RESUMEN
BACKGROUND: Poststroke cognitive impairment is prevalent worldwide, with no satisfactory preventative therapeutic strategies. We report on the effect of a cardiovascular polypill on cognitive performance among recent stroke survivors. METHODS AND RESULTS: The SMAART (Stroke Minimization through Additive Anti-atherosclerotic Agents in Routine Treatment) trial was a phase II randomized trial primarily assessing the polypill versus usual care for secondary prevention after a recent ischemic stroke. Participants allocated to the experimental arm were provided 2 Polycaps taken orally once a day for 12 months. A capsule of Polycap contained aspirin 100 mg, simvastatin 20 mg, hydrochlorothiazide 12.5 mg, ramipril 5 mg, and atenolol 50 mg. Participants in the usual care arm received standard secondary prevention therapy. We compared slopes of the trajectory of raw scores in the executive, language, memory, and visuospatial cognitive domains and aggregated cognitive scores over 12 months via a linear mixed-effects model. We enrolled 148 eligible participants (n=74 in each arm) and 59 versus 64 participants in the polypill and usual care arms, respectively, at month 12. Compared with the usual care arm, the slopes of cognitive performance over 12 months in the polypill arm were steeper by 2.02 units (95% CI, 0.52-3.53), P=0.009 in executive domain, 1.88 units (95% CI, 0.42-3.34), P=0.012 in language domain, 2.60 (0.03-5.17), P=0.049 in memory domain, 0.55 (-0.80 to 1.91), P=0.42 in the visuospatial domain, and global cognitive performance 6.87 units (95% CI, 1.44-12.30), P=0.013. CONCLUSIONS: The cardiovascular polypill is associated with a signal of better cognitive performance over 12 months among stroke survivors. Further definitive trials are warranted. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT03329599.
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Atenolol , Cognición , Combinación de Medicamentos , Hidroclorotiazida , Humanos , Femenino , Masculino , Persona de Mediana Edad , Cognición/efectos de los fármacos , Hidroclorotiazida/administración & dosificación , Atenolol/administración & dosificación , Atenolol/uso terapéutico , Aspirina/administración & dosificación , Prevención Secundaria/métodos , Anciano , Simvastatina/administración & dosificación , Simvastatina/uso terapéutico , Ramipril/administración & dosificación , Ramipril/uso terapéutico , Accidente Cerebrovascular Isquémico , Resultado del Tratamiento , Accidente Cerebrovascular , Factores de TiempoRESUMEN
Ramipril is an angiotensin-converting enzyme inhibitor used for hypertension and heart failure management. To date, scarce literature is available on pharmacogenetic associations affecting ramipril. The goal of this study was to investigate the effect of 120 genetic variants in 34 pharmacogenes (i.e., genes encoding for enzymes like CYPs or UGTs and transporters like ABC or SLC) on ramipril pharmacokinetic variability and adverse drug reaction (ADR) incidence. Twenty-nine healthy volunteers who had participated in a single-dose bioequivalence clinical trial of two formulations of ramipril were recruited. A univariate and multivariate analysis searching for associations between genetic variants and ramipril pharmacokinetics was performed. SLCO1B1 and ABCG2 genotype-informed phenotypes strongly predicted ramipril exposure. Volunteers with the SLCO1B1 decreased function (DF) phenotype presented around 1.7-fold higher dose/weight-corrected area under the curve (AUC/DW) than volunteers with the normal function (NF) phenotype (univariate p-value [puv] < 0.001, multivariate p-value [pmv] < 0.001, ß = 0.533, R2 = 0.648). Similarly, volunteers with ABCG2 DF + poor function (PF) phenotypes presented around 1.6-fold higher AUC/DW than those with the NF phenotype (puv = 0.011, pmv < 0.001, ß = 0.259, R2 = 0.648). Our results suggest that SLCO1B1 and ABCG2 are important transporters to ramipril pharmacokinetics, and their genetic variation strongly alters its pharmacokinetics. Further studies are required to confirm these associations and their clinical relevance.
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Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Inhibidores de la Enzima Convertidora de Angiotensina , Genotipo , Transportador 1 de Anión Orgánico Específico del Hígado , Proteínas de Neoplasias , Fenotipo , Ramipril , Humanos , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Ramipril/farmacocinética , Ramipril/administración & dosificación , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Masculino , Adulto , Inhibidores de la Enzima Convertidora de Angiotensina/farmacocinética , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Adulto Joven , Femenino , Voluntarios Sanos , Área Bajo la Curva , Variantes Farmacogenómicas , FarmacogenéticaRESUMEN
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.
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Antihipertensivos , Hipertensión , Nebivolol , Ramipril , Humanos , Nebivolol/administración & dosificación , Nebivolol/uso terapéutico , Ramipril/administración & dosificación , Ramipril/uso terapéutico , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Europa (Continente) , Anciano , Antihipertensivos/administración & dosificación , Antihipertensivos/uso terapéutico , Estudios Retrospectivos , Cumplimiento de la Medicación/estadística & datos numéricos , Adulto , Combinación de Medicamentos , Quimioterapia CombinadaRESUMEN
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.
