RESUMEN
OBJECTIVES: Lamotrigine (LTG) is a drug commonly used to treat epilepsy and can also be used to manage mood disorders, such as bipolar disorder. One of the most dangerous adverse effects of LTG is skin rash, which can make early cessation necessary. Here, we examine the adverse effects associated with long-term use of LTG for the treatment of mood disorders. METHODS: Data were obtained from the medical records of 101 psychiatric patients who were prescribed long-term treatment with LTG. Patients were retrospectively divided into those who discontinued treatment within 6 months and those who continued for longer, and the groups were compared for adverse effects. We also compared the incidence of adverse effects in high and low doses. RESULTS: Fifty-four patients continued LTG treatment for 6 months or longer; 47 discontinued within 6 months. A history of allergy was more prevalent among the patients who discontinued treatment early than in those who continued. Of the patients who continued treatment for 6 months or longer, only 2 later discontinued treatment because of adverse effects. Lamotrigine monotherapy showed no difference in the incidence of adverse effects for different doses of LTG (>200 mg = 4.8% vs >100 mg, ≤200 mg = 7.7%; P = 1, vs >50 mg, ≤100 mg = 0%; P = 1 vs ≤50 mg = 0%; P = 1). CONCLUSIONS: Clinicians must be mindful of the adverse effects occurring early during the titration phase. However, long-term use of LTG was very well tolerated, even at high maintenance doses.
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Antagonistas de Aminoácidos Excitadores/uso terapéutico , Trastornos Mentales/tratamiento farmacológico , Triazinas/uso terapéutico , Esquema de Medicación , Quimioterapia Combinada , Femenino , GABAérgicos/uso terapéutico , Humanos , Lamotrigina , Estudios Longitudinales , Masculino , Resultado del Tratamiento , Ácido Valproico/uso terapéuticoRESUMEN
OBJECTIVE: Azithromycin (AZM) is widely used as a first-line treatment option for children with mycoplasma pneumonia. Although pharmacists perform medication counseling in the pediatric ward, children often experience vomiting as a result of oral AZM administration. Drugs that are administered rectally are generally considered to enter the circulation system without passing through the liver first. The aim of our study was to prepare an AZM suppository and investigate the pharmaceutical properties and well as pharmacokinetics of the rectal administration route in humans. MATERIALS AND METHODS: Five healthy volunteers were enrolled in the study. All subjects provided written informed consent before participating in the study. Subjects were randomly assigned to either oral administration of oral AZM 500-mg tablet or rectal administration of 125-mg, 250-mg, or 500-mg AZM suppository. Blood samples for preparation of serum were collected predose as well as at 1, 2, 3, 4, 6, 12, and 24 hours following the first rectal dose. Serum concentrations of AZM were determined by high-performance liquid chromatography (HPLC) with electrochemical detection. RESULTS AND CONCLUSION: The bioavailability of the AZM suppository through rectal administration was 20.3% compared to oral administration. We hypothesize that the surface area where AZM is absorbed also affects the absorption by rectal administration. Although further investigation is necessary to improve the absorption of AZM by the rectum and to ensure safety in children, the AZM suppository may be an effective preparation in cases where oral administration is not tolerated.
Asunto(s)
Antibacterianos/administración & dosificación , Azitromicina/administración & dosificación , Administración Rectal , Adolescente , Azitromicina/farmacocinética , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Recto/metabolismo , SupositoriosRESUMEN
OBJECTIVE: To evaluate the role of bilirubin UDP-glucuronosyltransferase family 1, polypeptide A1 (UGT1A1) gene variations on prolonged unconjugated hyperbilirubinemia associated with breast milk feeding (breast milk jaundice [BMJ]). STUDY DESIGN: UGT1A1 gene allelic variation was analyzed in 170 Japanese infants with BMJ with polymerase chain reaction-direct sequencing, and their genotypes compared with serum bilirubin concentrations. In 62 of 170 infants, serum bilirubin concentration was followed after 4 months of life. Genotypes were examined in 55 infants without BMJ. RESULTS: Of 170 infants with BMJ, 88 (51.8%) were homozygous UGT1A1*6. Serum bilirubin concentrations (21.8 ± 3.65 mg/dL) were significantly greater than in infants with other genotypes (P < .0001). The Gilbert UGT1A1*28 allele was not detected in infants with BMJ, except in an infant who was compound heterozygous with UGT1A1*6. At 4 months of age, serum bilirubin concentration improved to >1 mg/dL, except in 2 infants who were homozygous UGT1A1*7. Homozygous UGT1A1*6 was not detected in the control group. CONCLUSION: One-half of the infants with BMJ were homozygous UGT1A1*6 and exhibited a serum bilirubin concentration significantly greater than other genotypes. This finding indicates that UGT1A1*6 is a major cause of BMJ in infants in East Asia. Previous finding have demonstrated that 5ß-pregnane-3α,20ß-diol present in breast milk inhibits p.G71R-UGT1A1 bilirubin glucuronidation activity. Thus, prolonged unconjugated hyperbilirubinemia may develop in infants with UGT1A1*6 who are fed breast milk.
