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1.
Artigo em Inglês | MEDLINE | ID: mdl-31915110

RESUMO

A novel, precise, accurate and rapid HPLC-UV method was developed, optimised and fully validated for simultaneous estimation of pitavastatin (PIT) and candesartan (CAN) in rat plasma using telmisartan as an internal standard. Following liquid-liquid extraction of the analytes from plasma, chromatographic separation was accomplished on a Waters Reliant C18 column (4.6 × 250 mm, 5 µm) using ACN-5 mM Sodium acetate buffer (80:20, v/v; pH adjusted to 3.5 with acetic acid) as mobile phase at a flow rate of 0.8 mL/min and wavelength of 234 nm. The calibration curves were linear over the concentration ranges of 2-400 ng/mL and 3-400 ng/mL for pitavastatin and candesartan respectively. The method when validated as per US-FDA guidelines was found to be precise as well as accurate. Extraction recovery observed for both analytes was above 90% as well as reproducible and consistent. Stability studies showed the samples to be stable over a long period covering from sample collection to final analysis. The method was successfully applied to investigate pharmacokinetic interaction between PIT and CAN in wistar rats. The mean plasma concentration-time curves of PIT and CAN showed that single PIT as well as CAN show similar pharmacokinetic properties to those obtained when co-administrated with each other (P value >0.05). Hence, there is no evidence for a potential drug-drug interaction between PIT and CAN. This information provides evidence for clinical rational use of CAN and PIT in cardiovascular patients.


Assuntos
Benzimidazóis/sangue , Benzimidazóis/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Quinolinas/sangue , Quinolinas/farmacocinética , Tetrazóis/sangue , Tetrazóis/farmacocinética , Animais , Benzimidazóis/química , Interações de Medicamentos , Modelos Lineares , Quinolinas/química , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrofotometria Ultravioleta , Tetrazóis/química
2.
Pharm Res ; 37(1): 2, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31823033

RESUMO

PURPOSE: Bosentan, clazosentan, and tezosentan are three small-molecule endothelin receptor antagonists (ERAs), displacing endothelin-1 (ET-1) from its binding site. A target-mediated drug disposition (TMDD) pharmacokinetic (PK) model described the non-linearity in the PK of bosentan caused by its high receptor binding affinity with time-dependent varying receptor expression or reappearance. The aim of this analysis was to investigate the presence of TMDD for clazosentan and tezosentan and to corroborate the hypothesis of a diurnal receptor synthesis. METHODS: PK data from healthy subjects after intravenous (i.v.) administration of single ascending doses of bosentan, clazosentan, and tezosentan were analyzed. Frequent blood samples for PK measurements were collected. Population analyses, simulations, and evaluations were performed using a non-linear mixed-effects modeling approach. RESULTS: Two-compartment TMDD models were successfully developed describing the PK of all three ERAs with different receptor-complex internalization properties. The observed multiple peaks in the concentration-time profiles were captured with cosine functions on the receptor synthesis rate mimicking a diurnal receptor expression or reappearance. The results strongly suggest that TMDD is a class effect of ERAs. CONCLUSION: The developed TMDD PK models are a next step towards understanding the complex PK of ERAs and further support the hypothesis that TMDD is a class effect of ERAs.


Assuntos
Bosentana/farmacocinética , Dioxanos/farmacocinética , Antagonistas dos Receptores de Endotelina/farmacocinética , Modelos Biológicos , Piridinas/farmacocinética , Pirimidinas/farmacocinética , Receptores de Endotelina/metabolismo , Sulfonamidas/farmacocinética , Tetrazóis/farmacocinética , Bosentana/administração & dosagem , Dioxanos/administração & dosagem , Relação Dose-Resposta a Droga , Antagonistas dos Receptores de Endotelina/administração & dosagem , Humanos , Infusões Intravenosas , Masculino , Dinâmica não Linear , Piridinas/administração & dosagem , Pirimidinas/administração & dosagem , Sulfonamidas/administração & dosagem , Espectrometria de Massas em Tandem , Tetrazóis/administração & dosagem
3.
Regul Toxicol Pharmacol ; 107: 104420, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31295511

RESUMO

To investigate the possibility of tedizolid phosphate's application in the treatment of intracranial infection, a preclinical comparative pharmacokinetic study was designed. Based on the assumption that the classic efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) may participate in the transportation of TDZ, two groups of rats were intravenously administered 6 mg/kg tedizolid phosphate alone or 6 mg/kg tedizolid phosphate combined with 1 mg/kg elacridar which was an inhibitor of P-gp and BCRP. Plasma and cerebrospinal fluid samples were collected according to a pharmacokinetic schedule. All the plasma and cerebrospinal fluid samples were assessed with a validated LC-MS/MS method. The penetration ratio of tedizolid from the blood to cerebrospinal fluid was calculated, and a comparison of the penetration ratios between the two groups was made. The mean Cmax of tedizolid in the CSF in the tedizolid phosphate group and the tedizolid phosphate combined with elacridar group was 154 ng/mL and 300 ng/mL, respectively, and the mean penetration ratio of tedizolid in the tedizolid phosphate group and the tedizolid phosphate combined with elacridar group was 2.16% and 3.53%, respectively. The relatively high Cmax in the CSF proved the possibility of tedizolid phosphate's application in the treatment of intracranial infection, and the higher penetration ratios, Cmax, csf and AUCcsf of the rats in co-administered elacridar group than those in the single-administration group indicated that the transporters P-gp and BCRP might be involved in the transportation of tedizolid.


