RESUMEN
A nanocomposite of Ce-doped ZnO/r-GO was synthesized using a conventional hydrothermal method. The synthesized nanocomposites were utilized for the purpose of sensitive and selective detection of cyclobenzaprine hydrochloride (CBP). The properties of the composite were extensively analyzed, including its morphology, structure, and electrochemical behavior. This study investigates the application of a modified glassy carbon electrode for the detection of CBP, a muscle relaxant used to treat musculoskeletal diseases that cause muscle spasms. The electrode is modified with Ce-doped ZnO/r-GO. Various detection methods, such as cyclic voltammetric and square wave techniques (SWV), were utilized. The composite material showed high effectiveness as an electron transfer mediator in the oxidation of CBP. The electrode showed a good response for SWV evaluations in CBP identification, with a minimum detection limit of 1.6 × 10-8 M and a wide linear range from 10 × 10-6 M to 0.6 × 10-7 M, under ideal conditions. The rate constant for charge transfer (ks) and the estimation of the electrochemical active surface area were obtained. A developed sensor exhibited desirable selectivity, long-lasting stability, and remarkable reproducibility. A sensor was used to analyze water, human serum, and urine samples, resulting in positive recovery results.
Asunto(s)
Amitriptilina , Técnicas Electroquímicas , Electrodos , Límite de Detección , Óxido de Zinc , Óxido de Zinc/química , Técnicas Electroquímicas/métodos , Técnicas Electroquímicas/instrumentación , Amitriptilina/química , Amitriptilina/orina , Amitriptilina/sangre , Amitriptilina/análogos & derivados , Nanocompuestos/química , Humanos , Relajantes Musculares Centrales/química , Relajantes Musculares Centrales/orina , Relajantes Musculares Centrales/sangre , Relajantes Musculares Centrales/análisis , Reproducibilidad de los ResultadosRESUMEN
Eperisone is an oral muscle relaxant used to treat musculoskeletal diseases, which exhibits high pharmacokinetic (PK) variability in bioequivalence studies. The aim of this study was to characterize the PKs of eperisone following its oral administration to Korean volunteers through the conduct of a noncompartmental and population analysis. A total of 360 concentration-time measurements collected on two separate occasions from 15 healthy volunteers during a bioequivalent study of eperisone 50 mg (Murex® ) were used in the PK analysis. Noncompartmental analysis was performed using WinNonLinTM and population analysis was performed using NONMEM® . The possible influence of thirty demographic and pathophysiological characteristics on the PKs of eperisone were explored. Based on noncompartmental analysis mean eperisone elimination half-life, apparent clearance (CL/F), and apparent volume of distribution were estimated to be 3.81 h, 39.24 × 103 l/h × 103 L, respectively. During population PK modeling a two-compartment model with first-order absorption rate constant (typical population K a = 1.5 h-1 ) and first-order elimination (typical population CL/F and apparent volume of distribution in the central compartment [V c /F] = 30.8 × 103 l/h and 86.2 × 103 l, respectively) best described the PKs of eperisone. Interindividual variability in CL/F and V c /F were estimated to be 87.9% and 130.3%, respectively and interoccasion variability in CL/F and V c /F were estimated to be 23.8% and 30.8%, respectively. Aspartate aminotransferase level and smoking status were identified as potential covariates that may influence the CL/F of eperisone. This is the first study to develop a disposition model for eperisone and investigate the potential influence of covariate factors on it PK variability.
