RESUMO
Medication-induced prolongation of the QT-interval (miQTP) can lead to cardiac arrhythmia. Our aim was to investigate the prevalence of forensic autopsy cases where fatal cardiac arrhythmia related to treatment with QT-prolonging medications (QT-PMs) could be suspected. We performed a cross-sectional study of 741 forensic autopsies undertaken at our institution in non-drug addicts aged 15 years or above from 2017 to 2019. We defined a high risk of miQTP by one detected QT-PM in a concentration above therapeutic level, or two or more detected QT-PMs in post mortem blood. We reviewed the autopsy reports from cases with a high miQTP-risk to identify cases with no other apparent cause of death. We discarded suicides and cases with lethal levels of QT-PMs. We identified 167 cases (22.5%) with high risk of miQTP, and discarded 36 suicides (4.9%) and 7 (0.9%) with lethal levels of QT-PMs. Apart from a high risk of miQTP, no other apparent explanation of the cause of death was present in seven (0.9%). In 18 cases (2.4%) with high miQTP-risk, the cause of death was primarily attributed to cardiac changes other than acute cardiovascular events. In conclusion, 22.5% had a high risk of miQTP, and fatal cardiac arrhythmia related to treatment with QT-PMs could be suspected in 0.9%. However, a genetic pro-arrhythmic background could not be excluded in our study. Furthermore, it is possible that QT-PMs could have played a role in some of the 2.4% of cases where the cause of death was mainly attributed to cardiac changes and the risk of miQTP was high.
Assuntos
Arritmias Cardíacas/induzido quimicamente , Adulto , Idoso , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/sangue , Anestésicos/efeitos adversos , Anestésicos/sangue , Antidepressivos/efeitos adversos , Antidepressivos/sangue , Antieméticos/efeitos adversos , Antieméticos/sangue , Antipsicóticos/efeitos adversos , Antipsicóticos/sangue , Autopsia , Estudos Transversais , Dinamarca , Diuréticos/efeitos adversos , Diuréticos/sangue , Feminino , Antagonistas dos Receptores Histamínicos/efeitos adversos , Antagonistas dos Receptores Histamínicos/sangue , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Lagopsis supina (Steph.) Ik. -Gal. ex Knorr. has been widely used as a remedy treatment for diuresis and edema in China over 2500 years. Our previous results showed that the aqueous soluble fraction from L. supina (LSB) possessed acute diuretic effect. AIM OF THE STUDY: The aim of this study was to appraise the acute (6 h) and prolonged (7 d) diuretic effects, underlying mechanisms, and chemical profiling of LSB. MATERIALS AND METHODS: The chemical profiling of LSB was performed by ultra-high-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UHPLC-qTOF-MS/MS). Then, oral administration of LSB (40, 80, 160 and 320 mg/kg) and furosemide (10 mg/kg) once daily for 7 consecutive days to evaluate the diuretic effects in saline-loaded rats. The body weight, food consumption, and water intake were recorded once daily. The urinary volume, pH and electrolyte concentrations (Na+, K+, Cl-, and Ca2+) were measured after administration drugs for acute and prolonged diuretic effects. In addition, the serum levels of Na+-K+-ATPase, angiotensin II (Ang II), anti-diuretic hormone (ADH), aldosterone (ALD), atriopeptin (ANP), aquaporins (AQPs)-1, 2 and 3 were determined by ELISA kits. The mRNA expressions and protein levels of AQPs-1, 2 and 3 were analyzed by real-time quantitative PCR and Western blot assays, respectively. RESULTS: 30 compounds were identified in LSB based on accurate mass and MS/MS fragmentation compared to literature, among which phenylpropanoids and flavonoids could be partly responsible for the major diuretic effect. Daily administration of LSB (160 or 320 mg/kg) prominently increased urinary excretion volume after the 2 h at the first day of treatment, remaining until the 7th day. LSB did not cause Na+ and K+ electrolyte abnormalities, and has minor effect on Cl- and Ca2+ concentrations at 320 mg/kg. Furthermore, LSB observably suppressed renin-angiotensin-aldosterone system (RAAS) activation, including decreased serum levels of Ang II, ADH, and ALD, and prominently increased serum level of ANP in rats. LSB treatment significantly down-regulated the serum levels, mRNA expressions and protein levels of AQP1, AQP2, and AQP3. CONCLUSION: LSB has a prominent acute and prolonged diuretic effects via suppression of AQP and RAAS pathways in saline-loaded rats, and support the traditional folk use of this plant. Taken together, LSB might be a potential diuretic agent.
