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1.
J Cardiovasc Pharmacol Ther ; 29: 10742484241258381, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38828542

RESUMO

BACKGROUND: Moxonidine, an imidazoline I1 receptor agonist, is an effective antihypertensive drug that was shown to improve insulin sensitivity. RAAS-blockers are recommended as first-line therapy in patients with diabetes, alone or in combination with a calcium-channel antagonist or a diuretic. AIMS: This study compared the effects of moxonidine and ramipril on blood pressure (BP) and glucose metabolism in overweight patients with mild-to-moderate hypertension and impaired fasting glucose or type 2 diabetes. METHODS: Treatment-naïve patients for hypertension and dysglycemia were randomized to 12 weeks of double-blind moxonidine 0.4 mg or ramipril 5 mg once-daily treatment. At 12 weeks, for a further 12 weeks non-responders received combination of mox/ram, while responders continued blinded treatment. RESULTS: Moxonidine and ramipril were equivalent in lowering SiDBP and SiSBP at the end of the first 12 weeks. The responder rate was approximately 50% in both groups, with a mean SiDBP and SiSBP decrease of 10 and 15 mm Hg in the responders, respectively. The normalization rate (SiDBP < 85 mm Hg) was non significantly different between treatments groups. Moxonidine reduced heart rate (HR) (average -3.5 bpm, p = 0.017) during monotherapy, and when added to ramipril. HbA1c decreased significantly at Week 12 in both groups. Neither drug affected glucose or insulin response to the oral glucose tolerance test. In non-responders, moxonidine/ramipril combination further reduced BP without compromising metabolic parameters. CONCLUSION: Moxonidine 0.4 mg and ramipril 5 mg were equally effective on BP lowering and were well tolerated and mostly metabolically neutral either as monotherapies or in combination. HR was lowered on moxonidine treatment.


Assuntos
Anti-Hipertensivos , Glicemia , Pressão Sanguínea , Diabetes Mellitus Tipo 2 , Quimioterapia Combinada , Frequência Cardíaca , Hipertensão , Imidazóis , Sobrepeso , Ramipril , Humanos , Ramipril/administração & dosagem , Ramipril/uso terapêutico , Ramipril/farmacologia , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Feminino , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Método Duplo-Cego , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Imidazóis/administração & dosagem , Anti-Hipertensivos/uso terapêutico , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/efeitos adversos , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Sobrepeso/tratamento farmacológico , Sobrepeso/fisiopatologia , Sobrepeso/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Idoso , Adulto , Resultado do Tratamento , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos
2.
Curr Med Res Opin ; 40(7): 1093-1102, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38832726

RESUMO

OBJECTIVES: To describe the clinical characteristics and treatment adherence in European adult hypertensive patients starting treatment with the extemporaneous combination of nebivolol and ramipril (NR-EXC). METHODS: Retrospective database analysis of patients receiving NR-EXC treatment across five European countries (Italy, Germany, France, Poland, Hungary) over a period ranging from 3 to 9 years (until 30 June 2020) according to data availability for the different data sources. Patient demographics, comorbidities, and treatment adherence were evaluated. RESULTS: We identified 592,472 patients starting NR-EXC. Most of them were over 60 years of age, with ramipril most commonly prescribed at 5 mg (from 30.0 to 57.2% of patients across the databases). Notable comorbidities included diabetes (19.2%) and dyslipidemia (18.2%). The study population was also highly subjected to polytherapy with antithrombotics, lipid-lowering agents, and other lowering blood pressure agents as the most co-prescribed medications, as resulted from Italian database. Up to 59% of the patients did not request a cardiologic visit during the study period. Adherence to therapy was low in 56.3% of the patients, and it was high only in 11.1% of them. CONCLUSIONS: The combination of nebivolol and ramipril is frequently prescribed in Europe, but adherence to treatment is suboptimal. The transition to a single pill combination could enhance treatment adherence and streamline regimens, potentially leading to significant benefits. Improved adherence not only correlates with better blood pressure control but also reduces the risk of cardiovascular events, underscoring the importance of this development.


Assuntos
Anti-Hipertensivos , Hipertensão , Nebivolol , Ramipril , Humanos , Nebivolol/administração & dosagem , Nebivolol/uso terapêutico , Ramipril/administração & dosagem , Ramipril/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Europa (Continente) , Idoso , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/uso terapêutico , Estudos Retrospectivos , Adesão à Medicação/estatística & dados numéricos , Adulto , Combinação de Medicamentos , Quimioterapia Combinada
3.
J Hypertens ; 42(8): 1350-1357, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38690937

