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BACKGROUND: Patients diagnosed as having multiple sclerosis (MS) experience a wide range of symptoms requiring pharmacologic management, and many do not achieve adequate symptom control. The purpose of this study was to evaluate the role of medical cannabis (MC) as part of a comprehensive treatment plan for patients with MS. METHODS: A retrospective medical record review of 141 patients with MS receiving MC for symptom management was conducted. Data were collected for up to 4 follow-up appointments after initiation of MC. Outcomes included changes in MS symptoms, medication changes, adverse events, and changes in cognition and mobility. RESULTS: Patients experienced extensive MS symptom improvement after initiation of MC, with alleviation of pain (72% of patients) and spasticity (48% of patients) and improvement in sleep (40% of patients) the most common. There was a significant reduction in concomitant opioid use after initiating MC as evidenced by a significant decrease in daily morphine milligram equivalents among patients prescribed opioid analgesics (P = .01). Decreases in muscle relaxant use and benzodiazepine use did not reach significance (P > .05). The most common adverse reaction to MC was fatigue (11% of patients). CONCLUSIONS: In many patients with MS, MC was well tolerated, eased pain and spasticity, improved sleep and other symptoms, and reduced use of concomitant opioid analgesics. Prospective studies are needed to further investigate the role of MC in the treatment of patients with MS.
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OBJECTIVES: Medical cannabis (MC) has recently garnered interest as a potential treatment for neurologic diseases, including Parkinson's disease (PD). A retrospective chart review was conducted to explore the impact of MC on the symptomatic treatment of patients with PD. METHODS: Patients with PD treated with MC in the normal course of clinical practice were included (n = 69). Data collected from patient charts included MC ratio/formulation changes, PD symptom changes after initiation of MC, and adverse events (AEs) from MC use. Information regarding changes in concomitant medications after MC initiation, including opioids, benzodiazepines, muscle relaxants, and PD medications, was also collected. RESULTS: Most patients were initially certified for a 1:1 (∆ 9 -tetrahydrocannabinol:cannabidiol) tincture. Eight-seven percent of patients (n = 60) were noted to exhibit an improvement in any PD symptom after starting MC. Symptoms with the highest incidence of improvement included cramping/dystonia, pain, spasticity, lack of appetite, dyskinesia, and tremor. After starting MC, 56% of opioid users (n = 14) were able to decrease or discontinue opioid use with an average daily morphine milligram equivalent change from 31 at baseline to 22 at the last follow-up visit. The MC was well-tolerated with no severe AEs reported and low rate of MC discontinuation due to AEs (n = 4). CONCLUSIONS: The MC may improve motor and nonmotor symptoms in patients with PD and may allow for reduction of concomitant opioid medication use. Large, placebo-controlled, randomized studies of MC use in patients with PD are required.
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Marihuana Medicinal , Enfermedad de Parkinson , Humanos , Marihuana Medicinal/efectos adversos , Enfermedad de Parkinson/complicaciones , Analgésicos Opioides , Estudios Retrospectivos , Temblor/tratamiento farmacológicoRESUMEN
BACKGROUND: Following the expiration of brand name exclusivity of Plavix® in 2012, generic clopidogrel bisulfate was approved. As a widely prescribed medication with significant inter-patient pharmacokinetic and pharmacodynamic variability, data regarding the impact of switching to generic clopidogrel bisulfate on patients is needed. OBJECTIVE: The objective of this study was to determine whether generic clopidogrel bisulfate is as efficacious as Plavix® for the inhibition of platelet aggregation. METHODS: Patients treated with Plavix® monotherapy (n = 254) or generic clopidogrel bisulfate monotherapy (n = 185) were included in this retrospective review. Confounding factors previously found to affect clopidogrel responsiveness (diabetes, female sex, and smoking) were assessed, as well as medications classified as substrates, inducers, and inhibitors of enzymes involved in clopidogrel metabolism. Whole blood impedance aggregometry was used to measure platelet aggregation in response to adenosine diphosphate. Patients were tested after ≥2 weeks of treatment and designated as non-responders if aggregation response exceeded sensitivity thresholds of 6 ohms of impedance. RESULTS: The introduction of generic clopidogrel bisulfate was associated with a decrease in antiplatelet resistance (44% to 31%, p < 0.01) and decreased mean ohms of resistance (5.06 ± 4.55 to 3.32 ± 4.03, p < 0.01). Prior to analysis of secondary outcomes, 217 patients were eliminated due to antiplatelet usage for longer than 3 years (n = 123 for Plavix® and n = 118 for clopidogrel). There was no statistically significant finding in prevalence of secondary events. CONCLUSION: Resistance rates to the antiplatelet, clopidogrel are significantly lower since the switch to generic formulations. Further investigation into the impact of variability between clopidogrel bisulfate formulations is needed.
