RESUMO
Hypofunction of the serotonin (5-HT) system might be involved in depression. Initial effects of the 5-HT reuptake inhibitor clomipramine (CMI) on plasma 5-HT have never been assessed. On Day 1, 27 depressed patients received either a 25-mg CMI slow infusion or a 25-mg CMI tablet in a randomized, double-blind, double-dummy design. The daily dose was subsequently titrated up to 75 mg i.v. or 150 mg orally. The Montgomery-Asberg Depression Rating Scale (MADRS) was rated on Days 1, 4, 7 and 14. High-performance liquid chromatography (HPLC-EC) assays of plasma 5-HT, platelet 5-HT, and CMI were performed on Day 1 before and after the infusion. On Day 1, both groups experienced a mean (nonsignificant) plasma 5-HT increase; in the i.v. group this initial increase correlated with MADRS decrease over 14 days (r = 0.76, p = .0025). Correlations between platelet 5-HT and MADRS decrease were not significant. These preliminary data show that: i) CMI administration results in initial changes in plasma 5-HT; and ii) i.v. CMI-induced initial plasma 5-HT increase is consistent with the CMI 5-HT profile, and might predict the clinical response to CMI.
Assuntos
Antidepressivos Tricíclicos/uso terapêutico , Clomipramina/uso terapêutico , Transtorno Depressivo/sangue , Transtorno Depressivo/tratamento farmacológico , Serotonina/sangue , Administração Oral , Adolescente , Adulto , Idoso , Antidepressivos Tricíclicos/administração & dosagem , Biomarcadores , Plaquetas/metabolismo , Cromatografia Líquida de Alta Pressão , Clomipramina/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Escalas de Graduação PsiquiátricaRESUMO
Plasma homovanillic acid (pHVA) was measured over a 13 hr-period in 16 DMS-III-R schizophrenic patients, all treated with neuroleptic drugs and in a stable clinical and therapeutic status for the preceeding 12 months. Patients were categorized into deficit (n = 9) and nondeficit (n = 7) forms of schizophrenia according to the Schedule for the Deficit Syndrome (SDS) criteria. As compared to the nondeficit group, deficit patients display significantly lower mean pHVA concentrations from 9 AM to 12 AM and a lack of diurnal variations. None of the demographic, clinical, and therapeutic variables can explain these biological differences. These data suggest a specific biochemical basis for the deficit syndrome of schizophrenia as defined by the SDS criteria, that is, primary, enduring, negative symptoms.
Assuntos
Nível de Alerta/fisiologia , Ácido Homovanílico/sangue , Escalas de Graduação Psiquiátrica , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico , Adulto , Feminino , Humanos , Masculino , Esquizofrenia/classificação , Esquizofrenia/diagnósticoRESUMO
The effects of okadaic acid, a polyether derivative of a 38-carbon monocarboxylic fatty acid obtained from a culture of the marine dinoflagellate, Prorocentrum lima, were studied on the human isolated bronchus. In low concentrations (0.01 and 0.03 microM), okadaic acid had no significant effect of its own on the human isolated bronchus, but in higher concentrations (0.1-10 microM) it induced a series of contractions and relaxations. The first contraction was of low intensity (5% of maximum response to acetylcholine 3 mM) and occurred early. The second contraction had a higher amplitude (30% of maximum response to acetylcholine 3 mM) and reached its peak with okadaic acid 0.3 microM. At higher concentrations (1-10 microM), following a relaxation phase, a later rebound contraction occurred between 70 and 120 min and corresponded to 40% of the maximum response to acetylcholine 3 mM. In addition, okadaic acid inhibited or abolished the contractile response evoked by either KCl 60 mM or acetylcholine 3 mM with IC50 of 0.04 and 0.12 microM, respectively. The second contraction evoked by 0.3 microM okadaic acid was partially inhibited in the presence of the Ca2+ channel blocker, nicardipine 1 microM, or after incubation of the human bronchus in a Ca(2+)-free solution and it was completely abolished in the presence of CdSO4 0.1 mM.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Brônquios/efeitos dos fármacos , Compostos de Cádmio , Éteres Cíclicos/farmacologia , Contração Muscular/efeitos dos fármacos , Sulfatos , Vasoconstritores/farmacologia , Acetilcolina/farmacologia , Brônquios/metabolismo , Brônquios/fisiologia , Cádmio/farmacologia , Cafeína/farmacologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Relaxamento Muscular/efeitos dos fármacos , Nicardipino/farmacologia , Ácido Okadáico , Papaverina/farmacologia , Fosfatidilinositóis/metabolismo , Cloreto de Potássio/farmacologiaRESUMO
