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1.
J Biol Chem ; 299(11): 105313, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37797695

RESUMO

Effective and safe therapies for the treatment of diseases caused by intraerythrocytic parasites are impeded by the rapid emergence of drug resistance and the lack of novel drug targets. One such disease is human babesiosis, which is a rapidly emerging tick-borne illness caused by Babesia parasites. In this study, we identified fosinopril, a phosphonate-containing, FDA-approved angiotensin converting enzyme (ACE) inhibitor commonly used as a prodrug for hypertension and heart failure, as a potent inhibitor of Babesia duncani parasite development within human erythrocytes. Cell biological and mass spectrometry analyses revealed that the conversion of fosinopril to its active diacid molecule, fosinoprilat, is essential for its antiparasitic activity. We show that this conversion is mediated by a parasite-encoded esterase, BdFE1, which is highly conserved among apicomplexan parasites. Parasites carrying the L238H mutation in the active site of BdFE1 failed to convert the prodrug to its active moiety and became resistant to the drug. Our data set the stage for the development of this class of drugs for the therapy of vector-borne parasitic diseases.


Assuntos
Babesia , Parasitos , Pró-Fármacos , Animais , Humanos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Fosinopril/farmacologia , Pró-Fármacos/farmacologia , Esterases/metabolismo
2.
Cochrane Database Syst Rev ; 2: CD005128, 2023 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-36853224

RESUMO

BACKGROUND: IgA vasculitis (IgAV), previously known as Henoch-Schönlein purpura, is the most common vasculitis of childhood but may also occur in adults. This small vessel vasculitis is characterised by palpable purpura, abdominal pain, arthritis or arthralgia and kidney involvement. This is an update of a review first published in 2009 and updated in 2015. OBJECTIVES: To evaluate the benefits and harms of different agents (used singularly or in combination) compared with placebo, no treatment or any other agent for (1) the prevention of severe kidney disease in people with IgAV with or without kidney involvement at onset, (2) the treatment of established severe kidney disease (macroscopic haematuria, proteinuria, nephritic syndrome, nephrotic syndrome with or without acute kidney failure) in IgAV, and (3) the prevention of recurrent episodes of IgAV-associated kidney disease. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 2 February 2023 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing interventions used to prevent or treat kidney disease in IgAV compared with placebo, no treatment or other agents were included. DATA COLLECTION AND ANALYSIS: Two authors independently determined study eligibility, assessed the risk of bias and extracted data from each study. Statistical analyses were performed using the random-effects model, and the results were expressed as risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: Twenty studies (1963 enrolled participants) were identified; one three-arm study has been assessed as two studies. Nine studies were at low risk of bias for sequence generation (selection bias), and nine studies were at low risk of bias for allocation concealment (selection bias). Blinding of participants and personnel (performance bias) and outcome assessment (detection bias) was at low risk of bias in four and seven studies, respectively. Nine studies reported complete outcome data (attrition bias), while 10 studies reported expected outcomes, so were at low risk of reporting bias. Five studies were at low risk of other bias. Eleven studies evaluated therapy to prevent persistent kidney disease in IgAV with or without kidney involvement at presentation. There was probably no difference in the risk of persistent kidney disease any time after treatment (5 studies, 746 children: RR 0.74, 95% CI 0.42 to 1.32) or at one, three, six and 12 months in children given prednisone for 14 to 28 days at presentation of IgAV compared with placebo or supportive treatment (moderate certainty evidence). There may be no differences in the risk of any persistent kidney disease with antiplatelet therapy (three studies) or heparin (two studies) in children with or without any kidney disease at study entry, although heparin may reduce the risk of proteinuria by three months compared with placebo or no specific treatment (2 studies, 317 children: RR 0.47, 95% CI 0.31 to 0.73). One study comparing montelukast with placebo found no differences in outcomes as assessed by severity scale scores. Nine studies examined the treatment of severe IgAV-associated kidney disease. In two studies (one involving 56 children and the other involving 54 adults), there may be no differences in efficacy outcomes or adverse effects with cyclophosphamide compared with placebo or supportive treatment. In two studies, there may be no differences in the numbers achieving remission of proteinuria with intravenous (IV) cyclophosphamide compared with mycophenolate mofetil (MMF) (65 children evaluated) or tacrolimus (142 children evaluated). In three small studies comparing cyclosporin with methylprednisolone (15 children), MMF with azathioprine (26 children), or MMF with leflunomide (19 children), it is unclear whether the treatment had any effect on the numbers in remission or the degree of proteinuria between treatment groups because of small numbers of included participants. In one study comparing plasmapheresis, cyclophosphamide and methylprednisolone with cyclophosphamide and methylprednisolone, there may be no difference in the numbers achieving remission. One study compared fosinopril with no specific therapy and reported fosinopril reduced the number of participants with proteinuria. No studies were identified that evaluated the efficacy of therapy on kidney disease in participants with recurrent episodes of IgAV. AUTHORS' CONCLUSIONS: There are no substantial changes in conclusions from this update compared with the initial review or the previous update despite the addition of five studies. From generally low to moderate certainty evidence, we found that there may be little or no benefit in the use of corticosteroids or antiplatelet agents to prevent persistent kidney disease in children with IgAV in participants with no or minimal kidney involvement at presentation. We did not find any studies which evaluated corticosteroids in children presenting with IgAV and nephritic and/or nephrotic syndrome, although corticosteroids are recommended in such children in guidelines. Though heparin may be effective in reducing proteinuria, this potentially dangerous therapy is not justified to prevent serious kidney disease when few children with IgAV develop severe kidney disease. There may be no benefit of cyclophosphamide compared with no specific treatment or corticosteroids. While there may be no benefit in the efficacy of MMF or tacrolimus compared with IV cyclophosphamide in children or adults with IgAV and severe kidney disease, adverse effects, particularly infections, may be lower in MMF or tacrolimus-treated children. Because of small patient numbers and events leading to imprecision in results, it remains unclear whether cyclosporin, MMF or leflunomide have any role in the treatment of children with IgAV and severe kidney disease. We did not identify any studies which evaluated corticosteroids.


