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1.
Biomed Chromatogr ; 35(5): e5047, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33352616

RESUMO

Fosinopril diacid is an angiotensin converting enzyme inhibitor with efficient antihypertensive action. It is an active metabolic product formed in the body from hydrolysis of its prodrug Fosinopril. A sensitive, rapid method with high recovery for Fosinopril diacid from human plasma was developed. Solid-phase extraction technique employing Waters Oasis SPE cartridges gave clean samples with very high recovery of 97%. The analyte along with its internal standard (Benazepril hydrochloride) were chromatographed on an XTerra RP8 column (4.6 × 50 mm, 5 µm) using methanol-ammonium acetate buffer (10 mm; 90:10, v/v) as the mobile phase. A triple quadrupole mass spectrometer equipped with electrospray ionization source operated in the negative ion mode was used for detection. Multiple reaction monitoring scan mode was used for monitoring the transitions from m/z 434.00 → 237.15 for Fosinopril diacid and m/z 423.10 → 174.00 for Benazepril hydrochloride. Beer-Lambert's law was obeyed in the range of 0.50-1,500.00 ng/ml (r = 0.9993). The stability of the drugs in human plasma and in stock solution was proved by performing stability tests as per US Food and Drug Administration guidelines. The method was successfully applied for a bioequivalence study of Fosinopril diacid in 36 healthy, adult, male volunteers under fasting conditions.


Assuntos
Inibidores da Enzima Conversora de Angiotensina , Cromatografia Líquida de Alta Pressão/métodos , Fosinopril/análogos & derivados , Espectrometria de Massas em Tandem/métodos , Adulto , Inibidores da Enzima Conversora de Angiotensina/sangue , Inibidores da Enzima Conversora de Angiotensina/farmacocinética , Benzazepinas/normas , Fosinopril/sangue , Fosinopril/metabolismo , Fosinopril/farmacocinética , Humanos , Masculino , Padrões de Referência , Equivalência Terapêutica
2.
Drug Des Devel Ther ; 14: 961-967, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32184565

RESUMO

OBJECTIVE: This study aimed to quantify the amount of perindopril and its active metabolite perindoprilat present in breast milk and corresponding maternal and infant plasma concentrations. DESIGN: Prospective, longitudinal, observational. SETTING: Tertiary specialist paediatric and obstetric hospital in Adelaide, South Australia. POPULATION: Breastfeeding women actively treated with perindopril for hypertensive disorders postpartum. METHODS: Eight breast milk samples and a single plasma sample were collected from each participant over a 24 hrs period, and plasma samples were taken from eligible breastfed infants. Breast milk and plasma concentrations of perindopril and perindoprilat were analysed using a validated Liquid Chromatography tandem-Mass Spectrometry (LC-MS/MS) method. MAIN OUTCOME MEASURES: Mean breast milk concentrations of perindopril and perindoprilat, Relative Infant Dose (RID) <10%, and Theoretical Infant Dose (TID). RESULTS: Ten women and three infants participated in the study. The mean concentration of perindopril in breast milk for each participant ranged from 0.003 to 1.2 ng/mL and perindoprilat 0.2-36 ng/mL. RID for perindopril was 0.0005-0.2% and perindoprilat 0.03-4.6%. TID for perindopril was 0.00045-0.18 µg/kg/day and perindoprilat 0.032-5.4 µg/kg/day. Infant plasma levels for perindopril ranged from 0.44 to 1.12 ng/mL and perindoprilat undetectable - 10.14 ng/mL. Maternal reports described normal infant growth and development. CONCLUSION: Infant exposure to perindopril and perindoprilat through breast milk is low. However, some infants were found to have plasma perindoprilat concentrations consistent with pharmacodynamic effects. Perindopril may be used in mothers of healthy term infants, provided the infant is carefully monitored.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/sangue , Leite Humano/química , Perindopril/sangue , Adulto , Aleitamento Materno/efeitos adversos , Feminino , Humanos , Indóis/sangue , Indóis/farmacocinética , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
3.
Eur J Nutr ; 59(3): 1135-1147, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31053882

