RESUMEN
Clock genes regulate mammalian circadian rhythms, and dysfunction of clock genes can contribute to various disorders. To investigate whether obstructive sleep apnoea syndrome (OSAS) influences clock gene function, the present authors examined Period1 (Per1) mRNA expression in vitro and in vivo. In eight healthy subjects and eight OSAS patients, plasma noradrenaline, serum interleukin (IL)-6, high-sensitivity C-reactive protein (hsCRP) and Per1 mRNA expression in peripheral whole blood were measured. Expression of Per1 mRNA in cultured cells was examined under IL-6 or noradrenaline stimulation in vitro. After noradrenaline was administered to mice in vivo, Per1 mRNA expression in the brain was examined. The concentrations of serum IL-6, hsCRP and plasma noradrenaline were elevated in OSAS patients, but improved by continuous positive airway pressure (CPAP) therapy. Per1 mRNA expression in the peripheral blood significantly decreased at 02:00 h by CPAP in OSAS patients. Stimulation with IL-6 did not directly induce Per1 mRNA in vitro. Administration of noradrenaline induced Per1 mRNA in the cerebral cortex of mice in vivo. The current study revealed that obstructive sleep apnoea syndrome caused clock gene dysfunction, and continuous positive airway pressure helped to improve it. Sympathetic activation and elevation of the plasma noradrenaline concentration in obstructive sleep apnoea syndrome may be one of the factors involved in disorders of Period1 mRNA expression.
Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Trastornos Cronobiológicos/genética , Ritmo Circadiano/genética , Proteínas Nucleares/metabolismo , Síndromes de la Apnea del Sueño/complicaciones , Adulto , Animales , Estudios de Casos y Controles , Proteínas de Ciclo Celular/genética , Células Cultivadas , Trastornos Cronobiológicos/terapia , Presión de las Vías Aéreas Positiva Contínua , Femenino , Fibroblastos , Humanos , Interleucina-6/fisiología , Leucocitos , Masculino , Ratones , Persona de Mediana Edad , Norepinefrina/fisiología , Proteínas Nucleares/genética , Proteínas Circadianas Period , ARN Mensajero/metabolismoRESUMEN
BACKGROUND AND PURPOSE: Secretory phospholipase A2 (sPLA2) is implicated in atherosclerosis, although the effects of specific sPLA2 inhibitors have not been studied. We investigated the effects of the indole analogue indoxam on low-density lipoprotein (LDL) modification by sPLA2 enzymes of different types and on the associated inflammatory responses in human umbilical vein endothelial cells (HUVEC). EXPERIMENTAL APPROACH: LDL modification was assessed by measuring the contents of two major molecular species of lysophosphatidylcholine (LPC) using electrospray ionization-liquid chromatography/mass spectrometry. The proinflammatory activity of the modified LDL was evaluated by determining monocyte chemoattractant protein-1 (MCP-1) mRNA expression and transcriptional factor nuclear factor-kappaB (NF-kappaB) activity in HUVEC. KEY RESULTS: Indoxam dose-dependently inhibited palmitoyl- and stearoyl-LPC production in LDL incubated with snake venom sPLA2 (IC50 1.2 microM for palmitoyl-LPC, 0.8 microM for stearoyl-LPC). MCP-1 mRNA expression and NF-kappaB activity were enhanced by venom sPLA2-treated LDL, which was completely suppressed by indoxam but not by thioetheramide-PC, a competitive sPLA2 inhibitor. Indoxam also suppressed LPC production in LDL treated with human synovial type IIA sPLA2. Tumour necrosis factor alpha (TNFalpha) increased type V sPLA2 expression in HUVEC. Indoxam dose-dependently suppressed LPC production in native and glycoxidized LDL treated with TNFalpha-stimulated HUVEC. Indoxam suppressed MCP-1 mRNA expression and NF-kappaB activity in TNFalpha-stimulated HUVEC incubated with native or glycoxidized LDL. CONCLUSIONS AND IMPLICATIONS: Indoxam prevented sPLA2-induced LPC production in native and glycoxidized LDL as well as LDL-induced inflammatory activity in HUVEC. Our results suggest that indoxam may be a potentially useful anti-atherogenic agent.