The determination of the concentrations of antipyrine metabolites in biological fluids is hampered by the difficulty in obtaining pure conjugated compounds to be used as standards. Most authors have proposed determination of total forms by high performance liquid chromatography (HPLC) after deconjugation of these metabolites using chemical or enzymatic hydrolysis. Up to now there is no satisfactory hydrolysis method for the study of all antipyrine metabolites. The situation is further complicated by the fact that the deconjugated metabolites are highly unstable whichever technique is being used. Because of the lack of stability of all these molecules it has been necessary to isolate the glucuroconjugated compounds from urine. We describe a method which allows us to obtain highly purified glucuroconjugated metabolites of antipyrine. Sulphoconjugated compounds have been synthesized previously. We are thus able to propose a chromatographic procedure which allows us to determine simultaneously all stable phase I and phase II metabolites of antipyrine in biological fluids without any step of extraction. This analytical technique allows us to study the activity of the different isoenzymes implicated in the metabolism of antipyrine.
Assuntos
Antipirina/urina , Cromatografia/métodos , Glucuronatos/urina , Antipirina/química , Antipirina/metabolismo , Líquidos Corporais/química , Soluções Tampão , Precipitação Química , Glucuronatos/química , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Fosfatos , Sulfatos/análiseRESUMO
A method has been developed for the separation and measurement of ethylene glycol and three other glycols (propylene glycol, 1,3-butylene glycol and 2,3-butylene glycol) in biological samples by wide-bore column gas chromatography with a flame ionization detector. The method used 1,3-propylene glycol (1,3-propanediol) as an internal standard. The method was linear at least from 2 to 1000 micrograms/ml, with a detection limit of 1 microgram/ml. Analytical recoveries were 89-98% for the different concentrations. Precision studies showed coefficients of variation of 1.5-7.7% for the different concentrations. The assay was applied to the analysis of biological samples from two patients who had ingested ethylene glycol and/or other glycols in a suicide attempt.
Assuntos
Glicóis/análise , Adulto , Ácidos Borônicos , Cromatografia Gasosa , Glicóis/sangue , Glicóis/urina , Humanos , Masculino , Desnaturação Proteica , Tentativa de SuicídioRESUMO
In one well-equilibrated parkinsonian patient treated with combined L-dopa and carbidopa (Sinemet), we have observed changes in treatment efficacy while receiving spiramycin (Rovamycine) for an intercurrent respiratory infection. A preliminary study of the pharmacokinetics of L-dopa and its main metabolites 3-O-methyldopa (3-OMD) and dihydroxyphenylacetic acid (dopac) in two parkinsonian patients treated with Sinemet has revealed a marked decrease in the AUC0-360 of these two metabolites after a 3-day course of Rovamycine. In order to confirm this interaction, we have studied the modifications of the pharmacokinetics of L-dopa, 3-OMD, dopac, and carbidopa in eight male healthy volunteers after a single dose of Sinemet 250 (L-dopa, 250 mg and carbidopa, 25 mg) before and after a 3-day course of Rovamycine. Our study confirms this interaction. After spiramycin, we observed a marked reduction in AUC0-360 for L-dopa (p less than 0.001), 3-OMD (p less than 0.001), and carbidopa (p less than 0.001), and an increase in AUC0-360 for dopac (p less than 0.01). The L-dopa elimination half-life was increased (p less than 0.012); differences in peak plasma concentrations did not attain statistical significance. We think that these modifications in L-dopa pharmacokinetics after spiramycin are due to nonabsorption of carbidopa secondary to modified gastrointestinal motility.