RESUMO

PURPOSE: The tryptophan-containing dipeptides isoleucine-tryptophan (IW) and tryptophan-leucine (WL) are angiotensin-converting enzyme (ACE)-inhibitors in vitro. These peptides are released by enzymatic hydrolysis of bovine whey protein. To exhibit ACE inhibition in vivo, peptides need to be absorbed into the circulatory system. This study aimed to determine the in vivo ACE-inhibitory potency of a whey protein hydrolysate (MPH), containing IW and WL, and to quantify plasma concentrations of these peptides after oral administration of MPH in healthy volunteers. Additionally, changes in blood pressure were investigated. RESULTS: After intake of 5 and 50 g MPH, plasma ACE activity was reduced to 86.4 ± 5.9 and 75.1 ± 6.9% of baseline activity, respectively. Although a clear ACE inhibition was measured, no effect on blood pressure was seen. Basal plasma concentrations of the tryptophan-containing dipeptides were 2.8 ± 0.7 nM for IW and 10.1 ± 1.8 nM for WL. After intake of 5-50 g MPH, peptide concentrations were dose dependently elevated to values between 12.5 ± 8.4 and 99.1 ± 58.7 nM for IW and 15.0 ± 4.3-34.9 ± 19.4 nM for WL. Administration of intact whey protein showed a minor ACE inhibition, probably caused by release of inhibitory peptides during gastrointestinal digestion. The increase of WL in plasma after intake of intact protein was similar to that determined after intake of MPH. In contrast, resulting IW concentrations were much lower after intake of intact whey protein when compared to MPH administration. CONCLUSION: After intake of MPH, plasma ACE activity decreased in parallel to the increase of IW and WL plasma concentrations. However, the resulting peptide concentrations cannot fully explain the reduction of ACE activity in plasma with a direct enzyme inhibition. Therefore, this study points to a gap in the understanding of the inhibitory action of these peptides in vivo. Thus, to further develop innovative food additives with ACE activity diminishing capabilities, it appears mandatory to better characterize the mode of action of these peptides.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Hidrolisados de Proteína/farmacologia , Triptofano/sangue , Triptofano/farmacologia , Proteínas do Soro do Leite/sangue , Proteínas do Soro do Leite/farmacologia , Adulto , Inibidores da Enzima Conversora de Angiotensina/sangue , Pressão Sanguínea/efeitos dos fármacos , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Hidrolisados de Proteína/sangue , Valores de Referência , Método Simples-Cego
4.
Am J Ther ; 27(4): e366-e370, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31833870

RESUMO

BACKGROUND: Although angiotensin-converting enzyme II inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) improve chronic heart failure (HF) outcomes, their potential harms and benefits in acute HF (AHF) is less clear. STUDY QUESTION: We explored the relationship between ACEI or ARB plasma concentrations among patients with AHF with in-hospital change in estimated glomerular filtration rate (eGFR). DATA SOURCES AND STUDY DESIGN: From August 2016-June 2017, patients with AHF prescribed an outpatient ACEI or ARB were enrolled before AHF treatment. All patients were given twice their home dose of diuretic intravenously and received clinical care at the discretion of the medical team. Of 61 patients in the parent study, saved plasma from 34 who were prescribed an outpatient ACEI or ARB was included in this substudy. MEASURES AND OUTCOMES: Liquid chromatography-tandem mass spectrometry was performed to assess ACEI or ARB plasma concentrations before AHF treatment. Change in eGFR was computed using the Chronic Kidney Disease Epidemiology Collaboration equation, which adjusts for age, sex, and race; diuretic dose and enrollment eGFR were used to adjust for HF severity. Multiple linear regression adjusting for enrollment eGFR and diuretic dose was performed to examine the relationship between drug concentration (undetectable/low vs. in/above-range) and in-hospital change in eGFR. RESULTS: Of 34 patients with AHF, median age was 63 years (interquartile range, 58-78 years), 19 (55.9%) were women, median eGFR at enrollment was 55.6 mL/min (interquartile range, 35.2-75.3 mL/min), and for 11 (32.4%), no ACEI or ARB was detectable in plasma. Medication concentrations in- or above-reference range were associated with in-hospital decrease in eGFR of 8.3 mL/min (95% confidence interval, 15.3-1.3 mL/min decrease), after adjusting for enrollment eGFR and diuretic treatment. CONCLUSIONS: Bioanalytical assessment of medication levels may be useful to guide in-hospital ACEI and ARB therapy for patients with AHF.


Assuntos
Antagonistas de Receptores de Angiotensina/sangue , Inibidores da Enzima Conversora de Angiotensina/sangue , Taxa de Filtração Glomerular/fisiologia , Insuficiência Cardíaca/tratamento farmacológico , Fatores Etários , Idoso , Cromatografia Líquida , Diuréticos/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Modelos Lineares , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Projetos Piloto , Fatores Sexuais
5.
JCI Insight ; 4(5)2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30843885

