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1.
Epilepsia ; 60(12): 2437-2447, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31755090

RESUMO

OBJECTIVE: A large-scale, double-blind trial (SP0993; NCT01243177) demonstrated that lacosamide was noninferior to controlled-release carbamazepine (carbamazepine-CR) in terms of efficacy, and well tolerated as first-line monotherapy in patients (≥16 years of age) with newly diagnosed epilepsy. We report primary safety outcomes from the double-blind extension of the noninferiority trial (SP0994; NCT01465997) and post hoc analyses of pooled long-term safety and efficacy data from both trials. METHODS: Patients were randomized 1:1 to lacosamide or carbamazepine-CR. Doses were escalated (lacosamide: 200/400/600 mg/d; carbamazepine-CR: 400/800/1200 mg/d) based on seizure control. Eligible patients continued randomized treatment in the extension. Primary outcomes of the extension were treatment-emergent adverse events (TEAEs), serious TEAEs, and discontinuations due to TEAEs. Post hoc analyses of data from combined trials included 12- and 24-month seizure freedom and TEAEs by number of comorbid conditions. RESULTS: A total of 886 patients were treated in the initial trial and 548 in the extension; 211 of 279 patients (75.6%) on lacosamide and 180/269 (66.9%) on carbamazepine-CR completed the extension. In the extension, 181 patients (64.9%) on lacosamide and 182 (67.7%) on carbamazepine-CR reported TEAEs; in both groups, nasopharyngitis, headache, and dizziness were most common. Serious TEAEs were reported by 32 patients (11.5%) on lacosamide and 22 (8.2%) on carbamazepine-CR; 12 (4.3%) and 21 (7.8%) discontinued due to TEAEs. In the combined trials (median exposure: lacosamide 630 days; carbamazepine-CR 589 days), Kaplan-Meier estimated proportions of patients with 12- and 24-month seizure freedom from first dose were 50.8% (95% confidence interval 46.2%-55.4%) and 47.0% (42.2%-51.7%) on lacosamide, and 54.9% (50.3%-59.6%) and 50.9% (46.0%-55.7%) on carbamazepine-CR. Incidences of drug-related TEAEs and discontinuations due to TEAEs increased by number of comorbid conditions and were lower in patients on lacosamide. SIGNIFICANCE: Long-term (median ~2 years) lacosamide monotherapy was efficacious and generally well tolerated in adults with newly diagnosed epilepsy. Seizure freedom rates were similar with lacosamide and carbamazepine-CR.


Assuntos
Anticonvulsivantes/administração & dosagem , Carbamazepina/administração & dosagem , Epilepsia/diagnóstico , Epilepsia/tratamento farmacológico , Lacosamida/administração & dosagem , Adulto , Anticonvulsivantes/efeitos adversos , Carbamazepina/efeitos adversos , Preparações de Ação Retardada , Tontura/induzido quimicamente , Tontura/diagnóstico , Método Duplo-Cego , Feminino , Cefaleia/induzido quimicamente , Cefaleia/diagnóstico , Humanos , Lacosamida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
2.
JAMA ; 322(19): 1887-1898, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31742631

RESUMO

Importance: Ubrogepant is an oral calcitonin gene-related peptide receptor antagonist under investigation for acute treatment of migraine. Objective: To evaluate the efficacy and tolerability of ubrogepant compared with placebo for acute treatment of a single migraine attack. Design, Setting, and Participants: Phase 3, multicenter, randomized, double-blind, placebo-controlled, single-attack, clinical trial (ACHIEVE II) conducted in the United States (99 primary care and research clinics; August 26, 2016-February 26, 2018). Participants were adults with migraine with or without aura experiencing 2 to 8 migraine attacks per month. Interventions: Ubrogepant 50 mg (n = 562), ubrogepant 25 mg (n = 561), or placebo (n = 563) for a migraine attack of moderate or severe pain intensity. Main Outcomes and Measures: Co-primary efficacy outcomes were pain freedom and absence of the participant-designated most bothersome migraine-associated symptom (among photophobia, phonophobia, and nausea) at 2 hours after taking the medication. Results: Among 1686 randomized participants, 1465 received study treatment (safety population; mean age, 41.5 years; 90% female); 1355 of 1465 (92.5%) were evaluable for efficacy. Pain freedom at 2 hours was reported by 101 of 464 participants (21.8%) in the ubrogepant 50-mg group, 90 of 435 (20.7%) in the ubrogepant 25-mg group, and 65 of 456 (14.3%) in the placebo group (absolute difference for 50 mg vs placebo, 7.5%; 95% CI, 2.6%-12.5%; P = .01; 25 mg vs placebo, 6.4%; 95% CI, 1.5%-11.5%; P = .03). Absence of the most bothersome associated symptom at 2 hours was reported by 180 of 463 participants (38.9%) in the ubrogepant 50-mg group, 148 of 434 (34.1%) in the ubrogepant 25-mg group, and 125 of 456 (27.4%) in the placebo group (absolute difference for 50 mg vs placebo, 11.5%; 95% CI, 5.4%-17.5%; P = .01; 25 mg vs placebo, 6.7%; 95% CI, 0.6%-12.7%; P = .07). The most common adverse events within 48 hours of any dose were nausea (50 mg, 10 of 488 [2.0%]; 25 mg, 12 of 478 [2.5%]; and placebo, 10 of 499 [2.0%]) and dizziness (50 mg, 7 of 488 [1.4%]; 25 mg, 10 of 478 [2.1%]; placebo, 8 of 499 [1.6%]). Conclusions and Relevance: Among adults with migraine, acute treatment with ubrogepant compared with placebo led to significantly greater rates of pain freedom at 2 hours with 50-mg and 25-mg doses, and absence of the most bothersome migraine-associated symptom at 2 hours only with the 50-mg dose. Further research is needed to assess the effectiveness of ubrogepant against other acute treatments for migraine and to evaluate the long-term safety of ubrogepant among unselected patient populations. Trial Registration: ClinicalTrials.gov Identifier: NCT02867709.