Asunto(s)
Modelos Biológicos , Relajantes Musculares Centrales/farmacocinética , Propiofenonas/farmacocinética , Administración Oral , Adulto , Estudios Cruzados , Voluntarios Sanos , Humanos , Masculino , Relajantes Musculares Centrales/sangre , Propiofenonas/sangre , República de Corea , Equivalencia Terapéutica , Adulto JovenRESUMEN
BACKGROUND: Paracetamol/Orphenadrine is a fixed dose combination containing 35 mg orphenadrine and 450 mg paracetamol. It has analgesic and muscle relaxant properties and is widely available as generics. This study is conducted to investigate the relative bioavailability and bioequivalence between one fixed dose paracetamol/orphenadrine combination test preparation and one fixed dose paracetamol/orphenadrine combination reference preparation in healthy volunteers under fasted condition for marketing authorization in Malaysia. METHOD: This is a single-center, single-dose, open-label, randomized, 2-treatment, 2-sequence and 2-period crossover study with a washout period of 7 days. Paracetamol/Orphenadrine tablets were administered after a 10-h fast. Blood samples for pharmacokinetic analysis were collected at scheduled time intervals prior to and up to 72 h after dosing. Blood samples were centrifuged, and separated plasma were kept frozen (- 15 °C to - 25 °C) until analysis. Plasma concentrations of orphenadrine and paracetamol were quantified using liquid-chromatography-tandem mass spectrometer using diphenhydramine as internal standard. The pharmacokinetic parameters AUC0-∞, AUC0-t and Cmax were determined using plasma concentration time profile for both preparations. Bioequivalence was assessed according to the ASEAN guideline acceptance criteria for bioequivalence which is the 90% confidence intervals of AUC0-∞, AUC0-t and Cmax ratio must be within the range of 80.00-125.00%. RESULTS: There were 28 healthy subjects enrolled, and 27 subjects completed this trial. There were no significant differences observed between the AUC0-∞, AUC0-t and Cmax of both test and reference preparations in fasted condition. The 90% confidence intervals for the ratio of AUC0-t (100.92-111.27%), AUC0-∞ (96.94-108.08%) and Cmax (100.11-112.50%) for orphenadrine (n = 25); and AUC0-t (94.29-101.83%), AUC0-∞ (94.77-101.68%) and Cmax (87.12-101.20%) for paracetamol (n = 27) for test preparation over reference preparation were all within acceptable bioequivalence range of 80.00-125.00%. CONCLUSION: The test preparation is bioequivalent to the reference preparation and can be used interchangeably. TRIAL REGISTRATION: NMRR- 17-1266-36,001; registered and approved on 12 September 2017.
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Acetaminofén/farmacocinética , Analgésicos no Narcóticos/farmacocinética , Ayuno/metabolismo , Relajantes Musculares Centrales/farmacocinética , Orfenadrina/farmacocinética , Acetaminofén/sangre , Adulto , Analgésicos no Narcóticos/sangre , Estudios Cruzados , Combinación de Medicamentos , Voluntarios Sanos , Humanos , Masculino , Relajantes Musculares Centrales/sangre , Orfenadrina/sangre , Equivalencia Terapéutica , Adulto JovenAsunto(s)
Baclofeno/administración & dosificación , Relajantes Musculares Centrales/administración & dosificación , Espasticidad Muscular/tratamiento farmacológico , Cuidado Terminal , Administración Rectal , Anciano , Baclofeno/sangre , Resultado Fatal , Humanos , Masculino , Persona de Mediana Edad , Relajantes Musculares Centrales/sangre , Espasticidad Muscular/sangre , Espasticidad Muscular/etiologíaRESUMEN
Baclofen is used to manage alcohol dependence. This study describes a simple method using liquid chromatography coupled to high-resolution mass spectrometry (LC-HR-MS) developed in plasma samples. This method was optimized to allow quantification of baclofen and determination of metabolic ratio of its metabolites, an oxidative deaminated metabolite of baclofen (M1) and its glucuronide form (M2). The LC-HR-MS method on Exactive® apparatus is a newly developed method with all the advantages of high resolution in full-scan mode for the quantification of baclofen and detection of its metabolites in plasma. The present assay provides a protein precipitation method starting with 100 µL plasma giving a wide polynomial dynamic range (R2 > 0.999) between 10 and 2000 ng/mL and a lower limit of quantitation of 3 ng/mL for baclofen. Intra- and inter-day precisions were <8.1% and accuracies were between 91.2 and 103.3% for baclofen. No matrix effect was observed. The assay was successfully applied to 36 patients following baclofen administration. Plasma concentrations of baclofen were determined between 12.2 and 1399.9 ng/mL and metabolic ratios were estimated between 0.4 and 81.8% for M1 metabolite and on the order of 0.3% for M2 in two samples.
