RESUMEN
A routine monitoring for subacute ruminal acidosis (SARA) on the individual level could support the minimization of economic losses and the ensuring of animal welfare in dairy cows. The objectives of this study were (1) to develop a SARA risk score (SRS) by combining information from different data acquisition systems to generate an integrative indicator trait, (2) the investigation of associations of the SRS with feed analysis data, blood characteristics, performance data, and milk composition, including the fatty acid (FA) profile, (3) the development of a milk mid-infrared (MIR) spectra-based prediction equation for this novel reference trait SRS, and (4) its application to an external data set consisting of MIR data of test day records to investigate the association between the MIR-based predictions of the SRS and the milk FA profile. The primary data set, which was used for the objectives (1) to (3), consisted of data collected from 10 commercial farms with a total of 100 Holstein cows in early lactation. The data comprised barn climate parameters, pH and temperature logging from intrareticular measurement boluses, as well as jaw movement and locomotion behavior recordings of noseband-sensor halters and pedometers. Further sampling and data collection included feed samples, blood samples, milk performance, and milk samples, whereof the latter were used to get the milk MIR spectra and to estimate the main milk components, the milk FA profile, and the lactoferrin content. Because all measurements were characterized by different temporal resolutions, the data preparation consisted of an aggregation into values on a daily basis and merging it into one data set. For the development of the SRS, a total of 7 traits were selected, which were derived from measurements of pH and temperature in the reticulum, chewing behavior, and milk yield. After adjustment for fixed effects and standardization, these 7 traits were combined into the SRS using a linear combination and directional weights based on current knowledge derived from literature studies. The secondary data set was used for objective (4) and consisted of test day records of the entire herds, including performance data, milk MIR spectra and MIR-predicted FA. At farm level, it could be shown that diets with higher proportions of concentrated feed resulted in both lower daily mean pH and higher SRS values. On the individual level, an increased SRS could be associated with a modified FA profile (e.g., lower levels of short- and medium-chain FA, higher levels of C17:0, odd- and branched-chain FA). Furthermore, a milk MIR-based partial least squares regression model with a moderate predictability was established for the SRS. This work provides the basis for the development of routine SARA monitoring and demonstrates the high potential of milk composition-based assessment of the health status of lactating cows.
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Acidosis , Lactancia , Acidosis/veterinaria , Animales , Bovinos , Dieta/veterinaria , Femenino , Leche , Factores de RiesgoRESUMEN
6-Hexadecanoylamino-4-methylumbelliferylphosphorylcholine (HMUPC) was shown to be a specific substrate for the determination of acid (lysosomal) sphingomyelinase (ASM; gene SMPD1). Fibroblasts (n = 27) and leukocytes (n = 8) from both the A and B types of Niemann-Pick disease showed < 6% and < 10% of mean normal ASM activity, respectively. Niemann-Pick A or B patients bearing the Q292K mutation had apparently normal ASM activity with our new artificial substrate. These patients with false-normal sphingomyelinase activity, however, could readily be detected by determining the extent of inhibition of enzymatic hydrolysis of the artificial substrate HMU-PC by an unlabelled natural substrate, in particular lysosphingomyelin. This approach is generally applicable. Our novel assay for ASM combines the ease of a rapid and robust enzyme assay using a fluorogenic substrate with the specificity of an ASM assay using a natural substrate. Such assays are obviously more convenient to the diagnostic laboratory, since radiolabelled substrates are not required.
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Análisis Químico de la Sangre/métodos , Química Clínica/métodos , Fluorometría/métodos , Enfermedades de Niemann-Pick/diagnóstico , Esfingomielina Fosfodiesterasa/química , Ceramidas/química , Pruebas Enzimáticas Clínicas , Diagnóstico Diferencial , Relación Dosis-Respuesta a Droga , Fibroblastos/enzimología , Fibroblastos/metabolismo , Regulación Enzimológica de la Expresión Génica , Hexosaminidasas/química , Humanos , Hidrólisis , Leucocitos/enzimología , Leucocitos/metabolismo , Mutación , Enfermedades de Niemann-Pick/enzimología , Éteres Fosfolípidos/química , Fosforilcolina/análogos & derivados , Fosforilcolina/química , Unión Proteica , Reproducibilidad de los Resultados , Piel/metabolismo , Esfingomielinas/química , Esfingosina/análogos & derivados , Esfingosina/química , Especificidad por Sustrato , Factores de TiempoRESUMEN
This study describes a diagnostic pitfall in the laboratory diagnosis of patients with sphingomyelinase deficiency (SMD; Niemann-Pick disease types A and B; NPA and NPB), in cases where sphingomyelinase activity was not determined with sphingomyelin as the natural enzymic substrate. Four of 24 SMD patients studied had falsely normal or enhanced activity, when a so-called artificial sphingomyelinase substrate, 2-N-(hexadecanoyl)-amino-4-nitrophenyl phosphorylcholine (HNP), was used, whereas SMD was clear with the sphingomyelin substrate. Those four patients had the Q292 K mutation of the acid sphingomyelinase gene (SMPD1) on at least one allele. Three of the four patients (no data available from one) experienced only late-infantile or juvenile, though distinct, neurological involvement, where learning disabilities, hypo- or areflexia or mild ataxia were initial signs. The laboratory pitfall with HNP substrate, which is used in many laboratories, raises the risk that some SMD patients are overlooked, and it prevents the consideration of a late-manifesting neurological course in some patients as well as the planning of enzyme substitution therapy in non-neurological SMD (NPB) patients. Since classical NPB is very rare, it is suggested that SMD patients with late- or mild-manifesting neurological symptoms should better be assigned to additional SMD subgroups than grouped with NPB.