RESUMO

OBJECTIVES: Blood pressure (BP) variability (BPV) can be assessed using office (OBP), home (HBP), or ambulatory BP (ABP) measurements. This analysis investigated the association and agreement between OBP, HBP, and ABP measurements for BPV assessment at baseline and 10 weeks after initiating antihypertensive drug therapy. METHODS: Untreated hypertensive patients with elevated BPV were randomized to receive an angiotensin-converting enzyme inhibitor (ramipril) or a calcium channel blocker (nifedipine GITS) in a 10-week, open-label, blinded-end point study. BPV was assessed using standard deviation (SD) and coefficient of variation (CV) (reading-to-reading analyses). RESULTS: Data from 146 participants from three research centers (Athens/Greece; Milan/Italy; Shanghai/China) were analyzed [mean age 53 ±â€Š10 (SD) years, male individuals 60%, baseline systolic OBP, HBP, and 24 h ABP 144 ±â€Š9, 138 ±â€Š10, and 143 ±â€Š10 mmHg, respectively]. Post-treatment minus pre-treatment systolic CV difference was: OBP: 0.3%, P  = 0.28; HBP: -0.2%, P  = 0.20; 24 h ABP: 1.1%, P  < 0.001. Home and ambulatory (not office) BPV indices presented weak-to-moderate correlation, both before and during treatment (range of coefficients 0.04-0.33). The correlation coefficient between systolic HBP and awake ABP CV was 0.21 and 0.28 before and during treatment, respectively ( P  < 0.05/< 0.001, respectively). Home and ambulatory (not office) BPV indices presented slight-to-fair agreement (range 64-73%) in detecting participants with high systolic BPV (top quartile of respective distributions) both before and during treatment (kappa range 0.04-0.27). CONCLUSION: These data showed a weak-to-moderate association between out-of-office (but not office) BPV indices both before and during BP-lowering treatment, with reasonable agreement in detecting individuals with high BPV. Out-of-office BP measurements provide more similar and consistent BPV information than office measurements.


Assuntos
Anti-Hipertensivos , Monitorização Ambulatorial da Pressão Arterial , Pressão Sanguínea , Hipertensão , Humanos , Masculino , Pessoa de Meia-Idade , Anti-Hipertensivos/uso terapêutico , Feminino , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Monitorização Ambulatorial da Pressão Arterial/métodos , Adulto , Ramipril/uso terapêutico , Idoso , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Nifedipino/uso terapêutico
4.
Acta Pharm ; 74(2): 315-328, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38815200

RESUMO

In patients with chronic heart failure (CHF), the use of angiotensin-converting enzyme inhibitors, including ramipril, is recommended to reduce the risk of heart failure worsening, hospitalisation, and death. Our aim was to investigate the influence of body composition on the pharmacokinetics of ramipril and its active metabolite ramiprilat and to evaluate the changes in pharmacokinetics after prolonged therapy. Twenty-three patients with CHF who were on regular therapy with ramipril participated at the first study visit ( median age 77 years, 65 % male, and 70 % New York Heart Association Class II); 19 patients attended the second study visit and the median time between the two visits was 8 months. Pharmacokinetics were assessed using a nonlinear mixed-effects parent-metabolite model comprising two compartments for ramipril and one compartment for ramiprilat. The influence of body size and composition was best described by an allometric relationship with fat-free mass. In addition, ramipril clearance was related to patient age and daily ramipril dose, while clearance of ramiprilat was influenced by glome rular filtration rate and daily ramipril dose. There were no clinically relevant changes in the pharmacokinetics of ramipril and ramiprilat between the study visits. Due to the relatively stable pharmacokinetics of ramipril, regular outpatient visits at 6-month intervals seem appropriate to evaluate ramipril therapy.


Assuntos
Inibidores da Enzima Conversora de Angiotensina , Insuficiência Cardíaca , Ramipril , Humanos , Ramipril/farmacocinética , Ramipril/administração & dosagem , Ramipril/análogos & derivados , Insuficiência Cardíaca/tratamento farmacológico , Masculino , Inibidores da Enzima Conversora de Angiotensina/farmacocinética , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Idoso , Feminino , Estudos Longitudinais , Doença Crônica , Idoso de 80 Anos ou mais , Pessoa de Meia-Idade , Composição Corporal
5.
Pharm Dev Technol ; 29(5): 468-476, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38662798

RESUMO

Carboxylesterase enzymes convert a prodrug ramipril into the biologically active metabolite ramiprilat. It is prescribed for controlling ocular hypertension after oral administration. High concentrations of carboxylesterase enzymes in rectal and colon tissue can transform ramipril significantly to ramiprilat. Sustained rectal delivery of ramipril has been developed for intra-ocular pressure lowering effect using a normotensive rabbit model. Rectal suppositories have been formulated using a matrix base of HPMC K100-PEG 400-PEG 6000, incorporating varying amounts of Gelucire by the fusion moulding method. The presence of Gelucire in the suppository exhibited sustained structural relaxation-based release kinetics of RM compared to its absence. Intravenous and oral administration of ramipril has decreased IOP in the treated rabbit up to 90 and 360 min, respectively. Treated rabbits with suppositories have revealed decreased IOP for an extended period compared to the above. Formulation containing GEL 3% reduced intra-ocular pressure to 540 min, with the highest area under the decreased IOP curve. Compared to oral, the pharmacodynamic bioavailability of ramipril has been improved significantly using a sustained-release rectal suppository. A rectal suppository for sustained delivery of ramipril could be used to lower IOP significantly.