Asunto(s)
Baclofeno/sangre , Cromatografía Líquida de Alta Presión/métodos , Monitoreo de Drogas/métodos , Agonistas de Receptores GABA-B/sangre , Relajantes Musculares Centrales/sangre , Espectrometría de Masas en Tándem/métodos , Baclofeno/metabolismo , Agonistas de Receptores GABA-B/metabolismo , Glucurónidos/sangre , Glucurónidos/metabolismo , Humanos , Límite de Detección , Relajantes Musculares Centrales/metabolismo , Oxidación-ReducciónRESUMEN
A method of identification and quantitative determination of baclofen in blood by HPLC with mass spectrometry detection has been developed. It is characterized by high sensitivity, specificity, linearity, accuracy, reproducibility, and a low detection for quantitative determination. The method has been used for diagnostics of acute baclofen poisoning in patients.
Asunto(s)
Baclofeno/sangre , Análisis Químico de la Sangre/métodos , Relajantes Musculares Centrales/sangre , Baclofeno/envenenamiento , Estudios de Casos y Controles , Cromatografía Líquida de Alta Presión/métodos , Humanos , Espectrometría de Masas/métodos , Relajantes Musculares Centrales/envenenamiento , Sensibilidad y EspecificidadRESUMEN
Methocarbamol (MCBL) is commonly used in performance horses for the treatment of skeletal muscle disorders. Current regulatory recommendations for show horses and racehorses are based on a single oral dose of 5 g, although doses in excess of this are often administered. The goal of the current study was to characterize the disposition of MCBL following higher dose administration and administration in combination with another commonly used drug in performance horses, phenylbutazone (PBZ). Exercised Thoroughbred horses were administered various doses of MCBL as a sole agent and MCBL in combination with PBZ. Blood samples were collected at various times, concentrations of MCBL and PBZ measured using LC-MS/MS and pharmacokinetic parameters calculated using compartmental analysis. Following administration of 15 g of MCBL, either as part of a single- or multiple-dose regimen, a number of horses exceeded the Association of Racing Commissioners International and the United States Equestrian Federation's recommended regulatory threshold at the recommended withdrawal time. There was not a significant difference between horses that received only MCBL and those that received MCBL and PBZ. Results of the current study support an extended withdrawal guideline when doses in excess of 5 g are administered.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacocinética , Metocarbamol/farmacocinética , Relajantes Musculares Centrales/farmacocinética , Fenilbutazona/farmacocinética , Administración Oral , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/sangre , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Caballos/sangre , Caballos/metabolismo , Inyecciones Intravenosas , Masculino , Metocarbamol/administración & dosificación , Metocarbamol/sangre , Relajantes Musculares Centrales/administración & dosificación , Relajantes Musculares Centrales/sangre , Pomadas/administración & dosificación , Fenilbutazona/administración & dosificación , Fenilbutazona/sangre , Condicionamiento Físico AnimalRESUMEN
Carisoprodol and meprobamate are centrally acting muscle relaxant/anxiolytic drugs that can exist in a parent-metabolite relationship (carisoprodol â meprobamate) or as a separate pharmaceutical preparation (meprobamate aka Equanil, others). The monitoring of the use of these drugs has both clinical and forensic applications in pain management applications and in overdose situations. LC-MS/MS is used to analyze urine or plasma/serum extracts with deuterated analogs of each analyte as internal standards to ensure accurate quantitation and control for any potential matrix effects. Positive ion electrospray is used to introduce the analytes into the mass spectrometer. Selected reaction monitoring of two product ions for each analyte allows for the calculation of ion ratios which ensures correct identification of each analyte, while a matrix-matched calibration curve is used for quantitation.