Asunto(s)
Carbamatos/farmacología , Inhibidores Enzimáticos/farmacología , Indolizinas/farmacología , Inhibidores de Fosfolipasa A2 , Factor de Necrosis Tumoral alfa/efectos de los fármacos , Carbamatos/administración & dosificación , Células Cultivadas , Quimiocina CCL2/efectos de los fármacos , Quimiocina CCL2/metabolismo , Relación Dosis-Respuesta a Droga , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Inhibidores Enzimáticos/administración & dosificación , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Indolizinas/administración & dosificación , Lipoproteínas LDL/efectos de los fármacos , Lipoproteínas LDL/metabolismo , Lisofosfatidilcolinas/metabolismo , FN-kappa B/efectos de los fármacos , FN-kappa B/metabolismo , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Venas Umbilicales/citología , Venas Umbilicales/metabolismoRESUMEN
OBJECTIVE: To clarify the observed variability of digoxin disposition by performing a population pharmacokinetic analysis in a Japanese population. DESIGN: Retrospective analysis of clinical pharmacokinetic data. PATIENTS AND PARTICIPANTS: Data were obtained from 106 patients with heart failure and atrial fibrillation (43 males and 63 females). METHODS: Digoxin concentrations in serum were measured by fluorescence polarisation immunoassay. Population pharmacokinetic analysis was performed using a 2-compartment open pharmacokinetic model with the computer program NONMEM. RESULTS: 246 serum concentrations were obtained. Final pharmacokinetic parameters were: CL (L/h) = (0.036 x TBW + 0.112 x CL(CR)) x 0.77SPI x 0.784CCB, V1 = 1.83 L/kg, V2 = 22.6 L/kg and Q = 0.629 L/h/kg, where CL is total body clearance, V1 and V2 are the apparent volumes of distribution in the central and peripheral compartments, Q is intercompartmental clearance, TBW is total bodyweight (in kg), CL(CR) is creatinine clearance (in ml/min), SPI = 1 for concomitant administration of spironolactone (and zero otherwise) and CCB = 1 for concomitant administration of calcium antagonists (and zero otherwise). Concomitant administration of digoxin and spironolactone resulted in a 23% decrease in digoxin clearance. Concomitant administration of digoxin and calcium antagonists (diltiazem, nicardipine, nifedipine or verapamil) resulted in a 21.6% decrease in digoxin clearance. CONCLUSIONS: The estimated population parameter values may assist clinicians in the individualisation of digoxin dosage regimens.
Asunto(s)
Cardiotónicos/farmacocinética , Digoxina/farmacocinética , Insuficiencia Cardíaca/tratamiento farmacológico , Modelos Biológicos , Cardiotónicos/sangre , Cardiotónicos/uso terapéutico , Computadores , Digoxina/sangre , Digoxina/uso terapéutico , Femenino , Insuficiencia Cardíaca/metabolismo , Humanos , Japón , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Estudios Retrospectivos , Distribución TisularRESUMEN
BACKGROUND: In antiepileptic drugs, the marked inter- and intrapatient variability of the level-dose ratio makes it difficult to predict serum concentrations from the administered per kg dose. It is therefore important to identify factors, such as age and comedication, that could contribute to this observed variability. OBJECTIVE: To investigate the effect of age and comedication on clonazepam (CZP) level-dose (L/D) ratios. METHOD: A retrospective evaluation of data from 137 epileptic patients who had received clonazepam. RESULTS: The CZP L/D ratio increased slowly with age up to 15 years in patients on monotherapy. Associated antiepileptic therapy affected the CZP L/D ratio, which was significantly reduced in patients on polytherapy as compared to patients on monotherapy. CONCLUSION: The study therefore suggests that routine monitoring of CZP serum levels is extremely useful, especially in the paediatric age group, and in patients who require associated antiepileptic medication.