Assuntos
Vasculite por IgA , Nefropatias , Vasculite , Adulto , Criança , Humanos , Fosinopril , Vasculite por IgA/complicações , Vasculite por IgA/tratamento farmacológico , Leflunomida , Proteinúria , Tacrolimo
3.
Sci Rep ; 12(1): 19160, 2022 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-36357407

RESUMO

Renal fibrosis (RF) is the common pathway for a variety of chronic kidney diseases that progress to end-stage renal disease. Chitosan oligosaccharide (COS) has been identified as possessing many health functions. However, it is not clear whether COS can prevent RF. The purpose of this paper was to explore the action and mechanism of COS in alleviating RF. First, an acute unilateral ureteral obstruction operation (UUO) in male BALB/c mice was performed to induce RF, and COS or fosinopril (positive control drug) were administered for 7 consecutive days. Data from our experiments indicated that COS treatment can significantly alleviate kidney injury and decrease the levels of blood urea nitrogen (BUN) and serum creatinine (SCr) in the UUO mouse model. More importantly, our results show that COS can reduce collagen deposition and decrease the expression of fibrosis proteins, such as collagen IV, fibronectin, collagen I, α-smooth muscle actin (α-SMA) and E-cadherin, ameliorating experimental renal fibrosis in vivo. In addition, we also found that COS suppressed oxidative stress and inflammation in RF model mice. Further studies indicated that the mechanism by which COS alleviates renal fibrosis is closely related to the regulation of the TGF-ß1/Smad pathway. COS has a therapeutic effect on ameliorating renal fibrosis similar to that of the positive control drug fosinopril. Taken together, COS can alleviate renal fibrosis induced by UUO by reducing oxidative stress damage and regulating the TGF-ß1/Smad pathway.


Assuntos
Quitosana , Nefropatias , Insuficiência Renal Crônica , Obstrução Ureteral , Masculino , Camundongos , Animais , Fator de Crescimento Transformador beta1/metabolismo , Quitosana/metabolismo , Fosinopril/farmacologia , Fibrose , Nefropatias/tratamento farmacológico , Nefropatias/etiologia , Nefropatias/metabolismo , Obstrução Ureteral/complicações , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/metabolismo , Rim/metabolismo , Insuficiência Renal Crônica/patologia , Camundongos Endogâmicos BALB C , Estresse Oxidativo , Oligossacarídeos/metabolismo
4.
J Hypertens ; 40(10): 1909-1917, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35881420

RESUMO

AIM: Little evidence is available on whether antihypertensive treatment lowers cardiovascular risk in white-coat hypertension (WCH). Protection might be indirectly inferred, however, from the blood pressure (BP) effects of treatment as in trials BP reduction is linearly related to outcome reduction. We analyzed the effect of antihypertensive treatment on office and ambulatory BP in WCH using data from the Plaque HYpertension Lipid-Lowering Italian Study (PHYLLIS). METHODS: : Office and ambulatory blood pressure were measured in 470 hypertensive patients randomized to fosinopril or hydrochlorothiazide alone or combined with a statin before treatment and at 6 month or yearly intervals during 2.6 years of follow-up. Patients were divided into two groups according to whether before randomization to treatment office and 24-h mean BP were elevated (sustained hypertension) or office BP was elevated but 24-h BP values were normal (WCH). RESULTS: : In both sustained hypertension and WCH antihypertensive treatment was associated with an early marked office BP reduction, which persisted virtually unchanged throughout the treatment period. In contrast, 24-h (and day and night) BP showed a marked and persistent treatment-related fall in sustained hypertension but no change in WCH. The results were similar when data were separately analyzed in patients under fosinopril or diuretic, with or without statin treatment. CONCLUSION: : In WCH, antihypertensive treatment can effectively and durably reduce office BP. This reduction is accompanied by the inability to lower ambulatory BP from the normal values characterizing this condition at baseline. This appears to be unrelated to the type of treatment employed.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Hipertensão , Hipertensão do Jaleco Branco , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/fisiologia , Monitorização Ambulatorial da Pressão Arterial , Fosinopril/farmacologia , Fosinopril/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipertensão/tratamento farmacológico , Lipídeos , Hipertensão do Jaleco Branco/tratamento farmacológico
5.
Phytomedicine ; 100: 154078, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35405613

