RESUMO
(exo, exo)-2-Aryltropane-3-carboxylic esters of types 6, 7, and 10 lower circulating blood glucose levels by 60--80%. This activity is accompanied by an analgesic activity roughly equal to that of codeine. Both of these activities reside in the 1R enantiomer and extensive structure-activity studies failed to separate them. The specific opioid antagonist nalorphine blocks the analgesic activity but does not diminish the hypoglycemic action. Conformational integrity afforded by the ethylene bridge is neccessary for the observed activities.
Assuntos
Analgésicos Opioides/síntese química , Hipoglicemiantes/síntese química , Tropanos/síntese química , Administração Oral , Animais , Catalepsia/induzido quimicamente , Remoção de Radical Alquila , Cães , Humanos , Hipoglicemiantes/administração & dosagem , Injeções Subcutâneas , Masculino , Camundongos , Conformação Molecular , Ratos , Insuficiência Respiratória/induzido quimicamente , Estereoisomerismo , Relação Estrutura-Atividade , Tropanos/administração & dosagem , Tropanos/farmacologiaRESUMO
The FT-IR (Fourier Transform Infrared) Spectrum of [Met 5]-enkephalinamide in aqueous solution shows the presence of both the beta-turn and beta-sheet conformations. The beta-turn and beta-sheet conformations of enkephalins have been proposed to play a role in receptor selectivity. Addition of ethanol alters these secondary structural features and hence the effect of ethanol on ligand-receptor interaction may be mediated primarily through conformational changes of the ligand rather than those of the receptor.
Assuntos
Etanol/farmacologia , Peptídeos/metabolismo , Receptores Opioides/metabolismo , Animais , Encefalina Metionina/análogos & derivados , Encefalina Metionina/metabolismo , Análise de Fourier , Conformação ProteicaRESUMO
A rapid and specific method for the determination of bleomycin A2 is described. A 50-microliter aliquot of 20% trichloroacetic acid was added to 200 microliter of plasma. The sample was vortexed and centrifuged, and 50 microliter of the clear supernate was injected into a liquid chromatograph equipped with a microparticulate reversed-phase column and a fixed wavelength detector. Elution was carried out using methanol-acetonitrile-0.0085 M heptanesulfonic acid-acetic acid. A linear calibration curve was found in the 0.05-5 microgram/ml range with an estimated precision of +/-6% (CV). Preliminary pharmacokinetic data in the rabbit also are reported.
Assuntos
Bleomicina/sangue , Animais , Cromatografia Líquida de Alta Pressão , Feminino , Cinética , Métodos , CoelhosRESUMO
A new rapid and inexpensive method for the determination of therapeutic plasma glycerin concentrations is described. In this method, acetic anhydride and pyridine are added to 15 microliter of plasma. After brief incubation and centrifugation, an aliquot of the supernate is injected directly onto the 3% OV-1 column. A linear calibration curve was found in the 0.05--3-mg/ml range, with the precision of the assay estimated to be +/-5.5% (RSD). The method was used to determining preliminary pharmacokinetic data in the rabbit.
Assuntos
Glicerol/sangue , Acetilação , Cromatografia Gasosa , Enzimas , Humanos , Métodos , Fatores de TempoRESUMO
A simple, sensitive, and specific high-performance liquid chromatographic procedure was developed to assay norethindrone--mestranol combination tablets. The method involves a chloroform extraction of a single pulverized tablet. After centrifugation, and aliquot of the supernate was injected into a modular high-performance liquid chromatograph. The effluent from the silica column was monitored serially with a fixed-wavelength UV detector (254 nm) for norethindrone quantitation and a fluorescence detector (230 nm for excitation and 280 nm cutoff filter for emission) for mestranol quantitation. Progesterone was used as an internal standard. The method was employed successfully in content uniformity studies of several brands of commercially available tablets.