Asunto(s)
Carisoprodol/sangre , Carisoprodol/orina , Meprobamato/sangre , Meprobamato/orina , Relajantes Musculares Centrales/sangre , Relajantes Musculares Centrales/orina , Espectrometría de Masas en Tándem/métodos , Cromatografía Liquida/métodos , HumanosAsunto(s)
Baclofeno/sangre , Baclofeno/envenenamiento , Monitoreo de Drogas/métodos , Hemiplejía/tratamiento farmacológico , Relajantes Musculares Centrales/sangre , Relajantes Musculares Centrales/envenenamiento , Adulto , Baclofeno/farmacocinética , Biomarcadores/sangre , Femenino , Humanos , Relajantes Musculares Centrales/farmacocinética , Intoxicación/sangre , Intoxicación/diagnóstico , Intoxicación/terapia , Valor Predictivo de las Pruebas , Intento de Suicidio , Factores de Tiempo , Resultado del TratamientoRESUMEN
The objective of the present study was to select and develop simpler methods for the quantitative determination of baclofen in blood with the use of HPLC and tandem MS (MS-MS) techniques and its qualitative determination in cadaveric organs by the GC/MS technique. These mathods were shown to be suitable for the purpose of forensic medical analysis, clinical, toxicological, and therapeutic monitoring. The special emphasis is laid on the methods used to investigate the biological materials obtained from the subjects who died from baclofen intoxication.
Asunto(s)
Baclofeno/análisis , Toxicología Forense/métodos , Relajantes Musculares Centrales/análisis , Suicidio , Adulto , Baclofeno/sangre , Baclofeno/farmacocinética , Baclofeno/envenenamiento , Cromatografía Líquida de Alta Presión , Resultado Fatal , Femenino , Toxicología Forense/instrumentación , Humanos , Límite de Detección , Hígado/metabolismo , Relajantes Musculares Centrales/sangre , Relajantes Musculares Centrales/farmacocinética , Relajantes Musculares Centrales/envenenamiento , Intoxicación/sangre , Intoxicación/etiología , Intoxicación/metabolismo , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem , Distribución TisularRESUMEN
PURPOSE: Overdose with baclofen, a derivative of the inhibitory neurotransmitter γ-aminobutyric acid, may lead to severe respiratory and central nervous system depression and can be life-threatening. Prolonged half-lives of baclofen, of up to 34 h, have been reported in patients after overdose. Hemodialysis has proven to be a successful approach to improve clearance of baclofen, but the value of continuous venovenous hemofiltration (CVVH) is unclear. We applied CVVH in a patient with acute baclofen overdose. METHODS: Pharmacokinetic measurements of baclofen in serum and hemofiltrate were made at six time points after hospital admission. Baclofen concentration-time data were analyzed using non-compartmental methods, and the relative contribution of clearance by hemofiltration to total baclofen clearance was calculated. RESULTS: Baclofen concentrations in serum varied between 1.81 and 0.05 mg/L. Concentrations of baclofen in hemofiltrate were within the same range (between 0.74 and 0.05 mg/L), and the elimination half-life during hemofiltration was estimated at 4.8 h. Total clearance and clearance via hemofiltration were estimated at 6.6 and 2.4 L/h, indicating that clearance could be increased by approximately 57 % by applying hemofiltration. CONCLUSIONS: The presented case demonstrates the usefulness of CVVH in the treatment of baclofen overdose and indicates that CVVH can be used as an alternative to hemodialysis in patients with overdose of baclofen.