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Pruebas Enzimáticas Clínicas , Errores Diagnósticos , Mutación , Enfermedades de Niemann-Pick/diagnóstico , Enfermedades de Niemann-Pick/genética , Fosforilcolina/análogos & derivados , Esfingomielina Fosfodiesterasa/deficiencia , Adolescente , Adulto , Anciano , Niño , Preescolar , Humanos , Lactante , Persona de Mediana Edad , Fosforilcolina/metabolismo , Esfingomielina Fosfodiesterasa/genética , Esfingomielinas/metabolismoRESUMEN
Xylazine (Rompun, Proxylaz) is a veterinary tranquilizing agent. A case of self-injection of 1.5 g xylazine by a 27-year-old farmer is reported. He subsequently became comatose, hypotensive, bradycardic, and mildly glycemic. An intensive supportive therapy including intubation and ventilation was required. The patient made a full recovery over the next 30 h. The largest concentrations measured were 4.6 mg/L in plasma, 446 mg/L in gastric fluid, and 194 mg/L in urine. The calculated plasma half-life was 4.9 h. Kinetic data correlated with clinical symptoms. Qualitative and quantitative analyses of xylazine were done by thin-layer chromatography, gas chromatography-mass spectrometry, and high-performance liquid chromatography. These methods allow the detection of small amounts substance in stomach, plasma, and urine. Liquid-liquid extraction was used for the isolation of drug. The sensitvity is high, and with these methods, a rapid analysis is possible. Xylazine intoxications in humans are rare. We describe the management of acute poisoning and present a review of xylazine toxicity in humans.
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Agonistas alfa-Adrenérgicos/envenenamiento , Xilazina/envenenamiento , Agonistas alfa-Adrenérgicos/sangre , Agonistas alfa-Adrenérgicos/orina , Adulto , Animales , Cromatografía Líquida de Alta Presión , Cromatografía en Capa Delgada , Cromatografía de Gases y Espectrometría de Masas , Mucosa Gástrica/metabolismo , Humanos , Masculino , Intento de Suicidio , Tranquilizantes/envenenamiento , Tranquilizantes/toxicidad , Drogas Veterinarias/envenenamiento , Xilazina/sangre , Xilazina/orinaRESUMEN
BACKGROUND: P-Glycoprotein is an efflux pump in many epithelial cells with excretory function. It has been demonstrated that rifampin (INN, rifampicin) induces P-glycoprotein, particularly in the gut wall. We therefore hypothesized that rifampin affects pharmacokinetics of the P-glycoprotein substrate talinolol, a beta1-blocker without appreciable metabolic disposition but intense intestinal secretion in human beings. METHODS: Pharmacokinetics of talinolol (a single dose of 30 mg administered intravenously or 100 mg administered orally for 7 days) and duodenal expression of the MDR1 gene product P-glycoprotein as assessed by reverse transcriptase-polymerase chain reaction of the MDR1-messenger ribonucleic acid, by immunohistochemistry and Western blot analysis were analyzed before and after coadministration of rifampin (600 mg per day for 9 days) in 8 male healthy volunteers (age 22 to 26 years). RESULTS: During rifampin treatment, the areas under the curve of intravenous and oral talinolol were significantly lower (21% and 35%; P < .05). Treatment with rifampin resulted in a significantly increased expression of duodenal P-glycoprotein content 4.2-fold (2.9, 6.51) (Western blot) and messenger RNA was increased in six of the eight volunteers. P-Glycoprotein expression in biopsy specimens of gut mucosa correlated significantly with the systemic clearance of intravenous talinolol (rs = 0.74; P < .001). CONCLUSIONS: Rifampin induces P-glycoprotein-mediated excretion of talinolol predominantly in the gut wall. Moreover, clearance of talinolol from the blood into the lumen of the gastrointestinal tract may be predicted by the individual intestinal P-glycoprotein expression. Thus we describe a new type of steady-state drug interaction affecting compounds that are subject to transport rather than metabolism.