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BACKGROUND AND PURPOSE: OnabotulinumtoxinA was effective and well tolerated for prophylaxis of headache in patients with chronic migraine (CM) in two randomized, double-blind, placebo-controlled, phase 3 trials. To further assess the safety and tolerability of onabotulinumtoxinA in CM prophylaxis in adults, the pooled safety data from four double-blind, placebo-controlled trials were analyzed. METHODS: The pooled analysis included two phase 2 and two phase 3 double-blind, placebo-controlled trials. The safety population was 2436 patients, 1997 of whom received ≥1 dose of onabotulinumtoxinA. The studies shared similar dosing intervals (approximately 12 weeks) with doses between 75 and 260 U. Safety assessments included adverse events (AEs), physical examination and clinical laboratory tests. RESULTS: OnabotulinumtoxinA was safe and well tolerated, with a low discontinuation rate (3.4%) due to AEs. The majority of patients in this pooled analysis received doses between 150 and 200 U, with an average of 163 U per treatment cycle. Of the 1997 patients who received any onabotulinumtoxinA injections, 1455 patients (72.9%) reported at least one AE. Neck pain (12.6%) was the most common onabotulinumtoxinA-associated AE, followed by muscle weakness (8.0%), musculoskeletal stiffness (6.1%) and eyelid ptosis (4.6%). Serious AEs were infrequent, occurring in 5.4% of patients who received any onabotulinumtoxinA treatment and 3.0% of patients receiving placebo. AEs were consistent with the known tolerability profile of onabotulinumtoxinA. CONCLUSIONS: Multiple treatments with onabotulinumtoxinA at doses of 75-260 U administered every 12 weeks, and up to five treatment cycles, were well tolerated for the prophylaxis of headache in adults with CM.
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Toxinas Botulínicas Tipo A/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Adolescente , Adulto , Idoso , Toxinas Botulínicas Tipo A/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto JovemRESUMO
To identify those patients most likely to benefit from a cerebral biopsy to diagnose dementia, we reviewed a series of 14 unselected biopsies performed during a 9-year period (1980 through 1989) at Duke University Medical Center, Durham, NC. Pathognomonic features allowed a definitive diagnosis in seven specimens. Nondiagnostic abnormalities but not diagnostic neuropathologic changes were seen in five additional specimens, and two specimens were normal. Creutzfeldt-Jakob disease was the most frequent diagnosis. One patient each was diagnosed as having Alzheimer's disease, diffuse Lewy body disease, adult-onset Niemann-Pick disease, and anaplastic astrocytoma. We conclude that a substantial proportion of patients presenting clinically with atypical dementia are likely to receive a definitive diagnosis from a cerebral biopsy. However, in those with coexisting hemiparesis, chorea, athetosis, or lower motor neuron signs, cerebral biopsies are less likely to be diagnostic.
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Encéfalo/patologia , Demência/patologia , Adulto , Idoso , Biópsia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Previous studies demonstrated that zolmitriptan at doses of 1 to 25 mg was highly effective in treating acute migraine attacks. The 2.5-mg dose had a favorable therapeutic effect with high efficacy and good tolerability. The objective of this study was to further evaluate the efficacy of a single 2.5-mg dose of zolmitriptan (Zomig, formerly known as 311C90) for acute treatment of a single moderate or severe migraine attack. The study was a randomized, double-blind, placebo-controlled clinical trial. Female and male patients, 12 to 65 years old, with migraine (with or without aura) for > or = 1 year, one to six migraines per month, and age at onset < 50 years were included; 327 patients were screened and randomized to receive either zolmitriptan (n = 219) or placebo (n = 108). Patients treated a single moderate or severe migraine headache with 2.5 mg zolmitriptan or placebo and recorded clinical efficacy and adverse events on a diary form. Headache response at 2 hours was 62% for zolmitriptan compared with 36% for placebo (p < 0.001); at 4 hours, headache response was 70% with zolmitriptan and 37% with placebo (p < 0.001). Headache recurrence in patients treated with 2.5 mg zolmitriptan was 22% (versus placebo 30%). The headache response at 4 hours, pain-free rate, and response rate of nonheadache symptoms favored zolmitriptan over placebo. No serious adverse events were associated with zolmitriptan treatment. A 2.5-mg dose of zolmitriptan is clinically effective and well tolerated for the acute treatment of migraine.