Assuntos
Carbidopa/farmacocinética , Levodopa/farmacocinética , Espiramicina/farmacologia , Adulto , Carbidopa/sangue , Humanos , Levodopa/sangue , MasculinoRESUMO
In a previous study we observed, during separation of total antipyrine metabolites by high-performance liquid chromatography and after enzymatic hydrolysis, an unidentified peak corresponding to an ionic compound with pyrazolinone features. In the present study, this compound was identified as the 4-hydroxyantipyrine sulphoconjugate, and its structure was definitively confirmed by gas chromatographic-mass spectrometric analysis and by the use of pure synthetic substance. We also demonstrated the inhibitory effect of sodium metabisulphite, a necessary preservative of urinary samples, on hydrolysis of this conjugate in the presence of sulphatases from Helix pomatia or Aerobacter aerogenes. This inhibitory effect makes it impossible to perform a global assay of antipyrine metabolites after enzymatic or chemical hydrolysis and confirms the value of direct assay of the 4-hydroxyantipyrine sulphoconjugate.
Assuntos
Antipirina/análogos & derivados , Adulto , Antipirina/metabolismo , Antipirina/urina , Fenômenos Químicos , Físico-Química , Cromatografia Gasosa , Cromatografia Líquida de Alta Pressão , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Hidrólise , Indicadores e Reagentes , Espectrometria de Massas , Sulfatases/metabolismo , SulfitosRESUMO
A method was developed for the separation and measurement of chloroquine and three metabolites (desethylchloroquine, bisdesethylchloroquine and 4-amino-7-chloroquinoline) in biological samples by ion-pair high-performance liquid chromatography with UV detection. The method uses 2,3-diaminoaphthalene as an internal standard and provides a limit of detection between 1 and 2 ng/ml for chloroquine and its metabolites. The assay was linear in the range 12.5-250 ng/ml and the analytical recovery and reproducibility were sufficient. The assay was applied to the analysis of biological samples from a patient undergoing chloroquine chemoprophylaxis and a patient who had ingested chloroquine in a suicide attempt.
Assuntos
Cloroquina/metabolismo , Cloroquina/sangue , Cloroquina/intoxicação , Cloroquina/urina , Cromatografia Líquida de Alta Pressão , Humanos , Íons , Intoxicação/metabolismo , Reprodutibilidade dos Testes , Espectrofotometria UltravioletaRESUMO
The fate of clomipramine (CMI) and its main demethylated metabolite demethylclomipramine (DCMI) was studied in two strains of Swiss mice (NMRI and CD1) after intraperitoneal injection. A study of its distribution among various tissues showed that fixation was most marked in lungs, perirenal fat and kidneys, and only moderate in the brain. The pharmacokinetic parameters of both molecules were determined in brain tissue and plasma. Absorption was rapid (tmax CMI = 14 min), metabolism prompt (tmax DCMI = 17 or 18 min according to the breed) and elimination rapid from both plasma and brain tissue. The first two stages were similar in the two strains, but elimination of CMI from both plasma and brain was faster in the NMRI mice (plasma t1/2 = 53 min against 165 min in the CD1 mice). Both values were well below that reported for man (mean plasma t1/2 = 24 h). The data presented can serve as a basis for designing true chronic administration protocol in animals.
Assuntos
Clomipramina/análogos & derivados , Clomipramina/farmacocinética , Animais , Clomipramina/sangue , Meia-Vida , Injeções Intraperitoneais , Masculino , Camundongos , Especificidade da Espécie , Distribuição TecidualRESUMO
The penetration of minocycline into different lung tissues and bronchial mucus was studied in 17 patients undergoing pulmonary surgery for cancer. The patients received oral minocycline 100 mg at night for 3 days preceding surgery. Minocycline concentrations were measured in plasma samples collected before the operation and in tissues and mucus taken from in and around the part of the lung that was surgically removed. Mean tissue or mucus concentration to plasma concentration ratios were 3.78 +/- 1.10 for lung parenchyma, 4.04 +/- 1.31 for bronchial walls, 3.37 +/- 1.00 for pulmonary arterial walls, 1.99 +/- 1.80 for intraluminal mucus collected from bronchi located in healthy tissue proximal to the tumour, 5.16 +/- 3.26 for intraluminal mucus collected in a bronchus distal to the tumour, and 3.06 +/- 1.99 for catheter-collected mucus from the trachea and principal bronchi. These results indicate that minocycline is found in high concentration in all types of lung tissue and mucus in man.
