RESUMO
SETTING: To assess the revised World Health Organization-recommended dose of 10-20 mg/kg rifampicin (RMP), we studied the steady state pharmacokinetics of RMP in South African children who received standard treatment for drug-susceptible tuberculosis (TB). OBJECTIVE: To determine the formulation effect on the pharmacokinetics of RMP. DESIGN: RMP plasma concentrations were characterised in 146 children (median age 1.4 years, range 0.2-10.2). The morning dose on the day of the pharmacokinetic evaluation was administered as one of two RMP single-drug oral suspensions. RESULTS: While one formulation achieved 2 h concentrations in the range of those observed in adults (median 6.54 mg/l, interquartile range [IQR] 4.47-8.84), the other attained a median bioavailability of only 25% of this, with a median 2 h concentration of 1.59 mg/l (IQR 0.89-2.38). CONCLUSION: RMP is a key drug for the treatment of TB. It is critical that the quality of RMP suspensions used to treat childhood TB is ensured.
Assuntos
Antibióticos Antituberculose/farmacocinética , Aprovação de Drogas , Licenciamento , Rifampina/farmacocinética , Tuberculose/tratamento farmacológico , Administração Oral , Antibióticos Antituberculose/administração & dosagem , Antibióticos Antituberculose/química , Antibióticos Antituberculose/normas , Disponibilidade Biológica , Criança , Pré-Escolar , Composição de Medicamentos , Monitoramento de Medicamentos , Feminino , Humanos , Lactente , Licenciamento/normas , Masculino , Soluções Farmacêuticas , Garantia da Qualidade dos Cuidados de Saúde , Controle de Qualidade , Rifampina/administração & dosagem , Rifampina/química , Rifampina/normas , África do Sul , Tuberculose/sangue , Tuberculose/diagnósticoRESUMO
OBJECTIVES: The liver has been shown to play a particularly important role in the initiation and progression of the early systemic inflammatory response (SIR) to spinal cord injury (SCI). The purpose of this study was to determine the time course of leucocyte recruitment to the liver, and to determine the effect of injury severity on the magnitude of leucocyte recruitment and hepatic injury. METHODS: Rats were randomly assigned to one of the following groups: uninjured, sham-injured (laminectomy and no cord injury), cord compressed or cord transected. At 30 min and 90 min after SCI rats had the left lobe of their livers externalised and visualised using intravital video microscopy. RESULTS: Thirty minutes after injury the total number of leucocytes per post-sinusoidal venule was significantly increased after cord transection compared to that in uninjured and sham-injured rats (P<0.05). Of these leucocytes, significantly more were adherent to venule walls (P<0.05). At 90 min the total number of leucocytes per post-sinusoidal venule and the number of adherent and rolling leucocytes was significantly increased after cord transection and cord compression (P<0.05). DISCUSSION: This is the first study to use intravital microscopy to visualise systemic inflammation in the liver following SCI. We have demonstrated immediate leucocyte recruitment to the liver within 30 min after injury and have shown that systemic inflammation increases with time after injury and with severity of injury.
Assuntos
Hepatite Animal/fisiopatologia , Leucócitos/citologia , Traumatismos da Medula Espinal/complicações , Animais , Movimento Celular/fisiologia , Modelos Animais de Doenças , Progressão da Doença , Hepatite Animal/patologia , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar , Traumatismos da Medula Espinal/fisiopatologiaRESUMO
A selective, sensitive and rapid liquid chromatography-tandem mass spectrometry method for the determination of alfuzosin in plasma was developed. A PE Sciex API 2,000 triple quadrupole mass spectrometer in multiple reaction monitoring (MRM) mode, using TurboIonSpray with positive ionisation was used. Using prazosin as an internal standard, liquid-liquid extraction was followed by C(18) reversed-phase liquid chromatography and tandem mass spectrometry. The mean recovery for alfuzosin was 82.9% with a lower limit of quantification set at 0.298 ng/ml, the calibration range being between 0.298 and 38.1 ng/ml. This assay method makes use of the increased sensitivity and selectivity of tandem mass spectrometric (MS-MS) detection to allow for a more rapid (extraction and chromatography) and selective method for the determination of alfuzosin in human plasma than has previously been described. The assay method was used to quantify alfuzosin in human plasma samples generated in a multiple-dose (5 mg bd.) study at steady state.