Asunto(s)
Baclofeno , Sobredosis de Droga/cirugía , Hemofiltración , Baclofeno/sangre , Baclofeno/farmacocinética , Baclofeno/envenenamiento , Humanos , Tasa de Depuración Metabólica , Persona de Mediana Edad , Relajantes Musculares Centrales/sangre , Relajantes Musculares Centrales/farmacocinética , Relajantes Musculares Centrales/envenenamientoRESUMEN
Our objective was to characterize baclofen pharmacokinetics and safety given orally and intravenously. Twelve healthy subjects were enrolled in a randomized, open-label, crossover study and received single doses of baclofen: 3 or 5 mg given intravenously and 5 or 10 mg taken orally with a 48-hour washout. Blood samples for baclofen analysis were collected pre-dose and at regular intervals up to 24 hours post-dose. Clinical response was assessed by sedation scores, ataxia, and nystagmus. Mean absolute bioavailability of oral baclofen was 74%. Dose-adjusted areas under the curve between the oral and intravenous arms were statistically different (P = .0024), whereas area under the curve variability was similar (coefficient of variation: 18%-24%). Adverse effects were mild in severity and not related to either dose or route of administration. Three- and 5-mg intravenous doses of baclofen were well tolerated. Seventy-four percent oral bioavailability indicates that smaller doses of intravenous baclofen are needed to attain comparable total drug exposures.
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Baclofeno/sangre , Baclofeno/farmacocinética , Relajantes Musculares Centrales/sangre , Relajantes Musculares Centrales/farmacocinética , Administración Intravenosa , Administración Oral , Adulto , Área Bajo la Curva , Disponibilidad Biológica , Estudios Transversales , Relación Dosis-Respuesta a Droga , Tolerancia a Medicamentos , Electrocardiografía , Femenino , Voluntarios Sanos , Humanos , Masculino , Proyectos Piloto , Factores de TiempoRESUMEN
Cytochrome P450s (CYPs) are the main catalytic enzymes for metabolism by a variety of endogenous and exogenous substrates in mammals, fish, insects, etc. We evaluated the application of a multidrug cocktail on changes in CYP1, CYP2, and CYP3 activity in Turbot Scophthalmus maximus. The probe drugs were a combination of caffeine (5 mg/kg body weight), dapsone (5 mg/kg), and chlorzoxazone (10 mg/kg). After a single intraperitoneal injection of the cocktail, the concentration of all three probe drugs in the plasma increased quickly to a peak and then decreased gradually over 24 h. Pharmacokinetic profiles of the three probe drugs were determined using a noncompartmental analysis, and the typical parameters were calculated. In the assay for CYP induction, pretreatment with rifampicin significantly reduced the typical pharmacokinetic metrics for caffeine and chlorzoxazone, but not dapsone, indicating that the activity of CYP1 and CYP2 in turbot were induced by rifampicin.
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Cafeína/farmacocinética , Clorzoxazona/farmacocinética , Sistema Enzimático del Citocromo P-450/metabolismo , Dapsona/farmacocinética , Peces Planos/metabolismo , Animales , Antituberculosos/sangre , Antituberculosos/metabolismo , Antituberculosos/farmacocinética , Área Bajo la Curva , Cafeína/sangre , Cafeína/metabolismo , Clorzoxazona/sangre , Clorzoxazona/metabolismo , Sistema Enzimático del Citocromo P-450/genética , Dapsona/sangre , Dapsona/metabolismo , Inducción Enzimática/efectos de los fármacos , Antagonistas del Ácido Fólico/sangre , Antagonistas del Ácido Fólico/metabolismo , Antagonistas del Ácido Fólico/farmacocinética , Relajantes Musculares Centrales/sangre , Relajantes Musculares Centrales/metabolismo , Relajantes Musculares Centrales/farmacocinética , Inhibidores de la Síntesis del Ácido Nucleico/farmacología , Inhibidores de Fosfodiesterasa/sangre , Inhibidores de Fosfodiesterasa/metabolismo , Inhibidores de Fosfodiesterasa/farmacocinética , Rifampin/farmacologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Schisandra chinensis (SC), officially listed as a sedative and tonic in the Chinese Pharmacopoeia, has been used as a common component in various prescriptions in Traditional Chinese Medicine (TCM) and more recently in western medicine for its antihepatotoxic effect. To assess the