RESUMO
Despite extensive surgery for glioblastoma, residual tumor cells always lead to relapse. Gene therapy based on retrovirus-mediated gene transfer of herpes simplex virus type 1 thymidine kinase (HSV-1 TK), which specifically sensitizes dividing cells to ganciclovir (GCV) toxicity, may help eradicate such cells. During glioblastoma surgery, HSV-1 TK retroviral vector-producing cells (M11) were injected into the surgical cavity margins after tumor debulking. After a 7-day transduction period, GCV was administered for 14 days. Safety was assessed by clinical and laboratory evaluations, and efficacy was assessed by MRI-based relapse-free survival at month 4 and by overall survival. Twelve patients with recurrent glioblastoma were treated without serious adverse events related to M11 cell administration or GCV. Quality of life was not negatively influenced by this treatment. Overall median survival was 206 days, with 25% of the patients surviving longer than 12 months. At 4 months after treatment, 4 of 12 patients had no recurrence; their median overall survival was 528 days, compared with 194 days for patients with recurrence (p=0.03 by the log rank test). One patient is still free of detectable recurrence, steroid free and independent, 2.8 years after treatment. Thus, brain injections of M11 retroviral vector-producing cells for glioblastoma HSV-1 TK gene therapy were well tolerated and associated with significant therapeutic responses. These results warrant further development of this therapeutic strategy in brain tumor, including recurrent glioblastoma.
Assuntos
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Herpesvirus Humano 1/genética , Timidina Quinase/genética , Adulto , Neoplasias Encefálicas/diagnóstico por imagem , Intervalo Livre de Doença , Feminino , Ganciclovir/uso terapêutico , Glioblastoma/diagnóstico por imagem , Herpesvirus Humano 1/enzimologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Radiografia , RecidivaRESUMO
We performed a dose-escalating phase I/II study of retrovirus-mediated herpes simplex virus type 1 thymidine kinase (HSV-1-TK) suicide gene therapy for metastatic melanoma. HSV-1 TK expression, which specifically sensitizes transduced and bystander cancer cells to ganciclovir (GCV) toxicity, was mediated by one (four patients, first dose step) to three (four patients, second dose step) injections of "M11" retrovirus vector-producing cells in melanoma cutaneous nodules. After a 7-day period allowed for cancer cell transduction, GCV was administered for 14 days. Safety was assessed by clinical and laboratory evaluations, and efficacy was assessed by tumor measurements and histology. M11 doses ranged from 76 to 1247 x 10(6) cells. Treatment-related adverse events were mild and transient, limited to inflammatory skin reactions at injection and fever on repeated injections. Plasma GCV was in the active range (>0.2 microg/ml); transgene was detected by polymerase chain reaction in three of six patients; treated tumor size was moderately affected under GCV as compared with untreated tumors, although 2 weeks after GCV administration important (>50%) treated-tumor necrosis was evidenced on histology in three of eight patients. All patients showed disease progression on long-term follow-up. Thus, M11-mediated HSV-1 TK gene therapy was well tolerated over a wide dose range. The limited tumor response is likely to be related to poor gene transfer efficiency. However, necrosis following GCV administration in transduced tumors indicates a potential for treatment efficacy.
