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1.
Forensic Sci Int ; 303: 109959, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31546164

RESUMO

The organ distribution of 3-fluorophenmetrazine (3-FPM), pyrazolam, diclazepam as well as its main metabolites delorazepam, lormetazepam and lorazepam, was investigated. A solid phase extraction (SPE) and a QuEChERS (acronym for quick, easy, cheap, effective, rugged and safe) - approach were used for the extraction of the analytes from human tissues, body fluids and stomach contents. The detection was performed on a liquid chromatography-tandem mass spectrometry system (LCMS/MS). The analytes of interest were detected in all body fluids and tissues. Results showed femoral blood concentrations of 10 µg/L for 3-FPM, 28 µg/L for pyrazolam, 1 µg/L for diclazepam, 100 µg/L for delorazepam, 6 µg/L for lormetazepam, and 22 µg/L for lorazepam. Tissues (muscle, kidney and liver) and bile exhibited higher concentrations of the mentioned analytes than in blood. Additional positive findings in femoral blood were for 2-fluoroamphetamine (2-FA, approx. 89 µg/L), 2-flourometamphetamine (2-FMA, hint), methiopropamine (approx. 2.2 µg/L), amphetamine (approx. 21 µg/L) and caffeine (positive). Delorazepam showed the highest ratio of heart (C) and femoral blood (P) concentration (C/P ratio = 2.5), supported by the concentrations detected in psoas muscle (430 µg/kg) and stomach content (approx. 210 µg/L, absolute 84 µg). The C/P ratio indicates that delorazepam displays susceptibility for post-mortem redistribution (PMR), supported by the findings in muscle tissue. 3-FPM, pyrazolam, diclazepam, lorazepam and lormetazepam did apparently not exhibit any PMR. The cause of death, in conjunction with autopsy findings was concluded as a positional asphyxia promoted by poly-drug intoxication by arising from designer benzodiazepines and the presence of synthetic stimulants.


Assuntos
Benzodiazepinas/farmacocinética , Drogas Desenhadas/farmacocinética , Diazepam/análogos & derivados , Fenmetrazina/análogos & derivados , Mudanças Depois da Morte , Adulto , Benzodiazepinas/análise , Bile/química , Líquidos Corporais/química , Química Encefálica , Drogas Desenhadas/análise , Diazepam/análise , Diazepam/farmacocinética , Toxicologia Forense , Conteúdo Gastrointestinal/química , Humanos , Rim/química , Fígado/química , Lorazepam/análogos & derivados , Lorazepam/análise , Lorazepam/farmacocinética , Pulmão/química , Masculino , Nordazepam/análogos & derivados , Nordazepam/análise , Nordazepam/farmacocinética , Líquido Pericárdico/química , Fenmetrazina/análise , Fenmetrazina/farmacocinética , Músculos Psoas/química , Espectrometria de Massas em Tandem
2.
Biopharm Drug Dispos ; 40(5-6): 176-187, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30985942

RESUMO

We previously verified a physiologically based pharmacokinetic (PBPK) model for mirabegron in healthy subjects using the Simcyp Simulator by incorporating data on the inhibitory effect on cytochrome P450 (CYP) 2D6 and a multi-elimination pathway mediated by CYP3A4, uridine 5'-diphosphate-glucuronosyltransferase (UGT) 2B7 and butyrylcholinesterase (BChE). The aim of this study was to use this PBPK model to assess the magnitude of drug-drug interactions (DDIs) in an elderly population with severe renal impairment (sRI), which has not been evaluated in clinical trials. We first determined the system parameters, and meta-analyses of literature data suggested that the abundance of UGT2B7 and the BChE activity in an elderly population with sRI was almost equivalent to and 20% lower than that in healthy young subjects, respectively. Other parameters, such as the CYP3A4 abundance, for an sRI population were used according to those built into the Simcyp Simulator. Second, we confirmed that the PBPK model reproduced the plasma concentration-time profile for mirabegron in an sRI population (simulated area under the plasma concentration-time curve (AUC) was within 1.5-times that of the observed value). Finally, we applied the PBPK model to simulate DDIs in an sRI population. The PBPK model predicted that the AUC for mirabegron with itraconazole (a CYP3A4 inhibitor) was 4.12-times that in healthy elderly subjects administered mirabegron alone, and predicted that the proportional change in AUC for desipramine (a CYP2D6 substrate) with mirabegron was greater than that in healthy subjects. In conclusion, the PBPK model was verified for the purpose of DDI assessment in an elderly population with sRI.


