RESUMO
ABSTRACT: The mechanisms of pain in postherpetic neuralgia (PHN) are still unclear, with some studies showing loss of cutaneous sensory nerve fibers that seemed to correlate with pain level. We report results of skin biopsies and correlations with baseline pain scores, mechanical hyperalgesia, and the Neuropathic Pain Symptom Inventory (NPSI) in 294 patients who participated in a clinical trial of TV-45070, a topical semiselective sodium 1.7 channel (Nav1.7) blocker. Intraepidermal nerve fibers and subepidermal Nav1.7 immunolabeled fibers were quantified in skin punch biopsies from the area of maximal PHN pain, as well as from the contralateral, homologous (mirror image) region. Across the entire study population, a 20% reduction in nerve fibers on the PHN-affected side compared with that in the contralateral side was noted; however, the reduction was much higher in older individuals, approaching 40% in those aged 70 years or older. There was a decrease in contralateral fiber counts as well, also noted in prior biopsy studies, the mechanism of which is not fully clear. Nav1.7-positive immunolabeling was present in approximately one-third of subepidermal nerve fibers and did not differ on the PHN-affected vs contralateral sides. Using cluster analysis, 2 groups could be identified, with the first cluster showing higher baseline pain, higher NPSI scores for squeezing and cold-induced pain, higher nerve fiber density, and higher Nav1.7 expression. While Nav1.7 varies from patient to patient, it does not seem to be a key pathophysiological driver of PHN pain. Individual differences in Nav1.7 expression, however, may determine the intensity and sensory aspects of pain.
Assuntos
Neuralgia Pós-Herpética , Neuralgia , Humanos , Idoso , Neuralgia Pós-Herpética/tratamento farmacológico , Pele/inervação , Administração Cutânea , Fibras NervosasRESUMO
AIMS: In previous studies, the histamine-3 receptor antagonist CEP-26401 had a subtle effect on spatial working memory, with the best effect seen at the lowest dose tested (20 µg), and a dose-dependent disruption of sleep. In the current study, 3 low-dose levels of CEP-26401 were compared with modafinil and donepezil. METHODS: In this double-blind, placebo- and positive-controlled, randomized, partial 6-way cross-over study, 40 healthy subjects received single doses of placebo, CEP-26401 (5, 25 or 125 µg) or modafinil 200 mg or donepezil 10 mg. Pharmacokinetic and pharmacodynamic measurements were performed predose and at designated time points postdose. RESULTS: The main endpoint between-errors of the spatial working memory-10-boxes task only improved for the 125 µg dose of CEP-26401 with a difference of 2.92 (confidence interval [CI] -1.21 to 7.05), 3.24 (CI -1.57 to 8.04) and 7.45 (CI 2.72 to 12.19) for respectively the 5, 25 and 125 µg dose of CEP-26401, -1.65 (CI -0.572 to 1.96) for modafinil and - 3.55 (CI -7.13 to 0.03) for donepezil. CEP-26401 induced an improvement of adaptive tracking, saccadic peak velocity and reaction time during N-back, but a dose-related inhibition of sleep and slight worsening of several cognitive parameters at the highest dose. CEP-26401 significantly changed several subjective visual analogue scales, which was strongest at 25 µg, causing the same energizing and happy feeling as modafinil, but with a more relaxed undertone. DISCUSSION: Of the doses tested, the 25 µg dose of CEP-26401 had the most optimal balance between favourable subjective effects and sleep inhibition. Whether CEP-26401 can have beneficial effects in clinical practice remains to be studied.