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Bilirrubina/sangre , Variación Genética/genética , Glucuronosiltransferasa/genética , Hiperbilirrubinemia Neonatal/genética , Ictericia Neonatal/genética , Leche Humana , Pueblo Asiatico/genética , Femenino , Genotipo , Humanos , Recién Nacido , Masculino , Reacción en Cadena de la PolimerasaRESUMEN
Imatinib is an oral tyrosine kinase inhibitor used for first-line treatment of chronic myeloid leukemia. Therapeutic drug monitoring targeting trough plasma levels of about 1000 ng/mL may help to optimize imantinib's therapeutic effect. This paper reports a specific and sensitive enzyme-linked immunosorbent assay (ELISA) for a pharmacokinetic evaluation of imatinib. Anti-imatinib antibody was obtained by immunizing rabbits with an antigen conjugated with bovine serum albumin and succinimidyl 4-{(4-methyl-1-piperazinyl)methyl}-benzoate. Enzyme labeling of imatinib with horseradish peroxidase was similarly performed using succinimidyl 4-{(4-methyl-1-piperazinyl)methyl}-benzoate. A simple ELISA for imatinib was developed using the principle of direct competition between imatinib and the enzyme marker for anti-imatinib antibody which had been adsorbed by the plastic surface of a microtiter plate. Serum imatinib concentrations lower than 40 pg/mL were reproducibly measurable using the ELISA. This ELISA was specific to imatinib and showed very slight cross-reactivity (1.2%) with a major metabolite, N-desmethyl imatinib. Using this assay, drug levels were easily measured in the blood of mice after their oral administration of imatinib at a single dose of 50 mg/kg. The specificity and sensitivity of the ELISA for imatinib should provide a valuable new tool for use in therapeutic drug monitoring and pharmacokinetic studies of imatinib.
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Benzamidas/análisis , Piperazinas/análisis , Inhibidores de Proteínas Quinasas/análisis , Pirimidinas/análisis , Animales , Anticuerpos/inmunología , Benzamidas/química , Benzamidas/inmunología , Benzamidas/farmacocinética , Monitoreo de Drogas , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Peroxidasa de Rábano Silvestre/química , Peroxidasa de Rábano Silvestre/metabolismo , Humanos , Mesilato de Imatinib , Ratones , Ratones Endogámicos BALB C , Piperazinas/química , Piperazinas/inmunología , Piperazinas/farmacocinética , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/inmunología , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/química , Pirimidinas/inmunología , Pirimidinas/farmacocinética , Conejos , Sensibilidad y Especificidad , Albúmina Sérica Bovina/químicaRESUMEN
This paper reports a specific and sensitive enzyme-linked immunosorbent assay (ELISA) for pharmacokinetic studies of vindesine (VDS). Anti-VDS antibody was obtained by immunizing rabbits with VDS conjugated with bovine serum albumin using N-[ß-(4-diazophenyl) ethyl] maleimide as a heterobifunctional coupling agent. An enzyme marker was similarly prepared by coupling VDS with horseradish peroxidase using N-(4-diazophenyl) maleimide. The detection limit of VDS by ELISA was approximately 24 pg/mL with 50-mL samples. This assay was specific for VDS and showed very slight cross-reactivity with other vinca alkaloids, vincristine (0.18%) and vinblastine (0.11%). The values for the VDS concentrations detected using this assay were comparable with those detected using HPLC. There was a good correlation between the values determined by the two methods. Moreover, ELISA was about 50-fold more sensitive in detecting VDS at lower concentrations. The sensitivity and specificity of ELISA should provide a useful tool for pharmacokinetic studies of VDS.