Assuntos
Acetanilidas/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Modelos Biológicos , Insuficiência Renal/metabolismo , Tiazóis/farmacocinética , Acetanilidas/sangue , Adolescente , Agonistas de Receptores Adrenérgicos beta 3/sangue , Adulto , Idoso , Envelhecimento/metabolismo , Butirilcolinesterase/metabolismo , Inibidores do Citocromo P-450 CYP2D6/sangue , Inibidores do Citocromo P-450 CYP2D6/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/sangue , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Desipramina/sangue , Desipramina/farmacocinética , Interações de Medicamentos , Feminino , Genfibrozila/sangue , Genfibrozila/farmacocinética , Glucuronosiltransferase/metabolismo , Humanos , Itraconazol/sangue , Itraconazol/farmacocinética , Lorazepam/sangue , Lorazepam/farmacocinética , Masculino , Pessoa de Meia-Idade , Insuficiência Renal/sangue , Tiazóis/sangue , Adulto Jovem , Zidovudina/sangue , Zidovudina/farmacocinética
3.
Biopharm Drug Dispos ; 40(3-4): 135-150, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30921829

RESUMO

Physiologically based pharmacokinetic (PBPK) modelling and simulation is a useful tool in predicting the PK profiles of a drug, assessing the effects of covariates such as demographics, ethnicity, genetic polymorphisms and disease status on the PK, and evaluating the potential of drug-drug interactions. We developed a Korean-specific virtual population for the SimCYP® Simulator (version 15 used) and evaluated the population's predictive performance using six substrate drugs (midazolam, S-warfarin, metoprolol, omeprazole, lorazepam and rosuvastatin) of five major drug metabolizing enzymes (DMEs) and two transporters. Forty-three parameters including the proportion of phenotypes in DMEs and transporters were incorporated into the Korean-specific virtual population. The simulated concentration-time profiles in Koreans were overlapped with most of the observed concentrations for the selected substrate drugs with a < 2-fold difference in clearance. Furthermore, we found some drug models within the SimCYP® library can be improved, e.g., the minor allele frequency of ABCG2 and the fraction metabolized by UGT2B15 should be incorporated for rosuvastatin and lorazepam, respectively. The Korean-specific population can be used to evaluate the impact of ethnicity on the PKs of a drug, particularly in various stages of drug development.


Assuntos
Grupo com Ancestrais do Continente Asiático , Modelos Biológicos , Software , Adulto , Simulação por Computador , Sistema Enzimático do Citocromo P-450/metabolismo , Feminino , Glucuronosiltransferase/metabolismo , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Lorazepam/farmacocinética , Masculino , Metoprolol/farmacocinética , Midazolam/farmacocinética , Pessoa de Meia-Idade , Omeprazol/farmacocinética , Rosuvastatina Cálcica/farmacocinética , Varfarina/farmacocinética , Adulto Jovem
4.
J Med Case Rep ; 13(1): 45, 2019 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-30808405

RESUMO

INTRODUCTION: Gastric pharmacobezoars are a rare entity that can induce mechanical gastric outlet obstructions and sometimes prolong toxic pharmacological effects. Certain medications, such as sustained-release forms, contain cellulose derivatives that may contribute to the adhesion between pills and lead to the creation of an aggregate resulting in a pharmacobezoar. Case reports are rare, and official guidelines are needed to help medical teams choose proper treatment options. CASE PRESENTATION: Our patient was a 40-year-old Caucasian woman with borderline personality disorder and active suicidal thoughts who was found unconscious after a massive drug consumption of slow-release clomipramine, lorazepam, and domperidone. On her arrival in the emergency room, endotracheal intubation was preformed to protect her airway, and a chest x-ray revealed multiple coffee grain-sized opaque masses in the stomach. She was treated with activated charcoal followed by two endoscopic gastric decontaminations 12 h apart in order to extract a massive gastric pharmacobezoar by manual removal of the tablets. CONCLUSION: This case demonstrates that in the case of a massive drug consumption, a pharmacobezoar should be suspected, particularly when cellulose-coated pills are ingested. Severe poisoning due to delayed drug release from the gastric aggregate is a potential complication. Detection by x-ray is crucial, and treatment is centered on removal of the aggregate. The technique of decontamination varies among experts, and no formal recommendations exist to date. It seems reasonable that endoscopic evaluation should be performed in order to determine the appropriate technique of decontamination. Care should be patient-oriented and take into account the clinical presentation and any organ failure, and it should not be determined solely by the suspected medication ingested. Thus, serum levels are not sufficient to guide management of tricyclic antidepressant intoxication.