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/efectos de los fármacos , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Antagonistas Adrenérgicos beta/farmacocinética , Antituberculosos/farmacología , Duodeno/metabolismo , Propanolaminas/farmacocinética , Rifampin/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/biosíntesis , Administración Oral , Antagonistas Adrenérgicos beta/administración & dosificación , Antagonistas Adrenérgicos beta/sangre , Adulto , Antiarrítmicos/farmacocinética , Antihipertensivos/farmacocinética , Área Bajo la Curva , Western Blotting , Endoscopía del Sistema Digestivo , Inducción Enzimática/efectos de los fármacos , Humanos , Inmunohistoquímica , Infusiones Intravenosas , Masculino , Propanolaminas/administración & dosificación , Propanolaminas/sangre , ARN Mensajero/análisis , Valores de Referencia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Regulación hacia ArribaRESUMEN
OBJECTIVE: Recent data indicated that disposition of oral digoxin is modulated by intestinal P-glycoprotein. The cardioselective beta-blocker talinolol has been described to be secreted by way of P-glycoprotein into the lumen of the gastrointestinal tract after oral and intravenous administration. We therefore hypothesized that coadministration of digoxin and talinolol may lead to a drug-drug interaction based on a competition for intestinal P-glycoprotein. METHODS: Pharmacokinetics of digoxin (0.5 mg orally), talinolol (30 mg intravenously and 100 mg orally), and digoxin plus talinolol orally, as well as digoxin plus talinolol intravenously, were assessed in five male and five female healthy volunteers (age range, 23 to 30 years; body weight, 60 to 95 kg) in a changeover study with at least a 7-day washout period. Digoxin and talinolol were analyzed by fluorescence polarization immunoassay and HPLC, respectively. RESULTS: Oral coadministration of 100 mg talinolol increased the area under the concentration-time curve (AUC) from 0 to 6 hours and the AUC from 0 to 72 hours of digoxin significantly by 18% and 23%, respectively (5.85+/-1.49 versus 7.22+/-1.29 ng x h/mL and 23.0+/-3.3 versus 27.1+/-3.7 ng x h/mL, for both P<.05) and the maximum serum levels by 45%. Renal clearance and half-life of digoxin remained unchanged. Coinfusion of 30 mg talinolol with oral digoxin had no significant effects on digoxin pharmacokinetics. Digoxin did not affect the disposition of talinolol after both oral and intravenous administration. CONCLUSION: We observed a significantly increased bioavailability of digoxin with oral coadministration of talinolol, which is most likely caused by competition for intestinal P-glycoprotein.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Antagonistas Adrenérgicos beta/farmacología , Cardiotónicos/farmacocinética , Digoxina/farmacocinética , Absorción Intestinal/efectos de los fármacos , Propanolaminas/farmacología , Administración Oral , Adulto , Área Bajo la Curva , Disponibilidad Biológica , Cromatografía Líquida de Alta Presión , Estudios Cruzados , Quimioterapia Combinada , Femenino , Inmunoensayo de Polarización Fluorescente , Semivida , Humanos , Infusiones Intravenosas , Masculino , Valores de Referencia , Factores de TiempoRESUMEN
X-linked Emery-Dreifuss muscular dystrophy (EDMD) is a relatively rare benign neuromuscular disorder which can vary remarkably in onset, course and severity. In the present study, a TCTAC deletion spanning the nucleotides 631-635 of the emerin gene caused an unusually severe disease phenotype including loss of ambulation and severe muscle wasting in two affected brothers. The same mutation has been reported previously in an unrelated family showing a significantly milder phenotype. The interfamilial heterogeneity in distribution and in severity of the features in the two families point to environmental or genetic modification as the cause of clinical variability in Emery-Dreifuss muscular dystrophy.