Assuntos
Antibacterianos/farmacocinética , Oxazolidinonas/farmacocinética , Tetrazóis/farmacocinética , Animais , Antibacterianos/sangue , Antibacterianos/líquido cefalorraquidiano , Masculino , Oxazolidinonas/sangue , Oxazolidinonas/líquido cefalorraquidiano , Ratos Sprague-Dawley , Tetrazóis/sangue , Tetrazóis/líquido cefalorraquidiano
4.
Neurology ; 93(6): e559-e567, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31292226

RESUMO

OBJECTIVE: To evaluate the effect of cenobamate in patients with photoparoxysmal-EEG response (PPR) to intermittent photic stimulation (IPS) as proof of principle of efficacy in patients with epilepsy. METHODS: In this multicenter, single-blind study, adults with photosensitive epilepsy, with/without concomitant antiepileptic drug therapy, underwent IPS under 3 eye conditions after a single dose of placebo (day -1, day 2) or cenobamate (day 1; 100, 250, or 400 mg). Complete suppression was a standardized photosensitivity range reduction to 0 over ≥1 time points for all eye conditions. Partial suppression was a ≥3-point reduction over ≥3 testing times vs the same time points on day -1 in ≥1 eye condition. Pharmacokinetics and safety were assessed. RESULTS: Of 6 evaluable patients, 5 reentered to receive higher doses. Cenobamate 100 mg produced partial suppression in 1 of 3 patients; 250 mg produced complete suppression in 1 of 4 and partial suppression in 4 of 4 patients; and 400 mg produced complete suppression in 1 of 4 and partial suppression in 2 of 4 patients. PPR was consistently reduced on days 1 and 2 (>24 hours after cenobamate) vs day -1 (placebo) with the 250- and 400-mg doses. Area under the plasma concentration-time curve (before dose to last measurable concentration) values between 201 and 400 µg/h/mL resulted in partial suppression in 4 of 6 (66%) patients. Most common adverse events were dizziness and somnolence. CONCLUSIONS: This proof-of-principle study demonstrated that cenobamate is a potentially effective product for epilepsy. CLINICALTRIALSGOV IDENTIFIER: NCT00616148. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that, for patients with photosensitive epilepsy, cenobamate suppresses IPS-induced PPR.


Assuntos
Anticonvulsivantes/uso terapêutico , Carbamatos/uso terapêutico , Clorofenóis/uso terapêutico , Epilepsia Reflexa/tratamento farmacológico , Tetrazóis/uso terapêutico , Adolescente , Adulto , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/farmacocinética , Área Sob a Curva , Carbamatos/efeitos adversos , Carbamatos/farmacocinética , Clorofenóis/efeitos adversos , Clorofenóis/farmacocinética , Relação Dose-Resposta a Droga , Eletroencefalografia , Feminino , Humanos , Masculino , Estimulação Luminosa , Método Simples-Cego , Tetrazóis/efeitos adversos , Tetrazóis/farmacocinética , Adulto Jovem
5.
Pak J Pharm Sci ; 32(3): 1019-1024, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31278715

RESUMO

To compare the pharmacokinetics of candesartan cilexetil in healthy male and female volunteers in order to identify possible influence of gender and to improve therapeutic outcomes, an HPLC method for the quantification of candesartan cilexetil was developed and validated. Total of 16 volunteers (8 male and 8 female) were registered. Candesartan cilexetil 16 mg was administered orally to all the volunteers and blood samples were collected at different time intervals between 0-72 hours. Plasma was separated and analysed by HPLC method. Pharmacokinetic parameters were calculated by using APO software MW/PHARM version 3.02 and compared in male and female volunteers. The developed HPLC method fulfils the criteria for linearity, accuracy and precision described in EMA guideline. The values for absorption rate constant (Ka), maximum plasma concentration (Cmax), volume of distribution (Vd) and Clearance (CL) were similar in male and female volunteers. No influence of gender was observed on overall pharmacokinetics of candesartan cilexetil. Therefore, no need for dose optimization while administering candesartan cilexetil in male and female patients was found based on the results of this study.