possible herb-drug interaction, effects of SC extracts on hepatic cytochrome P450 (P450, CYP) enzymes were studied. MATERIAL AND METHODS: Effects of SC extracts on rat hepatic CYP450 enzymes in vitro and in vivo were investigated by probe substrates method, real-time RT-PCR assay and Western blotting analysis. Furthermore, the effects of SC alcoholic extract on the PK of four SC lignans and the drugs possibly co-administrated in vivo were studied in male Sprague-Dawley rat. RESULTS: SC aqueous extract and alcoholic extract showed significant inhibitory effect on the activities of rat liver microsomal CYP1A2, 2C6, 2C11, 2D2, 2E1 and 3A1/2 in vitro. Multiple administrations of SC aqueous extract (1.5g/kg, qd×7d) and alcoholic extract (1.5g/kg, qd×7d) increased the activities, mRNA and protein expressions of CYP2E1 and CYP3A1/2, and meanwhile, inhibited the activities and mRNA expression of CYP2D2 in vivo. The in vivo metabolism of four SC lignans, such as schisandrin, schisantherin A, deoxyshisandrin and γ-schisandrin, and chlorzoxazone was significantly accelerated, exhibited by the reduced AUC and increased CLz/F, by 7-day pretreatment with SC alcoholic extract. However, both single and multiple dosing treatments of SC alcoholic extract remarkably decreased the in vivo metabolism of tacrolimus indicated by the enhanced AUC (7-12 fold) and elevated Cmax (10 fold). CONCLUSION: These results revealed that the SC extracts exhibited multifaceted effects on rat hepatic CYP450 enzymes. Herb-drug interaction should be paid intense attention between SC components and drugs metabolized by different CYP450 enzymes.
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Inhibidores Enzimáticos del Citocromo P-450/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Interacciones de Hierba-Droga , Extractos Vegetales/farmacología , Schisandra , Animales , Antidepresivos/sangre , Antidepresivos/farmacocinética , Clorzoxazona/sangre , Clorzoxazona/farmacocinética , Sistema Enzimático del Citocromo P-450/genética , Inmunosupresores/sangre , Inmunosupresores/farmacocinética , Isoenzimas/genética , Isoenzimas/metabolismo , Lignanos/sangre , Lignanos/farmacocinética , Lignanos/farmacología , Masculino , Medicina Tradicional China , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Relajantes Musculares Centrales/sangre , Relajantes Musculares Centrales/farmacocinética , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Sertralina/sangre , Sertralina/farmacocinética , Tacrolimus/sangre , Tacrolimus/farmacocinéticaRESUMEN
OBJECTIVE: To characterize the population pharmacokinetics (PK) of oral baclofen and assess impact of patient-specific covariates in children with cerebral palsy (CP) in order to support its clinical use. SUBJECTS DESIGN: Children (2-17 years of age) with CP received a dose of titrated oral baclofen from 2.5 mg 3 times a day to a maximum tolerated dose of up to 20 mg 4 times a day. PK sampling followed titration of 10-12 weeks. Serial R- and S-baclofen plasma concentrations were measured for up to 16 hours in 49 subjects. Population PK modeling was performed using NONMEM 7.1 (ICON PLC; Ellicott City, Maryland). RESULTS: R- and S-baclofen showed identical concentration-time profiles. Both baclofen enantiomers exhibited linear and dose/kg-proportional PK, and no sex differences were observed. Average baclofen terminal half-life was 4.5 hours. A 2-compartment PK model with linear elimination and transit absorption steps adequately described concentration-time profiles of both baclofen enantiomers. The mean population estimate of apparent clearance/F was 0.273 L/h/kg with 33.4% inter-individual variability (IIV), and the apparent volume of distribution (Vss/F) was 1.16 L/kg with 43.9% IIV. Delayed absorption was expressed by a mean transit time of 0.389 hours with 83.7% IIV. Body weight, a possible genetic factor, and age were determinants of apparent clearance in these children. CONCLUSION: The PK of oral baclofen exhibited dose-proportionality and were adequately described by a 2-compartment model. Our population PK findings suggest that baclofen dosage can be based on body weight (2 mg/kg per day) and the current baclofen dose escalation strategy is appropriate in the treatment of children with CP older than 2 years of age.