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Proteínas de la Membrana/genética , Distrofias Musculares/genética , Timopoyetinas/genética , Cromosoma X/genética , Adolescente , Adulto , Secuencia de Bases , Niño , Preescolar , ADN/química , ADN/genética , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Expresión Génica , Ligamiento Genético , Humanos , Lactante , Masculino , Distrofias Musculares/patología , Distrofia Muscular de Emery-Dreifuss , Proteínas Nucleares , Linaje , Fenotipo , Eliminación de SecuenciaRESUMEN
It is not generally possible to measure most organic acids in the serum of critically ill patients, due to rapid metabolism and methodological problems. Only the regular measurement of lactic acid and the arterial ketone body ratio (acetoacetate/beta-hydroxybutyrate, AKBR) have been introduced in clinical practice, but these parameters can represent only a part of the disturbed metabolism. In pediatric patients, a chromatographical urine analysis has been established for detection of inborn errors of metabolism, which allows the determination of more than 50 organic acids simultaneously (gas chromatographic (GC) analysis in combination with mass spectrometry (MS)]. In continuous treatment of acute renal failure, hemofiltrate is always available, but it contains only low protein concentrations and after the filtration process, metabolism is rapidly stopped. The sieving coefficient of lactic acid is nearly one in hemofiltration. The aim of our study was to compare results of the regular and CG/MS methods in blood and hemofiltrate for lactic acid, and to find other organic acids of possible clinical importance. We investigated serum (lactic acid) and hemofiltrate of 40 critically ill patitens, similar to the urine analysis method for infants. All patients suffered from acute renal failure and were treated by continuous veno-venous hemofiltration (CVVH). The conditions of treatment were standardized (spontaneous ultrafiltration in the first hour), and the material (blood/hemofiltrate) was taken one hour after the beginning of extracorporeal circulation. Statistical methods included correlation analysis, nonparametric ANOVA with Wilcoxon scores (ranks of data), and stepwise discriminant analysis. Regular and GC/MS methods in hemofiltrate showed a good correlation for lactic acid. The best correlation with lactic acid was found for 4-hydroxy-phenyllactic acid (n=20, r=0.866), 2-hydroxy-valeric acid (n=22, r=0.7491) and 2-hydroxybutyric acid (n=32, r=0.5148). Age, sex, diagnosis, and APACHE II score play a subordinate role, but the presence of glyceric and citric acid possibly have prognostic importance [nonparimetric ANOVA with Wilcoxon scores (ranks of data)], as does the combination of 3-hydroxypropionic acid, glyceric acid, and threonic-acid-4-lacton (stepwise discriminant analysis). It can be concluded that in acute renal failure, the measurement of lactic acid and AKBR can reflect only a small part of disturbed metabolism. Hemofiltrate can be a useful medium in describing metabolic processes in critically ill patients with acute renal failure. Some inherited metabolic diseases in infants (phenylketonuria, maple syrup disease) and ketoacidosis show similar metabolic modifications.
Asunto(s)
Lesión Renal Aguda/metabolismo , Hemofiltración , Ácido Láctico/análisis , APACHE , Acetoacetatos/análisis , Ácidos/análisis , Ácidos/sangre , Lesión Renal Aguda/terapia , Adulto , Niño , Cromatografía de Gases , Enfermedad Crítica , Femenino , Humanos , Hidroxibutiratos/análisis , Ácido Láctico/sangre , Masculino , Espectrometría de Masas , Persona de Mediana EdadRESUMEN
UNLABELLED: Extent and rate of absorption of acetylsalicylic acid (ASA) from rapidly dispersing (Acesal Extra) and plain tablets (Acesal) relative to reference 1 (plain tablets, Aspirin) and from microcapsuled tablets (Micristin) relative to comparable listed tablets (reference 2, Colfarit) were assessed in 2 single-dose (0.5 g ASA), open, randomized, crossover studies with intervals of 14 days between 2 periods. Both studies were performed in 24 male and female healthy volunteers each (age 18-32 years, body weight 48-90 kg, body height 161-190 cm). ASA and its metabolite salicylic acid (SA) were measured with an HPLC method validated for ASA between 0.2 and 20 microg/ml and for SA between 0.4 and 40 microg/ml. The test tablets were considered bioequivalent with reference in extent of absorption if the 90% confidence limits of the AUC0 to infinity ratio were within the range of 0.80-1.25, and in rate of absorption if the confidence limits of the Cmax/AUC0 to infinity ratios were within 0.70-1.43. RESULTS: Geometric means and 90% confidence limits for the test/reference ratios of the comparisons Acesal vs reference 1, Acesal Extra vs reference 1 and Micristin vs reference 2 were 1.05 (0.97-1.13), 1.13 (1.05-1.22), 1.02 (0.92-1.14) for ASA AUC0 to infinity and 1.02 (0.96-1.07), 1.05 (0.99-1.11), 0.98 (0.91-1.04) for SA AUC0 to infinity, respectively. The results for Cmax/AUC of ASA were 1.16 (1.00-1.34), 1.72 (1.49-1.99), 0.83 (0.73-0.94) and of SA 1.02 (0.98-1.07), 1.07 (1.02-1.12), 0.93 (0.88-0.97). CONCLUSION: Acesal and Micristin were bioequivalent with the respective references in both extent and rate of absorption. Acesal Extra and reference 1 were bioequivalent with regard to extent only. Acesal Extra was absorbed faster.