RESUMO

INTRODUCTION: A local renin-angiotensin system exists in the pulmonary nodules of lymphangioleiomyomatosis patients. Sirolimus, the standard treatment for lymphangioleiomyomatosis, stabilizes lung function, but all patients do not respond to or tolerate sirolimus. As renin-angiotensin systems may affect tumor growth and metastasis, we questioned if angiotensin-converting enzyme inhibitors affected lymphangioleiomyomatosis disease progression. METHODS: Retrospective study of 426 patients was performed, examining angiotensin-converting enzyme levels, pulmonary function data, and angiotensin-converting enzyme inhibitor treatment. RESULTS: Serum angiotensin-converting enzyme levels were elevated in approximately 33% of patients, increased with duration of disease, and were inversely correlated with pulmonary function. Levels decreased significantly over time with sirolimus treatment. Treatment with angiotensin-converting enzyme inhibitors was reported by approximately 15% of patients and was significantly associated with a slower rate of decline in percentage predicted forced expiratory volume (FEV1) and diffusing capacity of the lungs for carbon monoxide (DLCO) in patients not treated with sirolimus. No significant differences in rates of decline of FEV1 or DLCO were seen in patients treated with both inhibitors and sirolimus versus sirolimus alone. CONCLUSIONS: Angiotensin-converting enzyme inhibitors may slow decline of pulmonary function in patients with lymphangioleiomyomatosis not treated with sirolimus. These inhibitors may be an option or adjunct in the treatment of lymphangioleiomyomatosis. A clinical trial may be warranted to examine this possibility. FUNDING: NIH.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Pulmão/efeitos dos fármacos , Linfangioleiomiomatose/tratamento farmacológico , Sirolimo/farmacologia , Inibidores da Enzima Conversora de Angiotensina/sangue , Monóxido de Carbono , Progressão da Doença , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Linfangioleiomiomatose/fisiopatologia , Testes de Função Respiratória , Estudos Retrospectivos
6.
Clin Drug Investig ; 39(5): 485-489, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30805791

RESUMO

Lithium is a well established therapeutic agent in the treatment of uni- and bipolar affective disorders. Angiotensin-converting enzyme (ACE) inhibitors are the most frequently used class of drugs in the treatment of cardiovascular diseases. Combination therapy with both may be considered in clinical practice on occurrence of arterial hypertension after years of successful lithium therapy, yet an increased risk of lithium intoxication in combination with ACE inhibitors has been described and thus the combination has been warned against. We describe three cases in which enalapril, lisinopril or ramipril was combined with lithium. Either additional co-medication with hydrochlorothiazide or dehydration rather than co-medication with ACE inhibitors could be identified as necessary factors for lithium intoxication. These cases suggest that a combination of lithium with ACE inhibitors is possible when sufficient hydration is ensured and a combination with hydrochlorothiazide is avoided. Lithium concentration should be controlled on a regular level.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Transtorno Bipolar/tratamento farmacológico , Carbonato de Lítio/administração & dosagem , Transtornos Psicóticos/tratamento farmacológico , Idoso , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/sangue , Transtorno Bipolar/sangue , Transtorno Bipolar/complicações , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/tratamento farmacológico , Quimioterapia Combinada , Feminino , Humanos , Hipertensão/sangue , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Carbonato de Lítio/efeitos adversos , Carbonato de Lítio/sangue , Masculino , Pessoa de Meia-Idade , Transtornos Psicóticos/sangue , Transtornos Psicóticos/complicações
7.
Eur J Drug Metab Pharmacokinet ; 44(2): 229-236, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30151746

RESUMO

BACKGROUND AND OBJECTIVES: There have been no animal experiments and clinical studies on the pharmacokinetic interaction between rivaroxaban and enalapril. To investigate whether a potential pharmacokinetic interaction is present between rivaroxaban and enalapril, a rapid and sensitive Ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to determine the concentration of rivaroxaban and enalapril in rat plasma and was then applied to a pharmacokinetic interaction study. METHODS: The analytes were separated on an Acquity UPLC BEH C18 chromatography column (2.1 × 50 mm, 1.7 µm) with acetonitrile and 0.1% formic acid as the mobile phase with gradient elution. The mass spectrometer was operated in multiple reaction monitoring mode to monitor the precursor-to-product ion transitions of 436.1 → 145.1 m/z for rivaroxaban, 377.3 → 234.2 m/z for enalapril and 285.2 → 193.1 m/z for diazepam (IS). RESULTS: The method was validated over the concentration range of 1.0-200 ng/mL for rivaroxaban and 0.5-100 ng/mL for enalapril. The intra- and inter-day precision and accuracy of the quality control (QC) samples exhibited relative standard deviations (RSD) < 9.4% and the accuracy values ranged from - 8.3 to 9.6%. After co-administration of rivaroxaban and enalapril, the maximum plasma concentration (Cmax) and area under the systemic drug concentration-time curve from time 0 to infinity (AUC0-∞) of rivaroxaban were significantly increased by 19.6% (p < 0.05) and 21.3% (p < 0.05), respectively. On the contrary, the plasma clearance rate (CL/F) of rivaroxaban and enalapril was significantly decreased by 17.8% (p < 0.05) and 23.8% (p < 0.05), respectively. CONCLUSIONS: The UPLC-MS/MS method was successfully applied to simultaneous determination of rivaroxaban and enalapril in rat plasma and applied to study the pharmacokinetic interaction between rivaroxaban and enalapril. The co-administration of rivaroxaban and enalapril resulted in a significant drug interaction in rats.