Assuntos
Terapia Genética , Herpesvirus Humano 1/genética , Melanoma/terapia , Timidina Quinase/genética , Adulto , Idoso , Feminino , Ganciclovir/uso terapêutico , Terapia Genética/efeitos adversos , Herpesvirus Humano 1/enzimologia , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Metástase NeoplásicaRESUMO
Orthostatic hypotension, one of tricyclic antidepressant treatment's side effects, is also a factor in limiting adequate antidepressant dosing. We tested in a double-blind, crossover, placebo-controlled study the effect of low doses (4 mg/t.i.d.) of yohimbine in 12 patients with depression with clomipramine-induced orthostatic hypotension. Yohimbine, a selective alpha 2-adrenoceptor antagonist, had a favorable effect in orthostatic hypotension and induced a significant increase in blood pressure. A pharmacodynamic and pharmacokinetic interaction between yohimbine and clomipramine or demethylclomipramine was discussed.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Clomipramina/efeitos adversos , Depressão/tratamento farmacológico , Hipotensão Ortostática/tratamento farmacológico , Ioimbina/farmacologia , Adulto , Clomipramina/sangue , Clomipramina/uso terapêutico , Método Duplo-Cego , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipotensão Ortostática/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Distribuição Aleatória , Ioimbina/administração & dosagem , Ioimbina/farmacocinéticaRESUMO
We performed a 3-month, double-blind, placebo-controlled trial of 300 mg of gangliosides (Cronassial) in 40 outpatients with amyotrophic lateral sclerosis (ALS). We evaluated drug effect through physical examinations and symptom scales. Though this dosage had no major toxic effect, Cronassial treatment did not significantly benefit ALS patients.
Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Gangliosídeos/administração & dosagem , Ensaios Clínicos como Assunto , Método Duplo-Cego , Esquema de Medicação , Gangliosídeos/efeitos adversos , Gangliosídeos/uso terapêutico , Humanos , PlacebosRESUMO
ALS is a progressive motor neuron disease with no effective treatment. The anti-excitotoxic drug riluzole (100 mg/day) has been shown to decrease mortality and muscular deterioration in ALS patients. To confirm and extend the therapeutic effect of riluzole, we performed a double-blind, placebo-controlled, multicenter, international, dose-ranging (50, 100, 200 mg/day), stratified study in 959 ALS outpatients treated for up to 18 months. Primary efficacy criterion was survival and the effect of treatment was analyzed before (Wilcoxon and log rank tests) and after adjustment on prognostic factors (Cox model). Secondary efficacy criterion was disease progression assessed through change in functional measures. Tracheostomy-free survival rates were: 50.4% (placebo), 55.3% (50 mg riluzole) (p = 0.23, Wilcoxon test; p = 0.25, log-rank test), 56.8% (100 mg riluzole) (p = 0.05, Wilcoxon test; p = 0.076, log-rank test), and 57.8% (200 mg riluzole) (p = 0.061, Wilcoxon test; p = 0.075, log-rank test). At the end of the 18-month study, there was a significant dose-related decrease in risk of death or tracheostomy (p = 0.04). Adjustment for baseline prognostic factors showed a 35% decreased risk of death with the 100-mg dose compared with placebo (p = 0.002). No significant treatment effects were detected for the functional assessments. The most frequent dose-related adverse events included nausea, asthenia, and elevated liver enzyme levels. This study confirms the therapeutic effect of riluzole in a large representative ALS sample, over an 18-month period. Riluzole is well tolerated and decreases the risk of death or tracheostomy in ALS patients.
Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Tiazóis/uso terapêutico , Esclerose Lateral Amiotrófica/mortalidade , Esclerose Lateral Amiotrófica/fisiopatologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Riluzol , Análise de Sobrevida , Tiazóis/administração & dosagemRESUMO
Treatment with the neuroprotective drug riluzole has previously been shown to increase the probability of survival in patients with amyotrophic lateral sclerosis. This report describes a placebo-controlled, double-blind randomised clinical trial of riluzole carried out in ALS patients with advanced stage disease or aged over 75 years. The primary objective was to enable access to treatment to patients excluded from the pivotal trial which was run in parallel. Another goal was to assess the safety of riluzole in patients with advanced-stage disease. One hundred and sixty-eight patients were included, randomised to either riluzole 50 mg b. i. d. or to placebo, and treated for eighteen months. Riluzole was well-tolerated in this patient population, and the adverse events observed were similar in nature and frequency to those observed in previously published clinical trials in patients included in pivotal trials. The study could not include enough patients to reach adequate power to detect differences in survival between the two treatment groups, and no such difference was in fact observed. In conclusion, riluzole is well-tolerated in ALS patients with advanced stage disease.
Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Tolerância a Medicamentos/fisiologia , Fármacos Neuroprotetores/administração & dosagem , Riluzol/administração & dosagem , Riluzol/efeitos adversos , Fatores Etários , Idoso , Esclerose Lateral Amiotrófica/fisiopatologia , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Fármacos Neuroprotetores/efeitos adversos , Seleção de Pacientes , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Bullous pemphigoid (BP) occurs in many patients with multiple sclerosis. Isolated cases of BP in patients with other neurological disorders further support a pathogenic association between cutaneous and neurological diseases. Any description of BP in patients with amyotrophic lateral sclerosis is lacking. OBSERVATIONS: We studied a French population of 168 patients with typical amyotrophic lateral sclerosis. Among these, 3 had clinical and histological features of BP. The mean age of the patients was 54 years. None was known to have autoimmune disorders. Results of immunoblot analysis disclosed both anti-BP antigen 1 and anti-BP antigen 2 antibodies. CONCLUSIONS: Bullous pemphigoid seems to be unexpectedly associated with amyotrophic lateral sclerosis. On the basis of the cases presented herein, we discuss the epidemiological significance of the association and the possible interrelation between BP antigen 1 and neurofilaments in the pathogenesis of both disorders.
Assuntos
Esclerose Lateral Amiotrófica/diagnóstico , Proteínas de Transporte , Proteínas do Citoesqueleto , Proteínas do Tecido Nervoso , Colágenos não Fibrilares , Penfigoide Bolhoso/diagnóstico , Idoso , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/etiologia , Esclerose Lateral Amiotrófica/patologia , Autoanticorpos/sangue , Autoantígenos/imunologia , Colágeno/imunologia , Quimioterapia Combinada , Distonina , Evolução Fatal , Feminino , Humanos , Immunoblotting , Masculino , Pessoa de Meia-Idade , Penfigoide Bolhoso/tratamento farmacológico , Penfigoide Bolhoso/etiologia , Penfigoide Bolhoso/patologia , Recidiva , Colágeno Tipo XVIIRESUMO
It has been suggested that amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder resulting in motor neuron death, is associated with oxidative damage induced by free radicals. Our study aimed to get an assessment of the blood oxidative stress status in a population of 167 ALS patients (aged 59+/-13 years), treated or not with riluzole, compared with 62 age-matched healthy control subjects (aged 60+/-11 years) simultaneously included in the study. We determined the level of plasma lipid peroxidation (thiobarbituric acid-reactive substances, TBARS); the status of the major lipophilic plasma antioxidant defenses (vitamin E, vitamin A and beta-carotene); the activities of erythrocyte Cu,Zn-superoxide dismutase (Cu,Zn-SOD) and of plasma and erythrocyte glutathione peroxidase (GSH-Px). Plasma selenium was also determined as a trace element essential to the activity of the GSH-Px. In comparison with controls, we observed in ALS patients (mean+/-S.D.) significantly higher TBARS values (ALS=1.34+/-0.28 micromol/l; controls=1.11+/-0. 20 micromol/l) and a significant enhancement of the erythrocyte SOD activity (ALS=710+/-114 U/g Hb; controls=667+/-93 U/g Hb). No differences were observed for selenium level, GSH-Px activity, plasma vitamin E, beta-carotene and vitamin A concentrations. These data confirm the presence of an oxidative stress in blood of ALS patients. The elevated plasma TBARS, without any deficiency in plasma lipophilic antioxidants such as vitamin E, vitamin A and beta-carotene, suggest an enhancement in the production of free radicals. No correlation was found in our study between the level of any of the blood oxidative stress markers and the disease duration. Comparison between patients treated or not with riluzole did not display any modification of the plasma TBARS concentration, but we observed a slight decrease of erythrocyte SOD activity in treated patients (treated=705+/-113 U/g Hb; not treated=725+/-118 U/g Hb), suggesting a possible activity of riluzole on the oxygenated free radical production.