RESUMO

BACKGROUND: Zerumbone (ZER) is a humulane sesquiterpene isolated from Syringa pinnatifolia Hemsl., a representative Mongolian herbal medicine that is used to treat cardiovascular diseases. Cardiac fibrosis is a common pathological process in cardiovascular disease that results from the excessive accumulation of extracellular matrix (ECM), and the transforming growth factor (TGF)-ß/Smad pathway is a canonical signaling pathway that directly induces expressions of ECM-related genes. Currently, the cardioprotective effect and underlying mechanisms of ZER on the inhibition of cardiac fibrosis are not well known. PURPOSE: To explore the cardioprotective properties and pharmacological mechanism of ZER against cardiac fibrosis via the TGF-ß1/Smad signaling pathway. METHODS: Myocardial infarction (MI) model was induced by ligation of the left anterior descending coronary artery in ICR mice. The mice were randomly divided into six groups: sham, model, low-dose ZER (ZER-L), medium-dose ZER (ZER-M), high-dose ZER (ZER-H) and fosinopril. Mice in each group were intragastrically administered treatments for 21 days, and cardiac function was evaluated by 2D echocardiography. The pathological structure of the heart was examined by hematoxylin and eosin (HE) and Masson staining. Content of collagen I and collagen III were assessed by immunofluorescence methods. The inhibitory effect of ZER on TGF-ß1 protein expression was predicted by molecular docking technology. Reverse transcriptase polymerase chain reaction (RT-PCR) and western blotting were used to measure the levels of genes and proteins expressed in the TGF-ß1/Smad signaling pathway and MMPs. TGF-ß1-treated cardiac fibroblasts (CFs) of neonatal SD rats were adopted for in vitro studies. RESULTS: Cardiac ejection fraction (EF) and fractional shortening (FS) in the model group were markedly decreased compared with those in the sham group, indicating that the MI model was successfully established. ZER and fosinopril elevated EF and FS values, suggesting cardioprotective effects. Pathological staining and immunofluorescence analysis showed that the content of collagen I and collagen III increased in the cardiac tissue of mice in model group, while ZER treatment obviously reduced collagen levels. The molecular docking simulations predicted the hydrophobic interactions between ZER and TGF-ß1. In addition, the expression of TGF-ß1, p-Smad2/3 and MMPs in the ZER treatment group was significantly decreased compared with the model group. In vitro studies further confirmed that α-smooth muscle actin (α-SMA) and p-Smad2/3 increased markedly in cardiac fibroblasts after incubation with TGF-ß1, and treatment with ZER suppressed the expression of α-SMA and TGF-ß1 downstream proteins in cardiac fibroblasts. CONCLUSION: ZER rescues cardiac function by attenuating cardiac fibrosis, and the antifibrotic effect may be mediated by blocking the TGF-ß1/Smad pathway.


Assuntos
Infarto do Miocárdio , Sesquiterpenos , Syringa , Animais , Colágeno Tipo I/metabolismo , Fibrose , Fosinopril/farmacologia , Fosinopril/uso terapêutico , Camundongos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Infarto do Miocárdio/metabolismo , Ratos , Ratos Sprague-Dawley , Sesquiterpenos/farmacologia , Sesquiterpenos/uso terapêutico , Transdução de Sinais , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
6.
J Am Heart Assoc ; 11(7): e023182, 2022 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-35322670

RESUMO

Background Plasma fibroblast growth factor 23 (FGF23) has been reported to be a predictive biomarker for therapeutic effectiveness of angiotensin-converting enzyme inhibitors in heart failure. Higher plasma FGF23 levels have been shown in pediatric primary hypertension, but the predictive value of FGF23 for angiotensin-converting enzyme inhibitors' effectiveness in pediatric primary hypertension has not been documented. Methods and Results This is a prospective study. An exploratory study with 139 patients was first conducted to determine the cutoff value of FGF23 for the prediction of treatment responsiveness. After receiving fosinopril for 4 weeks, of all 139 patients, 91 responded, while 48 did not respond to the treatment, and the responders had a significantly higher baseline plasma FGF23 level than nonresponders (P<0.01). Multiple regression analysis revealed a significant impact of baseline plasma FGF23 levels on fosinopril responsiveness (P<0.05). The receiver operating characteristic curve analysis showed that the plasma FGF23 predicted the effectiveness of fosinopril treatment with an area under the curve of 0.784 (95% CI, 0.704-0.863) for a sensitivity and a specificity of 67.0% and 89.6%, respectively, for a cutoff value of 62.08 RU/mL. Subsequently, another group of 40 patients were recruited for validation. The blood pressure control rate in those (n=22) with baseline plasma FGF23 >62.08 RU/mL was significantly higher than that in children (n=18) with FGF23 ≤62.08 RU/mL (P<0.05). Conclusions Plasma FGF23 might be a valuable biomarker to guide fosinopril therapy for primary hypertension in children.