Assuntos
Aquaporinas/antagonistas & inibidores , Diuréticos/farmacologia , Lamiaceae/química , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Aquaporinas/sangue , Aquaporinas/genética , Aquaporinas/metabolismo , Peso Corporal/efeitos dos fármacos , Diuréticos/sangue , Diuréticos/uso terapêutico , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Eletrólitos/metabolismo , Masculino , Ratos Sprague-Dawley , Sódio/administração & dosagem , ATPase Trocadora de Sódio-Potássio/efeitos dos fármacos , Solubilidade , Urina , Água/químicaRESUMO
Many drug candidates have shown significant renoprotective effects in preclinical models; however, there is no clinically used effective pharmacotherapy for acute kidney injury. The failure to translate from bench to bedside could be due to misleading results from experimental animals with undetected congenital kidney defects. This study was performed to assess the effects of congenital hydronephrosis on the functional capacity of tubular renal transporters as well as kidney sensitivity to ischemia-reperfusion (I-R)-induced injury in male Wistar rats. Ultrasonography was used to distinguish healthy control rats from rats with hydronephrosis. L-carnitine or furosemide was administered, and serial blood samples were collected and analyzed to assess the effects of hydronephrosis on the pharmacokinetic parameters. Renal injury was induced by clamping the renal pedicles of both kidneys for 30 min with subsequent 24 hr reperfusion. The prevalence of hydronephrosis reached ~30%. The plasma concentrations after administration of L-carnitine or furosemide were similar in both groups. I-R induced more pronounced renal injury in the hydronephrotic rats than the control rats, which was evident by a significantly higher kidney injury molecule-1 concentration and lower creatinine concentration in the urine of the hydronephrotic rats than the control rats. After I-R, the gene expression levels of renal injury markers were significantly higher in the hydronephrotic kidneys than in the kidneys of control group animals. In conclusion, our results demonstrate that hydronephrotic kidneys are more susceptible to I-R-induced damage than healthy kidneys. Unilateral hydronephrosis does not affect the pharmacokinetics of substances secreted or absorbed in the renal tubules.
Assuntos
Injúria Renal Aguda/fisiopatologia , Hidronefrose/fisiopatologia , Rim/irrigação sanguínea , Traumatismo por Reperfusão/fisiopatologia , Injúria Renal Aguda/complicações , Animais , Carnitina/sangue , Carnitina/urina , Moléculas de Adesão Celular/metabolismo , Suscetibilidade a Doenças , Diuréticos/sangue , Diuréticos/urina , Furosemida/sangue , Furosemida/urina , Hidronefrose/complicações , Rim/diagnóstico por imagem , Masculino , Ratos , Ratos Wistar , Traumatismo por Reperfusão/complicações , UltrassonografiaRESUMO
The third trimester of pregnancy is related to physiological changes that can modify the process of absorption, distribution, metabolism, and excretion and, consequently, the efficacy and toxicity of drugs. However, little is known about furosemide pharmacokinetics and placental transfer in pregnancy. This study evaluated the maternal-fetal pharmacokinetics and distribution to amniotic fluid of furosemide in hypertensive parturient women under cesarean section. Twelve hypertensive parturient women under methyldopa (250 mg/8 h) and/or pindolol (10 mg/12 h) treatment received a 40-mg single oral dose of furosemide 1 to 10 hours before delivery by cesarean section. Blood and urine samples were collected for 12 hours after furosemide administration. At delivery, samples were obtained from maternal and umbilical cord blood (n = 8) to assess the transplacental transfer. Amniotic fluid (n = 4) was collected at the time of delivery. The following furosemide pharmacokinetic parameters were obtained as median (interquartile range): Cmax , 403 ng/mL (229 to 715 ng/mL); Tmax , 2.00 hours (1.50 to 4.83 hours); elimination half-life (t1/2 ), 2.50 hours (1.77 to 2.97 hours); AUC0-12 h , 1366 ngâ h/mL (927 to 2531 ngâ h/mL); AUC0-∞ , 1580 ngâ h/mL (1270 to 2881 ngâ h/mL); CL/F 25.3 L/h (13.8 to 31.4 L/h); CLR, 2.50 L/h (1.77 to 2.97 L/h); CLNR, 22.7 L/h (12.1 to 25.6 L/h); and Vd /F 82.8 L (34.4 to 173 L). The transplacental transfer of furosemide was 0.43 (0.10 to 0.73), and the amniotic fluid concentration was 11.0 ng/mL (5.51 to 14.6 ng/mL). From a clinical point of view, these results suggest that substrates of uridine diphosphate-glucuronosyltransferase isoenzymes such as furosemide may have increased clearance during pregnancy and could require dose adjustment in this population.
Assuntos
Líquido Amniótico/metabolismo , Diuréticos/farmacocinética , Furosemida/farmacocinética , Hipertensão Induzida pela Gravidez , Hipertensão/tratamento farmacológico , Troca Materno-Fetal/fisiologia , Administração Oral , Adulto , Cesárea , Diuréticos/administração & dosagem , Diuréticos/sangue , Diuréticos/urina , Cálculos da Dosagem de Medicamento , Vias de Eliminação de Fármacos , Feminino , Sangue Fetal/metabolismo , Furosemida/administração & dosagem , Furosemida/sangue , Furosemida/urina , Glucuronosiltransferase/metabolismo , Humanos , Hipertensão/sangue , Hipertensão/urina , Parto/sangue , Parto/urina , Projetos Piloto , GravidezRESUMO
Purpose: Toxicological screenings for identifying antihypertensive drugs proved to be a useful tool for assessing adherence. However, misinterpretation may occur in case of highly metabolised drugs with low renal excretion, as well as for drugs with a prolonged detectability. The aim of the present study was to compare a recently developed therapeutic drug monitoring (TDM) method based on serum concentrations to an urine drug detection method for assessing adherence in outpatients.Materials and methods: Corresponding urine and blood samples were obtained at the same time from 26 outpatients without supervised medication. Urine and serum analyses were performed using established high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodologies. Adherence was assumed if drugs were detectable in urine or if serum concentrations were above individually calculated lower dose-related concentrations (DRC) or literature-based therapeutic reference ranges (TRR) used as cut-off, respectively.Results: The identification of analytes in urine as well as the quantitative serum assay were performed for atenolol (n = 6 patients), bisoprolol (n = 8), nebivolol (n = 6), canrenone (n = 6, metabolite of spironolactone), hydrochlorothiazide (n = 12) and furosemide (n = 2). On the basis of drug detectability in urine, adherence was assumed in 88% of prescriptions. In 81% (DRC) and 50% (TRR) of the serum analyses the cut-off value was exceeded, which confirms patients' adherence in a lower number. Differences in adherence rates were found in five patients, mainly for ß-blockers.Conclusion: This study suggests that assessment of adherence can be performed more precisely on the basis of serum drug concentrations with individually calculated lower DRC than by using the TRR or qualitative urinalysis.