Assuntos
Administração Retal , Preparações de Ação Retardada , Pressão Intraocular , Pró-Fármacos , Ramipril , Animais , Coelhos , Pressão Intraocular/efeitos dos fármacos , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Ramipril/administração & dosagem , Ramipril/farmacocinética , Ramipril/farmacologia , Supositórios , Masculino , Disponibilidade Biológica , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/farmacologia , Lipídeos/química , Liberação Controlada de Fármacos , Administração Oral , Polietilenoglicóis
7.
Eur Rev Med Pharmacol Sci ; 28(5): 1821-1836, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38497865

RESUMO

OBJECTIVE: Sepsis-associated liver injury is responsible for the high morbidity and mortality rates seen with septic shock. Activation of the renin-angiotensin-aldosterone system (RAAS) is an essential counteractive mechanism during the hypotensive phase of sepsis; however, excessive activation is associated with exaggerated pro-oxidant and inflammatory response, which aggravates organ damage. This study aimed to evaluate the effect of RAAS inhibition on sepsis-induced liver damage. MATERIALS AND METHODS: The cecal ligation and puncture (CLP) model was employed as a model of sepsis. Rats were divided into five groups: sham-operated, vehicle-treated septic rats, septic rats treated with ramipril in a dose of 10 mg/kg, septic rats treated with losartan in a dose of 20 mg/kg, and finally septic rats treated with spironolactone in a dose of 25 mg/kg. Rats received the treatment one hour after induction. Twenty-four hours later, rats were euthanized, and serum samples and liver tissue were collected to evaluate liver function and hepatic oxidative, anti-oxidative, inflammatory, and apoptotic markers. The microscopic integrity of the hepatic tissue was also assessed. RESULTS: The results of our study showed that all the treatments used ameliorated sepsis-induced liver injury. This was reflected by improved liver function parameters and histopathological appearance of liver tissue. Treatment with ramipril, losartan, or spironolactone reduced tissue malondialdehyde (MDA), nitric oxide, activated caspase-3, and TNF-α. Moreover, these drugs increased hepatic reduced-glutathione (GSH) levels, superoxide dismutase (SOD) activity, and proliferating cell nuclear antigen (PCNA) expression. CONCLUSIONS: Administration of ramipril, losartan, or spironolactone after CLP produced a hepatoprotective effect in rats, possibly by reducing oxidative stress, inflammation, and apoptosis.


Assuntos
Losartan , Sepse , Animais , Ratos , Losartan/farmacologia , Losartan/uso terapêutico , Ramipril/farmacologia , Ramipril/uso terapêutico , Espironolactona/farmacologia , Espironolactona/uso terapêutico , Punções , Sepse/complicações , Sepse/tratamento farmacológico , Fígado
8.
J Am Coll Cardiol ; 83(9): 904-914, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38418004

RESUMO

BACKGROUND: Patients who sustain an acute myocardial infarction (AMI), including ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI), remain at high risk for heart failure (HF), coronary events, and death. Angiotensin-converting enzyme inhibitors have been shown to significantly decrease the risk for cardiovascular events in both STEMI and NSTEMI patients. OBJECTIVES: The objectives were to determine whether angiotensin-receptor blockade and neprilysin inhibition with sacubitril/valsartan, compared with ramipril, has impact on reducing cardiovascular events according to the type of AMI. METHODS: The PARADISE-MI (Prospective ARNI versus ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction) trial enrolled patients with AMI complicated by left ventricular dysfunction and/or pulmonary congestion and at least 1 risk-enhancing factor. Patients were randomized to either sacubitril/valsartan or ramipril. The primary endpoint was death from cardiovascular causes or incident HF. In this prespecified analysis, we stratified patients according to AMI type. RESULTS: Of 5,661 enrolled patients, 4,291 (75.8%) had STEMI. These patients were younger and had fewer comorbidities and cardiovascular risk factors than NSTEMI patients. After adjustment for potential confounders, the risk for the primary outcome was marginally higher in NSTEMI vs STEMI patients (adjusted HR: 1.19; 95% CI: 1.00-1.41), with borderline statistical significance (P = 0.05). The primary composite outcome occurred at similar rates in patients randomized to sacubitril/valsartan vs ramipril in STEMI (10% vs 12%; HR: 0.87; 95% CI: 0.73-1.04; P = 0.13) and NSTEMI patients (17% vs 17%; HR: 0.97; 95% CI: 0.75-1.25; P = 0.80; P interaction = 0.53). CONCLUSIONS: Compared with ramipril, sacubitril/valsartan did not significantly decrease the risk for cardiovascular death and HF in patients with AMI complicated by left ventricular dysfunction, irrespective of the type of AMI. (Prospective ARNI vs ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI; NCT02924727).