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Inhibidores de Agregación Plaquetaria , Ticlopidina , Clopidogrel , Medicamentos Genéricos/uso terapéutico , Femenino , Humanos , Agregación PlaquetariaRESUMEN
PURPOSE/AIM: A targeted questionnaire may help increase rates of reporting Parkinson's disease psychosis (PDP) symptoms. Despite the need for a rapid patient- and/or caregiver-administered screening tool for PDP symptoms, an appropriate tool is not yet available. This study developed a targeted PDP questionnaire and examined rates of reporting psychosis symptoms in response to the questionnaire compared to rates of reporting symptoms to healthcare providers during a routine visit. MATERIALS AND METHODS: This was a single-center, cross-sectional observational study of patients at an outpatient neurology practice. Medical charts were screened for eligibility, and patients were contacted by telephone for informed consent. RESULTS: A total of 25 patients (24%, N = 104) newly reported PDP symptoms in response to the targeted questionnaire. The frequency of reporting new symptoms in response to the questionnaire was statistically significantly greater compared to frequency of reporting symptoms without use of a targeted questionnaire (p < 0.0001). CONCLUSIONS: A targeted questionnaire increases rates of reporting PDP symptoms, and based on frequency, severity, and distress ratings, may allow for capture of PDP symptoms earlier in the course of the disease. By using a questionnaire, patients reported symptom onset an average of 1.4 years earlier than patients who reported symptoms to their providers according to patient medical records.
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Enfermedad de Parkinson , Trastornos Psicóticos , Estudios Transversales , Humanos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/epidemiología , Trastornos Psicóticos/diagnóstico , Trastornos Psicóticos/epidemiología , Encuestas y CuestionariosRESUMEN
PURPOSE/BACKGROUND: Extensive research has been conducted comparing the metabolic characteristics of older second-generation antipsychotics (SGAs); minimal data exist comparing the long-term metabolic effects of SGAs approved in the last 10 years. METHODS/PROCEDURES: A retrospective chart review of patients treated with brexpiprazole, lurasidone, asenapine, cariprazine, and iloperidone (newer SGAs) for at least 6 weeks at an outpatient psychiatric practice was conducted. Patients treated with olanzapine, an older SGA, were included as a comparator. Metabolic characteristics were collected at baseline, approximately 6 weeks, 12 weeks, and for up to 12 months. FINDINGS/RESULTS: Of the newer SGAs, there were statistically significant increases in patients' average weight at 12 weeks and 1 year or less with brexpiprazole (2.48 lb, P = 0.02; 5.97 lb, P = 0.01) and iloperidone (4.54 lb, P < 0.01; 5.13 lb, P = 0.02). Brexpiprazole and iloperidone resulted in significant increases in body mass index, up to a 0.90-kg/m2 average increase in patients taking brexpiprazole at 1 year or less. Minimal weight gain was seen with cariprazine (4.25 lb, P = 0.42) and asenapine (1.80 lb, P = 0.62) at 1 year or less after treatment initiation. Although not statistically significant, lurasidone showed an average weight loss of up to 0.60 lb at 1 year or less (P = 0.56). IMPLICATIONS/CONCLUSIONS: Although some weight gain was seen with the newer SGAs, all demonstrated significantly favorable metabolic characteristics compared with olanzapine. Monitoring of weight and metabolic parameters remain important in patients treated with SGAs.