Assuntos
Antagonistas Adrenérgicos beta/sangue , Anti-Hipertensivos/sangue , Diuréticos/sangue , Monitoramento de Medicamentos , Cooperação do Paciente , Antagonistas Adrenérgicos beta/urina , Adulto , Idoso , Anti-Hipertensivos/urina , Cromatografia Líquida/métodos , Diuréticos/urina , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Hipertensão/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Espectrometria de Massas em Tandem/métodos , Urinálise/métodosRESUMO
Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 × 10-8) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.
Assuntos
Negro ou Afro-Americano/genética , Diuréticos/sangue , Variação Genética/genética , Hipertensão/sangue , Hipertensão/genética , População Branca/genética , Diuréticos/efeitos adversos , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/tratamento farmacológico , Lipídeos/sangueRESUMO
BACKGROUND: The primary objective of this study was to assess the disposition of furosemide in Thoroughbred horses treated intravenously with 1 mg/kg of furosemide 4 and 24 h before supramaximal treadmill exercise without and with controlled access to water, respectively. Another objective was to determine whether furosemide was detectable in the plasma of horses after exposure to supramaximal treadmill exercise. Thoroughbred horses (n = 4-6) were administered single intravenous doses of 1 mg/kg of furosemide at 4 and 24 h before supramaximal exercise on a high-speed treadmill, with controlled and free access to water, respectively. Plasma furosemide concentrations were determined using liquid chromatography. RESULTS: Furosemide was detected in all the horses, regardless of whether they were treated 24 h or 4 h before excersice. In both treatment sequence groups of 2 horses, the concentration time profiles of furosemide during the first 4 h after its administration were relatively similar. The average maximum observed concentrations, AUC0-1.5h, and AUC0-3h, of both groups of horses were not different (p > 0.05). There were no significant differences in systemic clearance based on the geometric mean (95% confidence interval) (409 (347-482) mL/h/kg) for 4 h and 320 (177-580) mL/h/kg) for 24 h) between horses that were exercised 4- and 24-h post-furosemide administration. The plasma concentration of furosemide in all the horses fell below the limit of quantification (25 ng/mL) within 12 h after drug administration. In the group treated 24 h before exercise, none of the horses had detectable furosemide at the time of supramaximal treadmill exercise. In the group treated 4 h before exercise, furosemide was detected 1 h before and 2 h after supramaximal treadmill exercise in 4/4 and 3/4 horses, respectively. The mean AUC3-last h of both groups of horses were not different (p > 0.05). CONCLUSIONS: Water restriction did not exert any apparent effect on the disposition of furosemide. It remains to be determined, however, whether the attained plasma concentration of furosemide in combination with other controlled water access protocols have any direct or indirect pharmacological effect that may affect the athletic performance of the horse.
Assuntos
Diuréticos/farmacocinética , Furosemida/farmacocinética , Cavalos/sangue , Condicionamento Físico Animal , Animais , Área Sob a Curva , Diuréticos/sangue , Feminino , Furosemida/sangue , Masculino , Equilíbrio HidroeletrolíticoRESUMO
BACKGROUND: This study assessed the contribution of intracorporeal (IC) and extracorporeal clearance (EC) of furosemide in patients with septic acute kidney injury (AKI), and the relationship between plasma concentrations and urine volume. METHODS: Prospective cohort observational study of 15 patients with septic AKI undergoing continuous veno-venous hemodiafiltration (CVVHDF) divided according to urine volume (< 500 ml/12 h, Oliguria group, n = 5; > 500 ml/12 h, Diuresis group, n = 10) during continuous infusion of furosemide (120 mg/12 h) at steady-state condition. Plasma and effluent furosemide concentrations were determined by high-performance liquid chromatography (HPLC)-mass spectrometry every 12 h for 48 h. RESULTS: Furosemide plasma concentrations and total body clearance (TBC) were 6.14 mg/l and 22.1 ml/min for the Oliguria group, and 2.63 mg/l and 54.4 ml/min for the Diuresis group, respectively (p < 0.05). When urine volume was < 500 ml/24 h, the furosemide plasma concentrations peaked at the potentially toxic value of 13.0 mg/l. Furosemide EC was not relevant for the Diuresis group, but it represented 18% of TBC for the Oliguria group. Furosemide plasma concentrations correlated positively with dose infusion for both groups (r = 0.728 and 0.685, p < 0.05), and negatively with urine volume only for the Diuresis (r = - 0.578, p < 0.01) but not for the Oliguria group (r = - 0.089, p = 0.715). CONCLUSIONS: For patients with urine volume > 500 ml/12 h continuous infusion of furosemide up to 480 mg/24 h leads to increasing urine volume, which can predict furosemide plasma levels within its safety range. When the urine volume is lower, the furosemide plasma levels are increased beyond any further diuretic efficacy.