Assuntos
Antidepressivos Tricíclicos/envenenamento , Bezoares/induzido quimicamente , Clomipramina/envenenamento , Preparações de Ação Retardada/envenenamento , Domperidona/envenenamento , Overdose de Drogas/patologia , Lorazepam/envenenamento , Adulto , Antidepressivos Tricíclicos/farmacocinética , Bezoares/patologia , Carvão Vegetal/uso terapêutico , Clomipramina/farmacocinética , Preparações de Ação Retardada/farmacocinética , Domperidona/farmacocinética , Overdose de Drogas/complicações , Endoscopia , Feminino , Humanos , Lorazepam/farmacocinética , Tentativa de Suicídio , Resultado do Tratamento
5.
CPT Pharmacometrics Syst Pharmacol ; 7(11): 718-727, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30267478

RESUMO

Diazepam is labeled for status epilepticus (SE) in children, but there are limited data characterizing its disposition in pediatric patients. We developed a population pharmacokinetic (PK) model of i.v. diazepam in children with SE. We evaluated relationships between PK parameters and both safety and efficacy, and simulated exposures using dosing regimens from the product label and clinical practice. The model was developed using prospective data from a pediatric clinical trial comparing diazepam to lorazepam for treatment of SE. Altogether, 87 patients aged ≥ 3 months to < 18 years contributed 162 diazepam concentrations. Diazepam PKs were well characterized by a two-compartment model scaled by body size. No significant or clinically important relationships were observed between diazepam PKs and safety or efficacy. Simulations demonstrated that, compared with label dosing, the study dose (0.2 mg/kg i.v., maximum 8 mg) resulted in greater frequency in rapidly achieving the target therapeutic range of 200-600 ng/mL.


Assuntos
Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Diazepam/farmacocinética , Diazepam/uso terapêutico , Estado Epiléptico/tratamento farmacológico , Administração Intravenosa , Adolescente , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Lactente , Lorazepam/farmacocinética , Lorazepam/uso terapêutico , Masculino , Estudos Prospectivos
6.
Clin Ther ; 40(9): 1598-1615.e2, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30173953

RESUMO

PURPOSE: The pharmacokinetic (PK) parameters of many drugs are altered as a consequence of the pathophysiological changes associated with critical illness. The critically ill population presents challenges when titrating infusions of sedatives and analgesics to maintain optimal sedation and pain levels. This systematic review examined the PK data in critically ill adult patients with prolonged infusions (>24 hours) of commonly used sedatives and analgesics to highlight possible altered PK parameters compared with noncritically ill patients. METHODS: A literature search of PK studies was performed by using MEDLINE (1946-December 2017) and EMBASE (1910-December 2017); we identified further studies by citation tracking (Web of Science) and checked references of retrieved studies and review articles. All studies were included that were published in English, Chinese, or German; conducted in critically ill adult patients receiving lorazepam, midazolam, propofol, dexmedetomidine, sufentanil, alfentanil, remifentanil, morphine, or fentanyl infusion for ≥24 hours; and reported PK parameters. When appropriate, we conducted a meta-analysis on volume of distribution at steady state (Vdss) (liters), clearance (Cl) (liters per hour), and elimination t1/2 (hours) by using a DerSimonian-Laird random effects model to estimate the summary mean and 95% CIs. Results were compared with commonly reported PK ranges in 70-kg noncritically ill patients. FINDINGS: Thirty-three randomized controlled trials and prospective cohort studies were identified involving 1803 adult critically ill patients with 35 drug treatment arms: fifteen midazolam (n = 906) studies, three dexmedetomidine (n = 561), nine propofol (n = 165), four lorazepam (n = 86), one morphine (n = 20), two remifentanil (n = 55), and one sufentanil (n = 10). Each study showed large variations in Vdss, Cl, and elimination t1/2 within and between individual participants. High clinical and methodical heterogeneity between the dexmedetomidine studies prevented the direct comparison of PK parameters between critically ill and noncritically ill patients. Use of midazolam, propofol, and lorazepam in critically ill patients was associated with at least a 2- to 4-fold increase in Vdss compared with noncritically ill patients; Cl decreased ∼2-fold for midazolam and 10-fold for morphine. Critically ill patients receiving prolonged infusions of midazolam, propofol, remifentanil, and sufentanil had at least 2-fold longer elimination or terminal t1/2 than noncritically ill patients. IMPLICATIONS: These findings show a marked difference in many PK parameters from those reported for noncritically ill patients. Initiatives to improve the delivery of prolonged sedatives and analgesic infusions should be informed by PK parameters (Vdss, context-sensitive t1/2, and elimination t1/2) and data derived from critically ill patients.