Asunto(s)
Anticonvulsivantes/farmacocinética , Clonazepam/farmacocinética , Epilepsia/tratamiento farmacológico , Adolescente , Factores de Edad , Niño , Preescolar , Clonazepam/administración & dosificación , Clonazepam/sangre , Interacciones Farmacológicas , Quimioterapia Combinada , Epilepsia/sangre , Epilepsia/etnología , Femenino , Humanos , Lactante , Japón , Masculino , Análisis de Regresión , Estudios RetrospectivosRESUMEN
To investigate the effect of repeated administration time on the development of tolerance, male ICR mice, housed under 12:12-h light/dark cycle (7:00 AM, lights on), were treated with haloperidol 4 mg/kg/day i.p. at 9:00 AM or 9:00 PM, the time nearly corresponding to the maximal or minimal catalepsy responses to a single dose, respectively, for 14 days and catalepsy responses were monitored at 1 h after administration each day. The findings indicated that, on day 1 to day 6, a greater development of tolerance was seen in the group of mice treated at 9:00 AM, and catalepsy behavior exhibited a significant difference between the two dosing times (P < 0.01). The study of D(2) receptor mRNA expression in mouse striatum revealed that the phase of D(2) receptor mRNA rhythm was similar to that of catalepsy response, with the maximum around mid-light and the minimum around mid-dark. After repeated administration, the increase in D(2) receptor mRNA levels in mice treated with haloperidol at 9:00 AM was higher than that of mice treated with haloperidol at 9:00 PM. In addition, from a [(3)H]spiperone binding study, the amount of binding site [(3)H]spiperone after repeated injection of haloperidol at 9:00 AM was greater than that after repeated injection at 9:00 PM. These findings demonstrate the importance of dosing time on the susceptibility to extrapyramidal effects and the relation of administration time to D(2) receptor change and tolerance.
Asunto(s)
Antipsicóticos/farmacología , Catalepsia/inducido químicamente , Antagonistas de Dopamina/farmacología , Haloperidol/farmacología , Animales , Ritmo Circadiano/fisiología , Relación Dosis-Respuesta a Droga , Tolerancia a Medicamentos , Masculino , Ratones , Ratones Endogámicos ICR , Neostriado/efectos de los fármacos , Neostriado/metabolismo , ARN Mensajero/biosíntesis , ARN Mensajero/aislamiento & purificación , Receptores de Dopamina D2/biosíntesis , Receptores de Dopamina D2/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Espiperona , Factores de TiempoRESUMEN
Whether the diurnal rhythm of cell cycle is associated with that of interferon-alpha/beta receptor (IFNAR) expression was investigated in implanted-tumor cells. The expression of IFNAR mRNA significantly increased when the proportion of tumor cells in DNA synthesis (S) phase increased in vitro. A diurnal rhythm was observed for cell cycle distribution in implanted-tumor cells. The specific binding of interferon-alpha to receptor and IFNAR mRNA increased when the proportion of tumor cells in S phase increased in vivo. The time-dependent expression of IFNAR was supported by that of transcription factor level induced by interferon-beta. The present result suggests that the rhythm of IFNAR expression is closely related to that of cell cycle distribution in implanted-tumor cells.
Asunto(s)
Ciclo Celular/fisiología , Ritmo Circadiano/fisiología , Melanoma/metabolismo , Receptores de Interferón/metabolismo , Animales , Western Blotting , Citometría de Flujo , Interferón-alfa/metabolismo , Interferón beta/uso terapéutico , Melanoma/tratamiento farmacológico , Ratones , Trasplante de Neoplasias , ARN Mensajero/biosíntesis , Receptor de Interferón alfa y beta , Receptores de Interferón/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales CultivadasRESUMEN
OBJECTIVE: The steady-state concentrations of digoxin at trough levels were studied to establish the role of patient characteristics in estimating doses for digoxin using routine therapeutic drug monitoring data. METHOD: The data (n = 448) showing steady state after repetitive oral administration in 172 hospitalized neonates and infants were analyzed using Nonlinear Mixed Effect Model (NONMEM), a computer program designed to analyze pharmacokinetics in study populations by allowing pooling of data. Analysis of the pharmacokinetics of digoxin was accomplished using a simple steady-state pharmacokinetic model. The effects of a variety of developmental and demographic factors on the clearance of digoxin were investigated. RESULTS: Estimates generated using NONMEM indicated that clearance of digoxin (l.h-1) was influenced by the demographic variables of age, total body weight, serum creatinine, the coadministration of spironolactone, and the presence or absence of congestive heart failure. The interindividual variability in digoxin clearance was modeled with proportional errors with an estimated coefficient of variation of 32.1%, and the residual variability was 28.9%. In the validation set of 66 patients, the performance (bias, precision) of the final population model was good (mean prediction error -0.04 ng.ml-1; mean absolute prediction error 0.20 ng.ml-1).