Assuntos
Mestranol/análise , Noretindrona/análise , Cromatografia Líquida de Alta Pressão/métodos , Anticoncepcionais Orais Combinados/análise , Comprimidos/análiseRESUMO
The procedure for pancuronium bromid ion-pair extraction into chloroform using rose bengal and subsequent fluorometric measurement was modified by changing the extraction pH and eliminating phenol, ethanol, and acetone to give easier operation and enhanced fluorescence stability. Precision, accuracy, and sensitivty were evaluated over 0.14-0.82 microgram/ml (CV = 14; relative error = 9%) and 0.05-0.17 microgram/ml (CV = 19; relative error = 21%). Following a dose of 0.1 ml/kg for cesarean section in humans, the mean maternal arterial and umbilical venous serum concentrations of pancuronium bromide and metabolites were 0.52 and 0.12 microgram/ml, respectively, at delivery (mean of 13 min after injection).
Assuntos
Pancurônio/sangue , Feminino , Sangue Fetal/análise , Humanos , Concentração de Íons de Hidrogênio , Técnicas In Vitro , Métodos , Gravidez , Espectrometria de FluorescênciaRESUMO
The comparative toxicokinetics of oxazepam were studied in F344 rats, B6C3F1 mice, and Swiss-Webster mice of both sexes after an i.v. dose of 20 mg/kg and oral gavage doses of 50, 200, and 400 mg/kg. In addition, the toxicokinetics of oxazepam in a 3-week dosed-feed study of male B6C3F1 mice at 125 and 2500 ppm were also investigated. Results indicated that the elimination of oxazepam from plasma after i.v. injection in both rats and mice were first-order and could be best described by a two-compartment model with a terminal elimination half-life of 4-5 h for rats and 5-7 h for mice. After oral gavage dosing the peak oxazepam plasma concentrations in most rodents were reached within 2-3.5 h. At all doses studied, female rodents had significantly higher plasma concentrations than males. Absorption of oxazepam was significantly extended at higher oral doses of 200 and 400 mg/kg. At 50 mg/kg, the bioavailability of oxazepam in rats (< 50%) was lower than in Swiss-Webster mice (> 80%). The bioavailability of oxazepam in both B6C3F1 and Swiss-Webster mice decreased with increasing dose. A dose proportionality of Cmax was not observed in rats and mice after gavage doses of 50, 200, and 400 mg/kg. Plasma concentrations of oxazepam in the dosed-feed study increased with the concentration of oxazepam in the feed, a quasi-steady-state of plasma concentrations of oxazepam was reached after approximately 4 days ad libitum exposure. In B6C3F1 mice, the estimated relative bioavailability of oxazepam from dosed feed (relative to gavage study at 50 mg/kg) was about 43%.
Assuntos
Oxazepam/farmacocinética , Oxazepam/toxicidade , Animais , Relação Dose-Resposta a Droga , Vias de Administração de Medicamentos , Nutrição Enteral , Estudos de Avaliação como Assunto , Feminino , Injeções Intravenosas , Masculino , Camundongos , Camundongos Endogâmicos , Modelos Biológicos , Ratos , Ratos Endogâmicos F344RESUMO
The bioavailability of seven commercial trisulfapyrimidine suspensions was studied in 14 adult male volunteers. Fifteen blood samples were collected over a 48-hr period following administration of a 1-g dose of each suspension. Serum was assayed for each component (sulfadiazine, sulfamerazine, and sulfamethazine) by high-pressure liquid chromatography. Analysis of variance indicated several significant differences among the seven commercial preparations with respect to Cmax Tmax, and AUC for sulfadiazine, sulfamerazine, and sulfamethazine, The in vitro behavior of each suspension was then studied by the paddle method of the Food and Drug Administration. A 0.5-ml sample was introduced into 900 ml of hydrochloric acid (2.2 x 10(-4) M) at 37 degree and dissolved using a paddle speed of 25 rpm. Samples withdrawn at 15 and 30 min were analyzed by high-pressure liquid chromatography, and the percent of sulfadiazine, sulfamerazine, and sulfamethazine was calculated. Significant correlation was obtained between an in vivo parameter (Cmax for sulfadiazine) and an in vitro parameter (percent sulfadiazine dissolved in 30 min). Results indicate that this method is suitable for the in vitro screening of trisulapyrimidine suspensions.