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Antineoplásicos Fitogénicos/sangre , Ensayo de Inmunoadsorción Enzimática/métodos , Vindesina/sangre , Animales , Anticuerpos , Antineoplásicos Fitogénicos/farmacocinética , Conejos , Vindesina/inmunología , Vindesina/farmacocinéticaRESUMEN
We examined the antiemetic effect and impact of aprepitant on the quality of life (QOL) of outpatients receiving moderately emetogenic chemotherapy (MEC). Data were compared between patients who received aprepitant (aprepitant group, n=30, treated May to September 2010) and those who did not (control group, n=14, treated February to April 2010). Controls received antiemetic treatment with a serotonin receptor antagonist and dexamethasone on Day 1. The aprepitant group received oral aprepitant (125 mg) concomitantly with these drugs on Day 1, and aprepitant (80 mg) on Days 2 and 3. The percentages of subjects without vomiting and nausea during the overall phase (0-96 h), acute phase (0-24 h), and delayed phase (24-96 h), and without loss of appetite during the entire period and delayed phase, were significantly higher in the aprepitant group. A QOL evaluation using the Functional Living Index-Emesis (FLIE) questionnaire showed a significantly higher percentage of subjects without the impact of nausea and vomiting disturbing their daily lives during the overall phase, and a significant decrease in QOL disturbance in the aprepitant group. Our results suggest that nausea, vomiting, loss of appetite, and QOL disturbance occur in many outpatients undergoing MEC, and that concomitant therapy with 3 drugs including aprepitant can improve symptoms and QOL of these patients.
Asunto(s)
Antieméticos/uso terapéutico , Antineoplásicos/efectos adversos , Morfolinas/uso terapéutico , Náusea/prevención & control , Neoplasias/tratamiento farmacológico , Calidad de Vida , Vómitos/prevención & control , Antineoplásicos/uso terapéutico , Apetito/efectos de los fármacos , Aprepitant , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pacientes AmbulatoriosRESUMEN
New fluorescent compounds, benzo[4,5]thieno[3,2-d]pyrimidine 5,5-dioxides (3a-g), 2-amino-4-methylsulfanylbenzo[4,5]thieno[3,2-d]pyrimidine (6), and 2-amino-4-methylsulfanyl-7-methoxybenzo[4,5]furo[3,2-d]pyrimidine (7), were synthesized in good yields from heterocyclic ketene dithioacetals (1a-c) and guanidine carbonate (2a) or (S)-methylisothiourea sulfate (2b) in pyridine under reflux. Among the fused pyrimidine derivatives, compound 3c, which has an amino group at the 2-position and a benzylamino group at the 4-position of the pyrimidine ring, showed the strongest solid-state fluorescence. The absorption and emission properties of the compounds were quantitatively reproduced by a series of ab initio quantum-chemical calculations.
RESUMEN
The efficacy and safety of aprepitant(APR)were examined in cancer patients who received chemotherapy including cisplatin(CDDP)at a dose of ≥ 50mg/m2.APR was administered concomitantly with conventional antiemetic therapy to 20 patients(APR group)in a prospective study performed from May to July 2010. In addition, a retrospective study based on medical records of 20 patients(conventional therapy group)from February to April 2010 was performed.These patients received antiemetic therapy with a serotonin receptor antagonist and dexamethasone. Significantly more patients did not vomit in the 5-day study period(days 1-5).Also, severity of vomiting was significantly improved over the 5-day period and in the late phase(days 2-5)in the APR group, compared to the conventional therapy group. Loss of appetite was significantly improved over the 5-day period and the acute(day 1)and late phases, leading to increased food intake during the 5-day period and late phase. There were no adverse events with suspected involvement of APR, and the tolerability was favorable. These results suggest that APR is useful for nausea, vomiting, and appetite loss caused by CDDP, which is a highly emetic drug, and that such guideline-based antiemetic therapy might improve the quality of life of patients.