Asunto(s)
Cardiotónicos/farmacocinética , Digoxina/farmacocinética , Cardiotónicos/sangre , Distribución de Chi-Cuadrado , Digoxina/sangre , Diuréticos/farmacocinética , Monitoreo de Drogas/métodos , Monitoreo de Drogas/estadística & datos numéricos , Femenino , Humanos , Lactante , Recién Nacido , Japón , Masculino , Modelos Biológicos , Análisis de Regresión , Reproducibilidad de los Resultados , Espironolactona/farmacocinéticaRESUMEN
The clearance of recombinant human granulocyte-colony stimulating factor (rhG-CSF) is known to decrease with dose increase, and to be saturable. The average clearance after intravenous administration will be lower than that after subcutaneous administration. Therefore, the apparent absolute bioavailability with subcutaneous administration calculated from the AUC ratio is expected to be an underestimate. The absorption pharmacokinetics after subcutaneous administration was examined using the results of the bioequivalency study between two rhG-CSF formulations with a dose of 2 microg/kg. The analysis was performed using a modified Wagner-Nelson method with the nonlinear elimination model. The apparent absolute bioavailability for subcutaneous administration was 56.9 and 67.5% for each formulation, and the ratio between them was approximately 120%. The true absolute bioavailability was, however, estimated to be 89.8 and 96.9%, respectively, and the ratio was approximately 108%. The absorption pattern was applied to other doses, and the predicted clearance values for subcutaneous and intravenous administrations were then similar to the values for several doses reported in the literature. The underestimation of bioavailability was around 30%, and the amplification of difference was 2.5 times, from 8 to 20%, because of the nonlinear pharmacokinetics. The neutrophil increases for each formulation were identical, despite the different bioavailabilities. The reason for this is probably that the amount eliminated through the saturable process, which might indicate the amount consumed by the G-CSF receptor, was identical for each formulation.
Asunto(s)
Factor Estimulante de Colonias de Granulocitos/farmacocinética , Dinámicas no Lineales , Albúmina Sérica/metabolismo , Absorción , Análisis de Varianza , Disponibilidad Biológica , Humanos , Infusiones Intravenosas , Inyecciones Subcutáneas , Tasa de Depuración Metabólica , Proteínas Recombinantes/farmacocinética , Equivalencia TerapéuticaRESUMEN
The effectiveness and toxicity of many drugs vary depending on the relationship between the dosing schedule and the 24-hour rhythms of biochemical, physiological and behavioral processes. In addition, several drugs can cause alterations to the 24-hour rhythms leading to illness and altered homeostatic regulation. However, the mechanisms of this drug-based disruption of circadian 'clock' genes remain unclear. Here, we show the disruptive effect of interferon-alpha on the rhythm of locomotor activity, body temperature and clock-gene mRNA expression in the periphery and suprachiasmatic nuclei, a primary circadian pacemaker. The rhythmicity of clock genes and the photic induction of the Per gene in suprachiasmatic nuclei were disturbed by the repetitive administration of interferon-alpha. Moreover, alteration of clock function, a new concept of adverse effects, can be overcome by optimizing the dosing schedule to minimize adverse drug effects.
Asunto(s)
Relojes Biológicos/efectos de los fármacos , Interferón-alfa/farmacología , Animales , Temperatura Corporal , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Factor 3 de Genes Estimulados por el Interferón , Subunidad gamma del Factor 3 de Genes Estimulados por el Interferón , Interferón-alfa/administración & dosificación , Masculino , Ratones , Ratones Endogámicos ICR , Actividad Motora , Proteínas Nucleares/genética , Proteínas Circadianas Period , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Núcleo Supraquiasmático/efectos de los fármacos , Núcleo Supraquiasmático/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Nonlinear mixed effects modeling was used to estimate the effects of clonazepam-carbamazepine interaction on clearance values using 359 serum levels gathered from 183 pediatric and adult epileptic patients (age range, 0.3-26.8 years) during their clinical routine care. Patients received the administration of clonazepam and/or carbamazepine. The final model describing clonazepam clearance was CL = 179.0 x TBW(-0.231) x 1.22(CBZ), where CL is total body clearance (mL/kg/h) and TBW is total body weight (kg); CBZ = 1 for concomitant administration of carbamazepine and CBZ = zero otherwise. The final model describing carbamazepine clearance was CL = 92.7 x TBW(-0.394) x DOSE(0-397) x 0.795(CZP), where DOSE is the daily dose of carbamazepine (mg/kg/day); CZP = 1 for concomitant administration of clonazepam and CZP = zero otherwise. Concomitant administration of clonazepam and carbamazepine resulted in a 22% increase in clonazepam clearance and a 20.5% decrease in carbamazepine clearance.