Assuntos
Anti-Hipertensivos/sangue , Anti-Hipertensivos/farmacocinética , Benzimidazóis/sangue , Benzimidazóis/farmacocinética , Compostos de Bifenilo/sangue , Compostos de Bifenilo/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Tetrazóis/sangue , Tetrazóis/farmacocinética , Adolescente , Adulto , Anti-Hipertensivos/administração & dosagem , Benzimidazóis/administração & dosagem , Compostos de Bifenilo/administração & dosagem , Cromatografia de Fase Reversa/métodos , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Fatores Sexuais , Tetrazóis/administração & dosagem , Adulto Jovem
6.
Drug Des Devel Ther ; 13: 991-997, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31114155

RESUMO

Objective: The aim of this study was to compare the pharmacokinetic (PK) and safety profiles of a fixed dose combination (FDC) formulation and co-administration of amlodipine, olmesartan, and rosuvastatin. Materials and methods: This study was an open-label, randomized, cross-over design conducted in healthy male volunteers. All subjects received either a single FDC tablet containing amlodipine 10 mg/olmesartan 40 mg/rosuvastatin 20 mg, or were co-administered an FDC tablet containing amlodipine 10 mg/olmesartan 40 mg and a tablet containing rosuvastatin 20 mg, for each period, with 14-day washout periods. Plasma concentrations of amlodipine, olmesartan, and rosuvastatin were measured by liquid chromatography tandem mass spectrometry. Safety was evaluated by measuring vital signs, clinical laboratory parameters, physical examinations, and medical interviews. Results: Sixty-four subjects were enrolled, and 54 completed the study. The geometric mean ratios and 90% CI for the maximum plasma concentration (Cmax) and area under the curve from time zero to the last sampling time (AUCt) were 1.0716 (1.0369,1.1074) and 1.0497 (1.0243,1.0757) for amlodipine, 1.0396 (0.9818,1.1009) and 1.0138 (0.9716,1.0578) for olmesartan, and 1.0257 (0.9433,1.1152) and 1.0043 (0.9453,1.0669) for rosuvastatin. Fourteen cases of adverse events occurred in 12 subjects. There was no statistically significant clinical difference between the formulation groups. Conclusion: The 90% CI of the primary PK parameters were within the acceptance bioequivalence criteria, which is ln (0.8) and ln (1.25). These results indicate that the FDC formulation and co-administration of amlodipine, olmesartan and rosuvastatin are pharmacokinetically bioequivalent and have similar safety profiles.


Assuntos
Anlodipino/administração & dosagem , Anlodipino/farmacocinética , Imidazóis/administração & dosagem , Imidazóis/farmacocinética , Rosuvastatina Cálcica/administração & dosagem , Rosuvastatina Cálcica/farmacocinética , Tetrazóis/administração & dosagem , Tetrazóis/farmacocinética , Adulto , Anlodipino/sangue , Cromatografia Líquida , Estudos Cross-Over , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Voluntários Saudáveis , Humanos , Imidazóis/sangue , Masculino , Pessoa de Meia-Idade , Estrutura Molecular , Rosuvastatina Cálcica/sangue , Relação Estrutura-Atividade , Espectrometria de Massas em Tandem , Tetrazóis/sangue , Adulto Jovem
7.
Biomed Chromatogr ; 33(10): e4607, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31141832

RESUMO

A simple, precise and accurate HPLC method was developed, optimized and validated for simultaneous determination of rosuvastatin and candesartan in rat plasma using atorvastatin as an internal standard. Solid-phase extraction was used for sample cleanup and its subsequent optimization was carried out to achieve higher extraction efficiency and to eliminate matrix effect. A quality by design approach was used, wherein three-level factorial design was applied for optimization of mobile phase composition and for assessing the effect of pH of the mobile phase using Design Expert Software. Adequate separation for both analytes was achieved with a Waters C18 column (250 × 4.6 mm, 5 µm) using acetonitrile-5 mm sodium acetate buffer (70:30, v/v; pH adjusted to 3.5 with acetic acid) as a mobile phase at a flow rate of 1.0 mL/min and wavelength of 254 nm. The calibration curves were linear over the concentration ranges 5-150 and 10-300 ng/mL for rosuvastatin (ROS) and candesartan (CAN), respectively. The validated method was successfully applied to a pharmacokinetic study in Wistar rats and the data did not reveal any evidence for a potential drug-drug interaction between ROS and CAN. This information provides evidence for clinical rational use of ROS and CAN.


Assuntos
Benzimidazóis/sangue , Cromatografia Líquida de Alta Pressão/métodos , Rosuvastatina Cálcica/sangue , Tetrazóis/sangue , Animais , Benzimidazóis/química , Benzimidazóis/farmacocinética , Modelos Lineares , Masculino , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Rosuvastatina Cálcica/química , Rosuvastatina Cálcica/farmacocinética , Sensibilidade e Especificidade , Extração em Fase Sólida , Tetrazóis/química , Tetrazóis/farmacocinética
8.
Biomed Chromatogr ; 33(8): e4553, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30985934