Assuntos
Analgésicos/administração & dosagem , Transtornos de Enxaqueca/tratamento farmacológico , Dor/tratamento farmacológico , Piridinas/administração & dosagem , Pirróis/administração & dosagem , Adulto , Idoso , Analgésicos/efeitos adversos , Tontura/induzido quimicamente , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Manejo da Dor , Piridinas/efeitos adversos , Pirróis/efeitos adversos , Adulto Jovem
3.
Pediatrics ; 144(6)2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31740500

RESUMO

BACKGROUND: The 9-valent human papillomavirus vaccine (9vHPV) was approved for females and males aged 9 to 26 years in 2014. We analyzed postlicensure surveillance reports to the Vaccine Adverse Event Reporting System (VAERS). METHODS: We searched VAERS data for US reports of adverse events (AEs) after 9vHPV from December 2014 through December 2017. We calculated reporting rates and conducted empirical Bayesian data mining to identify disproportional reporting. Physicians reviewed reports for selected prespecified conditions. RESULTS: VAERS received 7244 reports after 9vHPV: 31.2% among females, 21.6% among males, and for 47.2%, sex was not reported. Overall, 97.4% of reports were nonserious. Dizziness, syncope, headache, and injection site reactions were most commonly reported; the most commonly reported AEs were similar between females and males. Two reports of death after 9vHPV were verified; no information in autopsy reports or death certificates suggested a causal relationship with vaccination. Approximately 28 million 9vHPV doses were distributed during the study period; crude AE reporting rates were 259 reports per million 9vHPV doses distributed for all reports and 7 per million doses distributed for serious reports. Syncope (a known AE associated with human papillomavirus vaccination) and several types of vaccine administration errors (eg, administered at wrong age) exceeded the statistical threshold for empirical Bayesian data mining findings. CONCLUSIONS: No new or unexpected safety concerns or reporting patterns of 9vHPV with clinically important AEs were detected. The safety profile of 9vHPV is consistent with data from prelicensure trials and from postmarketing safety data of its predecessor, the quadrivalent human papillomavirus vaccine.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos/tendências , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/administração & dosagem , Vacinas contra Papillomavirus/efeitos adversos , Adolescente , Adulto , Criança , Bases de Dados Factuais/tendências , Tontura/induzido quimicamente , Tontura/epidemiologia , Feminino , Cefaleia/induzido quimicamente , Cefaleia/epidemiologia , Humanos , Masculino , Estados Unidos/epidemiologia , Adulto Jovem
4.
N Engl J Med ; 381(10): 903-911, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31483961

RESUMO

BACKGROUND: Altered neurotransmission of γ-aminobutyric acid (GABA) has been implicated in the pathogenesis of depression. Whether SAGE-217, an oral, positive allosteric modulator of GABA type A receptors, is effective and safe for the treatment of major depressive disorder is unknown. METHODS: In this double-blind, phase 2 trial, we enrolled patients with major depression and randomly assigned them in a 1:1 ratio to receive 30 mg of SAGE-217 or placebo once daily. The primary end point was the change from baseline to day 15 in the score on the 17-item Hamilton Depression Rating Scale (HAM-D; scores range from 0 to 52, with higher scores indicating more severe depression). Secondary efficacy end points, which were assessed on days 2 through 8 and on days 15, 21, 28, 35, and 42, included changes from baseline in scores on additional depression and anxiety scales, a reduction from baseline of more than 50% in the HAM-D score, a HAM-D score of 7 or lower, and a Clinical Global Impression of Improvement score of 1 (very much improved) or 2 (much improved) (on a scale of 1 to 7, with a score of 7 indicating that symptoms are very much worse). RESULTS: A total of 89 patients underwent randomization: 45 patients were assigned to the SAGE-217 group, and 44 to the placebo group. The mean baseline HAM-D score was 25.2 in the SAGE-217 group and 25.7 in the placebo group. The least-squares mean (±SE) change in the HAM-D score from baseline to day 15 was -17.4±1.3 points in the SAGE-217 group and -10.3±1.3 points in the placebo group (least-squares mean difference in change, -7.0 points; 95% confidence interval, -10.2 to -3.9; P<0.001). The differences in secondary end points were generally in the same direction as those of the primary end point. There were no serious adverse events. The most common adverse events in the SAGE-217 group were headache, dizziness, nausea, and somnolence. CONCLUSIONS: Administration of SAGE-217 daily for 14 days resulted in a reduction in depressive symptoms at day 15. Adverse events were more common in the SAGE-217 group than in the placebo group. Further trials are needed to determine the durability and safety of SAGE-217 in major depressive disorder and to compare SAGE-217 with available treatments. (Funded by Sage Therapeutics; ClinicalTrials.gov number, NCT03000530.).


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Moduladores GABAérgicos/uso terapêutico , Pregnanos/uso terapêutico , Pirazóis/uso terapêutico , Receptores de GABA-A/metabolismo , Administração Oral , Adulto , Regulação Alostérica , Antidepressivos/efeitos adversos , Transtorno Depressivo Maior/classificação , Tontura/induzido quimicamente , Método Duplo-Cego , Feminino , Moduladores GABAérgicos/efeitos adversos , Humanos , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Pregnanos/efeitos adversos , Escalas de Graduação Psiquiátrica , Pirazóis/efeitos adversos
5.
Codas ; 31(3): e20180111, 2019 Jun 27.
Artigo em Português, Inglês | MEDLINE | ID: mdl-31271579

RESUMO

PURPOSE: to analyze the occurrence of psychiatric diagnosis and the use of psychotropics medications in subjects with vestibular complaints and to relate the presence of these conditions to the results of vestibulometry. METHODS: quantitative, observational, cross-sectional study with 131 patients, treated in a university hospital. They were submitted to anamnesis, visual inspection of the external ear canal, static and dynamic balance tests, Foam laser dynamic posturography and Computerized Vectoelectronystagmography. RESULTS: sample composed of 109 women and 22 men, with average age of 55 years and nine months. The most common type of dizziness was vertigo, with the presence of neurovegetative signals. A significant percentage of psychiatric complaint/diagnosis was observed, as well as the use of psychotropic medications, mainly serotonin uptake inhibitors, followed by benzodiazepines. There was a relation between the presence of psychiatric complaints with the female gender, alterations of the static balance and alterations in the Sensorial Organization Test positions III and VI. In the Vectoelectronystagmography, there was a relation between age and the presence of spontaneous nystagmus. CONCLUSION: There was a high occurrence of psychiatric complaint/diagnosis among patients with dizziness, with use of psychotropic medications substantially greater than the general population. The evaluation of postural balance revealed an association between anxiety/depression and alterations visual overload positions in the foam laser dynamic posturography. However, no relationship was found between these conditions and alterations in the Vectoelectronystagmography tests.