Assuntos
Fosinopril , Hipertensão , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Criança , Fator de Crescimento de Fibroblastos 23 , Fosinopril/farmacologia , Fosinopril/uso terapêutico , Humanos , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Estudos Prospectivos
7.
Chem Biol Interact ; 347: 109604, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34352275

RESUMO

Angiotensin-converting enzyme (ACE, EC 3.4.15.1) synthesized by endothelial cells and responsible for the regulation of blood pressure was purified from the bovine lung with affinity chromatography method. The purification rate of the ACE of the bovine lung was calculated as 1748- fold. Optimum pH and optimum temperature for the purified ACE were found to be 7.6 and 35-40 °C, respectively. The purity and molecular weight of the ACE were designated with SDS-PAGE. The ACE was found to have three subunits with molecular weights of 57 kDa, 66 kDa, and 190 kDa. Then, the total molecular weight of the ACE was designated as 303 kDa with gel filtration chromatography. The effects of ACE inhibitors captopril, fosinopril, lisinopril, and beta-blockers propranolol, atenolol, and diuretic triamterene on ACE activity were studied. ACE inhibitors lisinopril, captopril, fosinopril, and diuretic triamterene demonstrated an inhibition effect on ACE activity. Beta-blockers indicated no effect on ACE. IC50 values of captopril, fosinopril, lisinopril, and triamterene from the graphical equation were calculated as 0.835 nM, 1.159 µM, 4.085 nM, and 227 µM, respectively. The inhibition type and Ki values of these compounds were determined from Lineweaver-Burk plots. Captopril, fosinopril, lisinopril, and triamterene demonstrated a non-competitive inhibition effect on ACE activity. Ki constants were found as 1.057 nM, 1.675 µM, 6.449 nM, and 419.5 µM, respectively. Captopril indicated the highest inhibitor effect with an IC50 value of 0.835 nM.


Assuntos
Peptidil Dipeptidase A/isolamento & purificação , Inibidores da Enzima Conversora de Angiotensina/química , Animais , Captopril/química , Bovinos , Cromatografia de Afinidade , Fosinopril/química , Concentração de Íons de Hidrogênio , Cinética , Lisinopril/química , Pulmão/química , Peptidil Dipeptidase A/química , Estabilidade Proteica , Temperatura , Triantereno/química
8.
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
9.
Bull Exp Biol Med ; 170(1): 112-117, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33237531

RESUMO

We studied the effects of apoptotic bodies of cardiomyocytes (ApBc) and fibroblasts (ApBf) on myocardial regeneration and contractility in rats and the dynamics of RNA concentrations in cardiomyocytes and fibroblasts at different stages of apoptosis. ApBc increase the contractility of rat myocardium, while ApBf reduce it. ApBc stimulate the development of clones of cardiomyocyte precursors in the myocardium, while ApBf stimulate the formation of endothelial precursor clones. In doxorubicin cardiomyopathy, ApBc, similar to the reference drug (ACE inhibitor) improve animal survival, while ApBf produce no such effect. RNA concentrations in cardiomyocytes and fibroblasts before apoptosis and at the beginning of cell death significantly differed, while in apoptotic bodies of these cells, it was practically the same. It has been hypothesized that RNA complex present in ApBc and ApBf represents an "epigenetic code" of directed differentiation of cardiac stem cells.


Assuntos
Envelhecimento/metabolismo , Cardiomiopatias/metabolismo , Meios de Cultura/farmacologia , Vesículas Extracelulares/metabolismo , Fibroblastos/metabolismo , Miócitos Cardíacos/metabolismo , Células-Tronco/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/patologia , Diferenciação Celular , Células Clonais , Meios de Cultura/química , Doxorrubicina/toxicidade , Vesículas Extracelulares/química , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fosinopril/farmacologia , Masculino , Contração Miocárdica/efeitos dos fármacos , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Cultura Primária de Células , RNA/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos
10.
Medicine (Baltimore) ; 99(39): e22326, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991443

RESUMO

RATIONALE: The most common cardiac involvement of Fabry disease (FD) is left ventricular hypertrophy (LVH), which usually occurs in male patients over the age of 30. In rare cases, it can progress to ventricular dilation in the late stage of the disease. PATIENT CONCERNS: A 16-year-old boy presenting with recurrent extremity pain and chest distress was admitted to our hospital. Imaging examinations revealed ventricular dilation. DIAGNOSIS: α-Galactosidase A enzyme assay and GLA gene sequencing confirmed the diagnosis of FD and revealed a novel mutation c.76_77insT. INTERVENTIONS: The patient was treated using metoprolol (23.75 mg qd) and angiotensin-converting enzyme inhibitor (fosinopril sodium 5 mg qd). He refused enzyme replacement therapy for financial reasons. OUTCOMES: The echocardiography, electrocardiography, renal function, and routine blood and urine tests performed 20 months after the patients discharge from hospital showed no significant changes. The patient reported a slow and gradual decrease in the frequency and degree of pain and chest distress, starting approximately 24 months after discharge. LESSONS: Cardiac involvement of FD can progress rapidly in some cases. Screening for FD should be considered in patients with unexplained ventricular dilation, especially in those with a history of typical FD manifestations.