Assuntos
Antagonistas Adrenérgicos alfa/sangue , Cromatografia Líquida/métodos , Quinazolinas/sangue , Espectrometria de Massas por Ionização por Electrospray/métodos , Antagonistas Adrenérgicos alfa/farmacocinética , Humanos , Quinazolinas/farmacocinética , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Meloxicam was quantified in human plasma after a single 15 mg oral dose of the drug was given to 26 healthy volunteers. An Applied Biosystems Sciex API 2000 triple quadrupole mass spectrometer in multiple reaction monitoring (MRM) mode, using TurboIonSpray (TIS) in the positive ion mode, was used. Protein precipitation with acetonitrile was followed by C(18) reverse phase liquid chromatography and tandem mass spectrometry. The mean recovery for meloxicam was 92% with a lower limit of quantification of 8.96 ng/ml. Piroxicam was used as the internal standard. This assay method makes use of the increased sensitivity and selectivity of tandem mass spectrometry (MS-MS) detection to allow for a more rapid (extraction and chromatography) and selective method for the determination of meloxicam in human plasma than has previously been described.
Assuntos
Anti-Inflamatórios não Esteroides/sangue , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos , Tiazinas/sangue , Tiazóis/sangue , Humanos , Meloxicam , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
A rapid and sensitive method for the determination of domperidone in plasma was developed, using high-performance liquid chromatographic separation with tandem mass spectrometry detection. The samples were rendered basic with 1 M Na2CO3 and the domperidone extracted using tert.-butyl methyl ether, followed by back-extraction into formic acid (2% in water). Chromatography was performed on a Phenomenex Luna C8 (2), 5 microm, 150x2 mm column with a mobile phase consisting of acetonitrile-0.02% formic acid (300:700, v/v), delivered at 0.2 ml/min. Detection was performed using an Applied Biosystems Sciex API 2000 mass spectrometer set at unit resolution in the multiple reaction monitoring mode. TurbolonSpray ionisation was used for ion production. The mean recovery of domperidone was +/- 100%, with a lower limit of quantification set at 0.189 ng/ml. This assay method makes use of the increased sensitivity and selectivity of tandem mass spectrometric detection resulting in a rapid (extraction and chromatography) and sensitive method for the determination of domperidone in human plasma, which is more sensitive than previously described methods.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Domperidona/sangue , Antagonistas de Dopamina/sangue , Espectrometria de Massas por Ionização por Electrospray/métodos , Humanos , Sensibilidade e EspecificidadeRESUMO
A sensitive method for the determination of 3-desmethylthiocolchicine in plasma was developed, using high-performance liquid chromatographic separation with tandem mass spectrometric detection. The plasma samples were extracted with ethyl acetate and separated on a Phenomenex Luna C18(2) 5 microm, 150x2 mm column with a mobile phase consisting of acetonitrile-0.005% formic acid (350:650, v/v) at a flow rate of 0.35 ml/min. Detection was achieved by an Applied Biosystems API 2000 mass spectrometer (LC-MS-MS) set at unit resolution in the multiple reaction monitoring mode. TurbolonSpray ionisation was used for ion production. The mean recovery for 3-desmethylthiocolchicine was 70%, with a lower limit of quantification set at 0.39 ng/ml. The increased selectivity of mass spectrometric (MS-MS) detection allowed us to distinguish between thiocolchicoside and its primary metabolite 3-desmethylthiocolchicine in human plasma, thereby giving more insight about the pharmacokinetics of the drug in humans.
Assuntos
Cromatografia Líquida/métodos , Colchicina/análogos & derivados , Colchicina/sangue , Agonistas GABAérgicos/sangue , Espectrometria de Massas por Ionização por Electrospray/métodos , Administração Oral , Colchicina/administração & dosagem , Colchicina/farmacocinética , Agonistas GABAérgicos/farmacocinética , Meia-Vida , Humanos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Equivalência TerapêuticaRESUMO
Following a single 10-mg oral dose of cetirizine dihydrochloride to 24 healthy volunteers, the analyte was quantified in human plasma. Protein precipitation using acetonitrile (ACN) was followed by reversed-phase liquid chromatography and tandem mass spectrometry. The MS/MS method was optimised using a PE Sciex API 2000 triple quadrupole mass spectrometer in selected reaction monitoring (SRM) mode, using electrospray with positive ionisation. Oxybutynin was used as the internal standard. The assay method represents a robust, high-throughput, highly specific and sensitive quantitative assay procedure, with 0.5 ng/ml being the lowest plasma concentration that could be reliably quantified. The procedure involves minimal sample preparation, and is well suited to clinical studies of the drug involving large numbers of generated samples. Pre-dose as well as post-dose samples up to and including 48 h were quantified, and the data generated were used to determine the pharmacokinetic profile of the drug.