Assuntos
Insuficiência Cardíaca , Infarto do Miocárdio , Infarto do Miocárdio sem Supradesnível do Segmento ST , Infarto do Miocárdio com Supradesnível do Segmento ST , Disfunção Ventricular Esquerda , Humanos , Neprilisina , Ramipril , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Infarto do Miocárdio sem Supradesnível do Segmento ST/tratamento farmacológico , Angiotensinas , Receptores de Angiotensina , Estudos Prospectivos , Tetrazóis/farmacologia , Resultado do Tratamento , Valsartana , Aminobutiratos/farmacologia , Compostos de Bifenilo , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Disfunção Ventricular Esquerda/induzido quimicamente , Antagonistas de Receptores de Angiotensina/farmacologia
9.
Expert Rev Clin Pharmacol ; 17(2): 119-130, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38197151

RESUMO

INTRODUCTION: Clinical hypertension trials typically rely on homeostatic principles, including single time-of-day office blood pressure (BP) measurements (OBPM), rather than circadian chronopharmacological principles, including ambulatory monitoring (ABPM) done around-the-clock to derive the asleep systolic BP (SBP) mean and sleep-time relative SBP decline - jointly the strongest prognosticators of cardiovascular disease (CVD) risk and true definition of hypertension - to qualify participants and assess outcomes. AREAS COVERED: Eight chronopharmacological elements are indispensable for design and conduct of hypertension medication trials, mainly those on ingestion-time differences in effects, and also a means of rating quality of investigations. Accordingly, we highlight the findings and shortcomings of: (i) 155 such ingestion-time trials, 83.9% finding at-bedtime/evening treatment more beneficial than conventional upon-awakening/morning treatment; (ii) HOPE and ONTARGET CVD outcomes investigations assessing in the former add-on ramipril at-bedtime and in the latter telmisartan, ramipril, or both in combination in the morning; and (iii) pragmatic TIME CVD outcomes trial. EXPERT OPINION: Failure to incorporate chronopharmacological principals - including ABPM to derive asleep SBP and SBP dipping to qualify subjects as hypertensive and assess CVD risk - results in deficient study design, dubious findings, and unnecessary medical controversy at the expense of advances in patient care.


Assuntos
Fármacos Cardiovasculares , Hipertensão , Humanos , Anti-Hipertensivos/efeitos adversos , Ritmo Circadiano , Ramipril/farmacologia , Ramipril/uso terapêutico , Fatores de Risco , Monitorização Ambulatorial da Pressão Arterial , Ensaios Clínicos como Assunto , Hipertensão/tratamento farmacológico , Pressão Sanguínea
10.
Transplant Proc ; 56(1): 215-222, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38218697

RESUMO

BACKGROUND: It is known that the increase in oxidants and proinflammatory cytokines, as well as the decrease in antioxidants, play a role in ovarian ischemia-reperfusion (I/R) injury. The antioxidant and anti-inflammatory properties of ramipril have been studied in various diseases. This study aims to investigate the effect of ramipril on I/R-induced ovarian damage in rats. METHODS: Rats were divided into healthy (HG), sham (SG), ovary I/R (OIR), and ramipril + ovary I/R (ROIR) groups (n = 6/each group). One hour before the surgical procedures, ROIR was given 2 mg/kg ramipril. The lower abdomen of the SG, OIR, and ROIR was surgically opened. Right ovarian tissues of OIR and ROIR were subjected to 2 hours of ischemia and 6 hours of reperfusion. Then, all animals were euthanized, and their right ovaries were removed. Ovarian tissues were examined for oxidants (malondialdehyde), antioxidants (total glutathione, superoxide dismutase, and catalase), and proinflammatory cytokines (nuclear factor kappa-B, tumor necrosis factor-alpha, interleukin 1 beta, and interleukin-6) analysis was performed. Tissues were examined histopathologically. RESULTS: The ovarian tissue of the OIR, which underwent the I/R procedure, exhibited a significant increase in oxidant and proinflammatory cytokine levels, along with a decrease in antioxidant levels (P < .001). Ramipril suppressed the I/R-induced increase in oxidants and pro-inflammatory cytokines and the decrease in antioxidants (P < .001). Ramipril also attenuated I/R-induced histopathological damage in ovarian tissue (P < .05). CONCLUSION: Ramipril treatment may be a treatment strategy to protect ovarian tissue against oxidative and inflammatory damage of I/R.