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Antiinflamatorios no Esteroideos/farmacocinética , Aspirina/administración & dosificación , Aspirina/farmacocinética , Adulto , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/sangre , Área Bajo la Curva , Aspirina/sangre , Disponibilidad Biológica , Estudios Cruzados , Formas de Dosificación , Portadores de Fármacos , Composición de Medicamentos , Femenino , Humanos , Absorción Intestinal , Masculino , Valores de Referencia , Equivalencia TerapéuticaRESUMEN
Human epidermal melanocytes and keratinocytes express mRNA for all enzymes involved in de novo synthesis/recycling of the cofactor (6R) L-erythro 5,6,7,8 tetrahydrobiopterin (6BH4) in normal healthy individuals. An enhanced epidermal de novo synthesis was identified in association with decreased epidermal phenylalanine hydroxylase and 4a carbinolamine dehydratase in patients with vitiligo. The latter event leads to an accumulation of the nonenzymatic isomer (7R) L-erythro 5,6,7,8 tetrahydrobiopterin (7BH4) inhibiting phenylalanine hydroxylase (PAH) with an apparent Ki = 10(-6) M. One consequence of decreased epidermal PAH activities would be a build-up of L-phenylalanine. To substantiate this consideration, FT-Raman spectroscopy was utilised to study in vivo total phenylalanine levels at 1004 cm-1 in involved and uninvolved skin of 23 patients with vitiligo, showing in all cases increased levels of phenylalanine in involved compared to uninvolved skin of the same individual. Additionally the peripheral blood L-phenylalanine turnover was determined over time after a single oral loading with L-phenylalanine in 32 patients (100 mg/kg body weight). All patients demonstrated slower kinetics from L-phenylalanine to L-tyrosine, but 41% of the group showed significantly slower kinetics under these conditions. None of the patients presented peripheral hyperphenylalaninemia without loading. Our results demonstrate for the first time a phenylalanine build-up in the involved epidermis of patients with vitiligo. These data support the earlier observation of a defective epidermal pterin metabolism in this disease.
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Fenilalanina/análisis , Piel/química , Vitíligo/metabolismo , Adolescente , Adulto , Biopterinas/análogos & derivados , Biopterinas/biosíntesis , Biopterinas/metabolismo , Células Cultivadas , Femenino , GTP Ciclohidrolasa , Expresión Génica/genética , Humanos , Hidroliasas/genética , Cinética , Masculino , Persona de Mediana Edad , Fenilalanina/farmacocinética , Fenilalanina Hidroxilasa/genética , ARN Mensajero/análisis , Piel/patología , Espectrometría Raman , Tirosina/biosíntesisRESUMEN
UNLABELLED: Both single and multiple dose bioequivalence studies are required to assess the quality of modified release formulations of drugs. In bioequivalence studies of drugs with enzyme autoinducing properties such as carbamazepine (CBZ), the standard multiple dose study design must be modified to guarantee equivalence of drug elimination. This problem was considered with regard to carbamazepine 400 retard AWD (test) whose bioavailability relative to a listed reference (Tegretal 400 retard) was studied in 2 randomized, open, crossover studies both with 18 healthy volunteers of Caucasian origin (20-36 years, 61.5-92 kg, 172-195 cm). The single dose study was done with 400 mg CBZ. Serum concentration time profiles of CBZ and its active metabolite CBZ-10,11-epoxide were determined until 144 h after administration. The multiple dose study was performed with 400 mg CBZ b.i.d. for 15 days (first 2 days: 200 mg b.i.d.) followed by a 7-day study with the alternative investigational product. 24-hour serum concentration time profiles of CBZ and its metabolite were measured on days 15 and 22 of the study. The quantitative drug analysis was done with an HPLC method the quality of which fulfilled the requirements of bioequivalence studies. Test was considered bioequivalent to reference with regard to the extent of absorption, if the 90% confidence intervals of the AUC0-infinity ratio (single dose) and AUC0-24h ratio (multiple dose) were within the range of 0.80-1.25, and with regard to rate of absorption if the 90% confidence intervals of the Cmax/AUC ratio (single dose) or AUCF0-24h ratio were within 0.70-1.43. The point estimators (90% confidence limits) of the AUC ratio (test/reference) of CBZ were 0.979 (0.94, 1.02) for the single and 1.01 (0.947, 1.076) for the multiple dose comparison. The point estimator (90% confidence limits) of the Cmax/AUC ratio was 0.989 (0.959, 1.020) and of the AUCF0-24h ratio 1.066 (0.937, 1.212). There were no circadian time differences in any pharmacokinetic parameter. IN CONCLUSION: Carbamazepine 400 retard AWD tablets were bioequivalent to reference with regard to extent and rate of absorption after both single and multiple dose administration.