Assuntos
Enalapril/sangue , Rivaroxabana/sangue , Espectrometria de Massas em Tandem/métodos , Inibidores da Enzima Conversora de Angiotensina/sangue , Inibidores da Enzima Conversora de Angiotensina/farmacocinética , Animais , Cromatografia Líquida de Alta Pressão/métodos , Relação Dose-Resposta a Droga , Interações Medicamentosas/fisiologia , Enalapril/farmacocinética , Inibidores do Fator Xa/sangue , Inibidores do Fator Xa/farmacocinética , Masculino , Ratos , Ratos Sprague-Dawley , Rivaroxabana/farmacocinética
8.
Artigo em Inglês | MEDLINE | ID: mdl-29783197

RESUMO

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 (n = 3), in addition to one α1-selective alpha blocker. METHOD: A 200 µL serum sample was handled automatically using a pipetting robot. Protein precipitation was performed with 600 µL 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 µm) 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 µg/L. The stability of the drugs in serum at different conditions was tested. Diltiazem was not stable at 4-8 °C with up to 23.5 % 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 , Soro
9.
Nutrition ; 51-52: 66-72, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29605766

RESUMO

OBJECTIVES: We aimed to evaluate whether long-term treatment with the soluble non-bacterial fraction of kefir affects mean arterial pressure (MAP) and cardiac hypertrophy through the modulation of baroreflex sensitivity, ACE activity, and the inflammatory-to-anti-inflammatory cytokine ratio in spontaneously hypertensive rats (SHRs). METHODS: SHRs were treated with the soluble non-bacterial kefir fraction (SHR-kefir) or with kefir vehicle (SHR-soluble fraction of milk). Normotensive control Wistar Kyoto animals received the soluble fraction of milk. All treatments were administered by gavage (0.3 mL/100g/body weight), once daily for eight weeks. At the end, after basal MAP and Heart Rate (HT) measurement, barorreflex sensitivity was evaluated through in bolus administrations of sodium nitroprusside and phenylephrine (AP50 [arterial pressure 50%], the lower plateau, and HR range were measured). ACE activity and cytokines (TNF-α and IL-10) were evaluated by ELISA. Cardiac hypertrophy was analysed morphometrically. RESULTS: Compared to SHR control, SHR-kefir exhibited a significant decrease in both MAP (SHR: 184 ± 5; SHR-Kefir: 142 ± 8 mmHg), and HR (SHR: 360 ± 10; SHR-kefir: 310 ± 14 bpm). The non-bacterial fraction of kefir also reduced cardiac hypertrophy, TNF-α-to-IL10 ratio, and ACE activity in SHRs. SHR-kefir baroreflex sensitivity, resulted in a partial but significant recovery of baroreflex gain, as demonstrated by improvements in AP50, the lower plateau, and HR range. CONCLUSION: In summary, our results indicate that long-term administration of the non-bacterial fraction of kefir promotes a significant decrease in both MAP and HR, by improving baroreflex, and reduces cardiac hypertrophy in SHRs, likely via ACE inhibition, and reduction of the TNF-α-to-IL10 ratio.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/sangue , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Cardiomegalia/dietoterapia , Hipertensão/dietoterapia , Kefir , Animais , Cardiomegalia/sangue , Modelos Animais de Doenças , Frequência Cardíaca , Hipertensão/sangue , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
10.
Clin Interv Aging ; 12: 1753-1760, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29089749

RESUMO

BACKGROUND: The goal of this study was to assess whether angiotensin-converting enzyme (ACE) activity is related to muscle function (strength, power and velocity), as well as to assess if ACE inhibitors (ACEIs) and other angiotensin system blocking medications (ASBMs) influence muscle performance in elderly women. SUBJECTS AND METHODS: Ninety-five community-dwelling elderly women took part in this study. Anthropometric data, blood ACE activity analysis, maximum power (Pmax) and optimal shortening velocity (υopt) of the knee extensor muscles, handgrip strength, physical activity (PA) and functional performance were measured. RESULTS: Women taking ACEI were on average almost 2 years older than the women who did not take ACEI. They took more medicines and were also characterized by significantly lower level of ACE, but they did not differ in terms of PA level, results of functional performance and parameters characterizing muscle functions. No correlations of ACE activity with Pmax and handgrip strength, as well as with PA or functional performance were found. Higher ACE activity was connected with lower υopt for women who did not take any ASBMs (rho =-0.37; p=0.01). CONCLUSION: Serum ACE activity was not associated with muscle strength, power and functional performance in both ASBM users and nonusers, but was associated with optimal shortening velocity of quadriceps muscles in older women. Further prospective studies are needed to assess if ACEIs or other ASBMs may slow down the decline in muscle function and performance.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Força Muscular/efeitos dos fármacos , Músculo Quadríceps/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Inibidores da Enzima Conversora de Angiotensina/sangue , Pesos e Medidas Corporais , Exercício Físico/fisiologia , Feminino , Força da Mão/fisiologia , Humanos , Vida Independente , Articulação do Joelho/efeitos dos fármacos , Pessoa de Meia-Idade , Estudos Prospectivos
11.
Anal Bioanal Chem ; 409(26): 6141-6148, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28842738