Assuntos
Antioxidantes , Traumatismo por Reperfusão , Feminino , Ratos , Animais , Antioxidantes/farmacologia , Ramipril/farmacologia , Ratos Wistar , Oxidantes/farmacologia , Citocinas , Isquemia , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/patologia , Reperfusão , Malondialdeído , Estresse Oxidativo
11.
Forensic Sci Med Pathol ; 20(1): 100-105, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37060536

RESUMO

Ramipril is a popular angiotensin-converting enzyme inhibitor applied in the treatment of hypertension. Its therapeutic effect is oriented on the concentration of the active metabolite ramiprilat. The information about toxic drug levels is missing in the literature. Therefore, the aim of this work was an indication of possible toxic ranges based on the analysis of real samples with high ramiprilat concentrations. For these purposes, an appropriate analytical LC-MS/MS method was developed and validated according to forensic guidelines and applied in the routine. Most real samples targeted for ramipril/ramiprilat were associated with the typical therapeutic drug range of 1-40 ng/mL described in the literature. However, higher drug levels with ramiprilat concentrations above 100 ng/mL could also be observed infrequently in cases of driving under the influence of drugs or attempted suicides. To the best of the author's knowledge, this is the first time antemortem ramipril and ramiprilat concentrations associated with driving under the influence of drugs and suicide attempts were discussed from a forensic point of view. The collected data enabled an indication of the ramiprilat toxic concentration range from about 600 ng/mL to at least 3500 ng/mL. The toxic concentration range discussed can be applied in the forensic practice as a reference for future cases.


Assuntos
Ramipril/análogos & derivados , Espectrometria de Massas em Tandem , Humanos , Cromatografia Líquida , Toxicologia Forense
12.
Expert Rev Clin Pharmacol ; 17(1): 93-100, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38078460

RESUMO

BACKGROUND: Although a growing number of observational studies suggest that angiotensin-converting enzyme inhibitors (ACEIs) intake may be a risk factor for psoriasis, evidence is still insufficient to draw definitive conclusions. RESEARCH DESIGN AND METHODS: Drug-targeted Mendelian randomization (DTMR) was used to analyze the causality between genetic proxied ACEIs and psoriasis. Furthermore, we performed a disproportionality analysis based on the FDA adverse event reporting system (FAERS) database to identify more suspicious subclasses of ACEIs. RESULTS: Using two kinds of genetic proxy instruments, the present DTMR research identified genetic proxied ACEIs as risk factors for psoriasis. Furthermore, our disproportionality analysis revealed that ramipril, trandolapril, perindopril, lisinopril, and enalapril were associated with the risk of psoriasis, which validates and refines the findings of the DTMR. CONCLUSIONS: Our integrative study verified that ACEIs, especially ramipril, trandolapril, perindopril, lisinopril, and enalapril, tended to increase the risk of psoriasis statistically.


Assuntos
Inibidores da Enzima Conversora de Angiotensina , Psoríase , Humanos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Ramipril/efeitos adversos , Lisinopril/farmacologia , Perindopril/efeitos adversos , Farmacovigilância , Análise da Randomização Mendeliana , Enalapril/farmacologia , Psoríase/tratamento farmacológico , Psoríase/genética
13.
Int Urol Nephrol ; 56(4): 1395-1402, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37741921

RESUMO

PURPOSE: Diabetic kidney disease (DKD) is a devastating complication of diabetes mellitus. Inflammation and histamine are potentially involved in the disease progression. This study aimed to evaluate the role of fexofenadine in patients with DKD. METHODS: From January 2020 to February 2022, out of 123 patients screened for eligibility, 61 patients completed the study. Patients were randomized into two groups, the fexofenadine group (n = 30): received ramipril plus fexofenadine, and the control group (n = 31): received ramipril only for six months. Changes in urinary albumin to creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) were considered primary outcomes. Measurements of urinary cyclophilin A, monocyte chemoattractant protein-1 (MCP-1), 8-hydroxy-2' deoxyguanosine (8-OHdG), and podocalyxin (PCX) were considered secondary outcomes. The study was prospectively registered on clinicaltrial.gov on January 13, 2020, with identification code NCT04224428. RESULTS: At the end of the study, fexofenadine reduced UACR by 16% (95% CI, - 23.4% to - 9.3%) versus a noticeable rise of 11% (95% CI, 4.1% to 17.8%) in UACR in the control group, (p < 0.001). No significant difference in eGFR was revealed between the two groups. However, the control group showed a significant decrease of - 3.5% (95% CI, - 6.6% to - 0.3%) in eGFR, compared to its baseline value. This reduction was not reported in the fexofenadine group. Fexofenadine use was associated with a significant decline in MCP-1, 8-OHdG, and PCX compared to baseline values. CONCLUSION: Fexofenadine is a possible promising adjuvant therapy in patients with DKD. Further large-scale trials are needed to confirm our preliminary results.


Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Terfenadina/análogos & derivados , Humanos , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/complicações , Ramipril/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Testes de Função Renal , Taxa de Filtração Glomerular , Albuminúria/complicações
14.
Eur J Heart Fail ; 26(1): 130-139, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37933184

RESUMO

AIM: It is unknown whether safety and clinical endpoints by use of sacubitril/valsartan (an angiotensin receptor-neprilysin inhibitor [ARNI]) are affected by mineralocorticoid receptor antagonists (MRA) in high-risk myocardial infarction (MI) patients. The aim of this study was to examine whether MRA modifies safety and clinical endpoints by use of sacubitril/valsartan in patients with a MI and left ventricular systolic dysfunction (LVSD) and/or pulmonary congestion. METHODS AND RESULTS: Patients (n = 5661) included in the PARADISE MI trial (Prospective ARNI vs. ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI) were stratified according to MRA. Primary outcomes in this substudy were worsening heart failure or cardiovascular death. Safety was defined as symptomatic hypotension, hyperkalaemia >5.5 mmol/L, or permanent drug discontinuation. A total of 2338 patients (41%) were treated with MRA. Safety of ARNI compared to ramipril was not altered significantly by ± MRA, and both groups had similar increase in symptomatic hypotension with ARNI. In patients taking MRA, the risk of hyperkalaemia or permanent drug discontinuation was not significantly altered by ARNI (p > 0.05 for all comparisons). The effect of ARNI compared with ramipril was similar in those who were and were not taking MRA (hazard ratio [HR]MRA 0.96, 95% confidence interval [CI] 0.77-1.19 and HRMRA- 0.87, 95% CI 0.71-1.05, for the primary endpoint; p = 0.51 for interaction [Clinical Endpoint Committee adjudicated]); similar findings were observed if investigator-reported endpoints were evaluated (p = 0.61 for interaction). CONCLUSIONS: Use of a MRA did not modify safety or clinical endpoints related to initiation of ARNI compared to ramipril in the post-MI setting in patients with LVSD and/or congestion.


Assuntos
Insuficiência Cardíaca , Hiperpotassemia , Hipotensão , Infarto do Miocárdio , Humanos , Ramipril/uso terapêutico , Ramipril/farmacologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Hiperpotassemia/tratamento farmacológico , Estudos Prospectivos , Tetrazóis/uso terapêutico , Tetrazóis/farmacologia , Antagonistas de Receptores de Angiotensina/efeitos adversos , Valsartana/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Aminobutiratos/efeitos adversos , Combinação de Medicamentos , Hipotensão/induzido quimicamente , Infarto do Miocárdio/complicações , Infarto do Miocárdio/tratamento farmacológico , Volume Sistólico
15.
J Pathol ; 262(3): 296-309, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38129319

RESUMO

The standard of care for patients with Alport syndrome (AS) is angiotensin-converting enzyme (ACE) inhibitors. In autosomal recessive Alport (ARAS) mice, ACE inhibitors double lifespan. We previously showed that deletion of Itga1 in Alport mice [double-knockout (DKO) mice] increased lifespan by 50%. This effect seemed dependent on the prevention of laminin 211-mediated podocyte injury. Here, we treated DKO mice with vehicle or ramipril starting at 4 weeks of age. Proteinuria and glomerular filtration rates were measured at 5-week intervals. Glomeruli were analyzed for laminin 211 deposition in the glomerular basement membrane (GBM) and GBM ultrastructure was analyzed using transmission electron microscopy (TEM). RNA sequencing (RNA-seq) was performed on isolated glomeruli at all time points and the results were compared with cultured podocytes overlaid (or not) with recombinant laminin 211. Glomerular filtration rate declined in ramipril-treated DKO mice between 30 and 35 weeks. Proteinuria followed these same patterns with normalization of foot process architecture in ramipril-treated DKO mice. RNA-seq revealed a decline in the expression of Foxc2, nephrin (Nphs1), and podocin (Nphs2) mRNAs, which was delayed in the ramipril-treated DKO mice. GBM accumulation of laminin 211 was delayed in ramipril-treated DKO mice, likely due to a role for α1ß1 integrin in CDC42 activation in Alport mesangial cells, which is required for mesangial filopodial invasion of the subendothelial spaces of the glomerular capillary loops. Ramipril synergized with Itga1 knockout, tripling lifespan compared with untreated ARAS mice. © 2023 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Nefrite Hereditária , Podócitos , Humanos , Camundongos , Animais , Integrina alfa1/genética , Integrina alfa1/metabolismo , Ramipril/farmacologia , Ramipril/metabolismo , Longevidade , Membrana Basal Glomerular/metabolismo , Nefrite Hereditária/tratamento farmacológico , Nefrite Hereditária/genética , Nefrite Hereditária/metabolismo , Podócitos/metabolismo , Laminina/genética , Laminina/metabolismo , Camundongos Knockout , Proteinúria/tratamento farmacológico , Proteinúria/genética , Proteinúria/metabolismo , Análise de Sequência de RNA
16.
J Ethnopharmacol ; 323: 117661, 2024 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-38159824