RESUMO

Grapefruit juice inhibits esterase enzyme. Therefore, a possible interaction with ester prodrugs should be taken into consideration. In this study, the influence of grapefruit juice on sacubitril (SAC) rat liver S9 activation by esterase enzyme was evaluated. An RP-HPLC method was developed and validated for estimation of SAC in rat liver S9 fraction using a C18 Cyano column as stationary phase and acetonitrile-sodium di-hydrogen phosphate buffer (0.02 m, pH 4 adjusted by o-phosphoric acid, 40:60, v/v), as mobile phase at a flow rate of 1 mL/min and UV detection at 254 nm. The method was successfully applied to an in vitro study in which SAC was incubated with rat liver S9 fraction prepared from rats that had previously ingested grapefruit juice for a week. The calculated SAC concentration after incubation was compared with that of SAC incubated with rat liver S9 fraction from the rat control group. The statistical significance between the results of test and control incubation sets was assessed. In conclusion, the current study demonstrated that grapefruit juice decreased SAC hydrolysis, hence delaying its activation to sacubitrilat (active form) in gut lumen. Based on this food-drug interaction, it may be required that grapefruit juice should be consumed with caution in patients receiving SAC.


Assuntos
Aminobutiratos/farmacologia , Cromatografia Líquida de Alta Pressão/métodos , Citrus paradisi/química , Sucos de Frutas e Vegetais , Microssomos Hepáticos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Tetrazóis/farmacologia , Aminobutiratos/farmacocinética , Animais , Limite de Detecção , Modelos Lineares , Extratos Vegetais/farmacocinética , Ratos , Reprodutibilidade dos Testes , Tetrazóis/farmacocinética
9.
J Am Coll Cardiol ; 73(11): 1273-1284, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30898202

RESUMO

BACKGROUND: With sacubitril/valsartan treatment, B-type natriuretic peptide (BNP) concentrations increase; it remains unclear whether change in BNP concentrations is similar across all assays for its measurement. Effects of sacubitril/valsartan on atrial natriuretic peptide (ANP) concentrations in patients are unknown. Lastly, the impact of neprilysin inhibition on mid-regional pro-ANP (MR-proANP), N-terminal pro-BNP (NT-proBNP), proBNP1-108, or C-type natriuretic peptide (CNP) is not well understood. OBJECTIVES: This study sought to examine the effects of sacubitril/valsartan on results from different natriuretic peptide assays. METHODS: Twenty-three consecutive stable patients with heart failure and reduced ejection fraction were initiated and titrated on sacubitril/valsartan. Change in ANP, MR-proANP, BNP (using 5 assays), NT-proBNP (3 assays), proBNP1-108, and CNP were measured over 3 visits. RESULTS: Average time to 3 follow-up visits was 22, 46, and 84 days. ANP rapidly and substantially increased with initiation and titration of sacubitril/valsartan, more than doubling by the first follow-up visit (+105.8%). Magnitude of ANP increase was greatest in those with concentrations above the median at baseline (+188%) compared with those with lower baseline concentrations (+44%); ANP increases were sustained. Treatment with sacubitril/valsartan led to inconsistent changes in BNP, which varied across methods assessed. Concentrations of MR-proANP, NT-proBNP, and proBNP1-108 variably declined after treatment; whereas CNP concentrations showed no consistent change. CONCLUSIONS: Initiation and titration of sacubitril/valsartan led to variable changes in concentrations of multiple natriuretic peptides. These results provide important insights into the effects of sacubitril/valsartan treatment on individual patient results, and further suggest the benefit of neprilysin inhibition may be partially mediated by increased ANP concentrations.


Assuntos
Aminobutiratos , Insuficiência Cardíaca , Peptídeo Natriurético Encefálico , Neprilisina , Tetrazóis , Aminobutiratos/administração & dosagem , Aminobutiratos/farmacocinética , Antagonistas de Receptores de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/farmacocinética , Monitoramento de Medicamentos/métodos , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/análise , Peptídeo Natriurético Encefálico/sangue , Neprilisina/antagonistas & inibidores , Neprilisina/metabolismo , Fenômenos Farmacológicos , Volume Sistólico , Tetrazóis/administração & dosagem , Tetrazóis/farmacocinética
10.
Cardiology ; 142(1): 4-6, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30852576

RESUMO

The uptake of sacubitril/valsartan since the PARADIGM study confirmed its beneficial effects on outcomes over enalapril in chronic systolic heart failure has inevitably led to potential interactions with co-prescribed medications in real-world patients. We report two cases that raise the possibility of an interaction between sacubitril/valsartan and the class Ib anti-arrhythmic mexiletine resulting in proarrhythmic effects. We discuss the pharmacokinetics of both agents and posit potential mechanistic interactions that suggest caution should be used and careful monitoring for (ventricular) arrhythmias applied in patients receiving sacubitril/valsartan and mexiletine.


