FDA indications for use.Felbamate and gabapentin were the first two second-generation antiepileptic drugs to be approved in the US. Felbamate use has been limited because of the occurrence of hepatotoxicity and aplastic anemia. Although gabapentin is a fairly well tolerated antiepileptic drug, its use has also been limited as a result of inconsistent efficacy and concern about seizure exacerbation. Lamotrigine and topiramate are broad-spectrum antiepileptic drugs with efficacy in a wide variety of seizure types. Both agents have some tolerability concerns: rash with lamotrigine and neuropsychiatric events with topiramate. There are very little data on tiagabine use in children, but this agent appears to be effective and to have a good tolerability profile. Levetiracetam is a second-generation antiepileptic agent that is available intravenously. Considering its good efficacy, fast onset of action, and low incidence of serious adverse effects, its use in the acute setting could potentially increase. Oxcarbazepine and zonisamide have been relatively well studied in pediatric seizure patients, including use as monotherapy. Both agents have demonstrated good efficacy and tolerability for patients as young as 1 month old. Vigabatrin and rufinamide are currently not available in the US, but have been shown to have some success in other countries. Pregabalin is the newest antiepileptic agent, but lacks pediatric data currently.
Painful diabetic neuropathy: treatment and future aspects.
Diabetes Metab Res Rev. 2008 May-Jun; 24 Suppl 1: S52-7
Ziegler D
Around one of three diabetic patients is affected by distal symmetric polyneuropathy (DSP) which represents a major health problem, as it may present with partly excruciating neuropathic pain and is responsible for substantial morbidity and increased mortality. Treatment is based on four cornerstones: (1) multifactorial intervention aimed at (near)-normoglycaemia and reduction in cardiovascular risk factors, (2) treatment based on pathogenetic mechanisms, (3) symptomatic treatment, and (4) avoidance of risk factors and complications. Among the pathogenetic treatments only alpha-lipoic acid and epalrestat are available for treatment in several countries. Neuropathic pain, which is present in 8-26% of diabetic patients, exerts a substantial impact on the quality of life, particularly by causing considerable interference in sleep and enjoyment of life. Non-pharmacologic options such as nerve or muscle stimulation should always be given consideration. Among the centrally acting analgesic drugs for many years mainly the tricyclic antidepressants (TCA), carbamazepine, gabapentin, and opioids have been used to treat neuropathic pain. More recently, significant pain relief has been reported in clinical trials of painful diabetic neuropathy using agents such as the dual selective serotonin noradrenaline reuptake inhibitor (SNRI), duloxetine and the anticonvulsant pregabalin, a specific modulator of the alpha(2)delta subunit of the voltage-dependent calcium channels. A promising new anticonvulsant is lacosamide. In future, drug combinations might also include those aimed at symptomatic pain relief and quality of life on one hand and improvement or slowing the progression of the underlying neuropathic process on the other hand.
Mol Pharmacol. 2008 Jun 26;
Mich PM, Horne WA
Gabapentin is well-established as an effective treatment for neuropathic pain; however, little is known about its mechanism of action. It binds with high affinity to Ca(2+) channel alpha2delta subunits that are expressed in dorsal root ganglia. Mutation of a single alpha2delta amino acid, R217A, eliminates both gabapentin binding and analgesic efficacy. Gabapentin does not appear to have direct Ca(2+) channel blocking properties, but does affect overall levels of Ca(2+) channel surface expression in some circumstances. In this report we examined gabapentin effects on trafficking and voltage-dependent gating properties of recombinant Cav2.1 Ca(2+) channel complexes transiently expressed in Xenopus oocytes. We also determined electrophysiologically whether gabapentin causes displacement of beta subunits from Cav2.1 complexes. Our principal findings are: 1) gabapentin inhibits trafficking of recombinant Cav2.1 Ca(2+) channels in Xenopus oocytes; 2) gabapentin inhibition occurs in the presence of the Ca(2+) channel beta4a subunit, but not in the presence of beta4b; 3) gabapentin does not affect Cav2.1 voltage-dependent gating parameters; 4) inhibition of Cav2.1 trafficking is highly dependent on beta subunit concentration; and 5) gabapentin inhibition of Cav2.1 trafficking can be reversed by the alpha2delta R217A mutation. Overall, our results suggest that gabapentin reduces the number of beta4a-bound Cav2.1 complexes that are successfully trafficked to the plasma membrane. This mechanism may help to explain why gabapentin is both effective and selective in the treatment of neuropathic pain states that involve upregulation of alpha2delta subunits.