Asunto(s)
Anticonvulsivantes/farmacocinética , Carbamazepina/farmacocinética , Clonazepam/farmacocinética , Adolescente , Adulto , Anticonvulsivantes/sangre , Carbamazepina/sangre , Distribución de Chi-Cuadrado , Niño , Preescolar , Clonazepam/sangre , Interacciones Farmacológicas/fisiología , Quimioterapia Combinada , Femenino , Humanos , Lactante , Japón/epidemiología , Masculino , Modelos Biológicos , Modelos Químicos , Pacientes/estadística & datos numéricos , Farmacoepidemiología , Estudios RetrospectivosRESUMEN
The influences of dosing time and dosing schedule on the plasma alpha interferon (IFN-alpha) concentration and the production of anti-IFN-alpha neutralizing antibodies were investigated in ICR male mice adapted to cycles of 12 h of light and 12 h of dark. In mice pretreated with IFN-alpha for 21 days, the plasma IFN-alpha concentrations were significantly lower than those in control mice (P < 0.01). The clearance of IFN-alpha and its volume of distribution obtained at steady state were significantly higher in the animals with IFN-alpha pretreatment than in the mice without IFN-alpha pretreatment. The area under the concentration-time curve and the mean residence time of IFN-alpha were significantly smaller in IFN-alpha-pretreated animals than in control animals. The plasma IFN-alpha levels (measured 2 h after dosing) were significantly lower in mice treated daily with IFN-alpha, while the anti-IFN-alpha neutralizing antibody levels (measured 24 h after dosing) were significantly increased on days 15 and 21 of treatment. Plasma IFN-alpha levels were significantly decreased in association with the production of anti-IFN-alpha neutralizing antibodies in mice treated with IFN-alpha daily at either 0900 or 2100 h. By contrast, the plasma IFN-alpha levels (measured 2 h after dosing) remained stable in mice treated with IFN-alpha at 0900 h on alternate days, while they were significantly lower after 21 days of treatment in mice treated with IFN-alpha at 2100 h on alternate days. These changes were associated with a significant increase in the levels of anti-IFN-alpha neutralizing antibodies in the latter group. The present findings suggest that an appropriate dosing schedule and/or dosing time for IFN-alpha may reduce the level of production of anti-IFN-alpha neutralizing antibodies in experimental and clinical situations.
Asunto(s)
Anticuerpos Bloqueadores/metabolismo , Antivirales/farmacocinética , Interferón-alfa/farmacocinética , Animales , Antivirales/inmunología , Área Bajo la Curva , Semivida , Interferón alfa-2 , Interferón-alfa/inmunología , Masculino , Ratones , Ratones Endogámicos ICR , Proteínas RecombinantesRESUMEN
The steady-state trough concentrations of haloperidol were studied to clarify the role of the characteristics of Japanese patients in estimating haloperidol dosing regimens by using routine therapeutic drug-monitoring data. Nonlinear mixed-effects modeling (NONMEM) was used to estimate the effect of a variety of developmental and demographic factors on haloperidol clearance values using 270 serum level measurements obtained from 191 patients during their clinical course. The final model describing haloperidol's relative clearance was CL = 0.74 x TBW(0.594) x DOSE(0.326) x 1.32CO1 x 0.867AGE, where CL is clearance (measured in liters per hour), TBW is the total body weight (in kilograms), DOSE is the daily dose of haloperidol (in grams per kilogram per day), CO1 = 1 for concomitant administration of antiepileptic drugs (phenobarbital, phenytoin, or carbamazepine) and CO1 = 0 otherwise, and AGE = 1 for patients aged 55 years or older and AGE = 0 otherwise. Concomitant administration of haloperidol and antiepileptic drugs resulted in a 32% increase in haloperidol clearance. Patients aged 55 years or older showed a 13.3% reduction in clearance values compared with the younger population.