Assuntos
Tontura/induzido quimicamente , Transtornos do Humor/tratamento farmacológico , Equilíbrio Postural/efeitos dos fármacos , Psicotrópicos/efeitos adversos , Vertigem/induzido quimicamente , Testes de Função Vestibular/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/complicações , Psicotrópicos/classificação , Estudos Retrospectivos , Adulto Jovem
6.
Am J Psychiatry ; 176(6): 457-467, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30845818

RESUMO

OBJECTIVE: Preclinical evidence and data from a proof-of-concept study in healthy volunteers suggest that samidorphan, an opioid antagonist, mitigates weight gain associated with olanzapine. This study prospectively compared combination therapy of olanzapine plus either samidorphan or placebo for the treatment of schizophrenia. METHODS: This was an international, multicenter, randomized phase 2 study of olanzapine plus samidorphan in patients with schizophrenia. The study had a 1-week open-label olanzapine lead-in period followed by a 12-week double-blind treatment phase in which patients were randomly assigned in a 1:1:1:1 ratio to receive olanzapine plus placebo (N=75) or olanzapine plus 5 mg (N=80), 10 mg (N=86), or 20 mg (N=68) of samidorphan. The primary aims were to confirm that the antipsychotic efficacy of olanzapine plus samidorphan was comparable to olanzapine plus placebo, to assess the effect of combining olanzapine with samidorphan on olanzapine-induced weight gain, and to assess the overall safety and tolerability of olanzapine plus samidorphan. RESULTS: Antipsychotic efficacy, as assessed by total score on the Positive and Negative Syndrome Scale (PANSS), was equivalent across all treatment groups. Treatment with olanzapine plus samidorphan resulted in a statistically significant lower weight gain (37% lower weight gain compared with olanzapine plus placebo). The least square mean percent change from baseline in body weight was 4.1% (2.9 kg) for the olanzapine plus placebo group and 2.6% (1.9 kg) for the olanzapine plus samidorphan group (2.8% [2.1 kg] for the 5 mg group, 2.1% [1.5 kg] for the 10 mg group, and 2.9% [2.2 kg] for the 20 mg group). Adverse events reported at a frequency ≥5% in any of the olanzapine plus samidorphan groups and occurring at a rate ≥2 times greater than in the olanzapine plus placebo group were somnolence, sedation, dizziness, and constipation. Other safety measures were comparable between the olanzapine plus samidorphan groups and the olanzapine plus placebo group. CONCLUSIONS: The antipsychotic efficacy of olanzapine plus samidorphan was equivalent to that of olanzapine plus placebo, and olanzapine plus samidorphan was associated with clinically meaningful and statistically significant mitigation of weight gain compared with olanzapine plus placebo. Olanzapine plus samidorphan was generally well tolerated, with a safety profile similar to olanzapine plus placebo.


Assuntos
Antipsicóticos/uso terapêutico , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/uso terapêutico , Olanzapina/uso terapêutico , Esquizofrenia/tratamento farmacológico , Ganho de Peso , Adulto , Constipação Intestinal/induzido quimicamente , Tontura/induzido quimicamente , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Naltrexona/uso terapêutico , Sonolência
7.
Cochrane Database Syst Rev ; 1: CD007076, 2019 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-30673120

RESUMO

BACKGROUND: This review updates part of an earlier Cochrane Review titled "Pregabalin for acute and chronic pain in adults", and considers only neuropathic pain (pain from damage to nervous tissue). Antiepileptic drugs have long been used in pain management. Pregabalin is an antiepileptic drug used in management of chronic pain conditions. OBJECTIVES: To assess the analgesic efficacy and adverse effects of pregabalin for chronic neuropathic pain in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, and Embase for randomised controlled trials from January 2009 to April 2018, online clinical trials registries, and reference lists. SELECTION CRITERIA: We included randomised, double-blind trials of two weeks' duration or longer, comparing pregabalin (any route of administration) with placebo or another active treatment for neuropathic pain, with participant-reported pain assessment. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality and biases. Primary outcomes were: at least 30% pain intensity reduction over baseline; much or very much improved on the Patient Global Impression of Change (PGIC) Scale (moderate benefit); at least 50% pain intensity reduction; or very much improved on PGIC (substantial benefit). We calculated risk ratio (RR) and number needed to treat for an additional beneficial (NNTB) or harmful outcome (NNTH). We assessed the quality of the evidence using GRADE. MAIN RESULTS: We included 45 studies lasting 2 to 16 weeks, with 11,906 participants - 68% from 31 new studies. Oral pregabalin doses of 150 mg, 300 mg, and 600 mg daily were compared with placebo. Postherpetic neuralgia, painful diabetic neuropathy, and mixed neuropathic pain predominated (85% of participants). High risk of bias was due mainly to small study size (nine studies), but many studies had unclear risk of bias, mainly due to incomplete outcome data, size, and allocation concealment.Postherpetic neuralgia: More participants had at least 30% pain intensity reduction with pregabalin 300 mg than with placebo (50% vs 25%; RR 2.1 (95% confidence interval (CI) 1.6 to 2.6); NNTB 3.9 (3.0 to 5.6); 3 studies, 589 participants, moderate-quality evidence), and more had at least 50% pain intensity reduction (32% vs 13%; RR 2.5 (95% CI 1.9 to 3.4); NNTB 5.3 (3.9 to 8.1); 4 studies, 713 participants, moderate-quality evidence). More participants had at least 30% pain intensity reduction with pregabalin 600 mg than with placebo (62% vs 24%; RR 2.5 (95% CI 2.0 to 3.2); NNTB 2.7 (2.2 to 3.7); 3 studies, 537 participants, moderate-quality evidence), and more had at least 50% pain intensity reduction (41% vs 15%; RR 2.7 (95% CI 2.0 to 3.5); NNTB 3.9 (3.1 to 5.5); 4 studies, 732 participants, moderate-quality evidence). Somnolence and dizziness were more common with pregabalin than with placebo (moderate-quality evidence): somnolence 300 mg 16% versus 5.5%, 600 mg 25% versus 5.8%; dizziness 300 mg 29% versus 8.1%, 600 mg 35% versus 8.8%.Painful diabetic neuropathy: More participants had at least 30% pain intensity reduction with pregabalin 300 mg than with placebo (47% vs 42%; RR 1.1 (95% CI 1.01 to 1.2); NNTB 22 (12 to 200); 8 studies, 2320 participants, moderate-quality evidence), more had at least 50% pain intensity reduction (31% vs 24%; RR 1.3 (95% CI 1.2 to 1.5); NNTB 22 (12 to 200); 11 studies, 2931 participants, moderate-quality evidence), and more had PGIC much or very much improved (51% vs 30%; RR 1.8 (95% CI 1.5 to 2.0); NNTB 4.9 (3.8 to 6.9); 5 studies, 1050 participants, moderate-quality evidence). More participants had at least 30% pain intensity reduction with pregabalin 600 mg than with placebo (63% vs 52%; RR 1.2 (95% CI 1.04 to 1.4); NNTB 9.6 (5.5 to 41); 2 studies, 611 participants, low-quality evidence), and more had at least 50% pain intensity reduction (41% vs 28%; RR 1.4 (95% CI 1.2 to 1.7); NNTB 7.8 (5.4 to 14); 5 studies, 1015 participants, low-quality evidence). Somnolence and dizziness were more common with pregabalin than with placebo (moderate-quality evidence): somnolence 300 mg 11% versus 3.1%, 600 mg 15% versus 4.5%; dizziness 300 mg 13% versus 3.8%, 600 mg 22% versus 4.4%.Mixed or unclassified post-traumatic neuropathic pain: More participants had at least 30% pain intensity reduction with pregabalin 600 mg than with placebo (48% vs 36%; RR 1.2 (1.1 to 1.4); NNTB 8.2 (5.7 to 15); 4 studies, 1367 participants, low-quality evidence), and more had at least 50% pain intensity reduction (34% vs 20%; RR 1.5 (1.2 to 1.9); NNTB 7.2 (5.4 to 11); 4 studies, 1367 participants, moderate-quality evidence). Somnolence (12% vs 3.9%) and dizziness (23% vs 6.2%) were more common with pregabalin.Central neuropathic pain: More participants had at least 30% pain intensity reduction with pregabalin 600 mg than with placebo (44% vs 28%; RR 1.6 (1.3 to 2.0); NNTB 5.9 (4.1 to 11); 3 studies, 562 participants, low-quality evidence) and at least 50% pain intensity reduction (26% vs 15%; RR 1.7 (1.2 to 2.3); NNTB 9.8 (6.0 to 28); 3 studies, 562 participants, low-quality evidence). Somnolence (32% vs 11%) and dizziness (23% vs 8.6%) were more common with pregabalin.Other neuropathic pain conditions: Studies show no evidence of benefit for 600 mg pregabalin in HIV neuropathy (2 studies, 674 participants, moderate-quality evidence) and limited evidence of benefit in neuropathic back pain or sciatica, neuropathic cancer pain, or polyneuropathy.Serious adverse events, all conditions: Serious adverse events were no more common with placebo than with pregabalin 300 mg (3.1% vs 2.6%; RR 1.2 (95% CI 0.8 to 1.7); 17 studies, 4112 participants, high-quality evidence) or pregabalin 600 mg (3.4% vs 3.4%; RR 1.1 (95% CI 0.8 to 1.5); 16 studies, 3995 participants, high-quality evidence). AUTHORS' CONCLUSIONS: Evidence shows efficacy of pregabalin in postherpetic neuralgia, painful diabetic neuralgia, and mixed or unclassified post-traumatic neuropathic pain, and absence of efficacy in HIV neuropathy; evidence of efficacy in central neuropathic pain is inadequate. Some people will derive substantial benefit with pregabalin; more will have moderate benefit, but many will have no benefit or will discontinue treatment. There were no substantial changes since the 2009 review.