Assuntos
Aminobutiratos/efeitos adversos , Antagonistas de Receptores de Angiotensina/efeitos adversos , Arritmias Cardíacas/induzido quimicamente , Mexiletina/efeitos adversos , Tetrazóis/efeitos adversos , Idoso , Aminobutiratos/farmacocinética , Antagonistas de Receptores de Angiotensina/farmacocinética , Interações de Medicamentos , Feminino , Insuficiência Cardíaca Sistólica/tratamento farmacológico , Humanos , Masculino , Mexiletina/farmacocinética , Tetrazóis/farmacocinética
11.
Eur J Heart Fail ; 21(3): 337-341, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30741494

RESUMO

AIMS: To assess differences in diuretic dose requirements in patients treated with sacubitril/valsartan compared with enalapril in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial. METHODS AND RESULTS: Overall, 8399 patients with New York Heart Association class II-IV heart failure and reduced LVEF were randomized to sacubitril/valsartan 200 mg bid or enalapril 10 mg twice daily. Loop diuretic doses were assessed at baseline, 6, 12, and 24 months, and furosemide dose equivalents were calculated via multiplication factors (2x for torsemide and 40x for bumetanide). Percentages of participants with reductions or increases in loop diuretic dose were determined. At baseline, 80.8% of participants were taking any diuretics (n = 6290 for loop diuretics, n = 496 for other diuretics); of those, recorded dosage data for loop diuretics were available on 5487 participants. Mean baseline furosemide equivalent doses were 48.2 mg for sacubitril/valsartan and 49.6 mg for enalapril (P = 0.25). Patients treated with sacubitril/valsartan were more likely to reduce diuretic dose and less likely to increase diuretic dose relative to those randomized to enalapril at 6, 12, 24 months post-randomization, with an overall decreased diuretic use of 2.0% (P = 0.02), 4.1% (P < 0.001), and 6.1% (P < 0.001) at 6, 12, and 24 months, respectively, with similar findings in an on-treatment analysis. CONCLUSION: Treatment with sacubitril/valsartan was associated with more loop diuretic dose reductions and fewer dose increases compared with enalapril, suggesting that treatment with sacubitril/valsartan may reduce the requirement for loop diuretics relative to enalapril in patients with heart failure with reduced ejection fraction.


Assuntos
Aminobutiratos , Enalapril , Furosemida , Insuficiência Cardíaca , Volume Sistólico , Tetrazóis , Idoso , Aminobutiratos/administração & dosagem , Aminobutiratos/farmacocinética , Antagonistas de Receptores de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/farmacocinética , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Monitoramento de Medicamentos/estatística & dados numéricos , Enalapril/administração & dosagem , Enalapril/farmacocinética , Feminino , Furosemida/administração & dosagem , Furosemida/farmacocinética , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Conduta do Tratamento Medicamentoso/estatística & dados numéricos , Pessoa de Meia-Idade , Inibidores de Simportadores de Cloreto de Sódio e Potássio/administração & dosagem , Inibidores de Simportadores de Cloreto de Sódio e Potássio/farmacocinética , Tetrazóis/administração & dosagem , Tetrazóis/farmacocinética
12.
Eur J Med Chem ; 163: 404-412, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30530192

RESUMO

Tetrazole, a bioisostere of the carboxylic acid group, can replace the carboxyl group in drugs to increase the lipophilicity, bioavailability and reduce side effects. Tetrazole derivatives possess a broad-spectrum of biological properties including anti-tubercular and anti-malarial activities, and some tetrazole-based compounds have already been used in clinics for the treatment of various diseases. Therefore, tetrazole is an important pharmacophore in the development of new drugs. This review covers the recent advances of tetrazole derivatives as potential anti-tubercular and anti-malarial agents, and the structure-activity relationship is also discussed for the further rational design of tetrazole derivatives.


Assuntos
Antimaláricos/química , Antituberculosos/química , Tetrazóis/farmacocinética , Animais , Antimaláricos/farmacologia , Antituberculosos/farmacologia , Humanos , Relação Estrutura-Atividade , Tetrazóis/efeitos adversos , Tetrazóis/síntese química , Tetrazóis/farmacologia
13.
Drug Des Devel Ther ; 12: 3607-3615, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30464392

RESUMO

Purpose: A new fixed-dose combination (FDC) formulation of 120 mg fimasartan and 20 mg rosuvastatin was developed to increase therapeutic convenience and improve treatment compliance. Methods: A randomized, open-label, single-dose, two-treatment, two-way crossover study with a 7-day washout period was conducted to compare the pharmacokinetic (PK) characteristics and bioequivalence between an FDC of fimasartan/rosuvastatin and the separate co-administration of fimasartan and rosuvastatin in healthy Korean volunteers. The plasma concentrations of fimasartan and rosuvastatin were analyzed by a validated liquid chromatography-tandem mass spectrometry method, for which serial blood samples were collected for up to 48 hours post-administration of fimasartan and 72 hours post-administration of rosuvastatin, in each period. The PK parameters were calculated using a non-compartmental method. Results: A total of 78 subjects completed the study. All the 90% CIs of the geometric mean ratios (GMRs) fell within the predetermined acceptance range. The GMR and 90% CI for the area under the plasma concentration-time curve from time 0 to the last measurement (AUC0-t) and the maximum plasma concentration (Cmax) for fimasartan were 0.9999 (0.9391-1.0646) and 1.0399 (0.8665-1.2479), respectively. The GMR and 90% CI for the AUC0-t and Cmax for rosuvastatin were 1.0075 (0.9468-1.0722) and 1.0856 (0.9944-1.1852), respectively. Treatment with fimasartan and rosuvastatin was generally well tolerated without serious adverse events. Conclusion: The new FDC formulation of 120 mg fimasartan and 20 mg rosuvastatin can be substituted for the separate co-administration of fimasartan and rosuvastatin, for the advantage of better compliance with convenient therapeutic administration.