Assuntos
Injúria Renal Aguda/terapia , Diurese/efeitos dos fármacos , Diuréticos/farmacocinética , Furosemida/farmacocinética , Hemodiafiltração , Rim/efeitos dos fármacos , Oligúria/terapia , Choque Séptico/terapia , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/fisiopatologia , Injúria Renal Aguda/urina , Adulto , Idoso , Estado Terminal , Diuréticos/administração & dosagem , Diuréticos/efeitos adversos , Diuréticos/sangue , Feminino , Furosemida/administração & dosagem , Furosemida/efeitos adversos , Furosemida/sangue , Humanos , Infusões Intravenosas , Rim/fisiopatologia , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Oligúria/diagnóstico , Oligúria/fisiopatologia , Oligúria/urina , Estudos Prospectivos , Eliminação Renal , Choque Séptico/diagnóstico , Choque Séptico/fisiopatologia , Choque Séptico/urina , Urodinâmica/efeitos dos fármacosRESUMO
OBJECTIVES: To determine the relationship between theophylline trough levels and urine output in critically ill children administered aminophylline as adjunctive diuretic therapy. DESIGN: Retrospective cohort study. SETTING: The PICU of a tertiary care children's hospital. PATIENTS: A mixed population of medical/surgical including postoperative cardiothoracic surgery patients less than 18 years old. INTERVENTIONS: Electronic medical records of all PICU patients admitted from July 2010 to June 2015 were reviewed, and patients who received aminophylline as diuretic therapy were identified. MEASUREMENTS AND MAIN RESULTS: Patient cohort data including demographics, daily aminophylline, furosemide and chlorothiazide dosing, theophylline trough levels, fluid intake, urine output and total fluid balance, blood urea nitrogen, and creatinine levels were abstracted. Multivariate analysis based on a generalized estimating equations approach demonstrated that aminophylline administration, when analyzed as a categorical variable, was associated with an increase in urine output and decreased fluid balance. However, aminophylline dosing, when analyzed as a continuous variable, was associated with neither an increase in urine output nor decreased fluid balance. Theophylline trough levels were not correlated with urine output at 24 hours (p = 0.78) and were negatively correlated with urine output at 48 hours (r = 0.078; p < 0.005). CONCLUSIONS: Aminophylline administration provided a measure of increased diuresis, regardless of dosage, and theophylline trough levels. Therefore, achieving a prescribed therapeutic trough level may not be necessary for full diuretic effect. Because, as opposed to the diuretic effect, the side effect profile of aminophylline is dose-dependent, low maintenance dosing may optimize the balance between providing adjunctive diuretic effect while minimizing the risk of toxicity.
Assuntos
Aminofilina/administração & dosagem , Diuréticos/administração & dosagem , Hidratação/métodos , Equilíbrio Hidroeletrolítico/efeitos dos fármacos , Administração Intravenosa , Aminofilina/sangue , Aminofilina/farmacocinética , Criança , Pré-Escolar , Estado Terminal , Diuréticos/sangue , Diuréticos/farmacocinética , Feminino , Humanos , Lactente , Recém-Nascido , Unidades de Terapia Intensiva Pediátrica/estatística & dados numéricos , Masculino , Análise de Regressão , Estudos RetrospectivosRESUMO
BACKGROUND: Diuretic treatment is the mainstay for management of congestive heart failure in horses, and its use has been restricted to injectable medications because no currently data supports the use of PO administered loop diuretics. OBJECTIVES: To determine the pharmacokinetic and pharmacodynamic properties of PO administered torsemide and, determine if PO administered torsemide, could be used as an alternative to injectable diuretics in the horse. ANIMALS: Six healthy adult mares. METHODS: A 2-phase, prospective study, that consisted of pharmacokinetic profiling of a single dose (6 mg/kg PO) and pharmacodynamic effects of long-term torsemide administration (2 mg/kg PO q12h) for 6 days in healthy horses. RESULTS: Pharmacokinetic analysis identified a peak concentration (Cmax ) of 10.14 µg/mL (range, 6.79-14.69 µg/mL) and elimination half-life (T1/2 ) 9.2 hours (range, 8.4-10.4 hours). The area under the plasma drug concentration over time curve (AUC) was 80.7 µg × h/mL (range, 56.5-117.2 µg × h/mL). A statistically significant increase in urine volume and decrease in urine specific gravity were found from day 0 (baseline) to day 6 (P < .0001). Significant alterations in biochemical variables included hyponatremia, hypokalemia, hypochloremia, and increased serum creatinine concentration. Mean arterial blood pressure significantly decreased on day 6 (57.7 ± 8.8 mm Hg, P = .001) as compared with baseline (78 ± 6.1 mm Hg). Serum aldosterone concentrations significantly increased after 6 days of torsemide administration (P = .0006). CONCLUSIONS AND CLINICAL IMPORTANCE: PO administered torsemide (4 mg/kg/day) successfully reached therapeutic concentrations in blood, induced clinically relevant diuresis, and resulted in moderate pre-renal azotemia and electrolyte disturbances.