Assuntos
Cetirizina/sangue , Cromatografia Líquida/métodos , Antagonistas dos Receptores Histamínicos H1/sangue , Espectrometria de Massas/métodos , Humanos , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
A sensitive method for the determination of stavudine in plasma was developed, using high-performance liquid chromatographic separation with tandem mass spectrometric detection. The samples were extracted from plasma with Waters, Sep-Pak Vac, 100 mg, tC(18) solid-phase extraction (SPE) columns. Chromatography was performed on a Supelco Discovery C(18), 5 microm, 150 x 2 mm column with a mobile phase consisting of ammonium acetate (0.01 M)-acetonitrile-methanol (800:100:100, v/v/v) at a flow-rate of 0.3 ml/min. Detection was achieved by an Applied Biosystems API 2000 mass spectrometer (LC-MS-MS) set at unit resolution in the multiple reaction monitoring mode (MRM). Atmospheric pressure chemical ionization (APCI) was used for ion production. The mean recovery for stavudine was 94% with a lower limit of quantification set at 4 ng/ml. This assay method makes use of the increased sensitivity and selectivity of mass spectrometric (MS-MS) detection to allow for a more rapid (extraction and chromatography) and selective method for the determination of stavudine in human plasma than has previously been described.
Assuntos
Cromatografia Líquida/métodos , Espectrometria de Massas/métodos , Inibidores da Transcriptase Reversa/sangue , Estavudina/sangue , Humanos , Inibidores da Transcriptase Reversa/farmacocinética , Sensibilidade e Especificidade , Estavudina/farmacocinéticaRESUMO
A sensitive method for the determination of carbamazepine and carbamazepine 10,11-epoxide in plasma is described, using high-performance liquid chromatographic separation with tandem mass spectrometry. Samples were purified using liquid-liquid extraction and separated on a Phenomenex Luna C18 5 microm. 150 x 2 mm column with a mobile phase consisting of acetonitrile, methanol and formic acid (0.1%) (10:70:20, v/v). Detection was performed by a Micromass Quattro Ultima mass spectrometer in the MRM mode (LC-MS-MS) using electro spray ionisation (ESI+), monitoring the transition of the protonated molecular ion for carbamazepine at m/z 237.05 and carbamazepine 10,11-epoxide at m/z 253.09 to the predominant ions of m/z 194.09 and 180.04, respectively. The mean recovery was 95% for carbamazepine and 101% for carbamazepine 10,11-epoxide, with a lower limit of quantification of 0.722 ng/ml for carbamazepine and 5.15 ng/ml for carbamazepine 10,11-epoxide, when using 0.5 ml plasma. This high-throughput method was used to quantify 230 samples per day, and is sufficiently sensitive to be employed in pharmacokinetic studies.
Assuntos
Carbamazepina/análogos & derivados , Carbamazepina/sangue , Cromatografia Líquida/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos , Calibragem , Humanos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
A sensitive method for the determination of clarithromycin in plasma is described, using high-performance liquid chromatographic separation with tandem mass spectrometric detection. Samples were prepared using liquid-liquid extraction and separated on a Supelco Discovery C18 column with a mobile phase consisting of acetonitrile, methanol and acetic acid. Detection was performed by a PE SCIEX API 2000 mass spectrometer in the multiple reaction monitoring (MRM) mode (LC-MS-MS) using TurbolonSpray ionization and monitoring the transition of the protonated molecular ion for clarithromycin at m/z 748.5 (M+1) to the predominant product ion of m/z 158.2. The mean recovery of clarithromycin was 87.3%, with a lower limit of quantification of 2.95 ng/ml when using 0.3-ml plasma. This high-throughput method was used to quantify 230 samples per day, and is sufficiently sensitive to be employed in pharmacokinetic studies.