Assuntos
Compostos de Bifenilo/farmacocinética , Pirimidinas/farmacocinética , Rosuvastatina Cálcica/farmacocinética , Tetrazóis/farmacocinética , Administração Oral , Adulto , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/sangue , Estudos Cross-Over , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Pirimidinas/administração & dosagem , Pirimidinas/sangue , República da Coreia , Rosuvastatina Cálcica/administração & dosagem , Rosuvastatina Cálcica/sangue , Tetrazóis/administração & dosagem , Tetrazóis/sangue , Equivalência Terapêutica , Adulto Jovem
14.
Clin Infect Dis ; 67(suppl_3): S342-S348, 2018 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-30496456

RESUMO

Background: Children are often neglected during early development of antituberculosis agents, and most receive treatment after it is first tested in adults. However, very young children have tuberculosis that differs in many respects from adult cavitary pneumonia and could have different toxicity profiles to drugs. Linezolid is effective against intracellular tuberculosis, a common manifestation in young children. However, linezolid has considerable toxicity due to inhibition of mitochondrial enzymes. Tedizolid could be a replacement if it shows equal efficacy and reduced toxicity. Methods: We performed tedizolid dose-effect studies in the hollow fiber system model of intracellular tuberculosis. We measured linezolid concentrations, colony-forming units (CFU), time-to-positivity, and monocyte viability and performed RNA sequencing on infected cells collected from repetitive sampling of each system. We also compared efficacy of tedizolid vs linezolid and vs tedizolid-moxifloxacin combination. Results: There was no downregulation of mitochondrial enzyme genes, with a tedizolid 0-24 hour area under the concentration-time curve (AUC0-24) of up to 90 mg*h/L. Instead, high exposures led to increased mitochondrial gene expression and monocyte survival. The AUC0-24 to minimum inhibitory concentration ratio associated with 80% of maximal bacterial kill (EC80) was 184 by CFU/mL (r2 = 0.96) and 189 by time-to-positivity (r2 = 0.99). Tedizolid EC80 killed 4.0 log10 CFU/mL higher than linezolid EC80. The tedizolid-moxifloxacin combination had a bacterial burden elimination rate constant of 0.27 ± 0.05 per day. Conclusions: Tedizolid demonstrated better efficacy than linezolid, without the mitochondrial toxicity gene or cytotoxicity signatures encountered with linezolid. Tedizolid-moxifloxacin combination had a high bacterial elimination rate.


Assuntos
Antibacterianos/farmacocinética , Moxifloxacina/farmacocinética , Mycobacterium tuberculosis/efeitos dos fármacos , Oxazolidinonas/farmacocinética , Tetrazóis/farmacocinética , Tuberculose/tratamento farmacológico , Antibacterianos/uso terapêutico , Criança , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Moxifloxacina/uso terapêutico , Oxazolidinonas/uso terapêutico , Tetrazóis/uso terapêutico , Tuberculose/microbiologia
15.
Clin Infect Dis ; 67(suppl_3): S336-S341, 2018 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-30496463

RESUMO

Background: Linezolid exhibits remarkable sterilizing effect in tuberculosis; however, a large proportion of patients develop serious adverse events. The congener tedizolid could have a better side-effect profile, but its sterilizing effect potential is unknown. Methods: We performed a 42-day tedizolid exposure-effect and dose-fractionation study in the hollow fiber system model of tuberculosis for sterilizing effect, using human-like intrapulmonary pharmacokinetics. Bacterial burden was examined using time to positivity (TTP) and colony-forming units (CFUs). Exposure-effect was examined using the inhibitory sigmoid maximal kill model. The exposure mediating 80% of maximal kill (EC80) was defined as the target exposure, and the lowest dose to achieve EC80 was identified in 10000-patient Monte Carlo experiments. The dose was also examined for probability of attaining concentrations associated with mitochondrial enzyme inhibition. Results: At maximal effect, tedizolid monotherapy totally eliminated 7.1 log10 CFU/mL Mycobacterium tuberculosis over 42 days; however, TTP still demonstrated some growth. Once-weekly tedizolid regimens killed as effectively as daily regimens, with an EC80 free drug 0- to 24-hour area under the concentration-time curve-to-minimum inhibitory concentration (MIC) ratio of 200. An oral tedizolid of 200 mg/day achieved the EC80 in 92% of 10000 patients. The susceptibility breakpoint was an MIC of 0.5 mg/L. The 200 mg/day dose did not achieve concentrations associated with mitochondrial enzyme inhibition. Conclusions: Tedizolid exhibits dramatic sterilizing effect and should be examined for pulmonary tuberculosis. A tedizolid dose of 200 mg/day or 700 mg twice a week is recommended for testing in patients; the intermittent tedizolid dosing schedule could be much safer than daily linezolid.