RESUMO

A first of its kind, simple, rapid, and sensitive liquid chromatography mass spectrometry (LC-MS/MS) method was developed and validated for quantification of perindopril and perindoprilat in both human plasma and breast milk. The analytes and internal standards (phenazone and acetyl salicylic acid) were extracted from biological matrices by protein precipitation. A Phenomenex® C-18 column was used to provide an appropriate chromatographic separation of the analytes, followed by detection with tandem mass spectrometry. Gradient chromatographic and mass spectrometric detection conditions with mobile phases (A: 5% methanol + 0.1% formic acid in water v/v, and B: 95% methanol + 0.1% formic acid in water v/v) were developed to achieve a LOQ of 0.5 ng/mL in both human plasma and milk. The method was suitable of evaluating clinical samples. The mass transition was followed as m/z 369.10/172.00 for perindopril, m/z 339.00/168.10 for perindoprilat, m/z 188.90/55.95 for phenazone, and m/z 179.04/137.02 for acetyl salicylic acid. The developed method was optimized and validated with a linear range of 0.1-200 ng/mL (r 2 = better than 0.99 for both perindopril and perindoprilat). The precision and accuracy values were within 15% CV. The overall recovery of the analytes was 80-110%. The method has good specificity and repeatability. Stability studies were conducted in both human plasma and bovine milk for up to 3 months, at the storage conditions of 25, 4, and -80 °C.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/análise , Inibidores da Enzima Conversora de Angiotensina/sangue , Indóis/análise , Indóis/sangue , Leite Humano/química , Perindopril/análise , Perindopril/sangue , Aleitamento Materno , Cromatografia Líquida/economia , Cromatografia Líquida/métodos , Feminino , Humanos , Limite de Detecção , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/economia , Espectrometria de Massas em Tandem/métodos
12.
Pak J Pharm Sci ; 30(2(Suppl.)): 635-639, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28650333

RESUMO

The contemporary work describes a rapid and cost effective reversed phase High Performance Liquid Chromatography (RP-HPLC) method for the quantification of Captopril, Lisinopril and Dexibuprofen (DXP) simultaneously in dosage formulations, active pharmaceutical ingredients and human serum. The chromatographic system included LC-20A pump, Sil-20A auto sampler and SPD-20A UV/visible detector. The estimation was carried out by using a C18 (5µm, 250 ×4.6 mm) column with mobile phase methanol: water (80:20 v/v, pH 3.0) at 230 nm with a flow rate of 1.0 ml•min-1. The retention time of Dexibuprofen was 5.4 min while that of Captopril and Lisinopril were found to be 3.2 and 1.8 minutes respectively. There was no considerable variation exists in between the tested drug spiked in serum and the extent recovered, without interference of serum in concurrent approximation. The method developed was found to be precise, selective and validated for precision, linearity, specificity, accuracy, limit of detection and limit of quantitation. There is no such method reported earlier for the determination of ACE Inhibitors and DXP simultaneously. The present study helps in assessing the co-administration of both drugs in treatment and can be employed for quality control analysis and drug-drug interaction studies.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/análise , Inibidores da Enzima Conversora de Angiotensina/sangue , Captopril/análise , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia de Fase Reversa/métodos , Ibuprofeno/análogos & derivados , Lisinopril/análise , Anti-Inflamatórios não Esteroides/análise , Anti-Inflamatórios não Esteroides/sangue , Captopril/sangue , Humanos , Ibuprofeno/análise , Ibuprofeno/sangue , Limite de Detecção , Lisinopril/sangue , Comprimidos
13.
Appl Opt ; 56(11): E58-E63, 2017 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-28414342

RESUMO

In this work, a combined flow injection-photo thermal lens microscopy (FI-PTLM) system was used for highly sensitive determination of captopril as an angiotensin-converting enzyme inhibitor. Captopril has no absorption in the visible range, but due to its thiol group could interact with gold nanoparticles (GNPs). GNPs, because of their surface plasmon resonance (SPR), have absorption in the visible range, but their interaction with a low concentration of captopril shows no effective change in UV-Vis spectrophotometry because their aggregation is slight. On the contrary, at the same condition, the PTLM with a visible light source enables sensitive measurement of this compound. The thiol group of captopril binds to the surface of GNPs and decreases the SPR. At the optimum condition in the focal volume of 2.68 fL (f=10-15), the obtained range of linearity was 50-800 nM. The developed method was successfully applied for the determination of captopril in human serum and pharmaceutical samples.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/análise , Captopril/análise , Ouro , Nanopartículas Metálicas/análise , Microscopia Eletrônica de Transmissão , Inibidores da Enzima Conversora de Angiotensina/sangue , Inibidores da Enzima Conversora de Angiotensina/química , Captopril/sangue , Captopril/química , Desenho de Equipamento , Humanos , Lentes , Luz , Nanopartículas Metálicas/química , Espectrofotometria/instrumentação , Espectrofotometria/métodos , Ressonância de Plasmônio de Superfície , Comprimidos/química
14.
Res Vet Sci ; 114: 117-122, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28371693