Assuntos
Antibacterianos/sangue , Cromatografia Líquida/métodos , Claritromicina/sangue , Espectrometria de Massas/métodos , Antibacterianos/farmacocinética , Calibragem , Claritromicina/farmacocinética , Humanos , Sensibilidade e EspecificidadeRESUMO
A sensitive method for the simultaneous determination of loratadine and its major active metabolite descarboethoxyloratadine (DCL) in plasma was developed, using high-performance liquid chromatographic separation with tandem mass spectrometric detection. The samples were extracted from plasma with toluene followed by back-extraction into formic acid (2%) for DCL after which the toluene containing the loratadine was evaporated, the analyte reconstituted and combined with the DCL back-extract. Chromatography was performed on a Phenomenex Luna C18 (2) 5-microm, 150x2.1-mm column with a mobile phase consisting of acetonitrile-0.1% formic acid using gradient elution (10 to 90% acetonitrile in 2 min) at a flow-rate of 0.3 ml/min. Detection was achieved by a Perkin-Elmer API 2000 mass spectrometer (LC-MS-MS) set at unit resolution in the multiple reaction monitoring mode. TurbolonSpray ionisation was used for ion production. The mean recovery for loratadine and descarboethoxyloratadine was 61 and 100%, respectively, with a lower limit of quantification at 0.10 ng/ml for both the analyte and its metabolite. This is the first assay method described for the simultaneous determination of loratadine and descarboethoxyloratadine in plasma using one chromatographic run. The method is sensitive and reproducible enough to be used in pharmacokinetic studies.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Antagonistas dos Receptores Histamínicos H1/sangue , Loratadina/sangue , Espectrometria de Massas por Ionização por Electrospray/métodos , Humanos , Loratadina/análogos & derivados , Reprodutibilidade dos TestesRESUMO
A sensitive method for the simultaneous determination of fluoxetine and its major active metabolite norfluoxetine in plasma was developed, using high-performance liquid chromatographic separation with tandem mass spectrometric detection. The samples were extracted from alkalised plasma with hexane-isoamyl alcohol (98:2, v/v) followed by back-extraction into formic acid (2%). Chromatography was performed on a Phenomenex Luna C18 (2) 5 microm, 150x2 mm column with a mobile phase consisting of acetonitrile-0.02% formic acid (340:660, v/v) at a flow-rate of 0.35 ml/min. Detection was achieved by a Perkin-Elmer Sciex API 2000 mass spectrometer (LC-MS-MS) set at unit resolution in the multiple reaction monitoring mode. TurbolonSpray ionisation was used for ion production. The mean recoveries for fluoxetine and norfluoxetine were 98 and 97%, respectively, with a lower limit of quantification set at 0.15 ng/ml for the analyte and its metabolite. This assay method makes use of the increased sensitivity and selectivity of mass spectrometric (MS-MS) detection to allow for a more rapid (extraction and chromatography) and sensitive method for the simultaneous determination of fluoxetine and norfluoxetine in human plasma than has previously been described.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Fluoxetina/sangue , Espectrometria de Massas/métodos , Inibidores Seletivos de Recaptação de Serotonina/sangue , Fluoxetina/análogos & derivados , Humanos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
A simple and sensitive HPLC method for the simultaneous determination of cefotaxime (I) and desacetylcefotaxime (II) in human plasma and cerebrospinal fluid (CSF) is described. The assay involves deproteinisation and subsequent separation on a reversed-phase HPLC column, with ultraviolet detection at 262 nm. Retention times were 6.8 and 2.2 min for cefotaxime and desacetylcefotaxime, respectively. Average recoveries for the analytes were 78% (I) and 88% (II) from both matrices. Linear responses were observed over a wide range (0.58-940 microg/ml for (I) in plasma, 0.80-55.8 microg/ml for (I) in CSF, 0.54-148 microg/ml for (II) in plasma and 0.50-36.0 microg/ml for (II) in CSF).