Assuntos
Analgésicos/uso terapêutico , Neuropatias Diabéticas/tratamento farmacológico , Neuralgia Pós-Herpética/tratamento farmacológico , Neuralgia/tratamento farmacológico , Dor/tratamento farmacológico , Pregabalina/uso terapêutico , Doença Aguda , Adulto , Analgésicos/administração & dosagem , Analgésicos/efeitos adversos , Doença Crônica , Tontura/induzido quimicamente , Humanos , Pregabalina/administração & dosagem , Pregabalina/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Sonolência
8.
J Clin Pharm Ther ; 44(2): 285-291, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30569470

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Pregabalin is used for neuropathic and postherpetic pain and generalized anxiety. The aim of this study was to obtain the onset profiles of adverse events (AE) related to falls (AEFs) such as "somnolence," "dizziness," "loss of consciousness" and "fall" onset and several clinical factor combinations such as age and administered dose, using spontaneous reporting system (SRS) analysis such as the US Food and Drug Administration Adverse Event Reporting System (FAERS) database and the Japanese Adverse Drug Event Report (JADER) database. METHODS: We used the reporting odds ratio (ROR) to analyse the association between pregabalin and AEFs. Additionally, we used the time-to-onset analysis. RESULTS AND DISCUSSION: The crude RORs of AEFs such as somnolence and dizziness were higher than one for both the databases. The adjusted RORs for AEFs in the ≥60 years age group compared to those in the <60 years age group for the FAERS and JADER databases were 1.46 (95% CI = 1.39-1.53; P < 0.0001) and 2.58 (95% CI = 2.06-3.27; P < 0.0001), respectively. In the JADER database, the median and quartile range for AEFs with pregabalin, at ≤75 and ≥100 mg/d, were 2.0 (0.0-5.0) and 2.0 (1.0-4.3) days, respectively. Additionally, 57.2% of AEFs (four preferred terms) were observed within 2 days after administration. WHAT IS NEW AND CONCLUSIONS: This study is the first to evaluate the relationship between pregabalin and AEFs using the SRS analysis strategy. The risk of AEFs in the ≥60 years age group might increase compared to that in the <60 years age group. AEFs occurred almost within 1 week after pregabalin administration, and the median for AEF onset was 2 days. Our results show that patients should be closely monitored for AEFs for 1 week from the start of pregabalin administration.


Assuntos
Acidentes por Quedas/estatística & dados numéricos , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Analgésicos/efeitos adversos , Pregabalina/efeitos adversos , Distribuição por Idade , Bases de Dados Factuais , Tontura/induzido quimicamente , Tontura/epidemiologia , Humanos , Japão , Pessoa de Meia-Idade , Fatores de Tempo , Estados Unidos , United States Food and Drug Administration
9.
Br J Clin Pharmacol ; 85(3): 634-643, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30569481

RESUMO

AIMS: Human papilloma virus (HPV) is the cause of different types of carcinoma. Despite the remarkable effectiveness of the HPV vaccines, there have been many complaints about their risk-benefit profile due to adverse events following immunization (AEFI). The purpose of this study is to analyse the safety profile of the HPV vaccine basing on real-life data derived from reports of suspected AEFIs collected in the US Vaccine Adverse Events Reporting System (VAERS) and assess if the searches on Google overlap with spontaneous reporting. METHODS: We collected all the reports in VAERS between January 2007 to December 2017 related to the HPV vaccines. A disproportionality analysis using reporting odds ratio (ROR) with 95% confidence interval was performed. RESULTS: Over the 10-year period, 55 356 reports of AEFI related to HPV vaccines were retrieved in VAERS, corresponding to 224 863 vaccine-event pairs. The highest number of reports was related to Gardasil (n = 42 244). The two events more frequently reported and statistically significant for HPV vaccines were dizziness (n = 6259; ROR = 2.60; 95% confidence interval 2.53-2.66) and syncope (n = 6004; ROR = 6.28; 95% confidence interval 6.12-6.44). The trends of spontaneous reporting and Google searches overlap. CONCLUSION: The AEFI analysis showed that the events most frequently reported were non-serious and listed in the corresponding summary of product characteristics. Potential safety signals arose regarding less frequent AEFIs that would deserve further investigation. It is extremely important to disseminate correct and evidence-based scientific information.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Tontura/epidemiologia , Vacinas contra Papillomavirus/efeitos adversos , Síncope/epidemiologia , Vacinação/efeitos adversos , Adolescente , Adulto , Criança , Pré-Escolar , Mineração de Dados , Tontura/induzido quimicamente , Feminino , Humanos , Lactente , Internet/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/administração & dosagem , Autorrelato/estatística & dados numéricos , Síncope/induzido quimicamente , Estados Unidos/epidemiologia , Neoplasias do Colo do Útero/prevenção & controle , Vacinação/estatística & dados numéricos , Adulto Jovem
10.
Acta Neurol Scand ; 139(1): 49-63, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30176048