RESUMO

Pharmacokinetic and pharmacodynamic (PK/PD) properties of the angiotensin-converting enzyme inhibitor (ACEI) benazeprilat have not been evaluated in horses. This study was designed to establish PK profiles for benazepril and benazeprilat after intravenous (IV) and oral (PO) administration of benazepril using a PK/PD model. This study also aims to determine the effects of benazeprilat on serum angiotensin converting enzyme (ACE), selecting the most appropriate dose that suppresses ACE activity. Six healthy horses in a crossover design received IV benazepril at 0.50mg/kg and PO at doses 0 (placebo), 0.25, 0.50 and 1.00mg/kg. Blood pressures (BP) were measured and blood samples were obtained at different times in order to measure serum drug concentrations and serum ACE activity, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and spectrophotometry, respectively. Systemic bioavailability of benazeprilat after PO benazepril was 3-4%. Maximum ACE inhibitions from baseline were 99.63% (IV benazepril), 6.77% (placebo) and 78.91%, 85.74% and 89.51% (for the three PO benazepril doses). Significant differences in BP were not found. Although oral availability was low, benazeprilat 1.00mg/kg, reached sufficient serum concentrations to induce long lasting serum ACE inhibitions (between 88 and 50%) for the first 48h. Additional research on benazepril administration in equine patients is indicated.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacocinética , Benzazepinas/sangue , Benzazepinas/farmacocinética , Cavalos/sangue , Administração Intravenosa , Administração Oral , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/sangue , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Animais , Benzazepinas/metabolismo , Benzazepinas/farmacologia , Disponibilidade Biológica , Estudos Cross-Over , Cavalos/metabolismo , Masculino
15.
J Feline Med Surg ; 19(6): 706-709, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26927816

RESUMO

Objectives The aims of this study were to investigate the pharmacodynamics of alacepril and to determine the appropriate dose for clinical usage in cats. Methods Six experimental cats were used. Each cat received alacepril orally at a single dose of 1 mg/kg, 2 mg/kg and 3 mg/kg. Blood samples were collected before administration and at 2, 4, 6, 8, 12, 24, 36, 48 and 72 h after administration to measure serum angiotensin converting enzyme (ACE) activity. Systolic blood pressure was also measured at the same time point. Results Dose-dependent inhibition of ACE activity was observed. Doses of 2 mg/kg and 3 mg/kg alacepril were considered to effectively inhibit ACE activity. There were no significant differences in systolic blood pressue among groups at any time point. Conclusions and relevance Alacepril 2-3 mg/kg q24h may be an appropriate dosage for clinical use in cats.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Captopril/análogos & derivados , Gatos/sangue , Administração Oral , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/sangue , Animais , Pressão Sanguínea/efeitos dos fármacos , Captopril/administração & dosagem , Captopril/sangue , Captopril/farmacologia , Gatos/fisiologia , Estudos Cross-Over , Relação Dose-Resposta a Droga , Feminino , Masculino , Peptidil Dipeptidase A/sangue
16.
Ter Arkh ; 89(12): 97-102, 2017.
Artigo em Russo | MEDLINE | ID: mdl-29411767

RESUMO

AIM: To investigate the plasma concentrations of cytokines and vasoactive molecules in patients with coronary heart disease (CHD) in the presence of hypertension in relation to the angiotensin-converting-enzyme (ACE) inhibitor level reflecting the degree of renin-angiotensin-aldosterone system (RAAS) inhibition. SUBJECTS AND METHODS: 72 patients with NYHA functional class (FC) II-III angina pectoris and 40 healthy persons at the age of 47-65 years were examined in a controlled cohort study. Enzyme immunoassay was employed to determine the serum concentrations of interleukins (IL) (IL-2, IL-12, IL-17A, and IL-24), the vasoactive molecules of bradykinin, serotonin, ACE, angiotensin-II (AT-II), NO, and endothelin-1 (ET-1), and plasma renin activity. In addition, the plasma level of the tetrapeptide N-acetyl-Ser-Asp-Lys-Pro was used as a marker for ACE inhibition. RESULTS: The patients with CHD occurring in the presence of hypertension compared with the apparently healthy individuals displayed decreased ET-1 and NO production along with elevated levels of serotonin, AT-II, as well as IL-17A and IL-12. The found changes were accompanied by reduced renin activity. Thus, the individuals with low ACE inhibitor levels showed more pronounced production of the proinflammatory cytokine IL-17A, as well as high plasma concentrations of ACE and NO. The high ACE inhibitor level that reflects patient adherence to appropriate antihypertensive therapy is associated with the reduced production of IL-2 and with the minimum serum levels of ACE, AT-II, and NO, being characterized by the high production of IL-12 and serotonin at the same time. CONCLUSION: In patients with CHD and hypertension, the high plasma enzyme inhibitor concentration that reflects the activity of appropriate antihypertensive therapy, by contributing to the strengthening of the mechanisms of relaxation of blood vessels, is associated with the risk for proinflammatory activation of whole blood cells and platelets. The mean ACE inhibitor levels that reflect moderate RAAS suppression and are characterized by a relatively low proinflammatory activation of mononuclear cells may be more preferable than the maximum ones, from the point of view of slowing the progression of the subclinical inflammatory process of the vascular wall and preventing possible CHD exacerbations. This determines the feasibility of estimating the plasma level of an ACE inhibitor to control the depth of inhibition of RAAS activity.