Assuntos
Sulfadiazina/sangue , Sulfamerazina/sangue , Sulfametazina/sangue , Sulfonamidas/metabolismo , Adulto , Disponibilidade Biológica , Combinação de Medicamentos , Humanos , Masculino , Solubilidade , Sulfadiazina/administração & dosagem , Sulfamerazina/administração & dosagem , Sulfametazina/administração & dosagem , Sulfonamidas/administração & dosagem , SuspensõesRESUMO
A newly developed high-pressure liquid chromatographic method was used to study the optimum dosage regimen needed to suppress endogenous hydrocortisone. Nine volunteers were randomly placed in three groups. Each group received 1 mg of dexamethasone at 11 pm (Treatment A), 2 mg of dexamethasone at 11 pm (Treatment B), or 1 mg at 11 pm and an additional 1 mg at 6 am the following day (Treatment C). Analysis of multiple blood samples obtained the day before and the day after drug administration showed suppression in all three groups. Although the duration and extent of this suppression varied, adequate suppression to permit bioavailability studies was observed for Treatments B and C.
Assuntos
Dexametasona/farmacologia , Hidrocortisona/sangue , Adulto , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão/métodos , Depressão Química , Dexametasona/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
A comparative bioavailability study was performed using two commercially available, chemically equivalent brands of sulfamethizole suspension. One gram of each suspension was administered to 12 different subjects following a completely randomized crossover design. Serum levels and derived pharmacokinetic parameters were compared statistically. There were no significant differences in the extent of sulfamethizole absorption from the two suspensions as evidenced by the area under the serum level--time curves. Significant differences (p less than 0.05) in the mean serum levels at 0.5 and 0.75 hr and differences in Cmax and tmax indicated that the absorption rate differed for the two products. In vitro tests including particle-size analysis and dissolution studies were performed. The size--frequency distribution of particles in the suspensions was studied using a resistance particle counter. The dissolution characteristics of the two products were studied using the Food and Drug Administration's paddle method and the spin-filter apparatus. Suspension A had a significantly greater amount of drug dissolved at 15 and 30 min using either method. It also had a greater percentage of particles at the smaller size range, indicating that the greater dissolution rate may be related directly to the decreased particle size. A comparison of the in vivo and in vitro results demonstrated a definite rank-order correlation between the dissolution performance of the two suspensions and the in vivo parameters reflecting the absorption rate. Suspension A had a greater amount of drug dissolved at 15 and 30 min and resulted in higher serum levels at 0.5 and 0.75 hr, a higher Cmax, and a shorter tmax.
Assuntos
Sulfametizol/metabolismo , Sulfatiazóis/metabolismo , Adulto , Disponibilidade Biológica , Química Farmacêutica/instrumentação , Química Farmacêutica/métodos , Humanos , Masculino , Tamanho da Partícula , Solubilidade , Sulfametizol/análise , Sulfametizol/sangue , SuspensõesRESUMO
A simple and rapid high-pressure liquid chromatographic method was developed for the determination of sulfadiazine, sulfamerazine, and sulfamethazine in human serum. After the trichloroacetic acid precipitation of the serum proteins, an aliquot of the supernate is injected into a high-pressure liquid chromatograph equipped with a reversed-phase microparticulate column and a fixed wavelength UV detector. For each of the three components of trisulfapyrimidines, a linear calibration curve was observed in the 1-30-microgram/ml range, with the precision of the assay estimated to be +/- 2% (RSD). Preliminary pharmacokinetic data are also presented.