RESUMO

OBJECTIVES: To assess the effectiveness and safety/tolerability of eslicarbazepine acetate (ESL) monotherapy in clinical practice in Europe. MATERIALS AND METHODS: Euro-Esli was a pooled analysis of 14 European clinical practice studies. Responder rate (≥50% seizure frequency reduction) and seizure freedom rate (seizure freedom at least since prior visit) were assessed after 3, 6 and 12 months of ESL treatment and at last visit. Adverse events (AEs) and AEs leading to ESL discontinuation were assessed throughout follow-up. A subanalysis was conducted to assess outcomes for patients treated initially with ESL monotherapy and for patients treated at the last visit with ESL monotherapy. RESULTS: ESL was used as monotherapy in 88/2045 (4.3%) patients initially and in 229/1340 (17.1%) patients at the last visit. At 12 months, responder and seizure freedom rates were 94.1% and 88.2%, respectively, in patients treated initially with ESL monotherapy, and 93.2% and 77.4%, respectively, in patients treated at the last visit with ESL monotherapy. Corresponding values for patients treated initially with ESL adjunctive therapy were 74.8% and 39.0%, respectively; and for patients treated at the last visit with ESL adjunctive therapy, corresponding values were 70.4% and 25.9%, respectively. Safety and tolerability were generally comparable in patients treated with ESL as monotherapy or adjunctive therapy. The most commonly reported AEs (≥5% of patients in any group) were dizziness, somnolence, instability/ataxia, and fatigue. CONCLUSIONS: These clinical practice data support the use of ESL as monotherapy, as well as adjunctive therapy, for focal-onset seizures, complementing evidence from clinical trials.


Assuntos
Anticonvulsivantes/uso terapêutico , Dibenzazepinas/uso terapêutico , Convulsões/tratamento farmacológico , Adulto , Ataxia/induzido quimicamente , Tontura/induzido quimicamente , Europa (Continente) , Fadiga/induzido quimicamente , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sonolência , Vertigem/induzido quimicamente
11.
Cochrane Database Syst Rev ; 12: CD012346, 2018 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-30566235

RESUMO

BACKGROUND: Studies report that up to 80% of individuals with chronic obstructive pulmonary disease (COPD) may struggle with symptoms of depression. However, this major comorbidity in COPD is rarely managed effectively. A number of recent studies indicate that left untreated, COPD-related depression is associated with worse quality of life, worse compliance with COPD treatment plan, increased exacerbations, hospital admissions, and healthcare costs when compared to individuals with COPD without depression. Regrettably, COPD practice guidelines do not provide conclusive treatment recommendations for the use of antidepressants in patients with COPD, and base their guidelines on findings from trials in the general population. This may be problematic, as there is an elevated risk of respiratory issues associated with antidepressant treatment and COPD. Evaluating effectiveness and safety of pharmacological interventions specifically for patients with COPD and depression was therefore paramount. OBJECTIVES: To assess the effectiveness and safety of pharmacological interventions for the treatment of depression in patients with COPD. SEARCH METHODS: The last search was performed on 26 November 2018. We initially searched the following databases via the Specialised Trials Registers of the Cochrane Airways and Common Mental Disorders Groups (to June 2016): MEDLINE, Embase, PsycINFO, CINAHL, AMED, and the Cochrane Library trials register (CENTRAL). Searches from June 2016 to November 2018 were performed directly on Ovid MEDLINE, Embase, PsycINFO and the Cochrane Library (Issue 11, 2018). We searched ClinicalTrials.gov, the ISRCTN registry, and the World Health Organization International Clinical Trials Registry Platform to 26 November 2018. We searched the grey literature databases to identify studies not indexed in major databases and the reference lists of studies initially identified for full-text screening. SELECTION CRITERIA: All published and unpublished randomised controlled trials (RCTs) comparing the efficacy of pharmacological interventions with no intervention, placebo or co-intervention in adults with diagnosed COPD and depression were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed articles identified by the search for eligibility. Our primary outcomes were change in depressive symptoms and adverse events. The secondary outcomes were: change in quality of life, change in dyspnoea, change in forced expiratory volume in one second (FEV1), change in exercise tolerance, change in hospital utilisation (length of stay and readmission rates), and cost-effectiveness. For continuous outcomes, we calculated the pooled mean difference (MD) or standardised mean difference (SMD) with 95% confidence interval (CI) as appropriate. For dichotomous outcomes, we calculated the pooled odds ratio (OR) and corresponding 95% CI using a random-effects model. We assessed the quality of evidence using the GRADE framework. MAIN RESULTS: Of the 1125 records screened for eligibility, four RCTs (N = 201 participants), and one on-going study, met the inclusion criteria. Two classes of antidepressants were investigated in two separate comparisons with placebo: a tricyclic antidepressant (TCA) and selective serotonin reuptake inhibitors (SSRIs).TCA versus placeboOnly one RCT (N = 30 participants) provided results for this comparison.Primary outcomesThe TCA (nortriptyline) reduced depressive symptoms post-treatment compared to placebo (MD -10.20, 95% CI -16.75 to -3.65; P = 0.007; very low-quality evidence), as measured by the Hamilton Depression Rating Scale (HAM-D). Three participants withdrew from the trial due to adverse events related to the tested antidepressant (dry mouth, sedation, orthostatic hypotension).Secondary outcomesThe overall results post-treatment indicated that nortriptyline was not effective in improving the quality of life of individuals with COPD, as measured by the Sickness Impact Profile (MD -2.80, 95% CI -11.02 to 5.42; P = 0.50; very low-quality evidence).The results for the change in dyspnoea for the domains examined (e.g. dyspnoea scores for 'most day-to-day activities') post-treatment showed no improvement in the intervention group (MD 9.80, 95% CI -6.20 to 25.80; P = 0.23; very low-quality evidence).No data were reported for change in FEV1, change in exercise tolerance, change in hospital utilisation, or cost-effectiveness. The TCA study provided short-term results, with the last follow-up data collection at 12 weeks.The quality of the evidence for all the outcomes evaluated was very low due to a small sample size, imprecision, attrition, and selection and reporting bias.SSRIs versus placeboThree RCTs (N = 171 participants) provided results for this comparison.Primary outcomesThe pooled results for two studies showed no difference for the change in depressive symptoms post-intervention (SMD 0.75, 95% CI -1.14 to 2.64; 148 participants; 2 studies; P = 0.44; very low-quality evidence). High heterogeneity was observed (I² = 95%), limiting the reliability of these findings.While it was not possible to meta-analyse the total adverse events rates across the studies, it was possible to combine the results for two medication-specific adverse effects: nausea and dizziness. There were no significant post-treatment group differences for nausea (OR 2.32, 95% CI 0.66 to 8.12; 171 participants; 3 studies; P = 0.19; very low-quality evidence) or dizziness (OR 0.61, 95% CI 0.09 to 4.06; 143 participants; 2 studies; P = 0.61; very low-quality evidence).Secondary outcomesThe pooled analysis of two trials reporting data for the change in quality of life did not show improvement post-treatment in the intervention group compared to placebo (SMD 1.17, 95% CI -0.80 to 3.15; 148 participants; 2 studies; P = 0.25; very low-quality evidence).There was no difference between groups in change in FEV1 post-treatment (MD 0.01, 95% CI -0.03 to 0.05; 148 participants; 2 studies; P = 0.60; low-quality evidence). However, two trials reported improvement in exercise tolerance in the SSRI group versus the placebo group (MD 13.88, 95% CI 11.73 to 16.03; 148 participants; 2 studies; P < 0.001; very low-quality evidence).The trials included in this comparison did not report data related to the change in dyspnoea, hospital utilisation rates, or cost-effectiveness. AUTHORS' CONCLUSIONS: There is insufficient evidence to make definitive statements about the efficacy or safety of antidepressants for treating COPD-related depression. New RCTs are needed; with better methodological quality and more accurate reporting of the methods used. Moreover, longer-term follow-up data collection is needed, including outcomes such as adverse events, hospital utilisation and cost-effectiveness.