Assuntos
Antibacterianos/farmacocinética , Linezolida/farmacocinética , Mycobacterium tuberculosis/efeitos dos fármacos , Oxazolidinonas/farmacocinética , Tetrazóis/farmacocinética , Tuberculose Pulmonar/tratamento farmacológico , Antibacterianos/administração & dosagem , Humanos , Linezolida/administração & dosagem , Testes de Sensibilidade Microbiana , Método de Monte Carlo , Oxazolidinonas/administração & dosagem , Tetrazóis/administração & dosagem
16.
Pharm Res ; 35(12): 236, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30324316

RESUMO

PURPOSE: To build a physiologically based pharmacokinetic (PBPK) model for fimasartan, amlodipine, and hydrochlorothiazide, and to investigate the drug-drug interaction (DDI) potentials. METHODS: The PBPK model of each drug was developed using Simcyp software (Version 15.0), based on the information obtained from literature sources and in vitro studies. The predictive performance of the model was assessed by comparing the predicted PK profiles and parameters with the observed data collected from healthy subjects after multiple oral doses of fimasartan, amlodipine, and hydrochlorothiazide. The DDI potentials after co-administration of three drugs were simulated using the final model. RESULTS: The predicted-to-observed ratios of all the pharmacokinetic parameters met the acceptance criterion. The PBPK model predicted no significant DDI when fimasartan was co-administered with amlodipine or hydrochlorothiazide, which is consistent with the observed clinical data. In the simulation of DDI at steady-state after co-administration of three drugs, the model predicted that fimasartan exposure would be increased by ~24.5%, while no changes were expected for the exposures of amlodipine and hydrochlorothiazide. CONCLUSIONS: The developed PBPK model adequately predicted the pharmacokinetics of fimasartan, amlodipine, and hydrochlorothiazide, suggesting that the model can be used to further investigate the DDI potential of each drug.


Assuntos
Anlodipino/farmacocinética , Anti-Hipertensivos/farmacocinética , Compostos de Bifenilo/farmacocinética , Hidroclorotiazida/farmacocinética , Pirimidinas/farmacocinética , Tetrazóis/farmacocinética , Anlodipino/farmacologia , Anti-Hipertensivos/farmacologia , Compostos de Bifenilo/farmacologia , Simulação por Computador , Interações de Medicamentos , Humanos , Hidroclorotiazida/farmacologia , Modelos Biológicos , Pirimidinas/farmacologia , Software , Tetrazóis/farmacologia
17.
Bioorg Med Chem Lett ; 28(23-24): 3766-3773, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30340896

RESUMO

Endogenous nitrosothiols (SNOs) including S-nitrosoglutathione (GSNO) serve as reservoir for bioavailable nitric oxide (NO) and mediate NO-based signaling, inflammatory status and smooth muscle function in the lung. GSNOR inhibition increases pulmonary GSNO and induces bronchodilation while reducing inflammation in lung diseases. In this letter, design, synthesis and structure-activity relationships (SAR) of novel imidazole-biaryl-tetrazole based GSNOR inhibitors are described. Many potent inhibitors (30, 39, 41, 42, 44, 45 and 58) were identified with low nanomolar activity (IC50s: <15 nM) along with adequate metabolic stability. Lead compounds 30 and 58 exhibited good exposure and oral bioavailability in mouse pharmacokinetic (PK) study. Compound 30 was selected for further profiling and revealed comparable mouse and rat GSNOR potency, high selectivity against alcohol dehydrogenase (ADH) and carbonyl reductase (CBR1) family of enzymes, low efflux ratio and permeability in PAMPA, a high permeability in CALU-3 assay, significantly low hERG activity and minimal off-target activity. Further, an in vivo efficacy of compound 30 is disclosed in cigarette smoke (CS) induced mouse model for COPD.