Assuntos
Analgésicos/farmacocinética , Estado Terminal , Hipnóticos e Sedativos/farmacocinética , Adulto , Analgésicos/administração & dosagem , Dexmedetomidina/administração & dosagem , Dexmedetomidina/farmacocinética , Fentanila/administração & dosagem , Fentanila/farmacocinética , Humanos , Hipnóticos e Sedativos/administração & dosagem , Infusões Intravenosas , Lorazepam/administração & dosagem , Lorazepam/farmacocinética , Midazolam/administração & dosagem , Midazolam/farmacocinética , Morfina/administração & dosagem , Morfina/farmacocinética , Propofol/administração & dosagem , Propofol/farmacocinética , Remifentanil/administração & dosagem , Remifentanil/farmacocinética , Sufentanil/administração & dosagem , Sufentanil/farmacocinética , Fatores de Tempo
7.
Pediatr Crit Care Med ; 19(11): e569-e575, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30080777

RESUMO

OBJECTIVES: To evaluate if institutionally established calculations for transitioning continuous IV midazolam to enteral benzodiazepines maintain Withdrawal Assessment Tool-Version 1 scores equal to or less than preconversion values. DESIGN: Retrospective cohort study evaluating the effectiveness and safety of benzodiazepine conversion calculations embedded within an institution-specific clinical pathway for sedation and weaning of mechanically ventilated pediatric patients. SETTING: A 55-bed, mixed-medical, noncardiac surgical PICU in a tertiary care children's hospital. PATIENTS: All patients age 6 months to 18 years who received continuous midazolam for 5 days or longer while mechanically ventilated for 5-21 days and were then converted to either enteral diazepam or lorazepam following extubation (or return to baseline ventilator settings in tracheostomy-dependent patients) between January 1, 2015, and June 30, 2016. INTERVENTIONS: Benzodiazepine conversion calculations were applied according to institutional clinical pathway guidance. MEASUREMENTS AND MAIN RESULTS: Withdrawal Assessment Tool-Version 1 scores were compared pre and post benzodiazepine conversion. Patient demographics, benzodiazepine dose escalations, as needed benzodiazepine requirements, and severe adverse events within 48 hours of conversion were assessed. Seventy-one patient encounters were analyzed (median age, 2.5 yr; interquartile range, 1.2-5.3). The median Withdrawal Assessment Tool-Version 1 scores pre conversion and post conversion were not significantly different (1 [interquartile range, 0.75-2] and 1 [interquartile range, 0.25-2], respectively, p = 0.1). As needed benzodiazepine doses were administered in 38% of encounters post conversion, but escalation of a scheduled enteral benzodiazepine regimen was only required in 2.8% of encounters. Post conversion, one patient (1.4%) had increased seizure activity, and four patients (5.6%) required fluid boluses secondary to tachycardia or dehydration, but not hypotension. CONCLUSIONS: These findings suggest that standardized benzodiazepine conversions successfully achieved consistent Withdrawal Assessment Tool-Version 1 scores compared with preconversion values. Severe adverse events associated with oversedation and/or withdrawal were minimal and confounded by underlying disease states.


Assuntos
Diazepam/administração & dosagem , Cálculos da Dosagem de Medicamento , Substituição de Medicamentos , Hipnóticos e Sedativos/administração & dosagem , Lorazepam/administração & dosagem , Midazolam/administração & dosagem , Extubação/efeitos adversos , Pré-Escolar , Diazepam/farmacocinética , Feminino , Humanos , Hipnóticos e Sedativos/efeitos adversos , Hipnóticos e Sedativos/farmacocinética , Lactente , Infusões Intravenosas/métodos , Unidades de Terapia Intensiva Pediátrica , Lorazepam/farmacocinética , Midazolam/efeitos adversos , Midazolam/farmacocinética , Melhoria de Qualidade , Respiração Artificial/efeitos adversos , Estudos Retrospectivos , Síndrome de Abstinência a Substâncias/prevenção & controle
9.
Ann Pharmacother ; 52(6): 513-521, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29363356