Asunto(s)
Antieméticos/uso terapéutico , Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Morfolinas/uso terapéutico , Náusea/prevención & control , Neoplasias/tratamiento farmacológico , Vómitos/prevención & control , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Aprepitant , Cisplatino/uso terapéutico , Trastornos de Alimentación y de la Ingestión de Alimentos/inducido químicamente , Trastornos de Alimentación y de la Ingestión de Alimentos/prevención & control , Femenino , Humanos , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Estudios Retrospectivos , Vómitos/inducido químicamenteRESUMEN
The current study was conducted to retrospectively investigate the effects of reducing average relative dose intensity (ARDI) in response to adverse events on time to treatment failure (TTF) and overall survival (OS) in patients with metastatic or recurrent colorectal cancer receiving modified FOLFOX6 (mFOLFOX6) therapy between January 2006 and May 2010. Patients were divided into two groups based on ARDI: those with an ARDI of 85% or more (ARDI maintained; n = 12) and those with an ARDI of less than 85% (ARDI reduced; n = 37). In the ARDI-reduced group, out of a total of 402 treatment courses conducted, 25.9% involved treatment delays and 8.2% involved dose reductions, and the incidence rate of treatment delay was significantly higher than that of dose reduction (p < 0.001). Hematological toxicity was the main reason for both treatment delays and dose reductions. Reduced ARDI by dose reduction effectively prevented any increase in the severity of neutropenia and the treatment delays in the next courses, suggesting that the dose reductions were appropriately performed. Median TTF in the ARDI-maintained and ARDI-reduced groups was 5.2 and 5.8 months, respectively (p = 0.225). Median OS was 15.5 months and 33.9 months in the ARDI-maintained and ARDI-reduced groups, respectively (p = 0.347). These findings suggested that reductions in ARDI of mFOLFOX6 therapy for metastatic or recurrent colorectal cancer due to treatment delays and dose reductions in response to adverse events do not necessarily lead to shortened TTF and OS.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Femenino , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Humanos , Leucovorina/efectos adversos , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Compuestos Organoplatinos/efectos adversos , Compuestos Organoplatinos/uso terapéutico , Estudios RetrospectivosRESUMEN
With the revision of the Good Clinical Practice (GCP) in 1997, the Clinical Trial Center was established at Saga University Hospital in 1999, where clinical research coordinators (CRC) of nurses and pharmacists have been carrying out support for clinical trials since June 2000. At present, two pharmacists, two nurses, and three clerical work assistants support the execution of clinical trials; however, in recent years the number of clinical trial commissions has been gradually decreasing. On this occasion, in order to carry out even higher quality and smoother clinical trials, we conducted a questionnaire targeting the sponsors of clinical trials (head monitors) to evaluate this hospital's system for the execution of clinical trials from the sponsor's standpoint. Moreover, for the purpose of comparison with the systems of other institutions, the same questionnaire was conducted on two other hospitals-the University of Occupational and Environmental Health, Japan and the Social Insurance Shimonoseki Kousei Hospital. The problems of the clinical trial execution in our team turned out lack of knowledge concerning GCP and our complex system from the result of the questionnaire.
Asunto(s)
Ensayos Clínicos como Asunto , Hospitales , Humanos , Japón , Enfermeras y Enfermeros , Farmacéuticos , Encuestas y CuestionariosRESUMEN
We describe a case of West syndrome with the balanced translocation t(X;18)(p22;p11.2). Treatment with high-dose vitamin B6, adrenocorticotropic hormone, thyrotropin-releasing hormone, and antiepileptic compounds was not effective, and the patient exhibited persistent refractory seizures and severe developmental delays. Although no mutation analysis and X chromosome inactivation were performed, we suggest that the chromosomal abnormality in the present patient is the main etiologic factor responsible for the infantile spasms and severe developmental delay.