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Antipsicóticos/efectos adversos , Antipsicóticos/uso terapéutico , Trastorno Bipolar/tratamiento farmacológico , Aumento de Peso/efectos de los fármacos , Adulto , Anciano , Presión Sanguínea/efectos de los fármacos , Dibenzocicloheptenos/efectos adversos , Femenino , Humanos , Isoxazoles/efectos adversos , Clorhidrato de Lurasidona/efectos adversos , Masculino , Persona de Mediana Edad , Olanzapina/efectos adversos , Piperazinas/efectos adversos , Piperidinas/efectos adversos , Quinolonas/efectos adversos , Estudios Retrospectivos , Tiofenos/efectos adversosRESUMEN
Previous studies have shown l-methylfolate to be a safe and beneficial therapy for neuropsychiatric conditions, including major depressive disorder and schizophrenia in adults. The purpose of this study was to assess safety and describe patient experience using l-methylfolate calcium in a real-world pediatric and adolescent population. A retrospective chart review of patients (7 to 20 y of age, mean age 16 y) prescribed l-methylfolate calcium at a psychiatry clinic in Amherst, NY, between January 1, 2010 and November 10, 2015 was conducted. Patients to whom l-methylfolate calcium 15 mg/d (n=139) or 7.5 mg/d (n=7) was administered were identified; 44 patients who were prescribed but to whom l-methylfolate calcium was not administered were included as a comparator population. Common neuropsychiatric diagnoses included anxiety disorders (68% in the treatment population vs. 50% in the comparator population) and mood disorders (57% in the treatment population vs. 52% in the comparator population). Antidepressants (69% vs. 55%) and mood stabilizers or antiepileptic drugs (63% vs. 57%) were frequently prescribed in combination with l-methylfolate calcium. Adverse events occurred less frequently in the treated population, possibly due to the addition of l-methylfolate calcium (10% vs. 25%, P=0.02). The most common adverse events in the treated population were impaired sleep (5 patients) and increased anxiety (3 patients). Rates of laboratory abnormalities did not differ significantly between the treated and comparator populations (P=0.13). Positive subjective treatment experiences were reported by 22.5% of treated patients and negative subjective treatment experiences were reported by 5.4% of treated patients. L-methylfolate calcium was well-tolerated in a pediatric/adolescent population and may provide benefits for patients with a range of neuropsychiatric conditions.
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Tetrahidrofolatos/uso terapéutico , Adolescente , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/uso terapéutico , Antidepresivos/administración & dosificación , Antidepresivos/uso terapéutico , Trastornos de Ansiedad/tratamiento farmacológico , Niño , Quimioterapia Combinada , Femenino , Humanos , Masculino , Trastornos Mentales/tratamiento farmacológico , Trastornos del Humor/tratamiento farmacológico , Estudios Retrospectivos , Tetrahidrofolatos/administración & dosificación , Adulto JovenRESUMEN
Aspirin remains the standard for stroke prophylaxis. However, as many as 20%-25% of patients may fail to show a full response to aspirin. Ideally, patients who are resistant to aspirin could be identified, then receive an increased dose of aspirin or be changed to an alternative therapy more efficiently. We have developed an in vitro assay that may make this possible. Healthy volunteers (n = 13) between 18 and 50 years of age were tested for both ex vivo and in vivo responses to aspirin. Dimethyl sulfoxide (DMSO) was selected as the solvent for aspirin in the assay. DMSO can exhibit antiplatelet effects, necessitating the use of a concentration low enough to avoid such antiplatelet effects. Blood samples were tested against DMSO 0%, 0.05%, 0.5%, and 1% w/v with and without aspirin 0, 50, and 100 µM. The effects of both agents were measured via whole-blood aggregometry. A 3-dimensional response model described the data well, quantifying the combinatorial effect of DMSO and aspirin on platelet aggregation. Across all participants, baseline aggregation stimulated with collagen 1 µM or arachidonate 0.5 mM was approximately 18 and 13 Ω, respectively. The response model showed that 0.05% DMSO with 100 µM aspirin would provide platelet aggregation of 3.4 Ω. A DMSO concentration of 0.05% in the absence of aspirin would result in no discernable effects on platelet aggregation (17.7 Ω). Overall, the use of 100 µM of aspirin in 0.05% DMSO provides a robust method to test for ex vivo inhibition of platelet aggregation.