Assuntos
Diuréticos/farmacologia , Sulfonamidas/farmacologia , Administração Oral , Animais , Cloretos/sangue , Creatinina/sangue , Diuréticos/administração & dosagem , Diuréticos/sangue , Diuréticos/farmacocinética , Feminino , Meia-Vida , Doenças dos Cavalos/induzido quimicamente , Cavalos/sangue , Cavalos/metabolismo , Hipopotassemia/induzido quimicamente , Hipopotassemia/veterinária , Hiponatremia/induzido quimicamente , Hiponatremia/veterinária , Sulfonamidas/administração & dosagem , Sulfonamidas/sangue , Sulfonamidas/farmacocinética , TorasemidaRESUMO
BACKGROUND: Poor drug adherence in hypertensive patients can lead to treatment failure and increased cardiovascular morbidity, as well as increased costs to society. An analytical method based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MSMS) was developed and validated for use in routine therapeutic drug monitoring (TDM). The method includes 21 antihypertensive drugs or active metabolites from the groups beta blockers (n=5), calcium antagonists (n=5), angiotensin II receptor antagonists (n=4), angiotensin converting enzyme (ACE) inhibitors (n=3) and diuretics (nâ¯=â¯3), in addition to one α1-selective alpha blocker. METHOD: A 200⯵L serum sample was handled automatically using a pipetting robot. Protein precipitation was performed with 600⯵L of 1% formic acid in acetonitrile (v:v) and phospholipid removal was carried out using a Waters OSTRO™ 96-well plate. After evaporation and reconstitution the eluent was injected thrice with different inlet and mass spectrometric methods to cover the different physico-chemical properties of the drugs and the variations in therapeutic concentration ranges between drugs. Acquity UPLC BEH C18 (2.1x50mm, 1.7⯵m) column equipped with a corresponding pre-column was used for chromatographic separation. For every analyte an isotopically labelled analogue served as internal standard, except for lisinopril where enalaprilat-d5 was used. RESULTS: Accuracies were in the range of -13.7 to 13.2% and intra-day and inter-day precisions in the range of 1.1 to 10.5%. The linearity within the calibration ranges expressed as coefficient of determination was higher than 0.995 for all compounds. Matrix effects and recovery efficiencies were within acceptable limits. The limits of quantitation varied from 0.02 to 10.7⯵g/L. The stability of the drugs in serum at different conditions was tested. Diltiazem was not stable at 4-8⯰C with up to 23.5â¯% loss after six days. Degradation of atenolol, irbesartan, bendroflumethiazide, hydrochlorothiazide and diltiazem was observed when stored at 30⯰C. The suitability of the method was demonstrated in a routine TDM setting, analysing samples from 127 patients undergoing antihypertensive drug treatment.
Assuntos
Anti-Hipertensivos/sangue , Monitoramento de Medicamentos/métodos , Espectrometria de Massas em Tandem/métodos , Antagonistas Adrenérgicos alfa/sangue , Antagonistas Adrenérgicos beta/sangue , Antagonistas de Receptores de Angiotensina/sangue , Inibidores da Enzima Conversora de Angiotensina/sangue , Bloqueadores dos Canais de Cálcio/sangue , Calibragem , Cromatografia Líquida de Alta Pressão/métodos , Diuréticos/sangue , Humanos , Limite de Detecção , Metaboloma/fisiologia , Reprodutibilidade dos Testes , SoroRESUMO
INTRODUCTION: Diuretic failure is a potential life-ending event but is unpredictable and poorly understood. The objectives of this study were to evaluate pharmacodynamic markers of furosemide-induced diuresis and to investigate mechanisms of diuretic braking in dogs receiving constant rate infusion (CRI) of furosemide. ANIMALS: Six healthy male dogs. METHODS: Raw data and stored samples from one arm of a previously published study were further analyzed to mechanistically investigate causes of diuretic braking in these dogs. Urine volume was recorded hourly during a 5-h furosemide CRI. Urine and blood samples were collected hourly to measure serum and urine electrolytes, urine aldosterone, and plasma and urine furosemide. Serum electrolyte fractional excretion was calculated. Urine sodium concentration was indexed to urine potassium (uNa:uK) and urine furosemide (uNa:uFur) concentrations, plasma furosemide concentration was indexed to urine furosemide concentration (pFur:uFur), and urine aldosterone was indexed to urine creatinine (UAldo:C). Temporal change and the relationship to urine volume were evaluated for these measured and calculated variables. RESULTS: Urine volume was significantly correlated with urine electrolyte amounts and with uNa:uK. The ratio of pFur:uFur decreased during the infusion, whereas furosemide excretion was unchanged. CONCLUSIONS: There was a strong relationship between urine volume and absolute urine electrolyte excretion. Urine volume was strongly correlated to uNa:uK, giving it potential as a spot indicator of urine production during diuresis. The decrease in uNa:uK over time during the infusion is consistent with mineralocorticoid modification of urinary electrolyte excretion, supporting renin-angiotensin-aldosterone activation as a cause of diuretic braking in this model.
Assuntos
Diuréticos/farmacologia , Furosemida/farmacologia , Aldosterona/urina , Animais , Diuréticos/administração & dosagem , Diuréticos/sangue , Diuréticos/urina , Cães , Eletrólitos/urina , Furosemida/administração & dosagem , Furosemida/sangue , Furosemida/urina , Infusões Intravenosas , Masculino , Sistema Renina-Angiotensina/efeitos dos fármacosRESUMO
AIMS: Sacubitril/valsartan is indicated for the treatment of heart failure and reduced ejection fraction (HFrEF). Furosemide, a loop diuretic commonly used for the treatment of HFrEF, may be coadministered with sacubitril/valsartan in clinical practice. The effect of sacubitril/valsartan on the pharmacokinetics and pharmacodynamics of furosemide was evaluated in this open label, two-period, single-sequence study in healthy subjects. METHODS: All subjects (n = 28) received 40 mg oral single-dose furosemide during period 1, followed by a washout of 2 days. In period 2, sacubitril/valsartan 200 mg (97/103 mg) was administered twice daily for 5 days and a single dose of 40 mg furosemide was coadministered on day 6. Serial plasma and urine samples were collected to determine the pharmacokinetics of furosemide and sacubitril/valsartan and the pharmacodynamics of furosemide. The point estimates and the associated 90% confidence intervals for pharmacokinetic parameters were evaluated. RESULTS: Coadministration of furosemide with sacubitril/valsartan decreased the maximum observed plasma concentration (Cmax ) [estimated geometric mean ratio (90% confidence interval): 0.50 (0.44, 0.56)], area under the plasma concentration-time curve (AUC) from time 0 to infinity [0.72 (0.67, 0.77)] and 24-h urinary excretion of furosemide [0.74 (0.69, 0.79)]. When coadministered with sacubitril/valsartan, 0-4-h, 4-8-h and 0-24-h diuresis in response to furosemide was reduced by ~7%, 21% and 0.2%, respectively, while natriuresis was reduced by ~ 28.5%, 7% and 15%, respectively. Post hoc analysis of the pivotal phase III Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) indicated that the median furosemide dose was similar at baseline and at the end of the study in the sacubitril/valsartan group. CONCLUSIONS: Sacubitril/valsartan reduced plasma Cmax and AUC and 24-h urinary excretion of furosemide, while not significantly affecting its pharmacodynamic effects in healthy subjects.