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Transtornos de Enxaqueca/tratamento farmacológico , Oxazóis/administração & dosagem , Oxazolidinonas , Agonistas do Receptor de Serotonina/administração & dosagem , Doença Aguda , Adolescente , Adulto , Idoso , Criança , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxazóis/efeitos adversos , Agonistas do Receptor de Serotonina/efeitos adversos , TriptaminasRESUMO
This study investigated the efficacy of zolmitriptan (Zomig, formerly 311C90) in acute migraine therapy. Patients with a history of migraine were randomized in a double-blind, multicenter, placebo-controlled, dose range-finding study of oral zolmitriptan 1, 2.5, 5, or 10 mg versus placebo for the treatment of a severe or moderate migraine headache. Patients with persistent or recurrent headache 4 to 24 hours after the initial dose, who did not take escape medication, were eligible to receive a second blinded dose of either zolmitriptan or placebo. Of 1,144 patients treated, 999 evaluable patients completed the study. The headache response rates with zolmitriptan doses > or = 2.5 mg were 44 to 51% at 1 hour, 65 to 67% at 2 hours, and 75 to 78% at 4 hours (all significantly superior to placebo). Also, zolmitriptan effectively relieved migraine-associated symptoms such as nausea, photophobia and phonophobia, and reduced activity impairment. Rates of headache recurrence, headache persistence, and use of escape medication were lower with zolmitriptan doses > or = 2.5 mg than with placebo. In patients with persistent or recurrent headache, a second zolmitriptan dose effectively treated both headache and nonheadache symptoms. Zolmitriptan was well tolerated, with a lower incidence of adverse events being reported with doses < or = 2.5 mg than with those > or = 5 mg. Zolmitriptan is a well tolerated and effective acute migraine therapy providing rapid relief of migraine headache within 1 hour. A clear dose-response relationship between efficacy and tolerability suggests that 2.5 mg is the optimal initial dose for the acute treatment of a migraine attack.
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Transtornos de Enxaqueca/tratamento farmacológico , Oxazóis/administração & dosagem , Oxazolidinonas , Agonistas do Receptor de Serotonina/administração & dosagem , Doença Aguda , Adolescente , Adulto , Idoso , Criança , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxazóis/efeitos adversos , Recidiva , Agonistas do Receptor de Serotonina/efeitos adversos , TriptaminasRESUMO
BACKGROUND: Patients with rapid-cycling bipolar disorder are often treatment refractory. This study examined lamotrigine as maintenance monotherapy for rapid-cycling bipolar disorder. METHOD: Lamotrigine was added to patients' current psychotropic regimens and titrated to clinical effect during an open-label treatment phase. Stabilized patients were tapered off other psychotropics and randomly assigned to lamotrigine or placebo monotherapy for 6 months. Time to additional pharmacotherapy for emerging symptoms was the primary outcome measure. Secondary efficacy measures included survival in study (time to any premature discontinuation), percentage of patients stable without relapse for 6 months, and changes in the Global Assessment Scale and Clinical Global Impressions-Severity scale. Safety was assessed from adverse event, physical examination, and laboratory data. RESULTS: 324 patients with rapid-cycling bipolar disorder (DSM-IV criteria) received open-label lamotrigine, and 182 patients were randomly assigned to the double-blind maintenance phase. The difference between the treatment groups in time to additional pharmacotherapy did not achieve statistical significance in the overall efficacy population. However, survival in study was statistically different between the treatment groups (p = .036). Analyses also indicated a 6-week difference in median survival time favoring lamotrigine. Forty-one percent of lamotrigine patients versus 26% of placebo patients (p = .03) were stable without relapse for 6 months of monotherapy. Lamotrigine was well tolerated; there were no treatment-related changes in laboratory parameters, vital signs, or body weight. No serious rashes occurred. CONCLUSION: This was the largest and only prospective placebo-controlled study of rapid-cycling bipolar disorder patients to date; results indicate lamotrigine monotherapy is a useful treatment for some patients with rapid-cycling bipolar disorder.