Assuntos
Aldeído Oxirredutases/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Tetrazóis/química , Tetrazóis/farmacologia , Administração Oral , Aldeído Oxirredutases/metabolismo , Animais , Fumar Cigarros/efeitos adversos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Halogenação , Humanos , Imidazóis/administração & dosagem , Imidazóis/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Relação Estrutura-Atividade , Tetrazóis/administração & dosagem , Tetrazóis/farmacocinética
18.
Bioorg Med Chem Lett ; 28(19): 3155-3160, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30177375

RESUMO

Inspired by the well-known PPARγ partial agonism of angiotensin II type 1 receptor (AT1R) antagonists exemplified by an antihypertensive drug, Telmisartan, efforts to identify compounds with the dual activities have been pursued in order to control the two major metabolic disorders, hypertension and hyperglycemia simultaneously. Lead compound 18 derived from the AT1R antagonist, Fimasartan, has successfully presented the possibility to control the medical conditions by a single molecule.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Compostos de Bifenilo/farmacologia , PPAR gama/agonistas , Pirimidinas/farmacologia , Tetrazóis/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacocinética , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/farmacologia , Área Sob a Curva , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacocinética , Modelos Animais de Doenças , Descoberta de Drogas , Agonismo Parcial de Drogas , Meia-Vida , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Estudo de Prova de Conceito , Pirimidinas/química , Pirimidinas/farmacocinética , Relação Estrutura-Atividade , Tetrazóis/química , Tetrazóis/farmacocinética
19.
Drug Des Devel Ther ; 12: 2301-2309, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30087555

RESUMO

Introduction: Major cardiovascular risk factors, including hypertension and dyslipidemia, are often comorbidities, frequently leading to concurrent prescription of angiotensin receptor blockers and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins). The study's objective was to evaluate the effect of coadministration of fimasartan and atorvastatin on their pharmacokinetics (PKs). Subjects and methods: In a randomized, open-label, three-period, six-sequence, crossover, multiple-dose study, 36 healthy subjects received 120 mg fimasartan, 40 mg atorvastatin, or both (based on their assigned sequence) once daily for 7 days in each period, with a 7-day washout between periods. Blood samples for the PK analysis of fimasartan, atorvastatin, and the 2-hydroxy atorvastatin metabolite were collected up to 48 h after the last dose. Results: The coadministration of fimasartan and atorvastatin was well tolerated and led to an increase in the peak concentration and area under the concentration-time curve at steady state of fimasartan by 2.18-fold (95% confidence interval [CI], 1.79-2.65) and 1.35-fold (95% CI, 1.26-1.43) and those of atorvastatin increased by 1.82-fold (95% CI, 1.51-2.18) and 1.12-fold (95% CI, 1.04-1.22), respectively. Conclusion: Coadministration increased the systemic exposures of fimasartan and atorvastatin, but the clinical significance of this finding needs to be evaluated with respect to exposure responses and clinical outcomes.


Assuntos
Atorvastatina/farmacocinética , Compostos de Bifenilo/farmacocinética , Pirimidinas/farmacocinética , Tetrazóis/farmacocinética , Administração Oral , Adulto , Atorvastatina/química , Atorvastatina/metabolismo , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/química , Estudos Cross-Over , Combinação de Medicamentos , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Pirimidinas/administração & dosagem , Pirimidinas/química , Tetrazóis/administração & dosagem , Tetrazóis/química , Adulto Jovem
20.
Drug Des Devel Ther ; 12: 2475-2483, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30127595

RESUMO

Purpose: To evaluate the pharmacokinetics and pharmacodynamics of candesartan and amlodipine in the absence and presence of each other in healthy subjects. Methods: This study consisted of two parts: part 1, the effect of amlodipine on candesartan; part 2, the effect of candesartan on amlodipine. Each part was designed as a randomized, open-label, two-sequence, two-period, two-intervention crossover study with 20 subjects and performed separately in different populations. Pharmacokinetic assessments were performed over 48 hours for candesartan in part 1 and 72 hours for amlodipine in part 2 after drug administration on Day 10. Safety data included the results of physical examinations, clinical laboratory tests, vital signs, an electrocardiogram, and adverse events. Results: For both candesartan and amlodipine, the 90% confidence intervals for the geometric mean ratios of area under the concentration-time curve from time zero to the time of dosing interval of 24 hours and maximum concentration after drug administration fell within the bioequivalence acceptance criteria. Although this study was conducted in normotensive subjects, blood pressure lowering effects were observed in all intervention groups and co-administration of candesartan and amlodipine reduced blood pressure more than amlodipine alone, but similar to candesartan alone. No serious adverse event was reported throughout the study, and all treatment emergent adverse events were mild to moderate in severity and were recovered without sequelae. Conclusion: Co-administration of candesartan and amlodipine did not change the systemic exposure of each drug alone in healthy subjects. The administration of candesartan 32 mg alone, amlodipine 10 mg alone, and co-administration of candesartan and amlodipine were well tolerated during the study.


Assuntos
Anlodipino/administração & dosagem , Anlodipino/farmacocinética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacocinética , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacocinética , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/farmacocinética , Tetrazóis/administração & dosagem , Tetrazóis/farmacocinética , Administração Oral , Adulto , Anlodipino/efeitos adversos , Anlodipino/sangue , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/sangue , Benzimidazóis/efeitos adversos , Benzimidazóis/sangue , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/sangue , Estudos Cross-Over , Esquema de Medicação , Interações de Medicamentos , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , República da Coreia , Tetrazóis/efeitos adversos , Tetrazóis/sangue , Adulto Jovem
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