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Aspirina/administración & dosificación , Aspirina/farmacología , Agregación Plaquetaria/efectos de los fármacos , Adulto , Plaquetas/efectos de los fármacos , Femenino , Humanos , Masculino , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/farmacología , Pruebas de Función Plaquetaria , Adulto JovenRESUMEN
This study tested the capability of an assay to predict aspirin response and reduce ischemic events, and healthcare costs, and delays to optimal treatment. Patients who needed aspirin in the course of normal medical care were included. Patients were excluded if they had disorders affecting platelet function, alcohol use within 24 hours of a test, or NSAID use. Dose escalation of chewable aspirin from 81 mg, to 162 mg, to 325 mg daily occurred based on the results of whole blood impedance aggregation testing to the agonists, collagen (1ug/mL, 5 ug/mL) and arachidonate (0.5 mM) after 10-14 days of treatment. The experimental in vitro test was conducted in triplicate by performing aggregometry on samples spiked to a concentration of 10 uM of aspirin in 0.05% dimethyl sulfoxide. Of the 36 patients who were compliant 16 were found to be resistant to the antiplatelet effects of 81 mg daily aspirin. Nine of these patients were predicted to stay resistant despite dose increase. Once tested at higher doses, ten remained resistant. Seven of the 16 patients were predicted to become sensitive to a higher dose while six actually did. Predicted response to increased doses of aspirin was in good agreement with actual response. Sensitivity of the assay was 83% and specificity was 80%. Results are promising and indicate that it is possible to predict, with reasonable accuracy, if a patient will have an adequate platelet response to aspirin or if the patient will never respond to aspirin necessitating an alternative antiplatelet regimen. Larger, multisite studies are inevitably needed.
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Aspirina/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas de Función Plaquetaria/métodos , Valor Predictivo de las Pruebas , Estudios Prospectivos , Adulto JovenRESUMEN
BACKGROUND AND GOAL: Cytochrome P450 (CYP) enzymes are responsible for the conversion of clopidogrel into its active metabolite and the metabolism of proton pump inhibitors (PPIs), which may also inhibit CYP enzymes. A current Food and Drug Administration advisory suggests avoiding esomeprazole and omeprazole while taking clopidogrel because of concerns that PPIs may compromise clopidogrel's antiplatelet effects. The objective of the present study was to examine the robustness of this interaction using a well-controlled study design in a population of participants free of confounders. MATERIALS AND METHODS: Twenty-eight healthy male participants, with a mean age 24.2 ± 3.2, were randomized to an incomplete crossover design schedule. Participants underwent platelet aggregation testing after clopidogrel alone, while on clopidogrel in combination with 1 of 3 PPIs (40 mg of pantoprazole, 20 mg of omeprazole, 20 mg of rabeprazole, 40 mg of esomeprazole, 30 mg of lansoprazole, or 30 mg of dexlansoprazole), and during 1 week of clopidogrel-only washout periods. FINDINGS: The median platelet aggregation to adenosine diphosphate during a drug-free baseline was 10Ω (2.5 interquartile range) of impedance and decreased to 0Ω on clopidogrel alone. Aggregation did not significantly change with concomitant use of PPIs and clopidogrel. CONCLUSION: These data do not demonstrate a significant interaction between common individual PPIs and clopidogrel in healthy volunteers who respond to clopidogrel alone. This adds data to a growing body of evidence indicating that the addition of a PPI may have a weak effect on clopidogrel's antiplatelet properties, and may only be relevant in specific clinical circumstances.
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Inhibidores de Agregación Plaquetaria/administración & dosificación , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de la Bomba de Protones/administración & dosificación , Adulto , Estudios Cruzados , Interacciones Farmacológicas , Voluntarios Sanos , Humanos , Masculino , New York , Inhibidores de Agregación Plaquetaria/efectos adversos , Pruebas de Función Plaquetaria , Inhibidores de la Bomba de Protones/efectos adversos , Factores de Tiempo , Adulto JovenRESUMEN
PURPOSE: We sought to characterize the clinical experience of outpatients treated with brexpiprazole after achieving suboptimal outcomes with aripiprazole or bupropion as determined by the treating psychiatric provider. DESIGN AND METHODS: Case series; inefficacy, intolerability, or other unsatisfactory outcome to previous trial with aripiprazole or bupropion. FINDINGS: The majority of individuals in our sample exhibited tolerability of brexpiprazole. In addition, reduction in mean PHQ-9 scores was observed with brexpiprazole treatment. IMPLICATIONS: The results of our preliminary analysis suggest that a subpopulation of adults who have insufficient outcomes on aripiprazole or bupropion due to intolerability, inefficacy or other unsatisfactory outcome may benefit by switching to brexpiprazole treatment. Larger randomized controlled trials are needed, as well as sophisticated network analysis to further understand efficacy and tolerability differences between atypical antipsychotics.