Assuntos
Esclerose Lateral Amiotrófica/sangue , Superóxido Dismutase/sangue , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Idoso , Esclerose Lateral Amiotrófica/tratamento farmacológico , Análise de Variância , Feminino , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Análise de Regressão , Riluzol/farmacologia , Riluzol/uso terapêutico , Superóxido Dismutase/efeitos dos fármacosRESUMO
This study evaluated the effects of acute doses of zopiclone (7.5 mg), triazolam (0.25 mg) and placebo on memory and psychomotor performance of 12 normal volunteers. The subjects received both drugs in a repeated measure, double-blind Latin square design. The tests (CFF, CRT, DSST, memory assessments) were performed before and 2 and 6 hr after treatment. Zopiclone and triazolam induced an anterograde amnesia affecting short-term and long-term memory which lasted less than 6 hr. No retrograde amnesia was observed. Two hr after drug intake of both hypnotics psychomotor performances were significantly altered compared with placebo. The subjects also felt more drowsy, dizzy, clumsy and tired, and less alert and energetic 2 hr after zopiclone and triazolam compared to placebo. There was no difference between the effects of the two hypnotics at the doses studied.
Assuntos
Memória/efeitos dos fármacos , Piperazinas/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Triazolam/farmacologia , Adulto , Compostos Azabicíclicos , Método Duplo-Cego , Feminino , Humanos , Hipnóticos e Sedativos/farmacologia , MasculinoRESUMO
Neuropathological findings in Alzheimer's disease (AD) suggest a possible involvement of microtubule dysfunction in neurodegenerative process pathogenesis. Because microtubules have a major role in neuronal plasticity, microtubule disruption could be also directly responsible for cognitive defects in AD. We report that in rats, continuous microtubule disruption induced by chronic colchicine administration results in a dose-dependent learning deficit. In addition, retention is also impaired. These cognitive defects are specific, as chronic colchicine induces no other behavioral toxicity within the study dose range. Colchicine-induced cognitive defects resemble those of AD, which are characterised by amnesia of recent learning and loss of formerly established memories. This new procedure of pharmacologically induced cognitive impairment may prove useful, both towards understanding AD pathogenesis and towards drug screening.
Assuntos
Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Colchicina/farmacologia , Aprendizagem/efeitos dos fármacos , Microtúbulos/efeitos dos fármacos , Animais , Condicionamento Operante/efeitos dos fármacos , Relação Dose-Resposta a Droga , Lumicolchicinas/farmacologia , Masculino , Memória/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Ratos , Ratos EndogâmicosRESUMO
This article presents the rationale for the use of a preprosthetic surgical crown-lengthening procedure, particularly in the anterior region where esthetics is of great concern. Clinical cases illustrate the procedure and demonstrate how it can be used to provide enough sound tooth structure to restore teeth without impingement on the biologic width, at the same time reducing a "gingival smile" and creating new papillae.
Assuntos
Aumento da Coroa Clínica/métodos , Adulto , Alveoloplastia , Estética Dentária , Feminino , Gengivoplastia , Humanos , Pessoa de Meia-Idade , Periodonto/anatomia & histologiaRESUMO
Within the framework of an early drug access programme launched in 1995, a multicentre open study was initiated in France in order to assess, inter alia, the safety of riluzole (50 mg twice a day) in a total of 2069 patients from 28 centres. This programme, a phase IIIb study with direct individual benefit, had two main objectives: to enable patients to receive riluzole therapy pending regulatory approval and commercial availability and to provide further data on the safety of riluzole in a broader ALS population. The most frequent adverse events related to riluzole treatment were: asthenia, nausea and elevation of serum transaminase levels. These observations, similar to data derived from previous pivotal clinical trials, confirm that riluzole has a satisfactory tolerability profile.