Assuntos
Encéfalo/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos/administração & dosagem , Piridazinas/administração & dosagem , Pirrolidinas/administração & dosagem , Adolescente , Adulto , Encéfalo/fisiologia , Cognição/efeitos dos fármacos , Cognição/fisiologia , Disfunção Cognitiva/tratamento farmacológico , Estudos de Coortes , Estudos Cross-Over , Donepezila/administração & dosagem , Donepezila/farmacocinética , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Antagonistas dos Receptores Histamínicos/farmacocinética , Humanos , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Pessoa de Meia-Idade , Modafinila/administração & dosagem , Modafinila/farmacocinética , Piridazinas/farmacocinética , Pirrolidinas/farmacocinética , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Receptores Histamínicos H3/metabolismo , Sono/efeitos dos fármacos , Sono/fisiologia , Adulto JovemRESUMO
OBJECTIVE: The objective was to evaluate the safety and efficacy of TV-45070 ointment, as a treatment for postherpetic neuralgia, and to explore the response in patients with the Nav1.7 R1150W gain-of-function polymorphism. MATERIALS AND METHODS: This was a randomized, placebo-controlled, 2-period, 2-treatment crossover trial. Patients with postherpetic neuralgia with moderate or greater pain received TV-45070 and placebo ointments, each applied twice daily for 3 weeks. The primary efficacy measure was the difference in change in mean daily pain score from baseline compared with the last week of placebo and active treatment. Secondary endpoints included responder rate analyses and a further exploratory analysis of response in carriers of the Nav1.7 R1150W polymorphism was conducted. RESULTS: Seventy patients were enrolled and 54 completed the study. TV-45070 was safe and well tolerated. No statistical difference was observed between treatments for the primary endpoint. However, the proportion of patients with ≥50% reduction in mean pain scores at week 3 was greater on TV-45070 than on placebo (26.8% vs. 10.7%, P=0.0039). Similarly, a greater proportion of patients on TV-45070 had a ≥30% reduction in mean pain scores at week 3 (39.3% on TV-45070 vs. 23.2% on placebo, P=0.0784). Of note, 63% of patients with the R1150W polymorphism versus 35% of wild-type carriers had a ≥30% reduction in mean pain score on TV-45070 at week 3 (no inferential analysis performed). CONCLUSIONS: The 50% responder analysis suggests a subpopulation may exist with a more marked analgesic response to TV-45070.The trend toward a larger proportion of responders within Nav1.7 R1150W carriers warrants further investigation.
Assuntos
Indóis/uso terapêutico , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Neuralgia Pós-Herpética/tratamento farmacológico , Neuralgia Pós-Herpética/genética , Bloqueadores dos Canais de Sódio/uso terapêutico , Compostos de Espiro/uso terapêutico , Administração Tópica , Estudos Cross-Over , Feminino , Genótipo , Humanos , Indóis/efeitos adversos , Indóis/sangue , Masculino , Pessoa de Meia-Idade , Estudo de Prova de Conceito , Bloqueadores dos Canais de Sódio/efeitos adversos , Bloqueadores dos Canais de Sódio/sangue , Compostos de Espiro/efeitos adversos , Compostos de Espiro/sangue , Resultado do TratamentoRESUMO
PURPOSE: To test the efficacy of the novel candidate anticonvulsant talampanel (GYKI 53773) in a rodent model of hypoxic neonatal seizures. Talampanel is a noncompetitive antagonist of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid subtype of the glutamate receptor (AMPAR). We have previously shown that AMPARs play a critical role in the generation of acute seizures and later-life seizure susceptibility in this model of neonatal seizures. METHODS: Seizures were induced in postnatal day (P) 10 Long-Evans rat pups by a 15 min exposure to global hypoxia. Acute seizure activity at P10 and subsequent susceptibility to seizure-induced neuronal injury with a "second-hit" kainate-induced seizure at P30-31 were compared between animals receiving talampanel (1, 5, 7.5, or 10 mg/kg) intraperitoneally (i.p.) versus saline vehicle treatment. RESULTS: Talampanel treatment suppressed seizures in a dose-dependent manner, with maximal effect at 7.5 and 10 mg/kg. In addition, talampanel treatment 30 min before hypoxia prevented later-life increases in seizure-induced neuronal injury as assessed by in situ DNA nick end-labeling (ISEL). DISCUSSION: We have previously demonstrated efficacy of other AMPAR antagonists such as NBQX and topiramate in this model. The present finding shows that the novel agent talampanel, under evaluation as an antiepileptic drug in children and adults, may have clinical potential in the treatment of neonatal seizures, particularly those occurring in the context of hypoxic encephalopathy.