Assuntos
Pulmão/metabolismo , Minociclina/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromatografia Líquida de Alta Pressão , Humanos , Neoplasias Pulmonares/química , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Distribuição TecidualRESUMO
The pharmacokinetics of molsidomine were investigated in six healthy volunteers and in seven patients with alcoholic cirrhosis. After a 2 mg oral dose, molsidomine elimination half-life was prolonged in cirrhotic patients (13.1 +/- 10.0 h vs 1.2 +/- 0.2 h, P less than 0.01) because of a decrease in its apparent plasma clearance (CL/F) (39.8 +/- 31.9 ml h-1 kg-1 in patients with cirrhosis vs 590 +/- 73 ml h-1 kg-1 in volunteers). The elimination half-life of the active metabolite, linsidomine (SIN-1) was also prolonged in cirrhotic patients (7.5 +/- 5.4 h vs 1.0 +/- 0.19 h, P less than 0.05). The AUC values of both molsidomine and linsidomine were increased in the cirrhotic group, but the increase in the former was considerably greater than in the latter as shown by the significant decrease of the ratio AUClinsidomine/AUCmolsidomine x 100 (4.5 +/- 6.1 in cirrhotic patients vs 23.5 +/- 3.4 in healthy volunteers, P less than 0.001). These results suggest that liver cirrhosis profoundly alters the pharmacokinetics and metabolism of molsidomine.
Assuntos
Cirrose Hepática Alcoólica/metabolismo , Molsidomina/análogos & derivados , Molsidomina/farmacocinética , Adulto , Humanos , Cirrose Hepática Alcoólica/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Molsidomina/metabolismo , Molsidomina/uso terapêutico , Valores de ReferênciaRESUMO
The oxidative metabolism of xenobiotics is usually explored using the antipyrine test, which consists of determining the production clearances and urinary percentages of three major antipyrine metabolites 4-hydroxyantipyrine, norantipyrine and 3-hydroxymethylantipyrine. The total forms of these compounds are generally determined by high-performance liquid chromatography (HPLC). However, the 3-carboxylic acid metabolite (3-carboxyantipyrine), which is the ultimate oxidation form in the 3-hydroxylation pathway, should also be taken into account, but so far its determination by HPLC has not been reported. A simple and accurate HPLC method has now been developed to determine the three major metabolites plus 3-carboxyantipyrine. In this method, all compounds are extracted in an aprotic non-polar solvent, at pH 3.5 for the major metabolites and unchanged antipyrine, then at pH 0.9 for 3-carboxyantipyrine. Total forms are evaluated after enzymatic hydrolysis. Throughout the procedure, attention is paid to the relative instability of norantipyrine and 4-hydroxyantipyrine. Recovery, accuracy and precision are discussed. The method has been applied to the determination of relative amounts (percentage of the dose administered) excreted in the urine of ten adult subjects 48 h after ingestion of antipyrine (600 mg). The proportion of 3-carboxyantipyrine excreted was 4.5 +/- 0.2%, which is in agreement with published values obtained by gas chromatography. The excretion rates of the major metabolites also were similar to those reported in the literature, thereby confirming that the reported method is valid. 3-Carboxyantipyrine is totally excreted as the free form and norantipyrine almost completely as glucuroconjugate.