Assuntos
Cefotaxima/sangue , Cefotaxima/líquido cefalorraquidiano , Cefalosporinas/sangue , Cefalosporinas/líquido cefalorraquidiano , Cromatografia Líquida de Alta Pressão/métodos , Cefotaxima/análogos & derivados , Humanos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
A sensitive method for the simultaneous determination of doxepin and its active metabolite desmethyldoxepin in plasma was established, using high-performance liquid chromatographic separation with tandem mass spectrometric detection. The samples were extracted with hexane-isoamyl alcohol, separated on a Phenomenex Luna C18 5 microm, 150x2.1 mm column with a mobile phase consisting of methanol-water-formic acid (600:400:0.5, v/v) at a flow-rate of 0.25 ml/min. Detection was achieved by a Perkin-Elmer API 2000 mass spectrometer at unit resolution in multiple reaction monitoring mode monitoring the transition of the protonated molecular ions m/z 280.2, 266.2 and 250.1 to the product ions m/z 107.1, 107.1 and 191.0 for analyte, metabolite and internal standard (benzoctamine-HCl), respectively. TurbolonSpray ionisation was used for ion production. The mean recovery for doxepin and desmethyldoxepin was 90% and 75%, respectively, with a lower limit of quantification at 0.320 ng/ml and 0.178 ng/ml for the analyte and its metabolite, respectively, using 0.5 ml plasma for extraction. This is the first assay method described for the simultaneous determination of doxepin and desmethyldoxepin in plasma using LC-MS-MS. The method is sensitive enough to be used in drug bioavailability studies with doxepin.
Assuntos
Antidepressivos Tricíclicos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Doxepina/análogos & derivados , Doxepina/sangue , Humanos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
A stopped-flow mixing technique is used to determine clavulanic acid in human plasma after plasma deproteinisation with acetonitrile and removal of the organic solvent by extraction with dichloromethane. The reaction kinetic profiles for the reaction between clavulanic acid and imidazole are determined by measuring the absorbance at 312 nm of the imidazole derivative. The reaction rates are proportional to the concentration of the clavulanic acid and by plotting reaction rates against clavulanic acid concentrations linear calibration curves could be constructed over the range 0.30-10.0 microg/ml.
Assuntos
Antibacterianos/sangue , Ácido Clavulânico/sangue , Calibragem , Humanos , Concentração de Íons de Hidrogênio , Indicadores e Reagentes , Cinética , Controle de Qualidade , Reprodutibilidade dos Testes , SolventesRESUMO
Following oral administration of the prodrug nabumetone, the major metabolite 6-methoxy-2-naphthylacetic acid (6-MNA) was determined in human plasma. Minimal sample preparation was followed by reversed-phase liquid chromatography and UV detection, affording high sample throughput. The lower limit of quantification (LLOQ) was 70 ng/ml, at a signal-to-noise ratio of 8:1. The assay method displayed good correlation (r=0.997), and can be readily employed in pharmacokinetic and bioequivalence studies.
Assuntos
Anti-Inflamatórios não Esteroides/sangue , Butanonas/sangue , Ácidos Naftalenoacéticos/sangue , Adulto , Anti-Inflamatórios não Esteroides/farmacocinética , Área Sob a Curva , Disponibilidade Biológica , Butanonas/farmacocinética , Calibragem , Cromatografia Líquida de Alta Pressão , Estudos Cross-Over , Feminino , Meia-Vida , Humanos , Indicadores e Reagentes , Masculino , Nabumetona , Reprodutibilidade dos Testes , Espectrofotometria UltravioletaRESUMO
A sensitive method for the determination of linsidomine in plasma was developed, using high-performance liquid chromatographic (HPLC) separation with tandem mass spectrometric detection. Linsidomine was derivatised with propyl chloroformate and extracted with tert-butyl methyl ether/1,2-dichloroethane (55:45, v/v), back-extracted into HCl (0.01 M) followed by alkalinisation and back-extraction into ether; the final ether extract evaporated, reconstituted in mobile phase and then separated on a Phenomenex Luna C18 (2) 5 micron 2.1 x 150 mm column with a mobile phase consisting of methanol water formic acid (98/100%) (400:600:0.05, v/v/v) at a flow-rate of 0.4 ml min(-1). Detection was achieved by a Finnigan MAT mass spectrometer (LCQ) at unit resolution in the selected reaction monitoring (SRM) mode monitoring the transition of the protonated molecular ion m/z 257.0 to the product ion m/z 86.0. The mean recovery for linsidomine was 51% with a lower limit of quantification of 0.70 ng/ml using 1 ml plasma for extraction. This LC-MS/MS method for the determination of linsidomine in human plasma allows for better specificity and a higher sample throughput than the traditional LC-UV methods. It also demonstrates the profound effect that the composition of acidic modifiers and matrix constituents can have on the electrospray ionisation (ESI) of the analyte.