Assuntos
Anticonvulsivantes/uso terapêutico , Benzodiazepinas/uso terapêutico , Convulsões/tratamento farmacológico , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Morte Celular/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hipóxia/complicações , Ácido Caínico , Ratos , Ratos Long-Evans , Receptores de AMPA/antagonistas & inibidores , Convulsões/etiologia , Convulsões/patologia , Fatores de TempoRESUMO
PURPOSE: Drug resistance in brain tumors is partially mediated by the blood-brain barrier of which a key component is P-glycoprotein, which is highly expressed in cerebral capillaries. Tamoxifen is a nontoxic inhibitor of P-glycoprotein. This trial assessed, in primary and metastatic brain tumors, the differential deposition of paclitaxel and whether tamoxifen could increase paclitaxel deposition. EXPERIMENTAL DESIGN: Patients for surgical resection of their primary or metastatic brain tumors were prospectively randomized to prior paclitaxel alone (175 mg/m(2)/i.v.) or tamoxifen for 5 days followed by paclitaxel. Central and peripheral tumor, surrounding normal brain and plasma, were analyzed for paclitaxel and tamoxifen. RESULTS: Twenty-seven patients completed the study. Based on a multivariate linear regression model, no significant differences in paclitaxel concentrations between the two study arms were found after adjusting for treatment group (tamoxifen versus control). However, in analysis for tumor type, metastatic brain tumors had higher paclitaxel concentrations in the tumor center (1.93-fold, P = 0.10) and in the tumor periphery (2.46-fold, P = 0.039) compared with primary brain tumors. Pharmacokinetic analyses showed comparable paclitaxel areas under the serum concentration between treatment arms. CONCLUSIONS: Paclitaxel deposition was not increased with this tamoxifen schedule as the low plasma concentrations were likely secondary to concurrent use of P-450-inducing medications. However, the statistically higher paclitaxel deposition in the periphery of metastatic brain tumors provides functional evidence corroborating reports of decreased P-glycoprotein expression in metastatic versus primary brain tumors. This suggests that metastatic brain tumors may respond to paclitaxel if it has proven clinical efficacy for the primary tumor's histopathology.
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Antineoplásicos Hormonais/farmacocinética , Antineoplásicos Fitogênicos/farmacocinética , Neoplasias Encefálicas/sangue , Paclitaxel/farmacocinética , Tamoxifeno/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/patologia , Sinergismo Farmacológico , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
We identified 10 patients with symptomatic metastases to the pineal gland. We present the clinical and radiographic findings in this syndrome. Leptomeningeal metastases occur frequently and are a poor prognostic factor. In all cases, the primary cancer was clinically silent, either in remission (six cases) or previously undiagnosed (four cases). Hence, metastatic disease, albeit uncommon, should be considered in the differential diagnosis of pineal tumors.
Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias Gastrointestinais/epidemiologia , Neoplasias Pulmonares/epidemiologia , Pinealoma/epidemiologia , Pinealoma/secundário , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , New York/epidemiologia , Prevalência , Estudos RetrospectivosRESUMO
RMP-7, a bradykinin analog, temporarily increases the permeability of the blood-brain tumor barrier to chemotherapy drugs like carboplatin. We conducted a randomized, controlled trial of carboplatin and RMP-7 versus carboplatin and placebo in patients with recurrent malignant glioma. The primary outcome measure was time to tumor progression (TTP). Adults with recurrent glioblastoma multiforme or anaplastic glioma were randomized in a 1:1 ratio to receive carboplatin and either RMP-7 or placebo. Radiation therapy had failed in all patients, and they may have received prior chemotherapy. Carboplatin (dosed to achieve an area under the curve of 5 mg/ml x time for patients who had received prior chemotherapy, or 7 mg/ml x time for those who had not) was given intravenously every 4 weeks, followed by intravenous infusion of either RMP-7 or placebo (300 ng/kg). TTP, tumor response, neuropsychological assessments, functional independence, and quality of life assessments were analyzed every 4 weeks. There were 122 patients enrolled, 62 in the RMP-7 and carboplatin group and 60 in the placebo and carboplatin group. Median TTP was 9.7 weeks (95% CI, 8.3-12.6 weeks) for the RMP-7 and carboplatin group and 8.0 weeks (95% CI, 7.4-12.6 weeks) for the placebo and carboplatin group. Median survival times were 26.9 weeks (95% CI, 21.3-37.6 weeks) for the RMP-7 group and 19.9 weeks (95% CI, 15.0-31.3 weeks) for the placebo group. No differences were noted for time to worsening of neuropsychological assessments, functional independence, or quality of life assessments. The use of RMP-7 had no effect on the pharmacokinetics or toxicity of carboplatin. At the dose and schedule used in this trial, RMP-7 did not improve the efficacy of carboplatin. Recent preclinical pharmacokinetic modeling of RMP-7 suggests that higher doses of RMP-7 may be required to increase carboplatin delivery to tumor.