Assuntos
Aminobutiratos/farmacologia , Aminobutiratos/farmacocinética , Interações Medicamentosas , Furosemida/farmacologia , Furosemida/farmacocinética , Tetrazóis/farmacologia , Tetrazóis/farmacocinética , Adolescente , Adulto , Aminobutiratos/sangue , Aminobutiratos/urina , Antagonistas de Receptores de Angiotensina/sangue , Antagonistas de Receptores de Angiotensina/farmacocinética , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/urina , Compostos de Bifenilo , Ensaios Clínicos como Assunto/estatística & dados numéricos , Diurese/efeitos dos fármacos , Diuréticos/sangue , Diuréticos/farmacocinética , Diuréticos/farmacologia , Diuréticos/urina , Combinação de Medicamentos , Feminino , Furosemida/sangue , Furosemida/urina , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Natriurese/efeitos dos fármacos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Tetrazóis/sangue , Tetrazóis/urina , Valsartana , Adulto JovemRESUMO
Bumetanide is a loop diuretic that is proposed to possess a beneficial effect on disorders of the central nervous system, including neonatal seizures. Therefore, prediction of unbound bumetanide concentrations in the brain is relevant from a pharmacological prospective. A physiologically-based pharmacokinetic (PBPK) model was developed for the prediction of bumetanide disposition in plasma and brain in adult and paediatric populations. A compound file was built for bumetanide integrating physicochemical data and in vitro data. Bumetanide concentration profiles were simulated in both plasma and brain using the Simcyp PBPK model. Simulations of plasma bumetanide concentrations were compared against plasma levels published in the literature. The model performance was verified with data from adult studies before predictions in the paediatric population were undertaken. The adult and paediatric intravenous models predicted pharmacokinetic factors, namely area under the concentration-time curve, maximum concentration in plasma and time to maximum plasma concentration, within two-fold of observed values. However, predictions of plasma concentrations within the neonatal intravenous model did not produce a good fit with the observed values. The PBPK approach used in this study produced reasonable predictions of plasma concentrations of bumetanide, except in the critically ill neonatal population. This PBPK model requires more information regarding metabolic intrinsic clearance and transport parameters prior to further validation of drug disposition predictions in the neonatal population. Given the lack of information surrounding certain parameters in this special population, the model is not appropriately robust to support the recommendation of a suitable dose of bumetanide for use as an adjunct antiepileptic in neonates.
Assuntos
Encéfalo/metabolismo , Bumetanida/sangue , Bumetanida/farmacocinética , Modelos Biológicos , Adulto , Criança , Pré-Escolar , Simulação por Computador , Diuréticos/sangue , Diuréticos/farmacocinética , Feminino , Humanos , Lactente , MasculinoRESUMO
Furosemide is a diuretic agent used commonly in racehorses to attenuate the bleeding associated with exercise-induced pulmonary hemorrhage (EIPH). The current study describes serum and urine concentrations and the pharmacokinetics of furosemide following administration at 4 and 24 hrs prior to maximal exercise. Eight exercised adult Thoroughbred horses received a single IV administration of 250 mg of furosemide at 4 and 24 hrs prior to maximal exercise on a high-speed treadmill. Blood and urine samples were collected at time 0 and at various times for up to 72 hrs and furosemide concentrations determined using liquid chromatography-tandem mass spectrometry. Serum furosemide concentrations remained above the LOQ (0.05 ng/ml) for 36 hrs in 3/8 and 1/8 horses in the 4- and 24-hrs groups, respectively. Serum concentration data were best fit by a two-compartment model. There was not a significant difference in the volume of distribution at steady-state (0.594 ± 0.178 [4 hrs] and 0.648 ± 0.147 [24 hrs] L/kg) or systemic clearance (0.541 ± 0.094 [4 hrs] and 0.617 ± 0.114 [24 hrs] L/hrs/kg) between horses that were exercised at 4- and 24 hrs postdrug administration. The mean ± SD elimination half-life was 3.12 ± 0.387 and 3.23 ± 0.407 hrs following administration at 4 and 24 hrs prior to exercise, respectively.