RESUMO

BACKGROUND: The relationship between plasma concentration of sedatives and delirium is unknown. OBJECTIVE: We hypothesized that higher plasma concentrations of lorazepam are associated with increased delirium risk, whereas higher plasma concentrations of dexmedetomidine are associated with reduced delirium risk. METHODS: This prospective cohort study was embedded in a double-blind randomized clinical trial, where ventilated patients received infusions of lorazepam and dexmedetomidine. Plasma concentrations of these drugs and delirium assessments were measured at least daily. A multivariable logistic regression model accounting for repeated measures was used to analyze associations between same-day plasma concentrations of lorazepam and dexmedetomidine (exposures) and the likelihood of next-day delirium (outcome), adjusting for same-day mental status (delirium, coma, or normal) and same-day fentanyl doses. RESULTS: This critically ill cohort (n = 103) had a median age of 60 years (IQR: 48-66) with APACHE II score of 28 (interquartile range [IQR] = 24-32), where randomization resulted in assignment to lorazepam (n = 51) or dexmedetomidine (n = 52). After adjusting for same-day fentanyl dose and mental status, higher plasma concentrations of lorazepam were associated with increased probability of next-day delirium (comparing 500 vs 0 ng/mL; odds ratio [OR] = 13.2; 95% CI = 1.4-120.1; P = 0.02). Plasma concentrations of dexmedetomidine were not associated with next-day delirium (comparing 1 vs 0 ng/mL; OR = 1.1; 95% CI = 0.9-1.3; P = 0.45). CONCLUSIONS: In critically ill patients, higher lorazepam plasma concentrations were associated with delirium, whereas dexmedetomidine plasma concentrations were not. This implies that the reduced delirium risk seen in patients sedated with dexmedetomidine may be a result of avoidance of benzodiazepines, rather than a dose-dependent protective effect of dexmedetomidine.


Assuntos
Delírio/induzido quimicamente , Dexmedetomidina/sangue , Hipnóticos e Sedativos/sangue , Lorazepam/sangue , Idoso , Estado Terminal , Delírio/sangue , Dexmedetomidina/efeitos adversos , Dexmedetomidina/farmacocinética , Feminino , Humanos , Hipnóticos e Sedativos/efeitos adversos , Hipnóticos e Sedativos/farmacocinética , Unidades de Terapia Intensiva , Modelos Logísticos , Lorazepam/efeitos adversos , Lorazepam/farmacocinética , Masculino , Pessoa de Meia-Idade , Respiração Artificial
10.
Basic Clin Pharmacol Toxicol ; 122(2): 245-252, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28869786

RESUMO

Event-related potentials (ERPs) are commonly used in Neuroscience research, particularly the P3 waveform because it is associated with cognitive brain functions and is easily elicited by auditory or sensory inputs. ERPs are affected by drugs such as lorazepam, which increase the latency and decrease the amplitude of the P3 wave. In this study, auditory-evoked ERPs were generated in 13 older healthy volunteers using an oddball tone paradigm, after administration of single 0.5 and 2 mg doses of lorazepam. Population pharmacokinetics (PK)/pharmacodynamics (PD) models were developed using nonlinear mixed-effects methods in order to assess the effect of lorazepam on the latency and amplitude of the P3 waveforms. The PK/PD models showed that doses of 0.3 mg of lorazepam achieved approximately half of the maximum effect on the latency of the P3 waveform. For P3 amplitude, half the maximum effect was achieved with a dose of 1.2 mg of lorazepam. The PK/PD models also predicted an efficacious dose range of lorazepam, which was close to the recommended therapeutic range. The use of longitudinal P3 latency data allowed better predictions of the lorazepam efficacious dose range than P3 amplitude or aggregate exposure-response data, suggesting that latency could be a more sensitive parameter for drugs with similar mechanisms of action as lorazepam and that time course rather than single time-point ERP data should be collected. Overall, the results suggest that P3 ERP waveforms could be used as potential non-specific biomarkers for functional target engagement for drugs with brain activity, and PK/PD models can aid trial design and choice of doses for development of new drugs with ERP activity.


Assuntos
Córtex Auditivo/efeitos dos fármacos , Potencial Evocado P300/efeitos dos fármacos , Potenciais Evocados Auditivos/efeitos dos fármacos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/farmacocinética , Lorazepam/administração & dosagem , Lorazepam/farmacocinética , Modelos Biológicos , Estimulação Acústica , Córtex Auditivo/fisiologia , Estudos Cross-Over , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Dinâmica não Linear , Tempo de Reação/efeitos dos fármacos , Método Simples-Cego
11.
Clin Pharmacokinet ; 56(8): 941-951, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-27943220