Assuntos
Sulfadiazina/sangue , Sulfamerazina/sangue , Sulfametazina/sangue , Cromatografia Líquida de Alta Pressão , Colorimetria , Combinação de Medicamentos , Humanos , Métodos , Fatores de TempoRESUMO
Three fasted, male subjects received single 10-, 30-, and 50-mg oral doses of hydrocortisone tablets on separate occasions. Endogenous hydrocortisone was suppressed by giving 2 mg of dexamethasone 9 hr prior to dosing. Plasma samples obtained serially for 8 hr after hydrocortisone dosing were assayed by reversed-phase high-pressure liquid chromatography (HPLC) with UV detection and by normal-phase HPLC with fluorescence detection of the dansylhydrazine derivative of hydrocortisone. The two assay methods yielded equivalent plasma hydrocortisone concentrations. Metabolite interference was absent in both assay methods. Drug concentrations in plasma from all three doses of hydrocortisone were described by one-compartment open-model kinetics, with first-order absorption and elimination, and an absorption lag time. Mean Cmax values of 199, 393, and 419 ng/ml were obtained at 1.0, 1.0, and 1.7 hr following the 10-, 30-, and 50-mg doses, respectively. Hydrocortisone was cleared from plasma with an elimination half-life of approximately 1.5 hr. Within the dosage range studied, plasma levels of hydrocortisone were related, but not directly proportional, to dose size. This apparent lack of proportionality may be due to reduced drug availability or altered distribution with increasing dose.
Assuntos
Hidrocortisona/sangue , Administração Oral , Adulto , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Espectrometria de Fluorescência/métodos , Espectrofotometria Ultravioleta/métodosRESUMO
The relative bioavailability of hydrocortisone was determined from four different 20-mg tablet formulations and one suspension in 15 healthy male volunteers; results were compared with in vitro dissolution rates. Plasma levels of hydrocortisone were determined by a liquid chromatography method developed in this laboratory. Dissolution of the tablet formulations, using the official USP test, varied from 7.8 to 93.8% in 30 min. Similar plasma profiles were obtained from all tablet products, and there were no differences among tablets in the cumulative percentage of drug absorbed. There were no clear trends in any pharmacokinetic parameter values among the tablet dosages, and the four products were considered bioequivalent. The suspension dosage yielded significantly higher plasma levels compared with some of the tablet formulations during the initial 30-min postdose, significantly higher cumulative absorption at 0.5 and 1.0 h compared with one tablet formulation, and significantly higher ka and Cmax, and shorter tmax values, compared with some of the tablets.
Assuntos
Hidrocortisona/metabolismo , Adulto , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Humanos , Cinética , Masculino , Solubilidade , Espectrofotometria Ultravioleta , ComprimidosRESUMO
Effects of gavage versus dosed feed administration on the toxicokinetics of benzyl acetate were studied in male F344 rats and B6C3F1 mice. Benzyl acetate was rapidly hydrolysed to benzyl alcohol and then oxidized to benzoic acid. After gavage administration of benzyl acetate in corn oil at 500 mg/kg (rats) and 1000 mg/kg (mice), high benzoic acid plasma concentrations were observed. In contrast, much lower benzoic acid plasma concentrations were found after dosed feed administration at about 615 mg/kg/day for rats and about 850 mg/kg/day for mice. Results show that although the daily doses of benzyl acetate are comparable, bolus gavage administration effectively saturated the benzoic acid elimination pathway whereas dosed feed administration did not. In contrast, hippuric acid plasma concentrations were similar after both gavage and dosed feed administration due to the depletion of the glycine supply pool. Study results could explain the different toxicity and carcinogenicity responses of benzyl acetate observed in 2-yr chronic gavage and dosed feed studies.