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Antidepressivos/uso terapêutico , Transtorno Bipolar/prevenção & controle , Triazinas/uso terapêutico , Adolescente , Adulto , Idoso , Anticonvulsivantes/uso terapêutico , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/psicologia , Estudos de Coortes , Método Duplo-Cego , Feminino , Humanos , Lamotrigina , Masculino , Pessoa de Meia-Idade , Placebos , Estudos Prospectivos , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Análise de Sobrevida , Resultado do TratamentoRESUMO
A 39-year-old female presented to the Bryan Memory Disorders Clinic at Duke University with a 7-year history of an atypical progressive dementia, mildly impaired vertical gaze, dysarthria and mild ataxia. There was no evidence of organomegaly by clinical examination or by radionuclide liver/spleen scan. Brain biopsy disclosed a neuronal storage disorder characterized by ballooned neurons filled with oligo-lamellar cytosomes and lipid droplets. Cultured skin fibroblasts had diminished sphingomyelinase activity and impaired cholesterol esterification, although peripheral leukocyte sphingomyelinase activity was normal. Two years after biopsy, follow-up examination revealed marked progression of vertical gaze paralysis and ataxia. This case expands the clinical spectrum of Niemann-Pick disease type C by presenting in adulthood with subtle neurologic abnormalities; no visceromegaly and profound dementia.
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Encéfalo/patologia , Demência/patologia , Doenças de Niemann-Pick/patologia , Adulto , Biópsia , Diagnóstico Diferencial , Feminino , Fibroblastos/patologia , Hepatomegalia/patologia , Humanos , Metabolismo dos Lipídeos , Microscopia Eletrônica , Neurônios/patologia , Testes Neuropsicológicos , Pele/patologia , Esfingomielina Fosfodiesterase/deficiência , Esplenomegalia/patologia , Lobo Temporal/patologiaRESUMO
The present Investigation examined the biological correlates of the cognitive deficits of Alzheimer's disease and related dementias using the neuropsychological assessment battery of the Consortium to Establish a Registry of Alzheimer's Disease (CERAD) and positron emission tomography (PET). Resting state cerebral glucose metabolism was measured using the labelled radiotracer, [18F] Fluoro-2-deoxyglucose (FDG), in a sample of patients with mild to moderate dementia (n = 66). Specific and predictable relationships were seen between regional brain metabolism (left and right, frontal, temporal, and parietal lobes) and the neuropsychological measures of verbal fluency, constructional praxis, and verbal list learning. On tests of naming and delayed verbal recall only diminished FDG uptake in the left frontal lobe and the left temporal lobe, respectively, approached significance. This study demonstrates the expected relationships between neuropsychological performance and regional cerebral metabolism, thereby providing support for the CERAD battery as a valid measure in the clinical evaluation of dementia and for the use of FDG-PET in brain-behavior studies of dementia.
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OBJECTIVE: To evaluate the efficacy of ropinirole 24-hour prolonged release (ropinirole 24-hour) as an adjunct to levodopa in patients with Parkinson disease (PD) and motor fluctuations. METHODS: In a double-blind, placebo-controlled, 24-week study, 393 subjects with PD were randomized to ropinirole 24-hour (n = 202) or placebo (n = 191). The primary outcome measure was reduction in hours of daily "off" time. RESULTS: At week 24, the mean dose of ropinirole 24-hour was 18.8 mg/day with a mean reduction in daily levodopa of 278 mg. There was a mean reduction in daily "off" time of 2.1 hours in the ropinirole 24-hour group and 0.3 hours with placebo. Secondary outcome measures including change in hours and percent of daily "on" time and "on" time without troublesome dyskinesia, Unified PD Rating Scale motor and activities of daily living subscales, Beck Depression Inventory-II, PDQ-39 subscales of mobility, activities of daily living, emotional well-being, stigma and communication, and PD Sleep Scale were significantly improved at week 24 with ropinirole 24-hour. The most common adverse events (AE) with ropinirole 24-hour were dyskinesia, nausea, dizziness, somnolence, hallucinations, and orthostatic hypotension and AEs led to study withdrawal in 5% of both the active and placebo groups. CONCLUSION: Ropinirole 24-hour was effective and well tolerated as adjunct therapy in patients with Parkinson disease (PD) not optimally controlled with levodopa. Ropinirole 24-hour demonstrated an improvement in both motor and non-motor PD symptoms, while permitting a reduction in adjunctive levodopa dose.