RESUMO

BACKGROUND: Lorazepam is one of the preferred agents used for intravenous treatment of status epilepticus (SE). We combined data from two pediatric clinical trials to characterize the population pharmacokinetics of intravenous lorazepam in infants and children aged 3 months to 17 years with active SE or a history of SE. METHODS: We developed a population pharmacokinetic model for lorazepam using the NONMEM software. We then assessed exploratory exposure-response relationships using the overall efficacy and safety study endpoints, and performed dosing simulations. RESULTS: A total of 145 patients contributed 439 pharmacokinetic samples. The median (range) age and dose were 5.4 years (0.3-17.8) and 0.10 mg/kg (0.02-0.18), respectively. A two-compartment pharmacokinetic model with allometric scaling described the data well. In addition to total body weight (WT), younger age was associated with slightly higher weight-normalized clearance (CL). The following relationships characterized the typical values for the central compartment volume (V1), CL, peripheral compartment volume (V2), and intercompartmental CL (Q), using individual subject WT (kg) and age (years): V1 (L) = 0.879*WT; CL (L/h) = 0.115*(Age/4.7)0.133*WT0.75; V2 (L) = 0.542*V1; Q (L/h) = 1.45*WT0.75. No pharmacokinetic parameters were associated with clinical outcomes. Simulations suggest uniform pediatric dosing (0.1 mg/kg, to a maximum of 4 mg) can be used to achieve concentrations of 50-100 ng/mL in children with SE, which have been previously associated with effective seizure control. CONCLUSIONS: The population pharmacokinetics of lorazepam were successfully described using a sparse sampling approach and a two-compartment model in pediatric patients with active SE.


Assuntos
Anticonvulsivantes/farmacocinética , Lorazepam/farmacocinética , Estado Epiléptico/tratamento farmacológico , Adolescente , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/sangue , Anticonvulsivantes/farmacologia , Peso Corporal , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Lactente , Infusões Intravenosas , Lorazepam/administração & dosagem , Lorazepam/sangue , Lorazepam/farmacologia , Masculino , Modelos Biológicos , Estudos Prospectivos , Software/estatística & dados numéricos
12.
Artigo em Inglês | MEDLINE | ID: mdl-25195839

RESUMO

BACKGROUND: The benzodiazepine lorazepam is widely utilized in the treatment of elderly individuals with anxiety disorders and related conditions. Negative effects of acute lorazepam administration on cognitive performance, especially memory, have been reported in both previously untreated elderly and in individuals who have received short term (up to three weeks) treatment with therapeutic doses. However, it remains unclear if these adverse cognitive effects also persist after long-term use, which is frequently found in clinical practice. METHODS: Cognitively intact elderly individuals (n=37) on long-term (at least three months) daily treatment with lorazepam were studied using a double-blind placebo-controlled cross-over study design. Subjects were administered their highest daily unit dose of lorazepam (0.25-3.00 mg) or placebo on different days, approximately 1 week apart in a random order, and were assessed on memory, psychomotor speed, and subjective mood states. RESULTS: Subjects had significantly poorer recall and slowed psychomotor performance following acute lorazepam administration. There were no significant effects on self-ratings of mood, sedation, or anxiety in the whole group, but secondary analyses suggested a differential response in subjects with Generalized Anxiety Disorder. CONCLUSIONS: The reduced recall and psychomotor slowing that we observed, along with an absence of significant therapeutic benefits, following acute lorazepam administration in elderly long-term users reinforces the importance of cognitive toxicity as a clinical factor in benzodiazepine use, especially in this population.


Assuntos
Ansiolíticos/efeitos adversos , Ansiolíticos/farmacocinética , Lorazepam/efeitos adversos , Lorazepam/farmacocinética , Transtornos da Memória/induzido quimicamente , Desempenho Psicomotor/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Ansiedade/sangue , Ansiedade/tratamento farmacológico , Estudos Cross-Over , Método Duplo-Cego , Emoções , Feminino , Humanos , Estudos Longitudinais , Lorazepam/sangue , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica
13.
Int J Clin Pharmacol Ther ; 52(6): 519-24, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24755136

RESUMO

The aim of this study was to evaluate the effect of sleep disturbance on the pharmacokinetics, especially on the absorption, of lorazepam in humans. Eight healthy male volunteers received a single oral dose of lorazepam 1 mg before sleep on two occasions in a cross-over design. In either of the two doses, subjects were intermittently exposed to noise for 1.5 hours after oral lorazepam administration. Plasma lorazepam concentrations were measured by HPLC. The exposure to noise significantly prolonged tmax (control vs. noise: 2.0 vs. 3.0 hours) and significantly decreased AUC of lorazepam in the absorption phase. The reduction was 54% (95% CI, 15 - 75%) and 24% (3 - 40%) for AUC (0 - 1 hours) and AUC (0 - 3 hours), respectively. No significant changes were observed in other pharmacokinetic parameters. The results of this study suggest that the onset of drug action after oral lorazepam administration can be altered by sleep disturbance.