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Antipsicóticos/uso terapéutico , Aripiprazol/uso terapéutico , Bupropión/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Quinolonas/uso terapéutico , Tiofenos/uso terapéutico , Adulto , Antipsicóticos/efectos adversos , Aripiprazol/efectos adversos , Bupropión/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , New York , Escalas de Valoración Psiquiátrica , Quinolonas/efectos adversos , Estudios Retrospectivos , Tiofenos/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: To determine the effects of ropinirole on manic switching and disease severity in bipolar disorder. DESIGN AND METHODS: A cross-sectional survey was conducted in 23 bipolar depressed patients using ropinirole combination therapy (Young Mania Rating Scale [YMRS], Bipolar Inventory of Symptoms Scale [BISS]). Retrospective Clinical Global Impression of Change (CGI-C) and CGI-S (Severity) were captured via chart review. FINDINGS: One patient (4.3%) experienced induction of mania (YMRS). All patients responded or partially responded to ropinirole (CGIs). YMRS and BISS mania scores were correlated. PRACTICE IMPLICATIONS: Ropinirole has a low rate of manic switching and significantly reduces bipolar depression severity.
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Trastorno Bipolar/tratamiento farmacológico , Indoles/farmacología , Evaluación de Resultado en la Atención de Salud , Índice de Severidad de la Enfermedad , Adulto , Anciano , Estudios Transversales , Femenino , Humanos , Indoles/administración & dosificación , Indoles/efectos adversos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
This study demonstrates that patients who are taking 81 mg of aspirin and are nonresponsive benefit from a dose of 162 mg or greater vs a different antiplatelet therapy. We identified 100 patients who were nonresponsive to aspirin 81 mg via whole blood aggregometry and observed how many patients became responsive at a dose of 162 mg or greater. Platelet nonresponsiveness was defined as >10 Ω of resistance to collagen 1 µg/mL and/or an ohms ratio of collagen 1 µg/mL to collagen 5 µg/mL >0.5 and/or >6 Ω to arachidonate. Borderline response was defined as an improvement in 1 but not both of the above criteria. Of the initial 100 patients who were nonresponsive to an aspirin dose of 81 mg, 79% became responsive at a dose of 162 mg or >162 mg. Only 6% did not respond to any increase in dose. We believe that patients treated with low-dose aspirin who have significant risk for secondary vascular events should be individually assessed to determine their antiplatelet response. Those found to have persistent platelet aggregation despite treatment with 81 mg of aspirin have a higher likelihood of obtaining an adequate antiplatelet response at a higher aspirin dose.
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Aspirina/administración & dosificación , Plaquetas/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/administración & dosificación , Agregación Plaquetaria/efectos de los fármacos , Pruebas de Coagulación Sanguínea/métodos , Plaquetas/metabolismo , Colágeno/metabolismo , Resistencia a Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas de Función Plaquetaria/métodosRESUMEN
OBJECTIVE: To compare the efficacy of high-dose (3,600 mg/day) vs low-dose (1,200 mg/day) oral gabapentin enacarbil (GEn) on pain intensity in adults with postherpetic neuralgia (PHN) and a history of inadequate response to ≥1,800 mg/day gabapentin. DESIGN: Multicenter, randomized, double-blind, crossover study (NCT00617461). SETTING: Thirty-five outpatient centers in Germany and the United States. SUBJECTS: Subjects aged ≥18 years with a diagnosis of PHN. METHODS: During a 2-week baseline period, subjects received open-label treatment with 1,800 mg/day gabapentin. Subjects who had a mean 24-hour average pain intensity score ≥4 during the last 7 days of the baseline period were randomized to receive GEn (1,200 or 3,600 mg/day) for treatment period 1 (28 days), followed by GEn 2,400 mg/day (4 days), and the alternate GEn dose for treatment period 2 (28 days). RESULTS: There was a modest but significant improvement in pain intensity scores with GEn 3,600 mg vs 1,200 mg (adjusted mean [90% confidence interval] treatment difference, -0.29 [-0.48 to -0.10]; P = 0.013). The difference in efficacy between doses was observed primarily in subjects who received the higher dose during treatment period 2; certain aspects of the study design may have contributed to this outcome. Plasma steady-state gabapentin exposure during GEn treatment was as expected and consistent between treatment periods. No new safety signals or adverse event trends relating to GEn exposure were identified. CONCLUSIONS: While the overall results demonstrated efficacy in a PHN population, the differences between treatment periods confound the interpretation. These findings could provide insight into future trial designs.