Asunto(s)
Encéfalo/fisiopatología , Cromosomas Humanos Par 22/genética , Cromosomas Humanos X/genética , Espasmos Infantiles/genética , Espasmos Infantiles/fisiopatología , Translocación Genética , Electroencefalografía , Femenino , Humanos , Recién Nacido , Cariotipificación , Mutación Puntual/genética , Índice de Severidad de la Enfermedad , Espasmos Infantiles/diagnósticoRESUMEN
We have developed an enzyme-linked immunosorbent assay (ELISA) suitable for routine monitoring of serum levels of cibenzoline. Anti-cibenzoline antibody was obtained by immunizing rabbits with cibenzoline conjugated with bovine serum albumin using N-(4-maleimidobutyryloxy)succinimide as a heterobifunctional coupling agent. An enzyme marker was prepared by coupling 2,2-diphenylethylamine with beta-D-galactosidase using glutaraldehyde. The detection limit of cibenzoline by ELISA was approximately 640 pg/ml with 50-microl samples. Cross-reactivity data showed that the antibody well recognizes both the diphenyl and cyclopropyl moieties, and is thus specific enough to the structure of cibenzoline. The values for the cibenzoline concentrations detected using this assay were comparable with those detected using HPLC. There was a good correlation between the values determined by the two methods. Moreover, ELISA was about 15-fold more sensitive in detecting cibenzoline at lower concentrations. Using this assay, drug levels were easily measured in the serum of rabbits after oral administration of cibenzoline at a single dose of 3 mg/kg.
Asunto(s)
Antiarrítmicos/sangre , Ensayo de Inmunoadsorción Enzimática/métodos , Imidazoles/sangre , Animales , Monitoreo de Drogas/métodos , Femenino , Imidazoles/administración & dosificación , Conejos , Sensibilidad y EspecificidadRESUMEN
A rapid and sensitive high-performance liquid chromatographic method was validated and described for determination of paroxetine in human saliva. Following liquid-liquid extraction of the drug and an internal standard (dibucaine), chromatographic separation was accomplished using a C18 analytical column with a mobile phase consisting of 0.05 mol/L sodium phosphate buffer, pH 5.0, and acetonitrile (A 30:70, v/v; B 60:40, v/v). Paroxetine and the internal standard were detected by ultraviolet absorbance at 205 nm. The average recoveries of the drug and internal standard were 92.5% and 89%, respectively. The lower limits of detection and quantification were 1 and 4 ng/ml, respectively, and the calibration curve was linear over a concentration range of 4 ng/ml. The saliva level of paroxetine in patients with depression taking 10 to 40 mg/day of the drug was significantly correlated with the plasma level of paroxetine in each patient (r = 0.617, P < 0.004, n = 19). These data indicate that the saliva level of paroxetine could be a useful marker to predict the plasma level of the drug.
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Antidepresivos de Segunda Generación/análisis , Cromatografía Líquida de Alta Presión/métodos , Monitoreo de Drogas/métodos , Paroxetina/análisis , Saliva/química , Antidepresivos de Segunda Generación/sangre , Biomarcadores/sangre , Depresión/tratamiento farmacológico , Depresión/metabolismo , Humanos , Paroxetina/sangre , Cooperación del PacienteRESUMEN
The epidermal growth factor tyrosine kinase inhibitor gefitinib is a novel, molecularly targeted agent that has been approved for the treatment of advanced non-small cell lung cancer. This paper reports a specific and sensitive enzyme-linked immunosorbent assay (ELISA) for pharmacokinetic studies of gefitinib. Anti-gefitinib antibody was obtained by immunizing rabbits with an antigen conjugated with bovine serum albumin using diazotized 4-amino-2-methoxy-1-[3-(morpholin-4-yl)propoxy]benzene. Enzyme labeling of gefitinib with beta-D-galactosidase was similarly performed using a diazotized 4-amino-2-methoxy-1-[3-(morpholin-4-yl)propoxy]benzene. A simple ELISA for gefitinib was developed using the principle of direct competition between gefitinib and the enzyme marker for anti-gefitinib antibody which had been adsorbed to the plastic surface of a microtiter plate. Gefitinib concentrations in serum lower than 800 pg/ml were measurable reproducibly using the ELISA. Cross-reactivity data showed that the antibody well recognizes both the 3-morpholinopropoxy and methoxy moieties well, and thus is sufficiently specific for the structure of gefitinib. Using this assay, drug levels were easily measured in the serum of rabbits after oral administration of gefitinib at a single dose of 5 mg/kg. The specificity and sensitivity of the ELISA for gefitinib should provide a valuable new tool for use in pharmacokinetic and toxicity studies of gefitinib.