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Baclofeno/farmacocinética , Parálisis Cerebral/tratamiento farmacológico , Relajantes Musculares Centrales/farmacocinética , Absorción , Administración Oral , Adolescente , Baclofeno/sangre , Baclofeno/uso terapéutico , Peso Corporal , Parálisis Cerebral/sangre , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Semivida , Humanos , Masculino , Tasa de Depuración Metabólica , Modelos Estadísticos , Análisis Multivariante , Relajantes Musculares Centrales/sangre , Relajantes Musculares Centrales/uso terapéuticoRESUMEN
The pharmacokinetics of baclofen is well delineated in subjects with normal kidney function (KF); however, pharmacokinetics data in patients with chronic kidney disease (CKD) are not and dosage recommendations remain empirical. The effects of CKD on baclofen pharmacokinetics were assessed through a multi-center, open-label, single 5-mg dose, pharmacokinetics study. The KF was measured as the creatinine clearance (CrCL) calculated with the Cockroft-Gault (C-G) equation or as the estimated glomerular filtration rate (eGFR) using subjects' CKD-EPI equation. Subjects were assigned to 1 of 4 groups based on their CrCL (>80 mL/min, 50-80 mL/min; 30-50 mL/min and <30 mL/min). Cmax was not statistically different between the groups, while AUC and T1/2el increased, and CL/F decreased, with increasing severity of CKD. Baclofen's oral clearance and CrCL were statistically significantly correlated, and the trend was the same when classifying subjects either with the CKD-EPI or C-G equations. Linear equations using KF as variable were set to recommend individual dose reduction in CKD patients. Results suggest a mean dose reduction of 1/3, 1/2, and 2/3 in patients with mild, moderate, and severe CKD respectively, in order to achieve baclofen exposure comparable to that observed in healthy subjects.
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Baclofeno/farmacocinética , Agonistas de Receptores GABA-B/farmacocinética , Relajantes Musculares Centrales/farmacocinética , Insuficiencia Renal Crónica/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Baclofeno/administración & dosificación , Baclofeno/efectos adversos , Baclofeno/sangre , Creatinina/metabolismo , Femenino , Agonistas de Receptores GABA-B/administración & dosificación , Agonistas de Receptores GABA-B/efectos adversos , Agonistas de Receptores GABA-B/sangre , Tasa de Filtración Glomerular , Humanos , Masculino , Persona de Mediana Edad , Relajantes Musculares Centrales/administración & dosificación , Relajantes Musculares Centrales/efectos adversos , Relajantes Musculares Centrales/sangreRESUMEN
A simple LC/MSMS method has been developed and fully validated to determine concentrations and characterize the concentration vs. time course of methocarbamol (MCBL) and guaifenesin (GGE) in plasma after a single intravenous dose and multiple oral dose administrations of MCBL to conditioned Thoroughbred horses. The plasma concentration-time profiles for MCBL after a single intravenous dose of 15 mg/kg of MCBL were best described by a three-compartment model. Mean extrapolated peak (C0 ) plasma concentrations were 23.2 (± 5.93) µg/mL. Terminal half-life, volume of distribution at steady-state, mean residence time, and systemic clearance were characterized by a median (range) of 2.96 (2.46-4.71) h, 1.05 (0.943-1.21) L/kg, 1.98 (1.45-2.51) h, and 8.99 (6.68-10.8) mL/min/kg, respectively. Oral dose of MCBL was characterized by a median (range) terminal half-life, mean transit time, mean absorption time, and apparent oral clearance of 2.89 (2.21-4.88) h, 2.67 (1.80-2.87) h, 0.410 (0.350-0.770) h, and 16.5 (13.0-20) mL/min/kg. Bioavailability of orally administered MCBL was characterized by a median (range) of 54.4 (43.2-72.8)%. Guaifenesin plasma concentrations were below the limit of detection in all samples collected after the single intravenous dose of MCBL whereas they were detected for up to 24 h after the last dose of the multiple-dose oral regimen. This difference may be attributed to first-pass metabolism of MCBL to GGE after oral administration and may provide a means of differentiating the two routes of administration.