Asunto(s)
Antipsicóticos/farmacocinética , Haloperidol/farmacocinética , Modelos Biológicos , Adolescente , Adulto , Anciano , Antipsicóticos/sangre , Intervalos de Confianza , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas , Femenino , Haloperidol/sangre , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Esquizofrenia/sangreRESUMEN
The influence of dosing time on the pharmacological effect (antiviral activity) of interferon-alpha (IFN-alpha), and the pharmacological and pharmacokinetic mechanisms, were investigated in ICR male mice under a 12-h light/dark cycle (lights on from 7:00 AM to 7:00 PM). 2'-5'Oligoadenylate synthetase activity in plasma at 24 h after IFN-alpha (10 MI.U./kg, i.v.) injection, as an index of antiviral activity, was significantly higher for injections given at 9:00 AM than for injections given at 9:00 PM (P <.05). The uptake of [(3)H]thymidine by lymphocytes after 24-h incubation with IFN-alpha, as an index of lymphocyte-stimulating effect, was significantly higher in cells obtained at 9:00 AM than in the cells obtained at 9:00 PM (P <.01). The number of receptors per cell and the expression of interferon-stimulated gene factor in lymphocytes after 24-h incubation with IFN-alpha were significantly higher in the cells obtained at 9:00 AM than at 9:00 PM (P <.05). A significant dosing time-dependent difference was demonstrated for the pharmacokinetic parameters of IFN-alpha, which showed higher clearance for injections given at 9:00 PM than for those at 9:00 AM (P <.05). The metabolism of IFN-alpha was significantly higher in kidney obtained at 9:00 PM than at 9:00 AM (P <.05). These findings support that choosing the most appropriate time of day for administration of IFN-alpha, associated with the rhythmicity of IFN-alpha receptor function and IFN-alpha pharmacokinetics, may increase the antiviral activity in experimental and clinical situations.
Asunto(s)
Antivirales/farmacocinética , Interferón-alfa/farmacocinética , 2',5'-Oligoadenilato Sintetasa/sangre , Animales , Antivirales/administración & dosificación , Antivirales/farmacología , Fenómenos Cronobiológicos , Ritmo Circadiano/fisiología , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/sangre , Esquema de Medicación , Factor 1 Regulador del Interferón , Interferón-alfa/administración & dosificación , Interferón-alfa/farmacología , Radioisótopos de Yodo , Riñón/anatomía & histología , Riñón/metabolismo , Activación de Linfocitos/efectos de los fármacos , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Linfocitos/metabolismo , Masculino , Ratones , Ratones Endogámicos ICR , Fosfoproteínas/biosíntesis , Fosfoproteínas/sangre , Receptor de Interferón alfa y beta , Receptores de Interferón/metabolismo , Receptores de Interferón/fisiología , Factores de TiempoRESUMEN
The mechanisms underlying the dosing time-dependent change in the antitumor effect of interferon-beta (IFN-beta) were investigated based on the sensitivity of tumor cells and the pharmacokinetics of the drug. Tumor-bearing mice were housed under standardized light-dark cycle conditions (lights on at 7:00 AM, off at 7:00 PM) with food and water available ad libitum. The antitumor effect of IFN-beta (0.5 MI.U./kg, intratumoral) was more efficient in early light phase than in early dark phase. The higher antitumor effect of IFN-beta was observed when specific binding of IFN receptor and DNA synthesis in tumor cells increased, and the lower effect was observed when these levels decreased. The dosing time-dependent effect of IFN-beta was supported by the time-dependent expression of transcription factor (signal transducers and activators of transcription 1) and cell proliferation inhibitor (p21 wild-type p53-activated fragment 1) protein induced by IFN-beta. There was a significant dosing time-dependent change in IFN-beta concentration in tumor, with a higher level in early light phase and a lower level in early dark phase. The dosing time-dependent change of IFN-beta concentration in tumor was associated with that of IFN-beta-induced antitumor effect. These results suggest that by choosing the most suitable dosing time for IFN-beta, the efficacy of the drug can be increased in certain experimental and clinical situations.
Asunto(s)
Antineoplásicos/administración & dosificación , Ritmo Circadiano/fisiología , Interferón beta/administración & dosificación , Animales , Antineoplásicos/farmacocinética , Ciclo Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Ciclinas/metabolismo , Proteínas de Unión al ADN/metabolismo , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Humanos , Interferón-alfa/metabolismo , Interferón beta/farmacocinética , Masculino , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/metabolismo , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Receptor de Interferón alfa y beta , Receptores de Interferón/metabolismo , Factor de Transcripción STAT1 , Transactivadores/metabolismoRESUMEN
With antiepileptic drugs, the marked inter- and intrapatient variability of the concentration-dose ratio makes it difficult to predict serum concentrations from the dose administered per kilogram. The effects of comedication on steady-state serum concentration/dose ratios of antiepileptic drugs were evaluated retrospectively in 669 pediatric patients. To avoid complex pharmacokinetic interactions among multiple antiepileptic drugs, the data on serum concentrations in the current study were collected from patients who were co-administered only one additional antiepileptic drug (phenobarbital-carbamazepine, phenobarbital-valproic acid, or carbamazepine-valproic acid) or who received monotherapy. The concentration/dose ratio for the antiepileptic drugs increased significantly with body weight in children up to 15 years old. Associated therapy with antiepileptic drugs affected the concentration/dose ratio. Therefore, routine monitoring of serum concentrations of the antiepileptic drugs is extremely useful, particularly in children and in patients who require associated antiepileptic medication.