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Sangre , Ensayo de Inmunoadsorción Enzimática/métodos , Receptores ErbB/antagonistas & inhibidores , Quinazolinas/análisis , Animales , Femenino , Gefitinib , Humanos , Quinazolinas/inmunología , Quinazolinas/farmacocinética , Quinazolinas/farmacología , Conejos , Sensibilidad y EspecificidadRESUMEN
This paper reports a sensitive and specific enzyme-linked immunosorbent assay for screening of furanocoumarin derivatives as cytochrome P450 3A4 inhibitors in citrus fruits. Anti-6',7'-dihydroxybergamottin antibody was obtained by immunizing rabbits with 6',7'-dihydroxybergamottin conjugated with bovine serum albumin using the N-succinimidyl ester method. An enzyme marker was similarly prepared by coupling 6',7'-dihydroxybergamottin with beta-D-galactosidase. The enzyme-linked immunosorbent assay is capable of detecting as little as 800 pg/ml of 6',7'-dihydroxybergamottin and 4 ng/ml of bergamottin. Cross-reactivity data showed that the antibody well recognizes both the furanocoumarin and 6,7-dihydroxy-3,7-dimethyloct-2-enyloxy moieties of the 6',7'-dihydroxybergamottin, and is thus specific to the structure of furanocoumarin derivatives containing geranyloxy side chain as the cytochrome P450 3A4 inhibitors in grapefruit juice. The antibody was, therefore, used for screening a large number of citrus fruits for furanocoumarin derivatives such as 6',7'-dihydroxybergamottin. Fifteen citrus fruits were examined and significant reactivity was observed in 8 of these: red pummelo, sweetie, melogold, banpeiyu pummelo, hassaku, sour orange, lime and natsudaidai. This enzyme-linked immunosorbent assay may be a powerful tool for screening for furanocoumarin derivatives as cytochrome P450 3A4 inhibitors in grapefruit juice.
Asunto(s)
Bebidas/análisis , Citrus/enzimología , Frutas/enzimología , Furocumarinas/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática/métodos , Furocumarinas/químicaRESUMEN
A selective liquid chromatographic method has been developed for the assay of ethambutol in serum samples. The assay involves intramolecular excimer-forming derivatization with 4-(1-pyrene)butanoyl chloride (PBC) and isocratic reversed-phase chromatography with fluorescence detection. After acetonitrile-deproteinization of the serum sample, the derivatization reaction of ethambutol with PBC was completed within 30 min at 50 degrees C. N,N'-Diethylethylenediamine was used as an internal standard. The detection limit of ethambutol was 23 ng/ml serum, corresponding to 180 fmol on column at a signal-to-noise ratio of 3. The present method was selective enough to analyze ethambutol in rabbit serum without any tedious sample clean-up procedure because biogenic monoamines gave no peak in the chromatogram. The method was applicable to drug monitoring in rabbit serum.
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Antituberculosos/sangre , Etambutol/sangre , Animales , Antituberculosos/farmacocinética , Etambutol/farmacocinética , Etilenodiaminas , Colorantes Fluorescentes , Indicadores y Reactivos , Conejos , Estándares de Referencia , Reproducibilidad de los Resultados , Soluciones , Espectrometría de FluorescenciaRESUMEN
We have established an enzyme-linked immunosorbent assay suitable for routine monitoring of serum levels of sotalol. Anti-sotalol antibody was obtained by immunizing rabbits with sotalol conjugated with bovine serum albumin using the N-succinimidyl ester method. An enzyme marker was similarly prepared by coupling sotalol with beta-D-galactosidase. The detection limit of sotalol by the enzyme-linked immunosorbent assay was approximately 32 ng/ml with 50-microl samples. This assay was specific for sotalol because of very slight cross-reactivity with 4-(methanesulfonylamino)benzonitrile (1.6%), but none with D,L-isoproterenol. Using this assay, drug levels were easily measured in the serum of rabbits after oral administration of sotalol at a single dose of 3 mg/kg. The enzyme-linked immunosorbent assay should be a valuable tool in therapeutic drug monitoring and pharmacokinetic studies of sotalol.