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Antihipertensivos , Glucemia , Presión Sanguínea , Diabetes Mellitus Tipo 2 , Quimioterapia Combinada , Frecuencia Cardíaca , Hipertensión , Imidazoles , Sobrepeso , Ramipril , Humanos , Ramipril/administración & dosificación , Ramipril/uso terapéutico , Ramipril/farmacología , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Femenino , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Método Doble Ciego , Imidazoles/farmacología , Imidazoles/uso terapéutico , Imidazoles/administración & dosificación , Antihipertensivos/uso terapéutico , Antihipertensivos/farmacología , Antihipertensivos/efectos adversos , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Sobrepeso/tratamiento farmacológico , Sobrepeso/fisiopatología , Sobrepeso/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/fisiopatología , Anciano , Adulto , Resultado del Tratamiento , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversosRESUMEN
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 10âweeks 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 53â±â10 (SD) years, male individuals 60%, baseline systolic OBP, HBP, and 24âh ABP 144â±â9, 138â±â10, and 143â±â10âmmHg, respectively]. Post-treatment minus pre-treatment systolic CV difference was: OBP: 0.3%, P â=â0.28; HBP: -0.2%, P â=â0.20; 24âh ABP: 1.1%, P â<â0.001. 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 â<â0.05/<â0.001, 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.
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Antihipertensivos , Monitoreo Ambulatorio de la Presión Arterial , Presión Sanguínea , Hipertensión , Humanos , Masculino , Persona de Mediana Edad , Antihipertensivos/uso terapéutico , Femenino , Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Monitoreo Ambulatorio de la Presión Arterial/métodos , Adulto , Ramipril/uso terapéutico , Anciano , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Nifedipino/uso terapéuticoRESUMEN
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.
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Inhibidores de la Enzima Convertidora de Angiotensina , Insuficiencia Cardíaca , Ramipril , Humanos , Ramipril/farmacocinética , Ramipril/administración & dosificación , Ramipril/análogos & derivados , Insuficiencia Cardíaca/tratamiento farmacológico , Masculino , Inhibidores de la Enzima Convertidora de Angiotensina/farmacocinética , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Anciano , Femenino , Estudios Longitudinales , Enfermedad Crónica , Anciano de 80 o más Años , Persona de Mediana Edad , Composición CorporalAsunto(s)
Fármacos Cardiovasculares , Insuficiencia Cardíaca , Infarto del Miocardio , Humanos , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/prevención & control , Infarto del Miocardio/complicaciones , Infarto del Miocardio/tratamiento farmacológico , Factores de Riesgo , Fármacos Cardiovasculares/uso terapéutico , Factores de Riesgo de Enfermedad Cardiaca , Enfermedad Crónica , Antagonistas de Receptores de Angiotensina/uso terapéutico , Ramipril/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Volumen Sistólico , Disfunción Ventricular Izquierda/tratamiento farmacológico , Disfunción Ventricular Izquierda/etiología , Ensayos Clínicos como AsuntoRESUMEN
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.
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Administración Rectal , Preparaciones de Acción Retardada , Presión Intraocular , Profármacos , Ramipril , Animales , Conejos , Presión Intraocular/efectos de los fármacos , Profármacos/administración & dosificación , Profármacos/farmacocinética , Profármacos/farmacología , Ramipril/administración & dosificación , Ramipril/farmacocinética , Ramipril/farmacología , Supositorios , Masculino , Disponibilidad Biológica , Antihipertensivos/administración & dosificación , Antihipertensivos/farmacocinética , Antihipertensivos/farmacología , Lípidos/química , Liberación de Fármacos , Administración Oral , PolietilenglicolesRESUMEN
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.
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Losartán , Sepsis , Animales , Ratas , Losartán/farmacología , Losartán/uso terapéutico , Ramipril/farmacología , Ramipril/uso terapéutico , Espironolactona/farmacología , Espironolactona/uso terapéutico , Punciones , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , HígadoRESUMEN
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).
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Insuficiencia Cardíaca , Infarto del Miocardio , Infarto del Miocardio sin Elevación del ST , Infarto del Miocardio con Elevación del ST , Disfunción Ventricular Izquierda , Humanos , Neprilisina , Ramipril , Infarto del Miocardio con Elevación del ST/tratamiento farmacológico , Infarto del Miocardio sin Elevación del ST/tratamiento farmacológico , Angiotensinas , Receptores de Angiotensina , Estudios Prospectivos , Tetrazoles/farmacología , Resultado del Tratamiento , Valsartán , Aminobutiratos/farmacología , Compuestos de Bifenilo , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Disfunción Ventricular Izquierda/inducido químicamente , Antagonistas de Receptores de Angiotensina/farmacologíaRESUMEN
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.
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Fármacos Cardiovasculares , Hipertensión , Humanos , Antihipertensivos/efectos adversos , Ritmo Circadiano , Ramipril/farmacología , Ramipril/uso terapéutico , Factores de Riesgo , Monitoreo Ambulatorio de la Presión Arterial , Ensayos Clínicos como Asunto , Hipertensión/tratamiento farmacológico , Presión SanguíneaRESUMEN
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.