Assuntos
Diuréticos/farmacocinética , Furosemida/farmacocinética , Condicionamento Físico Animal/efeitos adversos , Animais , Diuréticos/administração & dosagem , Diuréticos/sangue , Diuréticos/urina , Feminino , Furosemida/administração & dosagem , Furosemida/sangue , Furosemida/urina , Hemorragia/etiologia , Hemorragia/prevenção & controle , Hemorragia/veterinária , Doenças dos Cavalos/etiologia , Doenças dos Cavalos/prevenção & controle , Cavalos/sangue , Cavalos/metabolismo , Cavalos/urina , Pneumopatias/etiologia , Pneumopatias/prevenção & controle , Pneumopatias/veterinária , Masculino , Condicionamento Físico Animal/fisiologiaRESUMO
BACKGROUND: Metolazone is a diuretic, saluretic and antihypertensive chemical compound from the quinazoline category that possesses medicinal features similar to those of other thiazide diuretic drugs. However, the pharmacokinetics of metolazone in the Chinese population has rarely been studied. This study aimed to examine the pharmacokinetic characteristics, safety characteristic, and tolerability of metolazone in healthy Chinese subjects after single and multiple doses taken orally as well as the effects that food and gender have on oral metolazone pharmacokinetic parameters. METHODS: An open-label, randomized, and single- and multiple-dosing investigation was performed in healthy Chinese subjects. The investigation included 3 study groups: the 0.5 mg, 1 mg and 2 mg dose groups were the single-dose study groups in the first stage. Eligible volunteers were randomly and orally administered a single 0.5 mg, 1 mg, or 2 mg metolazone tablet. The 0.5 mg dose group was also part of the multiple-dose study group, and the 1 mg dose group was the food-effect study group in the second stage. Human plasma samples were gathered pre-dosing and up to 48 h after dosing. The human plasma sample concentration of metolazone was quantified using a validated liquid chromatography tandem mass spectrometry method. Pharmacokinetic data were calculated by a noncompartmental analysis method using WinNonlin version 6.4. Tolerability was evaluated based on adverse events, medical examination, 12-lead ECG, and other clinical laboratory exams. RESULTS: Thirty eligible subjects (15 men and 15 women) were registered in our investigation and completed all of the study stages. The AUC and Cmax showed dose proportionality after a single dose based on the linear-regression analysis. A comparison of the pharmacokinetic data revealed that the differences between the male and female groups were not statistically significant. The tmax of metolazone was increased by approximately 100% in the fed condition. Metolazone was well tolerated at the tested dose, and no adverse effects were observed. CONCLUSIONS: Single dosing with 0.5 mg, 1 mg, or 2 mg metolazone yielded linear plasma pharmacokinetic properties in healthy Chinese subjects. Multiple oral doses of metolazone did not display significantly different distributions or elimination characteristics from those observed for a single dose. Gender factors did not appear to influence the pharmacokinetic parameter variation of metolazone. The tmax of metolazone increased in the fed condition. Metolazone was well tolerated at the tested dose in this study. TRIAL REGISTRATION: This investigation is retrospectively registered at chictr.org.cn (ChiCTR-IIR-17012929, October 09 2017).
Assuntos
Anti-Hipertensivos/farmacocinética , Diuréticos/farmacocinética , Metolazona/farmacocinética , Administração Oral , Adolescente , Adulto , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/sangue , Área Sob a Curva , Povo Asiático , Diuréticos/administração & dosagem , Diuréticos/sangue , Esquema de Medicação , Feminino , Interações Alimento-Droga , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Metolazona/administração & dosagem , Metolazona/sangue , Comprimidos , Adulto JovemRESUMO
Though numerous reports have demonstrated multiple mechanisms by which furosemide can exert its anti-hypertensive response. However, lack of studies describing PK-PD relationship for furosemide featuring its anti-hypertensive property has limited its usage as a blood pressure (BP) lowering agent. Serum concentrations and mean arterial BP were monitored following 40 and 80mgkg-1 multiple oral dose of furosemide in spontaneously hypertensive rats (SHR) and DOCA-salt induced hypertensive (DOCA-salt) rats. A simultaneous population PK-PD relationship using Emax model with effect compartment was developed to compare the anti-hypertensive efficacy of furosemide in these rat models. A two-compartment PK model with Weibull-type absorption and first-order elimination best described the serum concentration-time profile of furosemide. In the present study, post dose serum concentrations of furosemide were found to be lower than the EC50. The EC50 predicted in DOCA-salt rats was found to be lower (4.5-fold), whereas the tolerance development was higher than that in SHR model. The PK-PD parameter estimates, particularly lower values of EC50, Ke and Q in DOCA-salt rats as compared to SHR, pinpointed the higher BP lowering efficacy of furosemide in volume overload induced hypertensive conditions. Insignificantly altered serum creatinine and electrolyte levels indicated a favorable side effect profile of furosemide. In conclusion, the final PK-PD model described the data well and provides detailed insights into the use of furosemide as an anti-hypertensive agent.
Assuntos
Anti-Hipertensivos/farmacocinética , Pressão Sanguínea/efeitos dos fármacos , Diuréticos/farmacocinética , Furosemida/farmacocinética , Hipertensão , Modelos Biológicos , Animais , Anti-Hipertensivos/sangue , Anti-Hipertensivos/farmacologia , Diuréticos/sangue , Diuréticos/farmacologia , Furosemida/sangue , Furosemida/farmacologia , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Ratos Endogâmicos SHR , Ratos WistarRESUMO
The circadian clock controls a wide variety of metabolic and homeostatic processes in a number of tissues, including the kidney. However, the role of the renal circadian clocks remains largely unknown. To address this question, we performed a combined functional, transcriptomic, and metabolomic analysis in mice with inducible conditional knockout (cKO) of BMAL1, which is critically involved in the circadian clock system, in renal tubular cells (Bmal1lox/lox/Pax8-rtTA/LC1 mice). Induction of cKO in adult mice did not produce obvious abnormalities in renal sodium, potassium, or water handling. Deep sequencing of the renal transcriptome revealed significant changes in the expression of genes related to metabolic pathways and organic anion transport in cKO mice compared with control littermates. Furthermore, kidneys from cKO mice exhibited a significant decrease in the NAD+-to-NADH ratio, which reflects the oxidative phosphorylation-to-glycolysis ratio and/or the status of mitochondrial function. Metabolome profiling showed significant changes in plasma levels of amino acids, biogenic amines, acylcarnitines, and lipids. In-depth analysis of two selected pathways revealed a significant increase in plasma urea level correlating with increased renal Arginase II activity, hyperargininemia, and increased kidney arginine content as well as a significant increase in plasma creatinine concentration and a reduced capacity of the kidney to secrete anionic drugs (furosemide) paralleled by an approximate 80% decrease in the expression level of organic anion transporter 3 (SLC22a8). Collectively, these results indicate that the renal circadian clocks control a variety of metabolic/homeostatic processes at the intrarenal and systemic levels and are involved in drug disposition.