Assuntos
Inibidores da Enzima Conversora de Angiotensina , Doença das Coronárias/imunologia , Endotelina-1/sangue , Hipertensão , Interleucina-17/sangue , Peptidil Dipeptidase A/sangue , Sistema Renina-Angiotensina , Inibidores da Enzima Conversora de Angiotensina/sangue , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Doença das Coronárias/diagnóstico , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Masculino , Pessoa de Meia-Idade , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Reprodutibilidade dos Testes
17.
Biosens Bioelectron ; 88: 122-129, 2017 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-27499381

RESUMO

In this work, a novel biosensor based on electrochemically reduced graphene oxide and iridium oxide nanoparticles for the detection of angiotensin-converting enzyme inhibitor drug, captopril, is presented. For the preparation of the biosensor, tyrosinase is immobilized onto screen printed electrode by using 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide and N-Hydroxysuccinimide coupling reagents, in electrochemically reduced graphene oxide and iridium oxide nanoparticles matrix. Biosensor response is characterized towards catechol, in terms of graphene oxide concentration, number of cycles to reduce graphene oxide, volume of iridium oxide nanoparticles and tyrosinase solution. The designed biosensor is used to inhibit tyrosinase activity by Captopril, which is generally used to treat congestive heart failure. It is an angiotensin-converting enzyme inhibitor that operates via chelating copper at the active site of tyrosinase and thioquinone formation. The captopril detections using both inhibition ways are very sensitive with low limits of detection: 0.019µM and 0.008µM for chelating copper at the active site of tyrosinase and thioquinone formation, respectively. The proposed methods have been successfully applied in captopril determination in spiked human serum and pharmaceutical dosage forms with acceptable recovery values.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/análise , Inibidores da Enzima Conversora de Angiotensina/sangue , Técnicas Biossensoriais/métodos , Captopril/análise , Captopril/sangue , Grafite/química , Irídio/química , Agaricales/enzimologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Captopril/farmacologia , Técnicas Eletroquímicas/métodos , Enzimas Imobilizadas/química , Humanos , Limite de Detecção , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/química , Nanopartículas/química , Nanopartículas/ultraestrutura , Oxirredução
18.
Appl Physiol Nutr Metab ; 40(10): 1061-7, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26398443

RESUMO

Oxidative stress and inflammation are involved in the development and progression of diabetes and its complications. The renin-angiotensin system also plays an important role in the pathogenesis of diabetes and its complications. We hypothesized that curcumin and captopril would restore the kidney and nerve functions of diabetic rats through their angiotensin converting enzyme 1 (ACE1) inhibiting activity as well as their antioxidant and anti-inflammatory effects. Diabetes was induced by a single intraperitoneal injection of streptozotocin (100 mg·kg(-1) body weight). One week after induction of diabetes, rats were treated with 100 mg·kg(-1)·day(-1) curcumin or 50 mg·kg(-1)·day(-1) captopril orally for 6 weeks. Compared with diabetic control rats, curcumin- or captopril-treated diabetic rats had significantly improved blood glucose, lipid profile, kidney/body weight ratio, serum creatinine, blood urea nitrogen (BUN), and pain thresholds assessed by Von Frey filaments, hot plate test, and tail-flick test. Diabetic control rats showed increased levels of total peroxide, renal and neural tumor necrosis factor-α and interleukin-10, and renal ACE1 compared with nondiabetic rats. Although treatment with either curcumin or captopril restored the altered variables, captopril was more effective in reducing these variables. ACE1 was positively correlated with BUN and creatinine and negatively correlated with paw withdrawal threshold, hot plate reaction time, and tail-flick latency, suggesting a possible causal relationship. We conclude that curcumin and captopril protect against diabetic nephropathy and neuropathy by inhibiting ACE1 as well as oxidation and inflammation. These findings suggest that curcumin and captopril may have a role in the treatment of diabetic nephropathy and neuropathy.


Assuntos
Captopril/farmacologia , Curcumina/farmacologia , Nefropatias Diabéticas/tratamento farmacológico , Rim/efeitos dos fármacos , Rim/fisiopatologia , Peptidil Dipeptidase A/farmacologia , Inibidores da Enzima Conversora de Angiotensina/sangue , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Anti-Inflamatórios não Esteroides/sangue , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Glicemia/efeitos dos fármacos , Nitrogênio da Ureia Sanguínea , Captopril/sangue , Creatinina/sangue , Diabetes Mellitus Experimental , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/fisiopatologia , Inflamação/sangue , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Lipídeos/sangue , Masculino , Estresse Oxidativo/efeitos dos fármacos , Peptidil Dipeptidase A/sangue , Ratos , Ratos Wistar
19.
Blood Purif ; 40(3): 232-42, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26382240