Asunto(s)
Anticonvulsivantes/farmacocinética , Carbamazepina/farmacocinética , Epilepsia/metabolismo , Fenobarbital/farmacocinética , Ácido Valproico/farmacocinética , Adolescente , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/sangre , Disponibilidad Biológica , Carbamazepina/sangre , Niño , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Quimioterapia Combinada , Humanos , Japón , Fenobarbital/sangre , Estudios Retrospectivos , Ácido Valproico/sangreRESUMEN
Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is used to counter chemotherapy-induced neutropenia. Our previous study showed an inverse correlation between serum rhG-CSF levels and the number of circulating neutrophils in cancer patients (H. Takatani, H. Soda, M. Fukuda, M. Watanabe, A. Kinoshita, T. Nakamura, and M. Oka, Antimicrob. Agents Chemother. 40:988-991, 1996). The aim of this study was to clarify the relationship between rhG-CSF clearance and G-CSF receptors on circulating neutrophils. In five cancer patients receiving chemotherapy, a bolus dose of rhG-CSF (5 microg/kg) was injected intravenously during defined phases of posttreatment neutropenia and neutrophilia. Serum rhG-CSF levels were measured by a chemiluminescence enzyme immunoassay and analyzed by moment analysis. G-CSF receptors on neutrophils were detected by flow cytometry with biotinylated rhG-CSF. rhG-CSF clearance was significantly higher at neutrophilia than at neutropenia (1,497 +/- 132 versus 995 +/- 266 ml/h; P < 0.01). The percentage of G-CSF receptor-positive neutrophils, reflecting the number of G-CSF receptors per cell, was low at neutropenia without rhG-CSF therapy (44.5% +/- 22.1%) and high at neutrophilia with rhG-CSF therapy (73. 0% +/- 11.4%; P < 0.01). rhG-CSF clearance closely correlated with the percentage of G-CSF receptor-positive neutrophils (r2 = 0.91; P < 0.0001) and neutrophil count (r2 = 0.72; P < 0.005). Our results indicate that, in cancer patients receiving chemotherapy, rhG-CSF increases the number of G-CSF receptors per cell as well as circulating neutrophil counts, resulting in modulation of its own clearance.
Asunto(s)
Adyuvantes Inmunológicos/farmacocinética , Factor Estimulante de Colonias de Granulocitos/farmacocinética , Neoplasias Pulmonares/sangre , Neutrófilos/metabolismo , Neoplasias Ováricas/sangre , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/farmacología , Anciano , Anciano de 80 o más Años , Femenino , Citometría de Flujo , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/farmacología , Humanos , Inyecciones Intravenosas , Lenograstim , Masculino , Persona de Mediana Edad , Neutrófilos/efectos de los fármacos , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/efectos de los fármacos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/farmacologíaRESUMEN
Influence of dosing time on pharmacological effects and toxicity of KE-SI-TO (KST) components, as well as the role of each component in the circadian rhythms of KST, was investigated in ICR male mice under an LD (12:12) cycle. The mice given Cinnamomi Cortex (258 mg/kg, i.p.) or Paeoniae Radix (258 mg/kg, i.p.) showed a significant circadian rhythm in the time spent on the hot plate with the shortest latency at 0900 and the longest one at 0100 (p<0.01, respectively). The mice given Cinnamomi Cortex or Glycyrrhizae Radix (129 mg/kg, i.p.) showed a significant circadian rhythm with the lowest rectal temperature (RT) at 1700 and the highest one at 0500 (p<0.01, respectively). Cinnamomi Cortex (850 mg/kg, i.p.)- or Glycyrrhizae Radix (2500 mg/kg, i.p.)-induced toxicity showed a significant circadian rhythm with the highest mortality at 1700 and the lowest one at 0500 (p<0.05, respectively). The rhythmic patterns of the drug-induced analgesia, hypothermia and toxicity resembled the overall rhythms occurring after KST (1000 or 6000 mg/kg, i.p.) injection. These results suggest that the circadian rhythms in actions of Cinnamomi Cortex, Paeoniae Radix and Glycyrrhizae Radix are mainly responsible for the rhythm in the effects and toxicity of KST.