Assuntos
Fatores de Transcrição ARNTL/genética , Relógios Circadianos/genética , Diuréticos/metabolismo , Furosemida/metabolismo , Rim/metabolismo , Metaboloma/genética , Animais , Diuréticos/sangue , Furosemida/sangue , Camundongos , NéfronsRESUMO
OBJECTIVES: The aim of the present study was to compare the pharmacokinetic profiles between a new generic and a branded reference formulation of irbesartan/ hydrochlorothiazide FDC tablets, and to assess the bioequivalence of the two products in healthy Chinese male volunteers. MATERIALS AND METHODS: 24 male healthy volunteers participated in the open-label, single-dose, randomized-sequence, 2-way crossover study. Eligible subjects were randomly assigned (1:1) to receive a single 300/12.5-mg dose of either the test or reference formulation followed by a 1-week washout. Blood samples were obtained before (0 hours) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 36, 48, and 72 hours after dosing. Plasma concentrations of irbesartan and hydrochlorothiazide were analyzed by two separate validated liquid chromatography/tandem mass spectrometric (LC-MS/MS) methods. RESULTS: For irbesartan, the 90% confidence intervals (CIs) of AUC0-t, AUC0-∞, and Cmax were 103.27-116.71%, 105.01-121.47%, and 84.15-96.88%, respectively. For hydrochlorothiazide, the 90% CIs of AUC0-t, AUC0-∞, and Cmax were 96.11-109.02%, 95.15-107.35%, and 91.66-101.40%, respectively. A total of 3 mild AEs were reported in 3 subjects (12.5%). CONCLUSION: In this study, a single dose (300/12.5-mg) of the test formulation of irbesartan and hydrochlorothiazide FDC tablet in fasting healthy Chinese male volunteers met WHO's and China's FDA regulatory criteria for assumption of bioequivalence to the reference formulation based on AUC and Cmax. Both formulations were well tolerated.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacocinética , Anti-Hipertensivos/farmacocinética , Compostos de Bifenilo/farmacocinética , Diuréticos/farmacocinética , Medicamentos Genéricos/farmacocinética , Hidroclorotiazida/farmacocinética , Tetrazóis/farmacocinética , Administração Oral , Adulto , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/sangue , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/sangue , Área Sob a Curva , Povo Asiático , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/efeitos adversos , Compostos de Bifenilo/sangue , China , Cromatografia Líquida de Alta Pressão , Estudos Cross-Over , Diuréticos/administração & dosagem , Diuréticos/efeitos adversos , Diuréticos/sangue , Combinação de Medicamentos , Medicamentos Genéricos/administração & dosagem , Medicamentos Genéricos/efeitos adversos , Voluntários Saudáveis , Humanos , Hidroclorotiazida/administração & dosagem , Hidroclorotiazida/efeitos adversos , Hidroclorotiazida/sangue , Irbesartana , Masculino , Taxa de Depuração Metabólica , Comprimidos , Espectrometria de Massas em Tandem , Tetrazóis/administração & dosagem , Tetrazóis/efeitos adversos , Tetrazóis/sangue , Equivalência Terapêutica , Adulto JovemRESUMO
LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor in development for treatments of hypertension and heart failure indications. In 3 separate studies, pharmacokinetic drug-drug interactions (DDIs) potential was assessed when LCZ696 was coadministered with hydrochlorothiazide (HCTZ), amlodipine, or carvedilol. The studies used a open-label, single-sequence, 3-period, crossover design in healthy subjects. Blood samples were collected to determine the pharmacokinetic parameters of LCZ696 analytes (AHU377, LBQ657, and valsartan), HCTZ, amlodipine, or carvedilol (R[+]- and S[-]-carvedilol) for statistical analysis. When coadministered LCZ696 with HCTZ, the 90% CIs of the geometric mean ratios of AUCtau,ss of HCTZ and that of LBQ657 were within a 0.80-1.25 interval, whereas HCTZ Cmax,ss decreased by 26%, LBQ657 Cmax,ss increased by 19%, and the AUCtau,ss and Cmax,ss of valsartan increased by 14% and 16%, respectively. Pharmacokinetics of amlodipine, R(+)- and S(-)-carvedilol, or LBQ657 were not altered after coadministration of LCZ696 with amlodipine or carvedilol. Coadministration of LCZ696 400 mg once daily (qd) with HCTZ 25 mg qd, amlodipine 10 mg qd, or carvedilol 25 mg twice a day (bid) had no clinically relevant pharmacokinetic drug-drug interactions. LCZ696, HCTZ, amlodipine, and carvedilol were safe and well tolerated when given alone or concomitantly in the investigated studies.