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Analgésicos/administración & dosificación , Carbamatos/administración & dosificación , Neuralgia Posherpética/tratamiento farmacológico , Profármacos/administración & dosificación , Ácido gamma-Aminobutírico/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Resultado del Tratamiento , Ácido gamma-Aminobutírico/administración & dosificaciónRESUMEN
UNLABELLED: Gabapentin enacarbil (GEn) is an actively transported prodrug of gabapentin that provides sustained, dose-proportional exposure to gabapentin. This randomized, double-blind, parallel-group, placebo-controlled study evaluated the safety and efficacy of 3 different maintenance doses of oral GEn in subjects with postherpetic neuralgia. Adults with a 24-hour average pain intensity score of ≥4.0 received GEn 1,200 mg, 2,400 mg, 3,600 mg, or placebo for 14 weeks (including a 1-week up-titration, 12-week maintenance, and 1-week taper). The primary endpoint was change from baseline to end of maintenance treatment in mean 24-hour average pain intensity score. The intent-to-treat population consisted of 371 subjects (GEn 1,200 mg = 107, 2,400 mg = 82, 3,600 mg = 87, placebo = 95). With regard to the primary endpoint, all 3 GEn treatment groups demonstrated a statistically significant difference relative to placebo. The adjusted mean change from baseline for the treatment groups ranged from -2.36 to -2.72 versus -1.66 for the placebo group. Exposure-response modeling suggested an ED50 around 1,200 mg/day, which was consistent with historical findings reported for gabapentin. The most commonly reported adverse events were dizziness and somnolence. All studied doses of GEn significantly improved pain associated with postherpetic neuralgia as compared to placebo and were well tolerated. PERSPECTIVE: GEn provides clinically important pain relief with doses from 1,200 mg to 3,600 mg and is generally well tolerated and efficacious. As an actively transported prodrug of gabapentin, it provides dose-proportional and extended exposure to gabapentin.
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Anestésicos/uso terapéutico , Carbamatos/uso terapéutico , Neuralgia Posherpética/diagnóstico , Neuralgia Posherpética/tratamiento farmacológico , Ácido gamma-Aminobutírico/análogos & derivados , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Factores de Tiempo , Resultado del Tratamiento , Adulto Joven , Ácido gamma-Aminobutírico/uso terapéuticoRESUMEN
The antiepileptic, carbamazepine, is extensively metabolized via hepatic enzymes in the cytochrome P450 family and is therefore subject to a myriad of drug interactions. Concomitant administration with phenytoin enhances carbamazepine metabolism thus reducing serum concentrations and necessitating the use of a higher maintenance dose. Removal of phenytoin therapy in the absence of anticipatory dose adjustments and careful monitoring of serum concentrations may result in catastrophic outcomes. Reported herein are the events leading to the death of a 23-month old child who suffered a fatal carbamazepine overdose following withdrawal of phenytoin therapy.