Asunto(s)
Expectorantes/farmacocinética , Guaifenesina/farmacocinética , Caballos/sangre , Metocarbamol/farmacocinética , Relajantes Musculares Centrales/farmacocinética , Administración Oral , Animales , Esquema de Medicación , Expectorantes/administración & dosificación , Femenino , Guaifenesina/administración & dosificación , Caballos/metabolismo , Inyecciones Intravenosas/veterinaria , Masculino , Metocarbamol/administración & dosificación , Metocarbamol/sangre , Relajantes Musculares Centrales/administración & dosificación , Relajantes Musculares Centrales/sangreRESUMEN
BACKGROUND: Eperisone hydrochloride is a centrally acting muscle relaxant prescribed for muscle stiffness that acts by depressing the activities of α and γ efferent neurons in the spinal cord and supraspinal structures. Although a case of eperisone-induced severe QT prolongation had been reported, the relationship between serum eperisone concentration and QT interval remains obscure. OBJECTIVE: The aim of this study was to investigate the relationship between serum eperisone concentration and QT interval. METHODS: Four patients who overdosed on eperisone were admitted to our hospital between January 2010 and December 2011. We took simultaneous serial measurements of serum eperisone concentration and QT interval in the intensive care unit. In total, 22 measurement points were plotted for these patients. We analyzed the correlation between the serum eperisone concentration and corrected QT (QTc) interval. RESULTS: Three men and one woman (mean age, 50 years) overdosed on eperisone with an average dose of 3087.5 mg (therapeutic dose, 150 mg/day). The mean QTc interval at arrival was 592 ms (range, 444-825 ms), and the mean serum eperisone concentration at arrival was 1257.5 ng/mL (range, 14.5-4120.0 ng/mL). The correlation coefficient was 0.833 between serum eperisone concentration and QTc interval (P < .001). CONCLUSION: Serum eperisone concentration correlates with QTc interval in patients who overdose on eperisone.
Asunto(s)
Electrocardiografía/efectos de los fármacos , Corazón/efectos de los fármacos , Relajantes Musculares Centrales/sangre , Propiofenonas/sangre , Adolescente , Anciano , Sobredosis de Droga/sangre , Sobredosis de Droga/complicaciones , Sobredosis de Droga/fisiopatología , Femenino , Corazón/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Relajantes Musculares Centrales/efectos adversos , Propiofenonas/efectos adversos , Estudios RetrospectivosRESUMEN
The pharmacokinetics of dantrolene and its active metabolite, 5-hydroxydantrolene, after a single oral dose of either 5 or 10 mg/kg of dantrolene was determined. The effects of exposure to dantrolene and 5-hydroxydantrolene on activated whole-blood gene expression of the cytokines interleukin-2 (IL-2) and interferon-γ (IFN-γ) were also investigated. When dantrolene was administered at a 5 mg/kg dose, peak plasma concentration (Cmax ) was 0.43 µg/mL, terminal half-life (t1/2 ) was 1.26 h, and area under the time-concentration curve (AUC) was 3.87 µg·h/mL. For the 10 mg/kg dose, Cmax was 0.65 µg/mL, t1/2 was 1.21 h, and AUC was 5.94 µg·h/mL. For all calculated parameters, however, there were large standard deviations and wide ranges noted between and within individual dogs: t1/2 , for example, ranged from 0.43 to 6.93 h, Cmax ratios ranged from 1.05 to 3.39, and relative bioavailability (rF) values ranged from 0.02 to 1.56. While activated whole-blood expression of IL-2 and IFN-γ as measured by qRT-PCR was markedly suppressed following exposure to very high concentrations (30 and 50 µg/mL, respectively) of both dantrolene and 5-hydroxydantrolene, biologically and therapeutically relevant suppression of cytokine expression did not occur at the much lower drug concentrations achieved with oral dantrolene dosing.