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Evolvulus alsinoides L. (Sankhaholi) has been traditionally used in Unani (Greco-Arabic) medicine to treat diverse cardiovascular disorders. Notably, preclinical and clinical investigations have substantiated its remarkable potential as an antihypertensive agent. AIM OF THE STUDY: The aim of this study was to compare the efficacy of hydroalcoholic extract of Evolvulus alsinoides L. and ramipril in treating hypertension using a higher dose of the test drug within the recommended limit. MATERIALS AND METHODS: In this open-label randomized controlled trial, 57 participants (29 in the test group, 28 in the control group) completed the 42-day study. The test group received 630 mg of dried hydro-alcoholic extract of Evolvulus alsinoides L. in capsule form orally once daily, while the control group received 5 mg of Ramipril orally once daily. Participants in both groups were advised to adhere to the Dietary Approaches to Stop Hypertension (DASH) eating plan in terms of diet and lifestyle adjustments recommended by JNC-8. The primary outcome measures were changes in systolic and diastolic blood pressure as well as changes in plasma levels of hsCRP and IL6. Secondary outcome measures included changes in symptoms such as palpitations, giddiness, headaches, fatigue and shortness of breath. Headaches, palpitations, and giddiness were assessed using a customized Visual Analog Scale (VAS) graded as "none," "mild," "moderate," and "severe". Fatigue was assessed on a binary scale as either absent or present, and dyspnea was assessed using the modified Medical Research Council (mMRC) scale for breathlessness. Both primary and secondary outcomes were assessed at baseline and each follow-up visit (2nd week, 4th week, and 6th week) until the completion of the trial. RESULTS: At the end of the trial, the mean differences for the primary outcomes were as follows:SBP:-1.8895%CI:-4.82,1.05,p=0.203,d=0.33, DBP: -2.8395%CI:-4.67,-0.10,p=0.003,d=0.8, hsCRP: -1.4095%CI:-2.80,-0.003,p=0.49,d=0.53, and IL6: -88.6795%CI:-148.90,-28.43,p=0.005,d=0.78. No statistically significant differences were observed between the two groups for any of the secondary outcomes. CONCLUSIONS: Based on the preliminary results, it can be inferred that the hydro-alcoholic extract of Evolvulus alsinoides L. exhibits significant antihypertensive potential, comparable to that of ramipril. Furthermore, it appears that Evolvulus alsinoides L. may be more effective than ramipril in reducing the biochemical markers of inflammation associated with primary hypertension. However, additional research is required to validate these findings.


Assuntos
Convolvulaceae , Hipertensão , Humanos , Ramipril/uso terapêutico , Ramipril/farmacologia , Proteína C-Reativa , Interleucina-6 , Anti-Hipertensivos/uso terapêutico , Anti-Hipertensivos/farmacologia , Hipertensão/tratamento farmacológico , Pressão Sanguínea , Cefaleia/tratamento farmacológico , Hipertensão Essencial/tratamento farmacológico
18.
Wiad Lek ; 76(11): 2531-2534, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38112376

RESUMO

A 25-year-old male with known EDMD was referred for the cardiology consultation due to symptoms of heart failure. Echocardiography showed decrease left ventricular ejection fraction (LVEF) and therapy with ramipril, torsemide and rivaroxaban was initiated. Despite initial improvement, the patient later developed presyncope, bradycardia, irregular heartbeat and worsening of dyspnea. Therefore, implantation of resynchronization pacemaker with the function of implantable cardioverter-defibrillator (CRT-D/P) was performed. Ramipril was substituted by sacubitril/valsartan, and mineralocorticoid receptor antagonist and beta-blocker were initiated. Genetic testing found AD mutation in lamin A/C gene LMNA c.746G>A, p.(Arg249Gln). Upon follow-up, the patient demonstrated resolution of dyspnea and reverse remodeling of the left ventricle with complete restoration of the LVEF.


Assuntos
Distrofia Muscular de Emery-Dreifuss , Ramipril , Masculino , Humanos , Adulto , Volume Sistólico , Função Ventricular Esquerda , Distrofia Muscular de Emery-Dreifuss/diagnóstico , Distrofia Muscular de Emery-Dreifuss/genética , Distrofia Muscular de Emery-Dreifuss/terapia , Dispneia
19.
Rev. clín. esp. (Ed. impr.) ; 223(7): 414-422, ago.- sept. 2023. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-223437