Assuntos
Hipnóticos e Sedativos/farmacocinética , Lorazepam/farmacocinética , Transtornos do Sono-Vigília/tratamento farmacológico , Sono , Administração Oral , Adulto , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Estudos Cross-Over , Meia-Vida , Voluntários Saudáveis , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/sangue , Absorção Intestinal , Lorazepam/administração & dosagem , Lorazepam/sangue , Masculino , Ruído/efeitos adversos , Transtornos do Sono-Vigília/sangue , Transtornos do Sono-Vigília/fisiopatologia , Adulto Jovem
15.
AAPS J ; 15(2): 455-64, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23344790

RESUMO

The use of physiologically based pharmacokinetic (PBPK) models in the field of pediatric drug development has garnered much interest of late due to a recent Food and Drug Administration recommendation. The purpose of this study is to illustrate the developmental processes involved in creation of a pediatric PBPK model incorporating existing adult drug data. Lorazepam, a benzodiazepine utilized in both adults and children, was used as an example. A population-PBPK model was developed in PK-Sim v4.2® and scaled to account for age-related changes in size and composition of tissue compartments, protein binding, and growth/maturation of elimination processes. Dose (milligrams per kilogram) requirements for children aged 0-18 years were calculated based on simulations that achieved targeted exposures based on adult references. Predictive accuracy of the PBPK model for producing comparable plasma concentrations among 63 pediatric subjects was assessed using average-fold error (AFE). Estimates of clearance (CL) and volume of distribution (V(ss)) were compared with observed values for a subset of 15 children using fold error (FE). Pediatric dose requirements in young children (1-3 years) exceeded adult levels on a linear weight-adjusted (milligrams per kilogram) basis. AFE values for model-derived concentration estimates were within 1.5- and 2-fold deviation from observed values for 73% and 92% of patients, respectively. For CL, 60% and 80% of predictions were within 1.5 and 2 FE, respectively. Comparatively, predictions of V(ss) were more accurate with 80% and 100% of estimates within 1.5 and 2 FE, respectively. Using the presented workflow, the developed pediatric model estimated lorazepam pharmacokinetics in children as a function of age.


Assuntos
Pesquisa Biomédica/métodos , Cálculos da Dosagem de Medicamento , Lorazepam/administração & dosagem , Lorazepam/farmacocinética , Modelos Biológicos , Pediatria/métodos , Fluxo de Trabalho , Adolescente , Adulto , Fatores Etários , Composição Corporal , Tamanho Corporal , Criança , Pré-Escolar , Simulação por Computador , Humanos , Lactente , Recém-Nascido , Modelos Lineares , Lorazepam/sangue , Reprodutibilidade dos Testes
16.
Int J Pharm ; 441(1-2): 516-26, 2013 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-23147411

RESUMO

Thermo-sensitive gels containing lorazepam microspheres were developed and characterized for intranasal brain targeting. Pluronics (PF-127 and PF-68) have been selected since they are thermo-reversible polymers with the property of forming a solution at low temperatures (4-5 °C), and a gel at body temperature (37 °C). This property makes them an interesting material to work with, especially in case of controlled release formulations. The present study focuses on the development of an intranasal formulation for lorazepam, as an alternative route of drug delivery to the brain. Direct transport of drugs to the brain circumventing the brain barrier, following intranasal administration, provides a unique feature and better option to target brain. The presence of mucoadhesive microspheres in the gel vehicle via nasal route can achieve a dual purpose of prolonged drug release and enhanced bioavailability. To optimise the microsphere formulation, Box Behnken design was employed by investigating the effect of three factors, polymer concentration (chitosan), emulsifier concentration (Span 80) and cross-linking agent (glutaraldehyde) on the response variable which is the mean particle size. The concentration of 21% PF-127 and 1% PF-68 were found to be promising gel vehicles. The results showed that the release rate followed a prolonged profile dispersion of the microspheres in the viscous media, in comparison to the microspheres alone. Histopathological studies proved that the optimised formulation does not produce any toxic effect on the microscopic structure of nasal mucosa.