Assuntos
Antipirina/análogos & derivados , Antipirina/urina , Antipirina/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Edaravone , Humanos , Indicadores e Reagentes , OxirreduçãoRESUMO
The penetration of minocycline into lung tissue was evaluated in 14 patients about to undergo excision of the lung for cancer. The patients received minocycline orally in doses of 100 mg twice a day for 3 days, the 100 mg in the morning of the operation day. Minocycline concentrations were measured in plasma samples taken before surgery and in the lung tissue resected. The mean tissue/plasma concentration ration was 3.17 +/- 0.41 (range: 1.5 to 7.48). The same ratios were obtained in peritumoral and tumoral tissues. These results indicate that minocycline penetrates well into tissues.
Assuntos
Pulmão/metabolismo , Minociclina/farmacocinética , Adenocarcinoma/metabolismo , Adenocarcinoma/cirurgia , Adulto , Idoso , Carcinoma Adenoide Cístico/metabolismo , Carcinoma Adenoide Cístico/cirurgia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/cirurgia , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/cirurgia , Pessoa de Meia-IdadeRESUMO
The pharmacokinetics of molsidomine were investigated in six young (25.5 +/- 0.6 years) and in six elderly healthy volunteers (81.1 +/- 3.1 years). After a 2 mg oral administration, molsidomine elimination half-life was prolonged in elderly subjects (1.9 +/- 0.2 h versus 1.2 +/- 0.1 h, P less than 0.05) because of a decrease in its plasma clearance (15.1 +/- 3.2 l.h-1 versus 41.8 +/- 2.5 l.h-1 (P less than 0.01) in young volunteers). The elimination half-life of the active metabolite, SIN-1 or linsidomine was also prolonged in elderly subjects (1.8 +/- 0.2 h versus 1.0 +/- 0.08 h, P less than 0.05). AUCs of both molsidomine and SIN-1 were increased in the elderly subjects, but the increase in the former was greater (x 3.4) than the increase in the latter (x 1.6). These results suggest that pharmacokinetics and metabolism of molsidomine are impaired in elderly subjects.
Assuntos
Envelhecimento/metabolismo , Molsidomina/análogos & derivados , Molsidomina/farmacocinética , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromatografia Líquida de Alta Pressão , Feminino , Meia-Vida , Humanos , Masculino , Molsidomina/administração & dosagem , Molsidomina/sangueRESUMO
A reversed-phase high-performance liquid chromatographic method, with ultraviolet detection, is proposed for the plasma determination of SIN-1, the active metabolite of molsidomine, which involves propoxycarbonyl derivatization. The internal standard is the ethoxycarbonyl derivative of SIN-1 (i.e. molsidomine). Derivatization and extraction are each performed in one step (2 min) with 70% yield. The nature of a by-product is discussed. The method provides rapid elution (less than 15 min), linearity over the range 0.4-200 ng/ml, day-to-day precision between 2.5 and 11.3% and a limit of determination of 0.5 ng/ml. This method is also suitable for the simultaneous determination of molsidomine and SIN-1. In this case the internal standard is an ethoxycarbonyl derivative of a piperazino-3-sydnonimine, a SIN-1 analogue.
Assuntos
Molsidomina/análogos & derivados , Molsidomina/sangue , Anti-Hipertensivos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Pessoa de Meia-Idade , Molsidomina/farmacocinéticaRESUMO
The isocratic reversed phase high performance liquid chromatographic method proposed for quinidine metabolic studies facilitates particularly the separation of 10(R) and (S) isomers of quinidine 10,11-dihydrodiols. The finding of each of these forms following a new synthetic pathway allows us to identify and quantify them in biological fluids. These two isomers have especially been observed in rat bile and hepatocyte secretions. The metabolic inducing effect of phenobarbital on the oxidative metabolism of quinidine is verified in rat isolated hepatocytes. Simultaneous secretion of the two dihydrodiols is also verified in human urine by a gas chromatography/mass spectrometry procedure.