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Anticonvulsivantes/farmacocinética , Carbamazepina/farmacocinética , Adulto , Anticonvulsivantes/administración & dosificación , Área Bajo la Curva , Disponibilidad Biológica , Carbamazepina/administración & dosificación , Cromatografía Líquida de Alta Presión , Ritmo Circadiano/fisiología , Estudios Cruzados , Preparaciones de Acción Retardada , Inducción Enzimática/efectos de los fármacos , Humanos , Masculino , Espectrofotometría UltravioletaRESUMEN
Debrisoquine 4-hydroxylation and sulphamethazine N-acetylation phenotypes were determined in 115 Czech drug-free in-patients with schizophrenia (n = 64) or major depressive disorder (n = 51). These data were compared with a control group of 321 healthy volunteers from the North-East German area of Greifswald. The distribution of debrisoquine hydroxylator phenotypes was almost identical in patients and healthy controls. Thus, there were 8.7% (95% CI 5.4-12.0%) of poor metabolizers (PM) among patients while 8.7% (95% CI 23.6-13.8%) PM among the control group. The prevalences of PM amongst patients with chronic schizophrenia and major depression were 10.9% (95% CI 4.5-21.3%) and 5.9% (95% CI 1.24-16.3%), respectively (chi 2 schizophrenics vs control = 0.315, NS; chi 2 depressive patients vs control = 0.450, NS). However, within the group of EM patients there was a significant (P < 0.01) shift towards higher debrisoquine metabolic ratios, reflecting a lower hydroxylation capacity in EM patients compared with EM healthy controls. The proportion of slow acetylators (SA) was 60.0% (95% CI 51.0-68.9%) in the entire group of psychiatric patients and 57.5% (95% CI 52.1-62.9%) in the control group (chi 2 all patients vs control = 0.195, NS). Furthermore, there were no significant differences in the prevalence of the SA phenotype between controls and schizophrenics or patients with major depression. Although the results of this modest study were negative, the presence of subtle differences in the metabolic capacity between psychiatric patients and a healthy population cannot be ruled out.
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Sistema Enzimático del Citocromo P-450/metabolismo , Trastorno Depresivo/enzimología , Oxigenasas de Función Mixta/metabolismo , Esquizofrenia/enzimología , Sulfametazina/análogos & derivados , Acetilación , Adolescente , Adulto , Anciano , Citocromo P-450 CYP2D6 , Sistema Enzimático del Citocromo P-450/genética , República Checa , Femenino , Alemania , Humanos , Hidroxilación , Masculino , Persona de Mediana Edad , Oxigenasas de Función Mixta/genética , Fenotipo , Sulfametazina/metabolismoRESUMEN
Relative bioavailability of valproic acid after oral administration of 2 Convulsofin (test) tablets each containing 300 mg calcium valproate (263.4 mg valproic acid) was studied versus 2 references (2 dragees each of 300 mg calcium valproate, ref.A, 600 mg sodium valproate in liquid form (258.7 mg valproic acid), ref.B). The controlled, randomized, clinical trial was performed in 16 healthy volunteers (12 males, 4 females, body weight 58-100 kg, Broca index 0.85-1.15) according to a 3-period changeover design with 7 days wash-out between 2 periods. Valproic acid was measured in serum with a GC method. Pharmacokinetic evaluation was done by compartment free methods. Test was considered bioequivalent with ref.A or ref.B with reference to extent of absorption if the 90% confidence interval of their AUC ratio was within the range of 0.80-1.25, and with respect to rate of absorption if the 90% confidence intervals of Cmax/AUC ratios were within 0.70-1.43. The point estimators (90% confidence limits) of the AUC ratios of test/ref.A and test/ref.B were 0.952 (0.882-1.028) and 1.063 (0.989-1.141), respectively. The point estimators (90% confidence limits) of Cmax/AUC ratios were 1.005 (0.923-1.094, test/ref.A) and 0.915 (0.845-0.991, test/ref.B). The following Cmax ratios were calculated: 0.957 (0.866-1.057, test/ref.A) and 0.972 (0.886-1.067, test/ref.B). No serious and unexpected adverse events were observed during the clinical trial. Test was bioequivalent with the 2 reference formulations ref.A and ref.B with respect to extent and rate of absorption. However, according to the secondary criterion tmax test tablets were more rapidly bioavailable than ref.A dragees (tmax-difference: -2.6 (-4.8 to -0.3 h) but more slowly (tmax-difference:+0.8 (-1.3 to +2.9 h) than ref.B juice.