Assuntos
Antidepressivos Tricíclicos/uso terapêutico , Depressão/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/psicologia , Inibidores de Captação de Serotonina/uso terapêutico , Antidepressivos Tricíclicos/efeitos adversos , Depressão/etiologia , Tontura/induzido quimicamente , Dispneia/tratamento farmacológico , Tolerância ao Exercício/efeitos dos fármacos , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Náusea/induzido quimicamente , Nortriptilina/efeitos adversos , Nortriptilina/uso terapêutico , Paroxetina/efeitos adversos , Paroxetina/uso terapêutico , Placebos/uso terapêutico , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores de Captação de Serotonina/efeitos adversos , Sertralina/efeitos adversos , Sertralina/uso terapêutico
12.
BMC Geriatr ; 18(1): 293, 2018 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-30486785

RESUMO

BACKGROUND: Risk factors associated with opioid-induced adverse reactions (OIARs) in the elderly population have not been well defined. The objective of this study was to determine effects of various risk factors on incidence of OIARs in male elderly patients. METHODS: A retrospective cohort study in Korea Veterans Hospital was performed. Data were analyzed in male patients aged 65 years and older who received morphine, oxycodone, or codeine. Binomial variables describing patient-related and drug-related characteristics were constructed. Associations between these variables and frequency of OIARs were determined. Odds ratio (OR) and adjusted odds ratio (AOR) were calculated from univariate and multivariable analyses, respectively. Attributable risk was obtained by (1-1/OR)*100%. RESULTS: Of 316 patients, 28% experienced at least one adverse event. The most common adverse events were gastrointestinal problems (n = 59) and central nerve system adverse effects (n = 20). The odds of OIARs in patients with opioid use ≥12 weeks was increased by 80% compared to those with opioid use < 12 weeks. Attributable risk of GABA analogues was 64~78% in constructed Models. Compared to codeine users, patients using morphine and oxycodone had 653 and 473% increased odds for OIARs, respectively. MME ≥ 60 mg/day had a 317% increased odds for OIARs (95% CI: 1.92-9.04) compared to MME < 60 mg/day. Opioid combination therapy had a 139% increased odds for OIARs compared to monotherapy. CONCLUSIONS: These findings have significant implications for clinical use of opioid in elderly patients. Our study suggests that low dose short-term use will pose less risk of OIARs for the elderly, whereas concomitant use of GABA analogues, strong opioids and dual-opioid therapy may increase the risk of OIARs. Therefore, clinician should carefully monitor patients when starting opioid therapy in older population.


Assuntos
Analgésicos Opioides/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Hospitais de Veteranos/tendências , Ambulatório Hospitalar/tendências , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Tontura/induzido quimicamente , Tontura/diagnóstico , Tontura/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/diagnóstico , Gastroenteropatias/epidemiologia , Humanos , Masculino , Oxicodona/efeitos adversos , República da Coreia/epidemiologia , Estudos Retrospectivos , Fatores de Risco
13.
Artigo em Inglês | MEDLINE | ID: mdl-30224529

RESUMO

Chinfloxacin hydrochloride is a novel tricyclic fluorinated quinolone in development for treatment of conventional and biothreat infections. This first-in-human randomized study in Chinese healthy subjects was divided into 5 parts. Part A was a single-ascending-dose study to assess safety and tolerability of chinfloxacin. The single-dose pharmacokinetic study, a food effect study, and a multiple-dose pharmacokinetics study were conducted in parts B, C, and D, respectively. Part E was a randomized, placebo-controlled and positive-control single-dose, crossover study to evaluate the effect of chinfloxacin on thorough electrocardiographic QT/corrected QT (QTc) interval. The results suggest that single and multiple oral administrations of chinfloxacin were well tolerated. The observed adverse events (AEs) were dizziness, nausea, weakness, photosensitive dermatitis, and increased frequency of defecation. All AEs were mild and were resolved spontaneously without any treatment. The time to peak plasma concentration (T max and C max, respectively) was about 2 h, and the half-life was 14 to 16 h. Food slightly affected the drug's rate and extent of absorption, increasing the T max from 1.60 to 2.59 h and reducing the C max by 13.6% and area under the concentration-time curve by 8.95%. Chinfloxacin at 400 mg had no effect on prolongation of QT/QTc intervals. Although 600 mg chinfloxacin had a mild effect on the prolongation of the QT/QTc interval, the effect was less pronounced than that of the positive control, 400 mg moxifloxacin. The pharmacokinetics and safety profiles of chinfloxacin in healthy Chinese volunteers support its once-daily dosing in future clinical investigations. (This study has been registered at www.ChiCTR.org.cn under identifiers ChiCTR-TRC-10001619 for parts A to D and ChiCTR1800015906 for part E.).