Assuntos
Dilatação Patológica/diagnóstico por imagem , Doença de Fabry/complicações , Doença de Fabry/genética , Hipertrofia Ventricular Esquerda/etiologia , alfa-Galactosidase/genética , Adolescente , Assistência ao Convalescente , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Ecocardiografia/métodos , Eletrocardiografia/métodos , Terapia de Reposição de Enzimas/economia , Doença de Fabry/tratamento farmacológico , Fosinopril/uso terapêutico , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Masculino , Metoprolol/uso terapêutico , Mutação , Simpatolíticos/uso terapêutico , Resultado do Tratamento
11.
Int Immunopharmacol ; 85: 106686, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32531714

RESUMO

Diabetes mellitus (DM) is a systemic, chronic metabolic disease that is related to heredity and autoimmunity and is often accompanied by complications of retinopathy. However, the causative mechanism involved in the pathological process remains unclear. In this research, treatment with fosinopril or LY2109761 was found to be responsible for the improvement of the pathological processes, serum biochemical indexes and retinopathy in rats with streptozotocin-induced diabetes. In addition, the upregulation of angiotensin-converting enzyme (ACE) in the serum and the increased expression of TGF-ß1 in the pathological outer nuclear layer (ONL) and inner nuclear layer (INL) of the retina were also reduced. In vitro experiments demonstrated that ACE enhanced cell damage and TGF-ß1/Smad signaling pathway activation in retinal capillary endothelial cells (RCECs) under high glucose conditions. In addition, the activity of ACE was also considered to be related to the increasing levels of activated TGF-ß1 in both rat retinal Müller cells (RMCs) and RCECs, but ACE activity had no effect on the high glucose-mediated upregulation of total TGF-ß1 in RMCs. Coculture experiments with RCECs and RMCs showed that the barrier that was established under normal conditions was significantly impaired when exposed to high glucose combined with ACE, and damage of barrier can be prevented by adding fosinopril or LY2109761. Finally, a similar auxiliary effect of ACE was also observed in the activated TGF-ß1-mediated barrier damage in blood-retinal barrier model in vitro. In summary, ACE-mediated TGF-ß1/Smad signaling pathway activation was found to be involved in the destruction of the blood-retina barrier during diabetic retinopathy in a model of streptozotocin-induced diabetes, and these data may provide evidence to guide the treatment of the complications of diabetes mellitus.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Retinopatia Diabética/metabolismo , Peptidil Dipeptidase A/metabolismo , Retina/patologia , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Células Cultivadas , Técnicas de Cocultura , Diabetes Mellitus Experimental/patologia , Retinopatia Diabética/patologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Ependimogliais/efeitos dos fármacos , Células Ependimogliais/metabolismo , Fosinopril/farmacologia , Fosinopril/uso terapêutico , Masculino , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Ratos , Ratos Sprague-Dawley , Retina/efeitos dos fármacos , Retina/metabolismo , Transdução de Sinais/efeitos dos fármacos
12.
Naunyn Schmiedebergs Arch Pharmacol ; 393(9): 1649-1658, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32377771

RESUMO

The study aimed to investigate the effects of the sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin on chronic heart failure (HF) in normoglycemic rats. The effects of empagliflozin were compared with the standard medications for HF, e.g., angiotensin-converting enzyme (ACE) inhibitor fosinopril, beta-blocker bisoprolol, and aldosterone antagonist spironolactone. Myocardial infarction (MI) was induced in male Wistar rats via permanent ligation of the left descending coronary artery. One-month post MI, 50 animals were randomized into 5 groups (n = 10): vehicle-treated, empagliflozin (1.0 mg/kg), fosinopril (10 mg/kg), bisoprolol (10 mg/kg), and spironolactone (20 mg/kg). All medications except empagliflozin were titrated within a month and administered per os daily for 3 months. Echocardiography, 24-hour urine volume test, and treadmill exercise tests were performed at the beginning and at the end of the study. Treatment with empagliflozin slowed the progression of left ventricular dysfunction: LV sizes and ejection fraction were not changed and the minute volume was significantly increased (from 52.0 ± 15.5 to 61.2 ± 21.2 ml/min) as compared with baseline. No deaths occurred in empagliflozin group. The 24-hour urine volume tends to be higher in empagliflozin and spironolactone groups than in vehicle and fosinopril group. Moreover, empagliflozin exhibited maximal physical exercise tolerance in comparison with all investigated groups (289 ± 27 s versus 183 ± 61 s in fosinopril group, 197 ± 95 s in bisoprolol group, and 47 ± 46 s in spironolactone group, p = 0.0035 for multiple comparisons). Sodium-glucose co-transporter 2 inhibitor empagliflozin reduced progression of left ventricular dysfunction and improved tolerance of physical exercise in normoglycemic rats with HF. Empagliflozin treatment was superior with respect to physical tolerance compared with fosinopril, bisoprolol, and spironolactone.


Assuntos
Compostos Benzidrílicos/farmacologia , Fármacos Cardiovasculares/farmacologia , Tolerância ao Exercício/efeitos dos fármacos , Glucosídeos/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Infarto do Miocárdio/complicações , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Disfunção Ventricular Esquerda/tratamento farmacológico , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Bisoprolol/farmacologia , Doença Crônica , Modelos Animais de Doenças , Fosinopril/farmacologia , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Masculino , Ratos Wistar , Espironolactona/farmacologia , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/fisiopatologia
13.
J Biol Regul Homeost Agents ; 34(1): 57-67, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32466632