Assuntos
Anticonvulsivantes/administração & dosagem , Encéfalo/metabolismo , Sistemas de Liberação de Medicamentos , Lorazepam/administração & dosagem , Adesividade , Administração Intranasal , Animais , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/toxicidade , Disponibilidade Biológica , Transporte Biológico , Bovinos , Quitosana/química , Reagentes para Ligações Cruzadas/química , Preparações de Ação Retardada , Excipientes/química , Géis , Glutaral/química , Hexoses/química , Lorazepam/farmacocinética , Lorazepam/toxicidade , Microesferas , Mucosa Nasal/metabolismo , Tamanho da Partícula , Poloxâmero/química , Temperatura Ambiente
17.
J Pain Symptom Manage ; 43(5): 961-6, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22560361

RESUMO

BACKGROUND: Lorazepam (Ativan(®)), diphenhydramine (Benadryl(®)), haloperidol (Haldol(®)) (ABH) topical gel is currently widely used for nausea in hospice because of perceived efficacy and low cost and has been suggested for cancer chemotherapy. However, there are no studies of absorption, a prerequisite for effectiveness. We completed this study to establish whether ABH gel drugs are absorbed, as a prerequisite to effectiveness. INTERVENTION: Ten healthy volunteers, aged 25 to 58 years (mean 37 years), two African Americans and eight Caucasian Americans, applied the standard 1.0 mL dose (2mg of lorazepam, 25mg of diphenhydramine, and 2mg of haloperidol in a pluronic lecithin organogel), rubbed on the volar surface of the wrists by the subject. MEASURES: Blood samples were obtained at 0, 30, 60, 90, 120, 180, and 240 minutes. Plasma concentrations were analyzed by liquid chromatography-tandem mass spectrometry using deuterated internal standards for each drug. OUTCOMES: No lorazepam or haloperidol was detected in any sample from any of the 10 volunteers down to a level of 0.05 ng/mL. Diphenhydramine was found in multiple plasma samples at concentrations >0.05 ng/mL in three patients, with the highest concentration of 0.30 ng/mL in one person at 240 minutes. Overall, five of 10 patients exhibited detectable diphenhydramine in one or more samples, supporting limited absorption. No subject noted any side effects. CONCLUSIONS/LESSONS LEARNED: As commonly used, none of the lorazepam, haloperidol, or diphenhydramine in ABH gel is absorbed in sufficient quantities to be effective in the treatment of nausea and vomiting. Diphenhydramine is erratically absorbed at subtherapeutic levels. The efficacy of ABH gel should be confirmed in randomized trials before its use is recommended.


Assuntos
Antieméticos/farmacocinética , Difenidramina/farmacocinética , Haloperidol/farmacocinética , Lorazepam/farmacocinética , Pele/metabolismo , Absorção , Administração Cutânea , Adulto , Antieméticos/administração & dosagem , Antieméticos/sangue , Difenidramina/administração & dosagem , Difenidramina/sangue , Feminino , Haloperidol/administração & dosagem , Haloperidol/sangue , Humanos , Lorazepam/administração & dosagem , Lorazepam/sangue , Masculino , Pessoa de Meia-Idade
19.
AAPS J ; 14(2): 218-24, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22396304

RESUMO

The intranasal (IN) administration of lorazepam is desirable in order to maximize speed of onset and minimise carry-over sedation; however, this benzodiazepine is prone to chemical hydrolysis and poor airway retention, and thus, innovative epithelial presentation is required. The aim of this study was to understand how the in situ self-assembly of a mucoretentive delivery system, formed by the dissolution of vinyl polymer-coated microparticles in the nasal mucosa, would influence lorazepam pharmacokinetics (PK). IN administration of the uncoated lorazepam powder (particle size, 6.7 ± 0.1 µm) generated a biphasic PK profile, which was indicative of sequential intranasal and oral absorption (n = 6; dose, 5 mg/kg). Coating the drug with the vinyl polymer, MP1 (9.9 ± 0.5 µm with 38.8 ± 14.0%, w/w lorazepam) and MP2 (10.7 ± 0.1 µm with 47.0 ± 1.0%, w/w lorazepam), allowed rapid systemic absorption (MP1, T (max) 14.2 ± 4.9 min; MP2, T (max) 9.3 ± 3.8 min) in rabbits and modified the PK profiles in a manner that suggested successful nasal retention. The poly(vinyl pyrrolidone)-rich MP2 system provided the best comparative bioavailability, it prolonged the early-phase nasal drug absorption and minimised drug mucociliary clearance, which correlated well with the intermolecular hydrogen-bond-driven vinyl polymer interactions observed in vitro.


Assuntos
Lorazepam/administração & dosagem , Lorazepam/farmacocinética , Microesferas , Álcool de Polivinil/administração & dosagem , Álcool de Polivinil/farmacocinética , Administração Intranasal , Animais , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/farmacocinética , Avaliação Pré-Clínica de Medicamentos/métodos , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/metabolismo , Tamanho da Partícula , Coelhos , Distribuição Aleatória
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