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Antiparkinsonianos/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Indóis/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Idoso , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Cooperação Internacional , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Índice de Gravidade de Doença , Fatores de TempoRESUMO
The tolerability of 311C90, a novel, selective and highly effective 5-HT1D receptor agonist in development for the acute treatment of migraine, has been evaluated in a number of clinical pharmacology and patient studies across the dose range 1-50 mg. 311C90 has been well tolerated across the entire dose range and no clinically relevant changes in routine laboratory parameters, blood pressure or ECG recordings have been observed. Adverse experiences reported are generally dose related, mild to moderate and resolve spontaneously. Chest-related symptoms occur infrequently and the cardiovascular safety profile of 311C90 is considered particularly favourable. 311C90, therefore, possesses a desirable safety profile which is well suited to broad-based outpatient administration.
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Transtornos de Enxaqueca/tratamento farmacológico , Oxazóis/efeitos adversos , Oxazolidinonas , Agonistas do Receptor de Serotonina/efeitos adversos , Adulto , Idoso , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Valores de Referência , TriptaminasRESUMO
Caregivers of 35 mildly to moderately memory-impaired patients rated current and premorbid personalities with the NEO Personality Inventory. We then examined changes in the five domains of personality tapped by the NEO. There were significant changes in four of the five domains of normal personality functioning toward less conscientiousness, lower extraversion, higher neuroticism, and lower openness. The difference toward lower agreeableness was not significant when controlling for multiple comparisons. Spearman rank correlation coefficients indicated that changes in conscientiousness and vulnerability were not related to rated premorbid personality patterns and thus appear to describe shifts for all patients evaluated for memory disorders. These data suggest that personality inventories may be helpful in characterizing caregivers' observations of memory-impaired patients and thus represent a critical source of information for the clinician in charge of care.
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Doença de Alzheimer/psicologia , Cuidadores/psicologia , Transtornos da Memória/diagnóstico , Inventário de Personalidade , Adulto , Atitude Frente a Saúde , Feminino , Humanos , Masculino , Transtornos da Memória/psicologia , Estudos RetrospectivosRESUMO
PURPOSE: The present study was conducted to determine the rate of sudden unexplained death in epilepsy (SUDEP) in a well-defined cohort of patients included in the lamotrigine (LTG) clinical development database. METHODS: A panel of scientists experienced in the area of SUDEP was assembled and provided with case summaries on all deaths (n = 45) reported during the initial clinical development of LTG. The panel developed a set of criteria for classifying cases as SUDEP (definite or highly probable), possible SUDEP, or non-SUDEP. This classification algorithm was then applied to the LTG cases, and SUDEP rates were calculated using patient-years of exposure as the denominator. RESULTS: At the time of the study, 4,700 patients (5,747 patient-years of exposure) were included in the worldwide LTG clinical trials database. In this cohort, 45 deaths were reported. Eighteen were judged by the panel to be SUDEP, 6 were defined as possible SUDEP, 20 were judged to be due to other causes (non-SUDEP), and 1 lacked sufficient data from which to make a classification. The overall SUDEP rate (definite/ highly probable SUDEP and possible SUDEP combined) was calculated to be 3.5 in 1,000 patient-years of exposure to LTG. CONCLUSIONS: The rate of SUDEP in this cohort of patients was comparable to the rate that would be expected in young adults with severe epilepsy (the subgroup of patients believed to be at highest risk of SUDEP). The data suggest that the rate of SUDEP in the LTG clinical development program is a function of the clinical trial population and is unrelated to drug treatment.