RESUMO

Klotho is a putative aging suppressor gene that is primarily expressed in renal tubular epithelial cells. Its expression has been reported to protect against fibrosis in human chronic kidney disease. However, the roles of klotho in epithelial-mesenchymal transition (EMT) and renal fibrosis are yet to be elucidated. The present study aimed to investigate the putative roles of klotho in angiotensin (Ang) II-induced damage of renal tubular epithelial cells. NRK-52E rat cells were treated with various combinations of Ang II, the Ang-converting enzyme inhibitor fosinopril (Fos) and the Ang II receptor antagonist valsartan (Val). The levels of transforming growth factor (TGF)-ß1, soluble klotho, α-smooth muscle actin (α-SMA) and E-cadherin in NRK-52E culture supernatants were measured using enzyme-linked immunosorbent assays. Furthermore, the mRNA and protein expression of TGF-ß1, klotho, α-SMA and E-cadherin was detected using semiquantitative reverse transcription-polymerase chain reaction, immunocytochemistry and Western blot analysis. The results demonstrated that Ang II inhibited the expression of klotho and E-cadherin, while it upregulated the expression of TGF-ß1 and α-SMA, in NRK52E cells. Fos and/or Val were revealed to enhance klotho and E-cadherin expression, and suppress the expression of TGF-ß1 and α-SMA, compared with the Ang II-only group. Furthermore, a positive linear correlation was detected between the expression of klotho and E-cadherin, while negative linear correlations with klotho expression were detected for TGF-ß1 and α-SMA expression. In conclusion, the expression of klotho was demonstrated to be enhanced following treatment with Fos and Val in Ang II-treated NRK-52E cells. The present results indicate that klotho may be involved in the inhibition of Ang II-induced EMT in renal tubular epithelial cells. Therefore, klotho may serve as a protective factor in renal tubulointerstitial fibrosis and aid the treatment of chronic kidney disease (CKD) patients using precision therapy.


Assuntos
Células Epiteliais/citologia , Transição Epitelial-Mesenquimal , Glucuronidase/fisiologia , Sistema Renina-Angiotensina , Actinas/metabolismo , Angiotensina II/farmacologia , Animais , Caderinas/metabolismo , Linhagem Celular , Fibrose , Fosinopril/farmacologia , Humanos , Túbulos Renais/citologia , Proteínas Klotho , Ratos , Fator de Crescimento Transformador beta1/metabolismo , Valsartana/farmacologia
14.
Biochem J ; 476(22): 3505-3520, 2019 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-31682720

RESUMO

The mosquitoes of the Anopheles and Aedes genus are some of the most deadly insects to humans because of their effectiveness as vectors of malaria and a range of arboviruses, including yellow fever, dengue, chikungunya, West Nile and Zika. The use of insecticides from different chemical classes is a key component of the integrated strategy against An. gambiae and Ae. aegypti, but the problem of insecticide resistance means that new compounds with different modes of action are urgently needed to replace chemicals that fail to control resistant mosquito populations. We have previously shown that feeding inhibitors of peptidyl dipeptidase A to both An. gambiae and Ae. aegypti mosquito larvae lead to stunted growth and mortality. However, these compounds were designed to inhibit the mammalian form of the enzyme (angiotensin-converting enzyme, ACE) and hence can have lower potency and lack selectivity as inhibitors of the insect peptidase. Thus, for the development of inhibitors of practical value in killing mosquito larvae, it is important to design new compounds that are both potent and highly selective. Here, we report the first structures of AnoACE2 from An. gambiae in its native form and with a bound human ACE inhibitor fosinoprilat. A comparison of these structures with human ACE (sACE) and an insect ACE homologue from Drosophila melanogaster (AnCE) revealed that the AnoACE2 structure is more similar to AnCE. In addition, important elements that differ in these structures provide information that could potentially be utilised in the design of chemical leads for selective mosquitocide development.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Anopheles/enzimologia , Proteínas de Insetos/química , Peptidil Dipeptidase A/química , Aedes/química , Aedes/enzimologia , Aedes/genética , Animais , Anopheles/química , Anopheles/genética , Anopheles/crescimento & desenvolvimento , Drosophila melanogaster/química , Drosophila melanogaster/enzimologia , Fosinopril/análogos & derivados , Fosinopril/química , Humanos , Proteínas de Insetos/antagonistas & inibidores , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Inseticidas/química , Larva/química , Larva/enzimologia , Larva/genética , Larva/crescimento & desenvolvimento , Modelos Moleculares , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo
15.
Biomed Chromatogr ; 32(12): e4362, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30109716

RESUMO

Therapeutic drug monitoring of angiotensin-converting enzyme inhibitors has a great impact on blood pressure control in patients with heart failure and hepatic and renal impairment. To provide an efficient tool for drug assessment in plasma, a UPLC-MS/MS method was developed for simultaneous determination of benazepril hydrochloride, fosinopril sodium, captopril and hydrochlorothiazide in human plasma samples. Solid phase extraction was applied for sample preparation using OASIS® hydrophilic-lipophilic balanced reversed-phase sorbents cartridges. Chromatographic separation was performed using an Agilent SB-C18 column and methanol-0.1% formic acid in water (95:5, v/v) as mobile phase, at flow rate 0.3 mL/min. Detection was accomplished using a tandem mass spectrometer. The method was validated according to US Food and Drug Administration guidelines. It showed good linearity over concentration ranges 5-400 ng/mL for benazepril hydrochloride, fosinopril sodium and hydrochlorothiazide and 100-3500 ng/mL for captopril. CV% values were <13.92% whereas the mean accuracy ranged from 94.50 to 113.82% for quality control samples and their extraction recoveries ranged from 90.60 to 99.38%. In conclusion, the present study revealed method selectivity and sensitivity; it can be applied for estimation of angiotensin converting enzyme inhibitors and hydrochlorothiazide in human plasma for dose adjustment and therapeutic drug monitoring.