RESUMO

BACKGROUND/AIMS: Some angiotensin converting enzyme (ACE) inhibitors are efficiently removed from circulation by hemodialysis ('high dialyzability'), whereas others are not ('low dialyzability'). In patients receiving hemodialysis, this may influence the effectiveness of ACE inhibitors. METHODS: Using linked healthcare databases we identified older patients receiving chronic hemodialysis who filled new ACE inhibitor prescriptions. The low dialyzability group (n = 3,369) included fosinopril and ramipril. The high dialyzability group (n = 5,974) included enalapril, lisinopril, and perindopril. The primary outcome was all-cause mortality within 180 days of first ACE inhibitor prescription. RESULTS: There were 361 deaths among 5,974 patients (6.0%) prescribed with low dialyzability ACE inhibitors and 179 deaths among 3,369 patients (5.3%) prescribed with high dialyzability ACE inhibitors (relative risk 1.1, 95% CI 0.9-1.3, p = 0.6). CONCLUSION: In this study of older patients receiving hemodialysis, the dialyzability of ACE inhibitors was not associated with mortality or cardiovascular outcomes.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Cardiotônicos/uso terapêutico , Doenças Cardiovasculares/sangue , Falência Renal Crônica/sangue , Diálise Renal/métodos , Idoso , Idoso de 80 Anos ou mais , Inibidores da Enzima Conversora de Angiotensina/sangue , Inibidores da Enzima Conversora de Angiotensina/farmacocinética , Cardiotônicos/sangue , Cardiotônicos/farmacocinética , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/terapia , Enalapril/sangue , Enalapril/farmacocinética , Enalapril/uso terapêutico , Feminino , Fosinopril/sangue , Fosinopril/farmacocinética , Fosinopril/uso terapêutico , Hemorreologia , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/mortalidade , Falência Renal Crônica/terapia , Rins Artificiais , Lisinopril/sangue , Lisinopril/farmacocinética , Lisinopril/uso terapêutico , Masculino , Pessoa de Meia-Idade , Perindopril/sangue , Perindopril/farmacocinética , Perindopril/uso terapêutico , Ramipril/sangue , Ramipril/farmacocinética , Ramipril/uso terapêutico , Diálise Renal/instrumentação , Estudos Retrospectivos , Análise de Sobrevida
20.
Br J Clin Pharmacol ; 80(5): 1131-8, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25919042

RESUMO

AIM: The aim of the present study was to investigate the effects of the carboxylesterase 1 (CES1) c.428G > A (p.G143E, rs71647871) single nucleotide variation (SNV) on the pharmacokinetics of quinapril and enalapril in a prospective genotype panel study in healthy volunteers. METHODS: In a fixed-order crossover study, 10 healthy volunteers with the CES1 c.428G/A genotype and 12 with the c.428G/G genotype ingested a single 10 mg dose of quinapril and enalapril with a washout period of at least 1 week. Plasma concentrations of quinapril and quinaprilat were measured for up to 24 h and those of enalapril and enalaprilat for up to 48 h. Their excretion into the urine was measured from 0 h to 12 h. RESULTS: The area under the plasma concentration-time curve from 0 h to infinity (AUC0-∞) of active enalaprilat was 20% lower in subjects with the CES1 c.428G/A genotype than in those with the c.428G/G genotype (95% confidence interval of geometric mean ratio 0.64, 1.00; P = 0.049). The amount of enalaprilat excreted into the urine was 35% smaller in subjects with the CES1 c.428G/A genotype than in those with the c.428G/G genotype (P = 0.044). The CES1 genotype had no significant effect on the enalaprilat to enalapril AUC0-∞ ratio or on any other pharmacokinetic or pharmacodynamic parameters of enalapril or enalaprilat. The CES1 genotype had no significant effect on the pharmacokinetic or pharmacodynamic parameters of quinapril. CONCLUSIONS: The CES1 c.428G > A SNV decreased enalaprilat concentrations, probably by reducing the hydrolysis of enalapril, but had no observable effect on the pharmacokinetics of quinapril.


Assuntos
Hidrolases de Éster Carboxílico/genética , Enalapril/farmacocinética , Polimorfismo de Nucleotídeo Único/genética , Tetra-Hidroisoquinolinas/farmacocinética , Adulto , Inibidores da Enzima Conversora de Angiotensina/sangue , Inibidores da Enzima Conversora de Angiotensina/farmacocinética , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/urina , Pressão Sanguínea/efeitos dos fármacos , Estudos Cross-Over , Enalapril/sangue , Enalapril/farmacologia , Enalapril/urina , Enalaprilato/sangue , Enalaprilato/urina , Feminino , Genótipo , Voluntários Saudáveis , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Quinapril , Tetra-Hidroisoquinolinas/sangue , Tetra-Hidroisoquinolinas/farmacologia , Tetra-Hidroisoquinolinas/urina , Adulto Jovem
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