Assuntos
Antibacterianos/farmacocinética , Fluoroquinolonas/farmacocinética , Coração/efeitos dos fármacos , Administração Oral , Adulto , Antibacterianos/efeitos adversos , Antibacterianos/sangue , Grupo com Ancestrais do Continente Asiático , Estudos Cross-Over , Dermatite/etiologia , Dermatite/fisiopatologia , Tontura/induzido quimicamente , Tontura/fisiopatologia , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Ingestão de Alimentos/fisiologia , Eletrocardiografia , Fadiga/induzido quimicamente , Fadiga/fisiopatologia , Feminino , Fluoroquinolonas/efeitos adversos , Fluoroquinolonas/sangue , Interações Alimento-Droga , Meia-Vida , Voluntários Saudáveis , Coração/fisiologia , Humanos , Masculino , Moxifloxacina/efeitos adversos , Moxifloxacina/sangue , Moxifloxacina/farmacocinética , Náusea/induzido quimicamente , Náusea/fisiopatologia , Segurança do Paciente
14.
Eur J Clin Pharmacol ; 74(12): 1615-1622, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30167757

RESUMO

PURPOSE: Buprenorphine has low oral bioavailability. Regardless of sublingual administration, a notable part of buprenorphine is exposed to extensive first-pass metabolism by the cytochrome P450 (CYP) 3A4. As drug interaction studies with buprenorphine are limited, we wanted to investigate the effect of voriconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics and pharmacodynamics of oral buprenorphine. METHODS: Twelve healthy volunteers were given either placebo or voriconazole (orally, 400 mg twice on day 1 and 200 mg twice on days 2-5) for 5 days in a randomized, cross-over study. On day 5, they ingested 0.2 mg (3.6 mg during placebo phase) oral buprenorphine. We measured plasma and urine concentrations of buprenorphine and norbuprenorphine and monitored their pharmacological effects. Pharmacokinetic parameters were normalized for a buprenorphine dose of 1.0 mg. RESULTS: Voriconazole greatly increased the mean area under the plasma concentration-time curve (AUC0-18) of buprenorphine (4.3-fold, P < 0.001), its peak concentration (Cmax) (3.9-fold), half-life (P < 0.05), and excretion into urine (Ae; P < 0.001). Voriconazole also markedly enhanced the Cmax (P < 0.001), AUC0-18 (P < 0.001), and Ae (P < 0.05) of unconjugated norbuprenorphine but decreased its renal clearance (P < 0.001). Mild dizziness and nausea occurred during both study phases. CONCLUSIONS: Voriconazole greatly increases exposure to oral buprenorphine, mainly by inhibiting intestinal and liver CYP3A4. Effect on some transporters may explain elevated norbuprenorphine concentrations. Although oral buprenorphine is not commonly used, this interaction may become relevant in patients receiving sublingual buprenorphine together with voriconazole or other CYP3A4 or transporter inhibitors.


Assuntos
Analgésicos Opioides/farmacocinética , Antifúngicos/farmacologia , Buprenorfina/farmacocinética , Voriconazol/farmacologia , Adolescente , Adulto , Analgésicos Opioides/efeitos adversos , Antifúngicos/efeitos adversos , Área Sob a Curva , Biotransformação , Buprenorfina/efeitos adversos , Buprenorfina/análogos & derivados , Buprenorfina/metabolismo , Estudos Cross-Over , Citocromo P-450 CYP3A/metabolismo , Tontura/induzido quimicamente , Interações Medicamentosas , Feminino , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Voriconazol/efeitos adversos , Adulto Jovem
15.
Pharmacol Res Perspect ; 6(5): e00418, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30151212

RESUMO

Three phase 1 pharmacokinetic (PK)/pharmacodynamics (PD) studies were conducted in healthy men and women to further characterize the safety, tolerability, and PK/PD of mirogabalin administration with or without food and to guide the dose selection and regimen for phase 2 and 3 clinical development. The 3 studies included 2 randomized, double-blind, placebo-controlled, single- and multiple-ascending-dose studies, and 1 open-label, crossover study to evaluate the PK of mirogabalin administered under fasting and fed (high-fat meal) conditions. Forty-eight and 47 healthy volunteers completed the single- and multiple-dose studies, respectively. Thirty subjects were enrolled and completed the food effect study. Mirogabalin was well tolerated in the fed and fasted states. The most frequent treatment-emergent adverse events (TEAEs)-dizziness and somnolence-were expected based on mirogabalin's mechanism of action. Subjects receiving the highest mirogabalin doses (50 and 75 mg single dose) showed greater dizziness and sedation and higher rates of TEAEs than subjects receiving 3-30 mg. After oral administration, mirogabalin was rapidly absorbed (time to maximum concentration, ∼1 hour) and eliminated through urine unchanged (61%-72% urinary excretion). Exposure increased in a dose-proportional manner after single or multiple mirogabalin doses. No significant accumulation occurred with multiple doses over 14 days. After single doses of mirogabalin (15 mg), the bioavailability was considered equivalent in the fed and fasted states, indicating that mirogabalin can be taken without food restrictions. Based on these data, mirogabalin 15 mg twice daily was selected as the highest target dose for further clinical development.


Assuntos
Analgésicos/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Neuralgia/tratamento farmacológico , Administração Oral , Adulto , Compostos Bicíclicos com Pontes/uso terapêutico , Canais de Cálcio/metabolismo , Estudos Cross-Over , Tontura/induzido quimicamente , Tontura/epidemiologia , Relação Dose-Resposta a Droga , Jejum , Feminino , Interações Alimento-Droga , Voluntários Saudáveis , Humanos , Masculino , Taxa de Depuração Metabólica , Sonolência , Adulto Jovem
17.
Epilepsy Behav ; 85: 188-194, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30032806

RESUMO

AIM: This study investigated the efficacy and safety of perampanel (PER) adjunctive therapy in pediatric patients with epilepsy whose seizures are pharmacoresistant to existing antiepileptic drugs. METHODS: A clinical retrospective study was conducted from 2016 to 2017 in the pediatric neurology clinic at a tertiary children's hospital. We reviewed the data obtained from 66 children whose seizures were pharmacoresistant to more than two antiepileptic drugs, and could be followed up for a minimum of 3 months after PER adjunctive therapy initiation. The efficacy was estimated by the PER response rate at 3-, 6-, and 12-month follow-up evaluations, and adverse events were also recorded. RESULTS: The rate of seizure reduction of >50% was 30.3%, 37.5%, and 34.7% for all seizure types at 3, 6, and 12 months, in which 7.6%, 8.9%, and 14.3% of the patients became seizure-free at these time points, respectively. No significant differences were found between enzyme-inducing and nonenzyme-inducing antiepileptic drugs in combination with PER with regard to the responder rate. Five patients with Dravet syndrome were included in the study. Four of them (80%) exhibited 50% seizure reduction at the last visit, at which point, two patients (40.0%) were seizure-free. The retention rate was 51% at 12 months. Adverse events were documented in 25 patients (35.7%) and led to PER discontinuation in eight patients (12.1%). The most common adverse events comprised irritability, skin rash, dizziness, and somnolence; however, all were transient and successfully managed after PER dose reduction or discontinuation. CONCLUSION: The current data support the value of adjunctive PER in child and adolescent patients with pharmacoresistant epilepsy in daily clinical practice. Perampanel was efficacious and generally well-tolerated as an add-on treatment for epilepsy.