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Anticonvulsivantes , Carbamazepina , Simulación por Computador , Modelos Biológicos , Fenitoína , Convulsiones/tratamiento farmacológico , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/sangre , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/envenenamiento , Autopsia , Biotransformación , Carbamazepina/administración & dosificación , Carbamazepina/sangre , Carbamazepina/farmacocinética , Carbamazepina/envenenamiento , Esquema de Medicación , Interacciones Farmacológicas , Monitoreo de Drogas , Sobredosis de Droga/diagnóstico , Sobredosis de Droga/etiología , Sobredosis de Droga/patología , Quimioterapia Combinada , Resultado Fatal , Toxicología Forense , Humanos , Lactante , Masculino , Método de Montecarlo , Fenitoína/administración & dosificación , Fenitoína/sangre , Fenitoína/farmacocinética , Intoxicación/diagnóstico , Intoxicación/etiología , Intoxicación/patologíaRESUMEN
Multiple sclerosis is a chronic autoimmune disease affecting the central nervous system, more specifically, the myelin sheath covering of nerve fibers in the brain and spinal cord. This disease requires lifelong disease-modifying therapy, and all of the currently available first-line disease-modifying agents are parenteral formulations only. To date, eight drugs have entered or completed phases II and III clinical trials, four of which are oral drugs. These include five immunomodulators--cladribine, fingolimod, laquinimod, teriflunomide, and dimethyl fumarate--and three monoclonal antibodies--alemtuzumab, daclizumab, and rituximab. Although comparing these new drugs with available therapies is difficult, they do show promise as potential first-line agents for the treatment of multiple sclerosis. This marks a new frontier in the treatment of this disease, as the advent of new oral drugs will lead to increased patient compliance and contribute to longer sustained symptom-free periods and less marked disability.
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Anticuerpos Monoclonales/uso terapéutico , Factores Inmunológicos/uso terapéutico , Inmunosupresores/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Sistema Nervioso Central/efectos de los fármacos , Ensayos Clínicos como Asunto , Humanos , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/efectos adversos , Inmunosupresores/administración & dosificaciónRESUMEN
To determine the prevalence of platelet nonresponsiveness to aspirin treatment for secondary stroke prophylaxis, the authors studied consecutive patients during a 29-month period. Information regarding their ischemic events, risk factors, and medications was collected. Platelet aggregation in response to collagen and arachidonic acid was used to determine platelet responsiveness to aspirin. A total of 653 patients were evaluated. Of these, 129 patients (20%) were determined to be nonresponsive to aspirin based on continued platelet aggregation in response to collagen, arachidonic acid, or both. A total of 87 (13%) of the 653 patients were clinical aspirin failures (ie, presented with new focal cerebral ischemic symptoms while taking aspirin). Of the patients with new cerebral ischemic symptoms, 57 (66%) were determined to be platelet nonresponsive to aspirin. The odds ratio for platelet nonresponsiveness to aspirin in patients who suffered a recurrent ischemic event while taking aspirin was 14.25 (95% confidence interval: 8.5-23.7; P < .5). Continued platelet aggregation despite aspirin treatment occurred in 20% of ambulatory patients treated for secondary stroke prophylaxis. The prevalence of nonresponsiveness to aspirin was statistically higher in those patients who suffered recurrent cerebral ischemia while taking aspirin (P < .5) compared with patients who remained without new ischemic symptoms.