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Anticonvulsivantes/farmacocinética , Ácido Valproico/farmacocinética , Absorción , Administración Oral , Adulto , Análisis de Varianza , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/sangre , Disponibilidad Biológica , Calibración , Cromatografía de Gases , Sistemas de Liberación de Medicamentos , Evaluación de Medicamentos , Femenino , Humanos , Masculino , Estándares de Referencia , Comprimidos , Equivalencia Terapéutica , Ácido Valproico/administración & dosificación , Ácido Valproico/sangreRESUMEN
Bioavailability of Vagimid 500 tablets (film coated, 500 mg metronidazole) and absorption of metronidazole into the systemic circulation after vaginal administration of Vagimid vaginal tablets (100 mg metronidazole) relative to respective listed references were studied in 16 female healthy volunteers (age 21-37 years, weight 45-67 kg, height 158-179 cm). Metronidazole and its main hydroxylated metabolite were measured using an HPLC-method with detection limits of 0.025 and 0.25 micrograms/ml (for vaginal and oral studies), respectively. Extent of absorption was assessed by AUC0-infinity (bioequivalence range 0.80-1.25), rate of absorption by Cmax/AUC0-infinity (bioequivalence range 0.70-1.43). Geometric means and 90%-confidence intervals of the ratios of these primary characteristics were calculated using a multiplicative model. Vagimid 500 tablets were bioequivalent to the reference formulation with regard to extent and rate of absorption of metronidazole because of AUC0-infinity = 0.995 (0.84-1.18) and Cmax/AUC0-infinity = 1.11 (0.94-1.30). The absorption of metronidazole into the systemic circulation after vaginal administration of Vagimid vaginal tablets caused maximal serum concentrations between 433 and 1,156 ng/ml after 8-20 h which are bactericidal only for the most susceptible anaerobic germs and which are most likely only of marginal importance for drug safety.
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Metronidazol/farmacocinética , Absorción , Administración Intravaginal , Administración Oral , Adulto , Disponibilidad Biológica , Cromatografía Líquida de Alta Presión , Estudios Cruzados , Femenino , Humanos , Metronidazol/administración & dosificación , Metronidazol/efectos adversos , Estándares de Referencia , Método Simple Ciego , Equivalencia Terapéutica , Población BlancaRESUMEN
The cytoprotective prostaglandin E2 analog nocloprost clathrate (NOCLO) is tested as a prophylactic for gastrointestinal lesions of NSAID. The effects of 400 micrograms NOCLO versus respective placebos with and without equivalent amounts of beta-cyclodextrin on the pharmacokinetic behavior of acetylsalicylic acid (ASA), given 30 min after NOCLO, were studied in two single-blind, parallel-group trials. The trials were performed in 15 male healthy volunteers (age 21-25 years, body weight 62-94 kg, body height 172-187 cm) with known N-acetylation and debrisoquine type hydroxylation phenotype. ASA, salicylic acid (SA), and salicyluric acid (SU) in plasma and SA and SU in urine were measured by HPLC. NOCLO delayed the absorption of ASA (increased tmax, lower Cmax) significantly in comparison with both placebos. AUC and clearance values were not changed by NOCLO premedication. There were neither differences between the two placebo groups nor between the two groups pretreated with NOCLO with regard to any pharmacokinetic parameter. The changes in drug absorption are caused by the sum of those cytoprotective effects of prostaglandin which are also determinants of drug absorption.
Asunto(s)
Aspirina/metabolismo , Aspirina/farmacocinética , Prostaglandinas F Sintéticas/farmacología , Vasodilatadores/farmacología , beta-Ciclodextrinas , Acetilación , Administración Oral , Adulto , Aspirina/sangre , Cromatografía Líquida de Alta Presión , Ciclodextrinas/farmacología , Interacciones Farmacológicas , Hipuratos/sangre , Humanos , Absorción Intestinal/efectos de los fármacos , Masculino , Salicilatos/orina , Ácido Salicílico , Método Simple CiegoRESUMEN
Pharmacokinetic interactions of cytoprotective prostaglandin E2 analog nocloprost clathrate with theophylline and diclofenac were studied in two placebo controlled, single-blind studies with parallel groups (n = 8) in healthy male volunteers (age 20-32 years, body weight 63-95 kg, body height 169-193 cm, Broca index 0.81-1.18). Nocloprost (200 micrograms) or placebo tablets were given twice daily (07:00 h a.m. and p.m.) for 8 days. Thirty min after the first administration on the first day (single) and 30 min after the last administration in the morning of the 8th day (repeated premedication), pharmacokinetic examinations with retarded theophylline capsules (250 mg) or enteric coated tablets of diclofenac (50 mg) were performed. Theophylline was measured using an HPLC- and diclofenac with a GC-method. Both single and repeated premedication with nocloprost did not significantly change any pharmacokinetic parameter of theophylline. There was only a tendency towards lower AUC of theophylline after both regimens of premedication. As far as diclofenac is concerned, single premedication increased significantly the rate of absorption and total body clearance but lowered the AUC of the NSAID. After repeated premedication, no parameter was significantly influenced. All pharmacokinetic changes observed are most likely without any clinical importance.