Clin J Pain. 2008 Jul-Aug; 24(6): 544-9
Wallace MS, Schulteis G
OBJECTIVES: There is an abundance of literature on the efficacy of gabapentin for the treatment of neuropathic pain. Two studies have demonstrated an effect of a single dose of gabapentin on experimental cutaneous hyperalgesia. This study evaluated the effect of chronic delivery of oral gabapentin on experimentally induced cutaneous hyperalgesia. METHODS: A randomized, double-blinded, placebo-controlled crossover design methodology was conducted. Participants took part in two 10-day study sessions, separated by a 7-day washout period. One session was with gabapentin and one with placebo. Study drug was administered 300 mg b.i.d. from day 1 to 3, 300 mg q.i.d. from day 4 to 6 and 600 mg t.i.d. from day 7 to 10. At baseline, day 4, day 7, and day 10, quantitative sensory testing was performed to thermal and mechanical stimuli. On day 10, only intradermal capsaicin was injected on the volar aspect of the forearm followed by an assessment of pain and hyperalgesia. Side effects were recorded by the participants each evening. RESULTS: Thirteen participants were enrolled into the study. Three dropped out because of intolerable side effects. Ten participants completed the study and were able to tolerate the highest dose of gabapentin. Oral gabapentin had no significant effect on acute sensory thresholds, pain, secondary hyperalgesia, or flare response induced by intradermal capsaicin. There were significantly more side effects associated with gabapentin with sedation and dizziness being the most common. DISCUSSION: This study demonstrated a lack of effect of the chronic delivery of oral gabapentin on experimentally induced cutaneous hyperalgesia. The discrepancy of this finding with other studies using single oral doses may be the result of differences in the models used and differences in drug kinetics and plasma levels. The results of this study do not correlate with the clinical studies on gabapentin, which demonstrate efficacy at 1800 mg/d.
VEP indices of cortical lateral interactions in epilepsy treatment.
Vision Res. 2008 Jun 20;
Conte MM, Victor JD
We extend Spekreijse's strategy for analyzing lateral interactions in visual evoked potentials (VEPs) to clinical neurophysiologic testing of patients with epilepsy. Stimuli consisted of the radial windmill/dartboard pattern [Ratliff, F., & Zemon, V. (1982). Some new methods for the analysis of lateral interactions that influence the visual evoked potential. In: Bodis-Wollner (Ed.), Evoked potentials, Vol. 388. (pp. 113-124). New York: Annals of the New York Academy of Sciences.] and conventional checkerboards. The fundamental and 2nd-harmonic components of the steady-state responses were used to calculate indices reflecting facilitatory (FI) and suppressive (SI) cortical interactions. We carried out two studies. In the first, VEPs in 38 patients receiving antiepileptic drug (AED) therapy were compared to those of age-matched controls. For three AEDs (tiagabine, topiramate, and felbamate), addition of the drug did not change the FI and SI compared to baseline values or those of normal controls. However, the addition of gabapentin was associated with an increase of the FI, and this change was reversed when the medication was withdrawn. This suggested a medication-specific change in cortical lateral interactions. The second study focused on the effects of neurostimulation therapy. Eleven epilepsy patients receiving chronic vagus nerve stimulation (VNS) treatment were tested. By comparing VEPs recorded with the stimulator on (Stim-ON) and turned off (Stim-OFF) in the same session, we determined that VNS did not have a short-acting effect on lateral interactions. However, when compared with normal controls, the VNS patients had a significantly smaller SI (p
Lancet. 2008 Jun 21; 371(9630): 2120-33
Lunn MR, Wang CH
Spinal muscular atrophy is an autosomal recessive neurodegenerative disease characterised by degeneration of spinal cord motor neurons, atrophy of skeletal muscles, and generalised weakness. It is caused by homozygous disruption of the survival motor neuron 1 (SMN1) gene by deletion, conversion, or mutation. Although no medical treatment is available, investigations have elucidated possible mechanisms underlying the molecular pathogenesis of the disease. Treatment strategies have been developed to use the unique genomic structure of the SMN1 gene region. Several candidate treatment agents have been identified and are in various stages of development. These and other advances in medical technology have changed the standard of care for patients with spinal muscular atrophy. In this Seminar, we provide a comprehensive review that integrates clinical manifestations, molecular pathogenesis, diagnostic strategy, therapeutic development, and evidence from clinical trials.
Can J Anaesth. 2008 Jun; 55(6): 337-43
Huot MP, Chouinard P, Girard F, Ruel M, Lafontaine ER, Ferraro P
PURPOSE: Despite adequate epidural analgesia, up to 97% of patients undergoing thoracotomy experience ipsilateral shoulder pain. In this setting, this study evaluated the safety and the efficacy of pre-emptive gabapentin. METHODS: A double-blind, placebo-controlled study was undertaken in 51 patients randomized into two groups. Two hours before surgery, 23 patients received gabapentin 1200 mg po (Group G), and 28 patients received placebo (Group P). Shoulder pain and postoperative pain, at the surgical site, were monitored every four hours for 24 hr, using a numerical rating scale. Subcutaneous hydromorphone was administered for rescue analgesia against shoulder pain. RESULTS: Forty-four patients complained of shoulder pain (prevalence of 86%). Demographic and surgical data were similar between the two groups. There were no significant differences in the total cumulative doses of hydromorphone administered at eight, 16, and 24 hr, nor were there differences in individual numerical rating scale scores for shoulder pain. The groups were similar with respect to the degree of pain at the surgical site. The frequency of side effects between groups at corresponding time intervals was also similar, with the exception of sedation. At four hours, the incidence of sedation scores > 1 was greater in Group G (21/23 patients), compared to Group P (18/28 patients; P = 0.025). In contrast, by 24 hr, 5/18 patients in Group P had sedation scores > 1, compared to 0/28 patients in Group G (P = 0.05). CONCLUSION: Pre-emptively administered gabapentin, 1200 mg, does not reduce the incidence, or the severity, of post-thoracotomy shoulder pain in patients receiving thoracic epidural analgesia.
Post-thoracotomy shoulder pain and gabapentin: a tale of two enigmas.
Can J Anaesth. 2008 Jun; 55(6): 323-7
MacDougall P, Slinger P