Asunto(s)
Aspirina/uso terapéutico , Plaquetas/efectos de los fármacos , Ataque Isquémico Transitorio/prevención & control , Accidente Cerebrovascular/prevención & control , Factores de Edad , Anciano , Antiinflamatorios/administración & dosificación , Antiinflamatorios/uso terapéutico , Ácido Araquidónico/farmacología , Aspirina/administración & dosificación , Clopidogrel , Colágeno/farmacología , Enfermedad de la Arteria Coronaria/complicaciones , Dipiridamol/administración & dosificación , Dipiridamol/uso terapéutico , Quimioterapia Combinada , Femenino , Humanos , Ataque Isquémico Transitorio/sangre , Masculino , Oportunidad Relativa , Agregación Plaquetaria/efectos de los fármacos , Recurrencia , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/etiología , Ticlopidina/administración & dosificación , Ticlopidina/análogos & derivados , Ticlopidina/uso terapéutico , Factores de Tiempo , Insuficiencia del TratamientoRESUMEN
OBJECTIVE: The objective of this study was to develop a mechanism-based pharmacodynamic model that characterizes the antiplatelet effects of aspirin (acetylsalicylic acid) and ibuprofen alone and in combination. METHODS: Ten healthy volunteers were enrolled in a single-blinded, randomized, three-way crossover study. Treatments consisted of single doses of oral aspirin (325 mg) and ibuprofen (400 mg) and concomitant administration of aspirin (325 mg) and ibuprofen (400 mg). Ex vivo whole blood platelet aggregation induced by collagen (1 microg/mL) or arachidonic acid (0.5 mmol/L) was measured by impedance aggregometry. Model development and population parameter estimation were performed using nonlinear mixed-effects modelling implemented in NONMEM. RESULTS: Relatively complete inhibition of platelet aggregation was achieved following aspirin treatment (approximately 77% inhibition within 2 hours), and return to baseline values occurred within 72-96 hours after dosing. In contrast, treatment with ibuprofen alone or in combination with aspirin produced transient inhibition of platelet aggregation, with complete recovery observed in 6-8 hours. The final pharmacodynamic model was based on the turnover of cyclo-oxygenase-1 (COX-1) enzyme, and incorporated irreversible inhibition by aspirin and reversible binding and antiplatelet effects of ibuprofen. The temporal response profiles from all three study arms were well described by the final model, and the parameters were estimated with good precision. The apparent turnover rate constant for COX-1 (kout) and the irreversible inhibition rate constant for aspirin (K) were estimated to be 0.0209 h(-1) and 0.152 (mg/L)(-1).h(-1), with interindividual variability of 30.6% and 26.2%, respectively. Simulations were used to evaluate the influence of clinically relevant ibuprofen regimens on the antiplatelet effect of aspirin, confirming clinical reports that the antiplatelet effect of aspirin would be blocked when multiple daily doses of ibuprofen are given, even if taken after aspirin administration. CONCLUSIONS: A mechanism-based pharmacodynamic model has been developed that characterizes the antiplatelet effects of aspirin and ibuprofen, alone and concomitantly, and predicts a significant inhibition of aspirin antiplatelet effects in the presence of a typical ibuprofen dosing regimen.
Asunto(s)
Aspirina/farmacología , Ibuprofeno/farmacología , Agregación Plaquetaria/efectos de los fármacos , Administración Oral , Adulto , Ácido Araquidónico/farmacología , Aspirina/sangre , Aspirina/farmacocinética , Colágeno/farmacología , Estudios Cruzados , Inhibidores de la Ciclooxigenasa/administración & dosificación , Inhibidores de la Ciclooxigenasa/farmacocinética , Inhibidores de la Ciclooxigenasa/farmacología , Semivida , Humanos , Ibuprofeno/sangre , Ibuprofeno/farmacocinética , Persona de Mediana Edad , Modelos Biológicos , Método de Montecarlo , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacología , Método Simple Ciego , Factores de TiempoRESUMEN
This study was designed to measure the magnitude and duration of inhibition of platelet aggregation following doses of aspirin or ibuprofen alone or taken in combination in a group of healthy volunteers. Ten normal volunteer subjects underwent 3 randomized treatment sessions: aspirin 325 mg alone, ibuprofen 400 mg alone, and ibuprofen 400 mg, followed by dosing with aspirin 325 mg 2 hours thereafter. In addition, a confirmatory study was performed in patients. Over 27 months, a cohort of patients treated with aspirin for secondary stroke prophylaxis while concomitantly taking a nonsteroidal anti-inflammatory drug (NSAID) was identified. A significant reduction was found in both the magnitude and duration of aspirin's inhibitory effect on platelet aggregation when ibuprofen was given prior to aspirin administration in normal volunteer subjects. During a 27-month period, a cohort of 28 patients took regular daily doses of ibuprofen or naproxen. Of these 28 patients, 18 returned for follow-up testing in the absence of this pharmacodynamic interaction. None of these 18 patients demonstrated inhibition of platelet aggregation while on both NSAID and aspirin; however, all showed inhibition of aggregation following discontinuation of the NSAID. Notably, 13 of these 18 patients (72%) had experienced a recurrent ischemic episode while taking aspirin and NSAIDs concomitantly. These data suggest that ibuprofen prevents the irreversible inhibition of platelet aggregation produced by aspirin needed for secondary stroke prophylaxis, and this interaction can have clinical consequences for patients taking aspirin.