Asunto(s)
Diclofenaco/farmacocinética , Prostaglandinas F Sintéticas/farmacología , Teofilina/farmacocinética , Vasodilatadores/farmacología , Absorción , Adulto , Cápsulas , Cromatografía de Gases , Cromatografía Líquida de Alta Presión , Esquema de Medicación , Interacciones Farmacológicas , Humanos , Masculino , Placebos , Premedicación , Método Simple Ciego , Comprimidos RecubiertosRESUMEN
A pharmacokinetic study with 30 mg propiverine p.o. was performed in healthy volunteers (10 males, 6 females, age 36-56 years, body weight 55-100 kg, body height 162-184 cm, Broca index 0.96-1.19). 8 of them were poor and 8 extensive metabolizers of the debrisoquine type hydroxylation polymorphism. The total anticholinergic activity of the parent compound and active metabolites was measured with a radioreceptor assay calibrated with the metabolite M2. The affinity of this metabolite to the muscarinic receptors was similar to that of atropine. The urinary excretion of 3 major metabolites was determined with TLC and densitometry. Arterial blood pressure, heart rate, diameter of pupils, accommodation and parotic salivary flow were also measured. The concentrations of anticholinergic equivalents of propiverine were below 1 ng/ml of M2. 1.4-6.0% of the dose were excreted as N-oxidized metabolites into the urine. The poor and extensive metabolizers of debrisoquine did not differ significantly with regard to the concentration time behaviour of the active drug components, pattern of major metabolites, adverse drug reactions or any pharmacodynamic parameters measured.
Asunto(s)
Bencilatos/farmacocinética , Debrisoquina/metabolismo , Parasimpatolíticos/farmacocinética , Adulto , Bencilatos/administración & dosificación , Bencilatos/orina , Biotransformación , Citocromo P-450 CYP2D6 , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Femenino , Hemodinámica/efectos de los fármacos , Humanos , Hidroxilación , Masculino , Persona de Mediana Edad , Oxigenasas de Función Mixta/efectos de los fármacos , Parasimpatolíticos/administración & dosificación , Parasimpatolíticos/orina , Polimorfismo Genético , Ensayo de Unión Radioligante , Receptores Muscarínicos/metabolismoRESUMEN
Prostaglandins are known to interfere with drug metabolizing processes. Nocloprost (9 beta-chloro-16,16-dimethyl PG E2) is a promising new cytoprotective prostaglandin in clinical evaluation for the treatment of ulcer disease and prophylaxis of gastric lesions caused by NSAID. Pharmacokinetic interactions of 400 micrograms nocloprost with 15 mg/kg antipyrine and 500 mg sulfamethazine (all given p.o.) were studied with a controlled, single-blind crossover trial in 16 healthy male volunteers (age 22-25 years, body weight 63-94 kg, body height 175-187 cm) in order to measure potential interferences with oxidative and conjugative drug metabolism. All individuals were extensive metabolizers of debrisoquine, 9 were slow and 7 rapid acetylators of sulfamethazine. Antipyrine and its major metabolites were measured in serum respectively, urine with the HPLC-method, sulfamethazine and its acetylated metabolite with a colorimetric technique. Nocloprost premedication (30 min prior to the test drugs) did neither interfere significantly with the oxidative processes involved in the disposition of antipyrine nor with the N-acetylation of sulfamethazine. Higher metabolic and renal clearance values of sulfamethazine in slow acetylators were most likely the result of the affected drug absorption. Nocloprost significantly reduced absorption rates of antipyrine and sulfamethazine in the group of slow but not of rapid acetylators. The extent of bioavailability remained unchanged. This phenomenon was certainly caused by the effects of the cytoprotective prostaglandin on those gastrointestinal functions which are determinants of drug absorption.
Asunto(s)
Antipirina/farmacocinética , Prostaglandinas F Sintéticas/farmacología , Sulfametazina/farmacocinética , Vasodilatadores/farmacología , Acetilación , Adulto , Antipirina/administración & dosificación , Humanos , Absorción Intestinal , Masculino , Sulfametazina/administración & dosificaciónRESUMEN
The pharmacokinetics of theophylline (TPH, 10 mg/kg i.v.) were assessed in rats (natural light-dark span, June 9-10) after i.p. pretreatment with saline and 80 mg/kg phenobarbital (PB), respectively, for 3 consecutive days at either 07:00 h or at 19:00 h. Serum concentrations of TPH were assayed by high-performance liquid chromatography. No significant differences of the elimination rates of TPH could be found between the times of TPH administration (clearance: 1.17 +/- 0.17 ml/kg/min at 07:00 h vs. 1.23 +/- 0.17 ml/kg/min at 19:00 hours). PB premedication markedly accelerated TPH elimination. The increase in clearance values was more expressed when TPH was injected at 07:00 h than at 19:00 h (2.48 +/- 0.67 vs. 2.06 +/- 0.41 ml/kg/min, p < 0.01).