Assuntos
Poluentes Ocupacionais do Ar/toxicidade , Compostos de Benzil/toxicidade , Administração Oral , Poluentes Ocupacionais do Ar/metabolismo , Animais , Benzoatos/sangue , Ácido Benzoico , Álcool Benzílico , Álcoois Benzílicos/sangue , Álcoois Benzílicos/metabolismo , Compostos de Benzil/administração & dosagem , Compostos de Benzil/farmacocinética , Carcinógenos/metabolismo , Carcinógenos/toxicidade , Cromatografia Líquida de Alta Pressão , Simulação por Computador , Óleo de Milho , Glicina/metabolismo , Hipuratos/sangue , Hidrólise , Técnicas In Vitro , Masculino , Camundongos , Oxirredução , Ratos , Ratos Endogâmicos F344RESUMO
A study of the potential effects of microencapsulation on the toxicity of citral was conducted in 14-day continuous feeding studies with both sexes of F344 rats and B6C3F1 mice. Toxicity by the feeding route was compared with that from bolus doses of the neat chemical in corn oil administrated by gavage. Both sexes of rats and mice were given diet containing 0, 0.63, 1.25, 2.5, 5 and 10% citral microcapsules. These feed formulations were equivalent to daily doses of 0, 142, 285, 570, 1140 and 2280 mg citral/kg body weight for rats and 0, 534, 1068, 2137, 4275 and 8550 mg citral/kg body weight for mice. The daily gavage doses were 0, 570, 1140 and 2280 mg citral/kg body weight for both sexes of rats, and 0, 534, 1068 and 2137 mg citral/kg body weight for both sexes of mice. Citral microcapsules administered in the diet did not cause mortality in mice or rats. Toxicity was confined to decreases in body weight at the 10% concentration in mice, at the 5 and 10% concentrations in rats, and decreases in absolute weights of the liver, kidney and spleen at the 10% concentration in rats. The only histopathological change observed was minimal to mild hyperplasia and/or squamous metaplasia of the respiratory epithelium in the anterior portion of the nasal passages of rats fed 5 or 10% citral microcapsules. By contrast, citral gavage caused mortality in five out of five male and female mice at 2137 mg/kg body weight, and in two out of five male mice at 1068 mg/kg body weight. There were dose-related increases in absolute liver weights of male and female mice. Cytoplasmic vacuolization of hepatocytes occurred in all female mice gavaged with 1068 and 2137 mg citral/kg body weight, and in male mice from the 2137 mg/kg dose group. Necrosis, ulceration and/or acute inflammation of the forestomach occurred in the high-dose mice of both sexes. Inflammation and/or hyperplasia of the forestomach occurred in about half of the male and female mice dosed with 1068 mg citral/kg. Citral gavage at doses that were equivalent to up to 10% in the diet (2280 mg/kg body weight) did not cause toxicity in rats, except for minimal hyperplasia of the squamous epithelium of the forestomach in high-dose males.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Monoterpenos , Terpenos/administração & dosagem , Terpenos/toxicidade , Monoterpenos Acíclicos , Administração Oral , Ração Animal , Animais , Peso Corporal/efeitos dos fármacos , Óleo de Milho , Relação Dose-Resposta a Droga , Vias de Administração de Medicamentos , Composição de Medicamentos , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos , Ratos , Ratos Endogâmicos F344 , Especificidade da Espécie , Toxicologia/métodos , Vitamina A/antagonistas & inibidoresRESUMO
A rapid and sensitive high performance liquid chromatographic (HPLC) method is described for the quantitation of cinnamaldehyde (CNMA) in rat blood at concentrations of 0.1-100 micrograms/mL. One of the metabolites of CNMA, cinnamic acid, can also be quantified simultaneously. CNMA is unstable in rat blood, probably because of rapid oxidation to cinnamic acid by enzymatic catalysis and nonenzymatic Schiff base formation with free amine groups of blood proteins. The disappearance of CNMA from rat blood follows first-order reaction kinetics with a half-life of 9 min at room temperature. The current analysis method involves the addition of an agent that will prevent CNMA degradation by denaturing protein and competitively blocking nucleophilic addition reactions, resulting in the nearly complete recovery of CNMA from blood. Recovery of cinnamic acid was approximately 80% at concentrations of 1-10 micrograms/mL.
Assuntos
Acroleína/análogos & derivados , Cinamatos/sangue , Acroleína/sangue , Animais , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Masculino , RatosRESUMO
Gas chromatographic methodologies were developed for the analysis of microencapsulated trichloroethylene (TRI) in corn oil and feed dosage formulations as well as neat TRI in corn oil and whole blood. Recovery, precision, linearity, and the appropriateness of a linear regression model were evaluated for each method. In all cases recovery was greater than 96% and linearity of the standard curves was confirmed. Good precision and chromatographic resolution were obtained for all samples analyzed.