Assuntos
Cromatografia Líquida de Alta Pressão , Quinidina/análogos & derivados , Quinidina/metabolismo , Animais , Bile/metabolismo , Óxidos N-Cíclicos/análise , Óxidos N-Cíclicos/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Estrutura Molecular , Fenobarbital/farmacologia , Quinidina/análise , Quinidina/urina , Quinina/análogos & derivados , Quinina/análise , Quinina/metabolismo , Quinina/urina , Ratos , Ratos Endogâmicos , EstereoisomerismoRESUMO
Ceftriaxone is a third generation cephalosporin remarkable for its wide distribution in the biliary tract. The purpose of this study was to determine whether biliary tract pathology, as observed during surgery, had an influence on this distribution. 52 patients about to be operated upon and presenting with a high risk of bile infection received a single 1 or 2 g dose of ceftriaxone administered intravenously over 20 min during the hour that preceded surgery. Samples of blood and of bile from the gallbladder (GB) and the common bile duct (CBD), as well as specimens of the GB wall were taken during the operation. In patients whose GB was normal at laparotomy (apart from stones) ceftriaxone concentrations in bile and GB wall were 10-25 and 2 times respectively higher than in plasma. In patients with a grossly distended but not infected GB (hydrocholecystis) ceftriaxone levels were high in CBD bile but null in GB bile and only one-quarter to one-half of plasma levels in GB wall. In patients with stones in the CBD or inflamed GB wall ceftriaxone levels were high in bile (although lower than in cases with normal GB) and similar to plasma levels in GB wall. When malignant pancreatic lesions were present ceftriaxone concentrations could not be measured in both GB and CBD bile but reached 50% of plasma concentrations in GB wall.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Doenças Biliares/fisiopatologia , Sistema Biliar/metabolismo , Ceftriaxona/metabolismo , Idoso , Infecções Bacterianas/prevenção & controle , Doenças Biliares/metabolismo , Doenças Biliares/cirurgia , Ceftriaxona/administração & dosagem , Ceftriaxona/uso terapêutico , Humanos , Pessoa de Meia-Idade , Pré-MedicaçãoRESUMO
The pharmacokinetics of oral theophylline (250 mg) and the production of its metabolites (3-methylxanthine, 1-methyluric acid, 1,3-dimethyluric acid) were studied before and after the administration of oral terfenadine (120 mg twice daily for 16 days) in 10 healthy volunteers. Comparison of volumes of distribution, elimination half-lives, areas under the plasma concentration-time curves, plasma clearance of theophylline and elimination of theophylline metabolites indicated that terfenadine had no significant effect on theophylline pharmacokinetics and metabolism.
Assuntos
Compostos Benzidrílicos/farmacologia , Teofilina/farmacocinética , Adulto , Interações Medicamentosas , Humanos , Masculino , Terfenadina , Teofilina/sangue , Teofilina/metabolismo , Fatores de Tempo , Ácido Úrico/análogos & derivados , Ácido Úrico/sangue , Ácido Úrico/urina , Xantinas/sangue , Xantinas/urinaRESUMO
Pharmacokinetics and effects of oral hydroxy-3(S)-dihydroquinidine (3-OH-HQ) on heart rate (HR), blood pressure (BP), and ECG intervals were studied in 12 healthy volunteers. Three oral single doses of 3-OH-HQ (225, 450, and 900 mg) and placebo were randomly administered to each subject at one week intervals. Pharmacokinetics of 3-OH-HQ was linear in the range of administered doses, with rapid absorption (tmax 0.5-2.5 h) and distribution (t1/2 alpha 0.8-1.2 h) phases. Elimination half-lives did not significantly change with the three doses (15 +/- 4.3, 13.7 +/- 3.9, and 13 +/- 2.2 h). Unchanged 3-OH-HQ was partially eliminated by urine (mean renal clearance 0.24 +/- 0.02 L h-1 kg-1). 3-OH-HQ significantly increased HR after the three doses as compared to placebo. PR interval was not significantly modified but QRS duration significantly increased from 91 +/- 7 to 108 +/- 11 ms (p less than 0.001) 2 h after the 900 mg dose. QTc interval was significantly prolonged from 0.5 to 8 h after the highest dose (14.4 +/- 8.7% 1 h after dosing). Heart rate QRS, and QTc variations were significantly correlated to 3-OH-HQ plasma levels.