Assuntos
Cromatografia Líquida/métodos , Espectrometria de Massas/métodos , Molsidomina/análogos & derivados , Vasodilatadores/sangue , Humanos , Troca Iônica , Molsidomina/sangue , Controle de Qualidade , Reprodutibilidade dos TestesRESUMO
After repeated topical application of a piroxicam gel preparation to the knee, piroxicam was quantified in plasma, subcutaneous tissue, synovial capsule and synovial fluid, using specimens obtained during knee surgery. Electrochemical detection was used and the limit of quantification (LOQ) was 0.72 ng/ml in plasma at a signal-to-noise ratio of 10:1. The chromatographic method was optimised to determine piroxicam in all four matrices, and the analyte was quantified using a calibration line constructed from plasma calibration standards. Levels in subcutaneous tissue, synovial capsule and synovial fluid were compared to plasma steady-state levels and expressed as a ratio, in order to ascertain bioavailability.
Assuntos
Anti-Inflamatórios não Esteroides/análise , Cromatografia Líquida de Alta Pressão/métodos , Piroxicam/análise , Anti-Inflamatórios não Esteroides/sangue , Eletroquímica , Humanos , Piroxicam/sangue , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
An ultra-sensitive method for the determination of fluspirilene in plasma was established, using high-performance liquid chromatographic separation with tandem mass spectrometric detection. The samples were extracted with hexane/isoamyl alcohol, separated on a Phenomenex Luna C18 5 mu 150 x 2.1 mm column with a mobile phase consisting of methanol-water-acetic acid (600:400:1) at a flow-rate of 0.3 ml/min. Detection was achieved by a Finnigan Matt mass spectrometer (LCQ) at unit resolution in full scan mode scanning the product ion spectrum from m/z 130-500 and monitoring the transition of the protonated molecular ion at m/z 476.2, to the sum of the largest product ions m/z 371, 342 and 274 (MS-MS). Electrospray ionisation was used for ion production. The mean recovery for fluspirilene was 90% with a lower limit of quantification of 21.50 pg/ml using 1 ml plasma for extraction. This is the first chromatographic method described for the determination of fluspirilene in plasma that is accurate and sensitive enough to be used in pharmacokinetic studies.
Assuntos
Antipsicóticos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Fluspirileno/sangue , Espectrometria de Massas/métodos , Humanos , Padrões de Referência , Valores de Referência , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
AIMS: To evaluate the interaction of meloxicam with frusemide in patients with compensated cardiac failure. METHODS: Nineteen patients with Grade II or III compensated chronic cardiac failure completed this randomized, double-blind, cross-over study. The patients received 40 mg frusemide day(-1) for 7 days. Thereafter, patients received either 15 mg meloxicam plus 40 mg frusemide day(-1), or one placebo tablet plus 40 mg frusemide day(-1) for 7 days. After a washout period of 7 days during which patients received 40 mg frusemide day(-1) for 7 days, the patients were crossed over to the alternate treatment. The effect of concomitant ingestion of meloxicam and frusemide on frusemide-induced diuresis, urine and serum electrolytes, urinary frusemide excretion, and plasma frusemide pharmacokinetics was also determined. RESULTS: The estimate (90% confidence interval) of the '(frusemide + meloxicam)/(frusemide alone)' mean ratio of the variables Cmax, AUC(SS) and Cmax/AUC(SS) for plasma frusemide were 121% (101% to 145%), 106% (96.4% to 117%), and 114% (98.3% to 132%), respectively. Similarly, the estimate (90% confidence interval) of the '(frusemide + meloxicam)/(frusemide alone)' of the mean ratio of the variable cumulative urinary frusemide excretion after multiple doses of frusemide were 123% (101% to 150%) for the period 0-8 h, and 122% (105% to 142%) for the period 0-24 h after drug administration on day 7. The estimate (90% confidence interval) of the '(frusemide + meloxicam)/(frusemide alone)' mean ratio of the pharmacodynamic variables cumulative sodium excretion was 105% (95.2% to 116%) for the period 0-8 h and 108% (96.5% to 121%) for the period 0-24 h after drug administration on day 7. CONCLUSIONS: Meloxicam may lead to slightly increased maximum concentrations of frusemide in plasma, as well as to slightly increased urinary excretion of frusemide, without affecting the pharmacodynamics of frusemide. Thus there is no clinically significant pharmacokinetic or pharmacodynamic interaction of meloxicam with frusemide following repeated co-administration of meloxicam and frusemide to patients with compensated chronic cardiac failure.