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Antagonistas Adrenérgicos beta/análisis , Sotalol/análisis , Antagonistas Adrenérgicos beta/farmacocinética , Animales , Especificidad de Anticuerpos , Biotransformación , Ensayo de Inmunoadsorción Enzimática , Inmunoglobulina G/análisis , Indicadores y Reactivos , Masculino , Conejos , Sotalol/farmacocinética , Distribución Tisular , beta-Galactosidasa/químicaRESUMEN
This paper reports a sensitive and specific enzyme-linked immunosorbent assay for determination of the antiarrhythmic drug mexiletine in human serum. Anti-mexiletine antibody was obtained by immunizing rabbits with an antigen conjugated with mercaptosuccinyl bovine serum albumin using N-(epsilon-maleimidocaproyloxy)succinimide as a heterobifunctional coupling agent. Enzyme labeling of mexiletine with beta-D-galactosidase was performed using glutaraldehyde. In this assay, the mexiletine to be quantified is chemically modified by acetic anhydride allowed to compete with a mexiletine-beta-D-galactosidase conjugate for binding to a limited amount of an anti-mexiletine antibody which was used to coat the wells of a microtiter plate. Mexiletine concentrations lower than 80 ng/ml were measurable reproducibly by the enzyme-linked immunosorbent assay. This assay was specific for mexiletine and showed very slight cross-reactivity with its major metabolite, 2-hydroxymethylmexiletine (1.5%), but none with p-hydroxymexiletine. The values of serum mexiletine levels from 15 patients by this enzyme-linked immunosorbent assay were comparable with those measured by HPLC. There was a good correlation between the values determined by the two methods. The enzyme-linked immunosorbent assay should be a valuable tool in therapeutic drug monitoring and pharmacokinetic studies of mexiletine.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Especificidad de Anticuerpos/inmunología , Mexiletine/sangre , Animales , Anticuerpos Monoclonales/química , Unión Competitiva , Cromatografía Líquida de Alta Presión , Monitoreo de Drogas/métodos , Ensayo de Inmunoadsorción Enzimática/métodos , Humanos , Mexiletine/química , Mexiletine/inmunología , Conejos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , beta-Galactosidasa/químicaRESUMEN
A sensitive and specific enzyme-linked immunosorbent assay for an antiarrhythmic drug, amiodarone (AMI), was developed, which is capable of measuring levels as low as 16 ng/ml. Anti-AMI antibody was obtained by immunizing rabbits with an antigen conjugated with bovine serum albumin using diazotized 4-amino-1-(2-diethylaminoethoxy)-2,6-diiodobenzene. Enzyme labeling of AMI with beta-D-galactosidase was similarly performed using a diazotized 4-amino-1-(2-diethylaminoethoxy)-2,6-diiodobenzene. This enzyme-linked immunosorbent assay was specific for AMI and showed a very slight cross-reactivity (1.25%) with its major metabolite, mono-N-desethylamiodarone. The values of the AMI concentrations measured by this assay were in good correlation to those by HPLC. Its analytical applicability was demonstrated by a kinetic study with human liver microsomes. The enzyme-linked immunosorbent assay should be a valuable tool in therapeutic drug monitoring and pharmacokinetic studies of AMI.
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Amiodarona/análisis , Amiodarona/metabolismo , Amiodarona/química , Animales , Ensayo de Inmunoadsorción Enzimática/métodos , Estudios de Evaluación como Asunto , Femenino , Humanos , Microsomas Hepáticos , ConejosRESUMEN
A highly selective and simple fluorimetric liquid chromatographic method for the determination of triethylenetetramine (TETA), a therapeutic drug for Wilson's disease, in human and rabbit sera is described. This method is based on intramolecular excimer-forming fluorescence derivatization, which allows spectrofluorometric discrimination of polyamino compounds from monoamino species, followed by liquid chromatography. TETA and 1,6-hexanediamine (internal standard) were converted to the corresponding excimer-forming derivatives with a pyrene reagent, 4-(1-pyrene)butyric acid N-hydroxysuccinimide ester. The derivatives were separated within 20 min on a reversed-phase column using isocratic elution and detected spectofluorometrically at 480 nm with excitation at 345 nm. This method was successfully applied to the monitoring of TETA in human and rabbit sera with a simple pretreatment. The detection limit for TETA in serum was 18 ng/ml (0.13 nmol/ml) corresponding to 0.2 pmol on column at a signal-to-noise ratio of 3.