Assuntos
Anticonvulsivantes/uso terapêutico , Grupo com Ancestrais do Continente Asiático , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia Resistente a Medicamentos/epidemiologia , Ambulatório Hospitalar/tendências , Piridonas/uso terapêutico , Adolescente , Instituições de Assistência Ambulatorial/tendências , Anticonvulsivantes/efeitos adversos , Criança , Tontura/induzido quimicamente , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Neurologia/métodos , Neurologia/tendências , Pediatria/métodos , Pediatria/tendências , Piridonas/efeitos adversos , Estudos Retrospectivos , Síndrome de Rett/diagnóstico , Síndrome de Rett/tratamento farmacológico , Síndrome de Rett/epidemiologia , Resultado do Tratamento
18.
Exp Clin Psychopharmacol ; 26(3): 320-326, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29863388

RESUMO

Adverse events in clinical drug trials are often poorly assessed and reported. The absence of baseline assessment and structured symptom lists, as well as the fact that most drug trials are industry-sponsored are common sources of bias. In addition, adverse events are usually assessed in patient samples, which can bias results because of the misattribution of symptoms that are part of the illness to medication intake. We aimed to identify amitriptyline's placebo- and baseline-controlled side effects by examining a sample of healthy adults, using structured assessments via a symptom list. Forty healthy individuals were randomized equally to either a group taking 50 mg amitriptyline on four consecutive days or to a placebo control group. Complaints were assessed via the Generic Assessment of Side Effects Scale prior to and after four days of medication intake. Frequency of complaints and their intensity were compared after medication intake between the two groups while controlling for complaints at baseline. The amitriptyline group's participants reported having suffered from "dry mouth," "dizziness," "subjective blood circulation-associated problems," and "constipation" significantly more often. When taking into account the complaint's intensity, the amitriptyline group also reported higher intensities for "dry mouth," "dizziness," and "subjective blood circulation-associated problems." Our results emphasize the importance of a structured and well-controlled harm assessment. Future drug trials should report the placebo- and baseline-controlled side effects with a clear causal relationship to the intake of the drug under investigation, in addition to the frequency of complaints and their odds ratios. (PsycINFO Database Record


Assuntos
Amitriptilina/efeitos adversos , Antidepressivos Tricíclicos/efeitos adversos , Tontura/induzido quimicamente , Xerostomia/induzido quimicamente , Adulto , Tontura/diagnóstico , Tontura/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Humanos , Masculino , Xerostomia/diagnóstico , Xerostomia/epidemiologia , Adulto Jovem
19.
Clin Transl Sci ; 11(5): 523-531, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29877614

RESUMO

Dizziness, the most frequently observed adverse event in patients with major depressive disorder, was observed with basimglurant, a selective, orally active metabotropic glutamate receptor subtype 5 negative allosteric modulator. The potential relationship between dizziness and basimglurant exposure was explored. The pharmacokinetics of basimglurant was characterized with nonlinear mixed effects modeling using data from 288 trial participants enrolled in five clinical trials. The pharmacokinetics of basimglurant after daily oral administration of a modified release formulation was best described by a two-compartment disposition model with a transit compartment, lag time for the absorption, and first-order elimination. The largest covariate effects were the effect of smoking and male gender on apparent clearance followed by the effect of body weight on distribution volumes. Clearance was twofold higher in smokers and 40% higher in males. A logistic regression model showed a statistically significant correlation between basimglurant Cmax and incidence of dizziness. An increased risk of dizziness is predicted with increasing doses.


Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Tontura/induzido quimicamente , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Modelos Biológicos , Piridinas/efeitos adversos , Piridinas/farmacocinética , Receptor de Glutamato Metabotrópico 5/metabolismo , Regulação Alostérica , Humanos , Imidazóis/uso terapêutico , Piridinas/uso terapêutico
20.
Pharmacoepidemiol Drug Saf ; 27(8): 912-920, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29896933

RESUMO

PURPOSE: To date, there is little information on the utilization of anticholinergic and sedative (AS) medications to vertigo or dizziness (VoD) patients in the German primary care setting. The objective of this study was to evaluate AS medication use and its association with VoD within the German primary care setting. METHODS: Cases with VoD from the CONTENT (CONTinuous morbidity registration Epidemiologic NeTwork) database were 1:1 matched to controls on age, sex, and comorbidities by propensity score matching. AS medication was defined using the fourth level of Anatomical Therapeutic Chemical Classification (ATC) Codes. A prescription of AS medication any time within the study period formed the primary exposure. Multivariable conditional logistic regression examined the association between AS use and VoD. RESULTS: Of a total of N = 151 446 patients, 6971 (4.6%) cases and 6971 corresponding controls were analyzed (mean age (sd): 59.9 years (20.9), 64.2% female). Dizziness and giddiness (ICD-10 Code R42) were diagnosed most prominently (87.2%). AS medication was prescribed on 1072 of 10 552 (10.2%) consultation days with VoD diagnoses. After adjusting for covariates, AS use was significantly and independently associated with VoD, adjusted odds ratio (1.37; 95% CI: 1.18-1.58), compared with no AS use. CONCLUSION: Primary care practitioners should consider AS medication as a risk factor for VoD and avoid prescribing AS medications after a VoD diagnosis. Caution should also be taken when prescribing AS medications to older adults (≥65 years). Systematical calculations of AS medication burden for patients could help acknowledge this issue and raise awareness for prescription habits in primary care.


Assuntos
Antagonistas Colinérgicos/efeitos adversos , Tontura/epidemiologia , Hipnóticos e Sedativos/efeitos adversos , Atenção Primária à Saúde/estatística & dados numéricos , Vertigem/epidemiologia , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Tontura/induzido quimicamente , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros/estatística & dados numéricos , Fatores de Risco , Vertigem/induzido quimicamente , Adulto Jovem
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