Assuntos
Esclerose Lateral Amiotrófica/complicações , Fármacos Neuroprotetores/efeitos adversos , Riluzol/efeitos adversos , Idoso , Esclerose Lateral Amiotrófica/tratamento farmacológico , Feminino , França/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/uso terapêutico , Vigilância de Produtos Comercializados , Riluzol/uso terapêuticoRESUMO
The pharmacology of memory is fraught with problems. For one thing, the lack of consensus on the definition of memory and the absence of reference compound create clinical validation problems for new drugs. Then, it is difficult to predict clinical effectiveness on the basis of animal experiments and data obtained from healthy subjects, and this is due to the lack of analogy between animal models and clinical situations. Finally, to this must be added the complexity and variety of the possible modes of action of the agents under study. Thus, the pharmacology of cognition activators is closely dependent upon both fundamental research and clinical research.
Assuntos
Cognição/efeitos dos fármacos , Memória/efeitos dos fármacos , Animais , Humanos , Técnicas In Vitro , Transtornos da Memória/tratamento farmacológico , Farmacologia , Estimulação QuímicaAssuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Antibacterianos/uso terapêutico , Minociclina/uso terapêutico , Animais , Antibacterianos/efeitos adversos , Quimioterapia Combinada , Humanos , Camundongos , Minociclina/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
The objective of this study was to identify prognostic factors for survival in amyotrophic lateral sclerosis from a large prospective observational study performed in France. The study included a cohort of 2069 patients fulfilling broad entry criteria treated with riluzole. Over 100 demographic, biological, clinical and quality-of-life variables were monitored and assessed for their effect on survival. Patients were randomized post hoc into two groups: one group (two-thirds of the patients) to generate the prognostic models and one group (one-third of the patients) to validate the resulting models. Thirteen variables were found to affect survival independently and were used to construct a survival prediction score, RL401. These included age, disease duration, slow vital capacity, intensity of tiredness (visual analogue scale), number of body levels with spasticity, atrophy and/or fasciculations, cough, distal muscle strength, household income, depression and two biological parameters, plasma creatinine levels and neutrophil counts. A simplified score, RL401S, was constructed, designed to be easy to use and interpret. The predictive powers of the two scores were similar.
Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/mortalidade , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Riluzol/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/epidemiologia , Estudos de Coortes , Demografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Prognóstico , Estudos Retrospectivos , Sobrevida , Análise de Sobrevida , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Amyotrophic lateral sclerosis is a progressive motor neuron disease for which there is no adequate treatment. Some research suggests that the excitatory amino acid neurotransmitter glutamate may be involved in the pathogenesis. METHODS: To evaluate the efficacy and safety of the antiglutamate agent riluzole, we conducted a prospective, double-blind, placebo-controlled trial in 155 outpatients with amyotrophic lateral sclerosis. The dose of riluzole was 100 mg per day. Randomization was stratified according to the site of disease onset (the bulbar region or the limbs). The primary end points were survival and rates of change in functional status. The main secondary end point was change in muscle strength. Analyses were undertaken after 12 months of treatment and at the end of the placebo-controlled period (median follow-up, 573 days). RESULTS: After 12 months, 45 of 78 patients (58 percent) in the placebo group were still alive, as compared with 57 of 77 patients (74 percent) in the riluzole group (P = 0.014). For patients with bulbar-onset disease, one-year survival rates were 35 percent (6 of 17) with placebo and 73 percent (11 of 15) with riluzole (P = 0.014), whereas for those with limb-onset disease one-year survival was 64 percent and 74 percent, respectively (P = 0.17). The survival advantage with riluzole was smaller (37 percent [29 of 78] with placebo vs. 49 percent [38 of 77] with riluzole) at the end of the placebo-controlled period, but it remained significant in the overall population (P = 0.046) as well as in the patients with bulbar-onset disease (18 percent [3 of 17] vs. 53 percent [8 of 15], P = 0.013). The deterioration of muscle strength was significantly slower in the riluzole group than in the placebo group (P = 0.028). Adverse reactions to riluzole included asthenia, spasticity, and mild elevations in aminotransferase levels. Twenty-seven patients in the riluzole group withdrew from the study, as compared with 17 in the placebo group. CONCLUSIONS: The antiglutamate agent riluzole appears to slow the progression of amyotrophic lateral sclerosis, and it may improve survival in patients with disease of bulbar onset.