Assuntos
Anti-Hipertensivos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia de Fase Reversa/métodos , Espectrometria de Massas em Tandem/métodos , Benzazepinas/sangue , Captopril/sangue , Fosinopril/sangue , Humanos , Hidroclorotiazida/sangue , Interações Hidrofóbicas e Hidrofílicas , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , Extração em Fase Sólida/métodos
16.
Toxicol Lett ; 295: 32-40, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29859236

RESUMO

Hepatocellular carcinoma (HCC) is a major global health problem. Therapeutic interventions of HCC are still limited because of its complicated molecular pathogenesis. Many reports showed that renin-angiotensin system (RAS) contributes to the development of different types of malignancies. Therefore, the present study aimed to examine the effect of RAS inhibition using perindopril (1 mg/kg), fosinopril (2 mg/kg), or losartan (10 mg/kg) on diethylnitrosamine-induced HCC compared to sorafenib (30 mg/kg). The administration of RAS inhibitors resulted in improved liver function and histologic picture with a reduction in AFP levels. These effects found to be mediated through inactivation of NFкB pathway by the inhibition of NFĸB p65 phosphorylation at the Ser536 residue and inhibition of the phosphorylation-induced degradation of NFĸBia. Consequently, expression levels of cyclin D1 mRNA were significantly lowered. In addition, NFкB-induced TNF-α and TGF-ß1 levels were reduced leading to lower levels of MMP-2 and VEGF. We concluded that RAS inhibition either through inhibiting the ACE or the blockade of AT1R has the same therapeutic benefit and that the tissue affinity of the ACEIs has no impact on its anti-tumor activity. These results suggest that ACEIs and ARBs can serve as promising candidates for further clinical trials in the management of HCC.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Dietilnitrosamina , Fosinopril/farmacologia , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Losartan/farmacologia , NF-kappa B/metabolismo , Perindopril/farmacologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Ciclina D1/genética , Ciclina D1/metabolismo , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Inibidor de NF-kappaB alfa/metabolismo , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Compostos de Fenilureia/farmacologia , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Sorafenibe , Fatores de Tempo , Fator de Transcrição RelA/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
17.
J Mol Recognit ; 31(8): e2716, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29659061

RESUMO

The intermolecular interaction of fosinopril, an angiotensin converting enzyme inhibitor with bovine serum albumin (BSA), has been investigated in physiological buffer (pH 7.4) by multi-spectroscopic methods and molecular docking technique. The results obtained from fluorescence and UV absorption spectroscopy revealed that the fluorescence quenching mechanism of BSA induced by fosinopril was mediated by the combined dynamic and static quenching, and the static quenching was dominant in this system. The binding constant, Kb , value was found to lie between 2.69 × 103 and 9.55 × 103  M-1 at experimental temperatures (293, 298, 303, and 308 K), implying the low or intermediate binding affinity between fosinopril and BSA. Competitive binding experiments with site markers (phenylbutazone and diazepam) suggested that fosinopril preferentially bound to the site I in sub-domain IIA on BSA, as evidenced by molecular docking analysis. The negative sign for enthalpy change (ΔH0 ) and entropy change (ΔS0 ) indicated that van der Waals force and hydrogen bonds played important roles in the fosinopril-BSA interaction, and 8-anilino-1-naphthalenesulfonate binding assay experiments offered evidence of the involvements of hydrophobic interactions. Moreover, spectroscopic results (synchronous fluorescence, 3-dimensional fluorescence, and Fourier transform infrared spectroscopy) indicated a slight conformational change in BSA upon fosinopril interaction.


Assuntos
Fosinopril/química , Ligação Proteica , Soroalbumina Bovina/química , Animais , Sítios de Ligação/efeitos dos fármacos , Ligação Competitiva/efeitos dos fármacos , Bovinos , Diazepam/química , Fosinopril/farmacologia , Concentração de Íons de Hidrogênio , Simulação de Acoplamento Molecular , Fenilbutazona/química , Soroalbumina Bovina/efeitos dos fármacos , Espectrometria de Fluorescência , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura
18.
J Rheumatol ; 45(5): 655-662, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29449503