RESUMO

Introducción y objetivos A pesar de los avances en el tratamiento, la enfermedad cardiovascular es la segunda causa de muerte en España. El objetivo de este estudio fue determinar el coste-efectividad de la estrategia polipíldora CNIC (ácido acetilsalicílico 100mg, atorvastatina 20/40mg, ramipril 2,5/5/10mg) comparada con los mismos monocomponentes por separado para la prevención secundaria de eventos cardiovasculares recurrentes en adultos en España. Materiales y métodos Se adaptó un modelo Markov considerando 4 estados de salud (estable, evento cardiovascular adverso mayor posterior, ictus isquémico posterior y muerte) y la ecuación de riesgo SMART con un horizonte temporal de toda la vida desde la perspectiva del Sistema Nacional de Salud español. La estrategia polipíldora CNIC se comparó con monocomponentes en una cohorte hipotética de 1.000 pacientes en prevención secundaria.Los datos de efectividad, epidemiológicos, de costes y de utilidades se obtuvieron del estudio NEPTUNO, de bases de datos oficiales y de la literatura. Los resultados fueron los costes (en euros de 2021) por año de vida (AV) ganados y por años de vida ajustados por calidad (AVAC) ganados. Se aplicó una tasa de descuento del 3%. Se realizaron análisis de sensibilidad determinísticos univariantes y probabilísticos para evaluar la solidez del modelo. Resultados La estrategia polipíldora CNIC, en prevención secundaria, produce más ganancias de AV (13,22) y AVAC (11,64) a un coste inferior que los monocomponentes. La polipíldora CNIC es dominante y ahorra 280,68euros por paciente en comparación con los monocomponentes por separado. El análisis de sensibilidad probabilístico muestra que el 82,4% de las simulaciones están por debajo del umbral de 25.000euros por AVAC ganado (AU)


Introduction and objectives Despite advances in treatment, cardiovascular disease is the second leading cause of death in Spain. The objective of this study was to determine the cost-effectiveness of the CNIC-Polypill strategy (acetylsalicylic acid 100mg, atorvastatin 20/40mg, ramipril 2.5/5/10mg) compared with the same separate monocomponents for the secondary prevention of recurrent cardiovascular events in adults in Spain. Materials and methods A Markov cost-utility model was adapted considering four health states (stable, subsequent major adverse cardiovascular event, subsequent ischemic stroke and death) and the SMART risk equation over a lifetime horizon from the perspective of the Spanish National Healthcare System. The CNIC-Polypill strategy was compared with monocomponents in a hypothetical cohort of 1000 secondary prevention patients. Effectiveness, epidemiological, cost and utilities data were obtained from the NEPTUNO study, official databases and literature. Outcomes were costs (in 2021euros) per life-year (LY) and quality-adjusted LY (QALY) gained. A 3% discount rate was applied. Deterministic one-way and probabilistic sensitivity analyses evaluated the robustness of the model. Results The CNIC-Polypill strategy in secondary prevention results in more LY (13.22) and QALY (11.64) gains at a lower cost than monocomponents. The CNIC-Polypill is dominant and saves €280.68 per patient compared with monocomponents. The probabilistic sensitivity analysis shows that 82.4% of the simulations are below the threshold of €25,000 per QALY gained. Conclusions The CNIC-Polypill strategy in secondary cardiovascular prevention is cost-effective compared with the same separate monocomponents, resulting in a cost-saving strategy to the Spanish National Healthcare System (AU)


Assuntos
Humanos , Doenças Cardiovasculares/prevenção & controle , Análise Custo-Benefício , Aspirina/administração & dosagem , Atorvastatina/administração & dosagem , Ramipril/administração & dosagem , Cadeias de Markov , Espanha
20.
J Am Heart Assoc ; 12(17): e028942, 2023 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-37609931

RESUMO

Background Studies demonstrated sex differences in outcomes following acute myocardial infarction, with women more likely to develop heart failure (HF). Sacubitril/valsartan has been shown to reduce cardiovascular death and HF hospitalizations in patients with HF with reduced ejection fraction. Methods and Results A total of 5661 patients (1363 women [24%]) with acute myocardial infarction complicated by reduced left ventricular ejection fraction (≤40%), pulmonary congestion, or both and ≥1 of 8 risk-augmenting factors were randomized to receive sacubitril/valsartan or ramipril. The primary outcome was cardiovascular death or incident HF. Baseline characteristics, clinical outcomes, and safety events were compared according to sex, a prespecified subgroup. Female participants were older and had more comorbidities. After multivariable adjustment, women and men were at similar risks for cardiovascular death or all-cause death. Women were more likely to have first HF hospitalization (hazard ratio [HR], 1.34 [95% CI, 1.05-1.70]; P=0.02) and total HF hospitalizations (HR, 1.39 [95% CI, 1.05-1.84]; P=0.02). Sex did not significantly modify the treatment effect of sacubitril/valsartan compared with ramipril on the primary outcome (P for interaction=0.11). Conclusions In contemporary patients who presented with reduced left ventricular ejection fraction, pulmonary congestion, or both, following acute myocardial infarction, women had a higher incidence of HF during follow-up. Sex did not modify the treatment effect of sacubitril/valsartan relative to ramipril. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02924727.


Assuntos
Insuficiência Cardíaca , Infarto do Miocárdio , Feminino , Humanos , Masculino , Ramipril , Caracteres Sexuais , Volume Sistólico , Função Ventricular Esquerda , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/epidemiologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/epidemiologia , Valsartana/uso terapêutico
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