Asunto(s)
Ritmo Circadiano/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Analgésicos/farmacología , Analgésicos/toxicidad , Animales , Temperatura Corporal/efectos de los fármacos , Fenómenos Cronobiológicos , Medicamentos Herbarios Chinos/toxicidad , Hipotermia/inducido químicamente , Masculino , Ratones , Ratones Endogámicos ICR , Actividad Motora/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Factores de TiempoRESUMEN
OBJECTIVE: Nonlinear mixed-effects modeling (NONMEM) was used to estimate the effects of drug drug interaction on phenobarbitone clearance values, using 648 serum levels gathered during the routine clinical care of 349 pediatric and adult epileptic patients (age range, 0.4-33.3 years). Patients received phenobarbitone as monotherapy or in combination with either of the antiepileptic drugs carbamazepine or valproic acid. RESULTS: The final model describing phenobarbitone clearance was CL = 52.3 x TBW(-0.567) x CO, where CL is clearance (ml x kg(-1) x h(-1)), TBW is total body weight (kg) and CO is a scaling factor for concomitant medication with a value of 1 for patients on phenobarbitone monotherapy, 46.4(-1/TBW) for those patients receiving concomitant carbamazepine and 0.642 for those patients receiving concomitant valproic acid. Phenobarbitone CL was highest in the very young and decreased in a weight-related fashion in children, with minimal changes observed in adults. This pattern was consistent whether phenobarbitone was administered alone or coadministered with carbamazepine or valproic acid. When phenobarbitone was coadministered with carbamazepine or valproic acid, phenobarbitone CL decreased compared with that in monotherapy. Its magnitudes in the presence of carbamazepine are maximal in early childhood (about 54%) and decreased in a weight-related fashion in older children, with minimal changes observed in adults. Concomitant administration of phenobarbitone and valproic acid resulted in a 35.8% decrease of phenobarbitone CL.
Asunto(s)
Anticonvulsivantes/farmacocinética , Fenobarbital/farmacocinética , Adolescente , Adulto , Factores de Edad , Anticonvulsivantes/uso terapéutico , Peso Corporal , Carbamazepina/farmacología , Carbamazepina/uso terapéutico , Niño , Preescolar , Interacciones Farmacológicas , Quimioterapia Combinada , Epilepsia/tratamiento farmacológico , Femenino , Humanos , Lactante , Masculino , Fenobarbital/uso terapéutico , Estudios Prospectivos , Análisis de Regresión , Factores Sexuales , Ácido Valproico/farmacología , Ácido Valproico/uso terapéuticoRESUMEN
The role of the sensitivity of bone marrow cells to, and the pharmacokinetics of granulocyte colony-stimulating factor (G-CSF) on the rhythm of leukocyte-increasing effect was investigated in ICR male mice housed under a standardized light-dark cycle (lights on at 0700, off at 1900). A significant circadian rhythm was demonstrated for leukocyte counts at 24 hr after G-CSF (250 microg/kg, s.c.) injection at six different circadian times (P < .01). The leukocyte counts of mice given G-CSF at 0500, 0900, 1300 or 1700 were significantly higher than those of mice given G-CSF at 2100 (P < .01, respectively). The rhythmic pattern resembled overall the rhythm occurring after saline injection. In the comparison between leukocyte counts after G-CSF injection at 0700 and 1900, the time when leukocyte counts are equal in nondrugged state, the leukocyte counts at 24 hr after G-CSF (250 microg/kg, i.v.) injection were approximately 50% higher in mice injected with the drug at 0700 than at 1900 (P < .01). Bone marrow cultures obtained at two times of day resulted in different numbers of myeloid colonies even when treated with the same concentrations of G-CSF in vitro. The colony-forming activity of G-CSF was significantly more potent at 0700 than at 1900 (P < .01). The plasma G-CSF concentrations after G-CSF (250 or 5 microg/kg, i.v.) injection were significantly higher in mice receiving injections with the drug at 0700 than at 1900 (P < .05, respectively). The area under the curve and mean residence time were significantly larger in mice injected with the drug at 0700 than at 1900 (P < .01, P < .05, respectively). Our suggests that the rhythm of G-CSF activity is caused by that of the sensitivity of bone marrow cells to, and the pharmacokinetics of the drug.