RESUMO

OBJECTIVE: To investigate the renal protective effects of early renin-angiotensin-aldosterone system (RAAS) blockade with renin-angiotensin system inhibitors (RASI) in systemic lupus erythematosus (SLE) patients with antiphospholipid-associated nephropathy (aPLN). METHODS: Medical data of 57 SLE patients with biopsy-proven aPLN were analyzed. Early RAAS blockade was defined as administration of RASI within 3 months after kidney biopsy and continued for ≥ 12 months. RESULTS: There was no significant difference in demographic data, laboratory findings, and renal histology by the time of kidney biopsy, except that the RASI group had higher proteinuria levels vs the non-RASI group [5.2 (2.8-8.8) vs 1.9 (0.6-2.8) g/d, p = 0.005, respectively] and higher prevalence of hypertension (75% vs 29%, p = 0.001, respectively). No significant difference between the 2 groups was observed in estimated glomerular filtration rate (eGFR), mean arterial pressure, and proteinuria level at 12 months after kidney biopsy. The improvement ratio of eGFR at 12 months was significantly higher in the RASI group versus the non-RASI group [26% (-5 to 86) vs -2% (-20 to 20), p = 0.028, respectively], and the rate of change in eGFR beyond 12 months was similar between the 2 groups. During a mean followup of 80 months, 4 (23%) patients in the non-RASI group and 3 (8%) patients in the RASI group developed kidney disease progression. Early RAAS blockade significantly decreased the risk of kidney disease progression [HR = 0.11 (0.02-0.59); p = 0.010]. Proteinuria and hypertension controls were similar between the 2 groups. CONCLUSION: Early RAAS blockade improved the short-term and longterm renal outcomes in SLE patients with aPLN. The renal protective effect of RASI was independent of its antihypertensive and antiproteinuric effects.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anticorpos Antifosfolipídeos/sangue , Fosinopril/uso terapêutico , Lúpus Eritematoso Sistêmico/complicações , Nefrite Lúpica/complicações , Nefrite Lúpica/patologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Adulto , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Biópsia , Distribuição de Qui-Quadrado , Progressão da Doença , Feminino , Seguimentos , Fosinopril/administração & dosagem , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Hipertensão/tratamento farmacológico , Rim/patologia , Modelos Logísticos , Nefrite Lúpica/imunologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Proteinúria/tratamento farmacológico , Fatores de Risco , Estatísticas não Paramétricas , Resultado do Tratamento , Adulto Jovem
19.
Georgian Med News ; (271): 55-61, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29099702

RESUMO

Purpose - to improve antihypertensive therapy on the basis of studying the antioxidant properties of an angiotensin-converting enzyme (ACE) inhibitor (fosinopril sodium) and a diuretic (hydrochlorothiazide), their impact on endothelial dysfunction and pro-inflammatory cytokines activity in hypertensive patients with overweight and obesity. A combination of fosinopril sodium 20 mg/day and hydrochlorothiazid 12.5 mg/day was prescribed to 54 patients with essential hypertension of 1-3 grades, 30 to 65 years old . The control group included 10 healthy subjects matched for age and sex. During the course of combined antihypertensive therapy we observed a significant decrease of i-NOS activity, reduce of TNF-α type I of its soluble receptor (sTNF-αRI), and 8-iso-PgF2α in the patients. Activity of e-NOS, superoxide dismutase and catalase, in contrast, were increased in patients with hypertension and concomitant obesity. Thus, the improvement of endothelial function, a significant decrease autoimmune activation due to lower tension of oxidative stress in the examined patients optimizes use of a combination of fosinopril sodium and hydrochlorothiazid for differentiated therapy in hypertensive patients with obesity.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Diuréticos/uso terapêutico , Hipertensão Essencial/tratamento farmacológico , Fosinopril/uso terapêutico , Hidroclorotiazida/uso terapêutico , Sobrepeso/complicações , Adulto , Idoso , Estudos de Casos e Controles , Dinoprosta/análogos & derivados , Dinoprosta/sangue , Quimioterapia Combinada , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Hipertensão Essencial/complicações , Hipertensão Essencial/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo II/sangue , Obesidade/complicações , Obesidade/fisiopatologia , Sobrepeso/fisiopatologia , Receptores Tipo I de Fatores de Necrose Tumoral/sangue , Fator de Necrose Tumoral alfa/metabolismo
20.
Sci Rep ; 7: 45409, 2017 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-28345667

RESUMO

The control of mosquitoes is threatened by the appearance of insecticide resistance and therefore new control chemicals are urgently required. Here we show that inhibitors of mosquito peptidyl dipeptidase, a peptidase related to mammalian angiotensin-converting enzyme (ACE), are insecticidal to larvae of the mosquitoes, Aedes aegypti and Anopheles gambiae. ACE inhibitors (captopril, fosinopril and fosinoprilat) and two peptides (trypsin-modulating oostatic factor/TMOF and a bradykinin-potentiating peptide, BPP-12b) were all inhibitors of the larval ACE activity of both mosquitoes. Two inhibitors, captopril and fosinopril (a pro-drug ester of fosinoprilat), were tested for larvicidal activity. Within 24 h captopril had killed >90% of the early instars of both species with 3rd instars showing greater resistance. Mortality was also high within 24 h of exposure of 1st, 2nd and 3rd instars of An. gambiae to fosinopril. Fosinopril was also toxic to Ae. aegypti larvae, although the 1st instars appeared to be less susceptible to this pro-drug even after 72 h exposure. Homology models of the larval An. gambiae ACE proteins (AnoACE2 and AnoACE3) reveal structural differences compared to human ACE, suggesting that structure-based drug design offers a fruitful approach to the development of selective inhibitors of mosquito ACE enzymes as novel larvicides.


Assuntos
Aedes/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anopheles/efeitos dos fármacos , Larva/efeitos dos fármacos , Animais , Captopril/farmacologia , Vetores de Doenças , Fosinopril/análogos & derivados , Fosinopril/farmacologia , Humanos , Resistência a Inseticidas/efeitos dos fármacos , Inseticidas/farmacologia , Mosquitos Vetores/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo
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