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Antioxidantes , Daño por Reperfusión , Femenino , Ratas , Animales , Antioxidantes/farmacología , Ramipril/farmacología , Ratas Wistar , Oxidantes/farmacología , Citocinas , Isquemia , Daño por Reperfusión/etiología , Daño por Reperfusión/prevención & control , Daño por Reperfusión/patología , Reperfusión , Malondialdehído , Estrés OxidativoRESUMEN
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.
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Insuficiencia Cardíaca , Hiperpotasemia , Hipotensión , Infarto del Miocardio , Humanos , Ramipril/uso terapéutico , Ramipril/farmacología , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Antagonistas de Receptores de Mineralocorticoides/farmacología , Hiperpotasemia/tratamiento farmacológico , Estudios Prospectivos , Tetrazoles/uso terapéutico , Tetrazoles/farmacología , Antagonistas de Receptores de Angiotensina/efectos adversos , Valsartán/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Aminobutiratos/efectos adversos , Combinación de Medicamentos , Hipotensión/inducido químicamente , Infarto del Miocardio/complicaciones , Infarto del Miocardio/tratamiento farmacológico , Volumen SistólicoRESUMEN
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.
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Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Terfenadina/análogos & derivados , Humanos , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/complicaciones , Ramipril/uso terapéutico , Diabetes Mellitus Tipo 2/complicaciones , Pruebas de Función Renal , Tasa de Filtración Glomerular , Albuminuria/complicacionesRESUMEN
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.
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Inhibidores de la Enzima Convertidora de Angiotensina , Psoriasis , Humanos , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Ramipril/efectos adversos , Lisinopril/farmacología , Perindopril/efectos adversos , Farmacovigilancia , Análisis de la Aleatorización Mendeliana , Enalapril/farmacología , Psoriasis/tratamiento farmacológico , Psoriasis/genéticaRESUMEN
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.
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Ramipril/análogos & derivados , Espectrometría de Masas en Tándem , Humanos , Cromatografía Liquida , Toxicología ForenseRESUMEN
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.
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Nefritis Hereditaria , Podocitos , Humanos , Ratones , Animales , Integrina alfa1/genética , Integrina alfa1/metabolismo , Ramipril/farmacología , Ramipril/metabolismo , Longevidad , Membrana Basal Glomerular/metabolismo , Nefritis Hereditaria/tratamiento farmacológico , Nefritis Hereditaria/genética , Nefritis Hereditaria/metabolismo , Podocitos/metabolismo , Laminina/genética , Laminina/metabolismo , Ratones Noqueados , Proteinuria/tratamiento farmacológico , Proteinuria/genética , Proteinuria/metabolismo , Análisis de Secuencia de ARNRESUMEN
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.
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Convolvulaceae , Hipertensión , Humanos , Ramipril/uso terapéutico , Ramipril/farmacología , Proteína C-Reactiva , Interleucina-6 , Antihipertensivos/uso terapéutico , Antihipertensivos/farmacología , Hipertensión/tratamiento farmacológico , Presión Sanguínea , Cefalea/tratamiento farmacológico , Hipertensión Esencial/tratamiento farmacológicoRESUMEN
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.
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Distrofia Muscular de Emery-Dreifuss , Ramipril , Masculino , Humanos , Adulto , Volumen Sistólico , Función Ventricular Izquierda , Distrofia Muscular de Emery-Dreifuss/diagnóstico , Distrofia Muscular de Emery-Dreifuss/genética , Distrofia Muscular de Emery-Dreifuss/terapia , DisneaRESUMEN
Danon disease is a rare X-linked genetic disease resulting from LAMP2 mutations leading to defective lysosomal function. Heart failure is the main causes of morbidity and mortality. Mice with an LAMP2-exon-6-deletion (L2Δ6), develop cardiac hypertrophy followed by dilated cardiomyopathy, in association with accumulation of autophagosomes, fibrosis and oxidative stress. We investigated the effect of drugs used to treat heart failure and of LAMP2 gene therapy on the phenotype, molecular markers and ROS in LAMP2 cardiomyopathy. L2Δ6 mice were treated with Angiotensin II, Ramipril, Metoprolol or Spironolactone. Gene therapy was delivered by IP injection of Adeno-associated-virus (AAV9) -LAMP2 vector to neonates ("AAVLAMP2-Prevention"), or at 15 weeks of age ("AAVLAMP2-Treatment"). Angiotensin II markedly aggravated the cardiac phenotype. Ramipril and Spironolactone were effective in attenuating left ventricular hypertrophy and preserving the systolic function. Cardiac protection was associated with decreased autophagosome accumulation, reduced fibrosis and oxidative stress. Gene therapy effectively attenuated autophagosome accumulation and ROS in L2Δ6 hearts, lowering troponin release to nearly normal levels. AAVLAMP2-Prevention protected against systolic dysfunction and decreased hypertrophy. AAVLAMP2-Treatment prevented ventricular dilatation and dysfunction but had no effect on wall thickness. We conclude that RAAS inhibitors are highly effective against cardiomyopathy progression in an experimental mouse model of Danon's and shall be considered in human patients for this purpose until novel therapies become clinically available.