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Paclitaxel, a widely used cancer chemotherapeutic agent, has high incidence of neurotoxicity associated with the production of neuropathic pain, for which only duloxetine has shown significant but moderate analgesic effect. Since statins, classically used to reduce hypercholesterolemia, have shown antinociceptive effect in preclinical studies on neuropathic pain, we studied whether the antinociceptive efficacy of duloxetine could be synergistically potentiated by rosuvastatin in a model of paclitaxel-induced neuropathy in mice. The astrocytic and microglial responses in the spinal cord of paclitaxel-treated mice were also assessed by measuring GFAP and CD11b proteins, respectively. Paclitaxel treatment did not impair motor coordination and balance in rotarod testing. Rosuvastatin, duloxetine, and the rosuvastatin/duloxetine combination (combined at equieffective doses) dose-dependently decreased mechanical allodynia (ED30, von Frey testing) and thermal hyperalgesia (ED50, hot plate testing) in paclitaxel-treated mice. Isobolographic analysis showed a superadditive interaction for rosuvastatin and duloxetine, as both the ED30 and ED50 for the rosuvastatin/duloxetine combination contained only a quarter of each drug compared to the individual drugs. The rosuvastatin/duloxetine combination reversed paclitaxel-induced GFAP overexpression, indicating that such effects might depend in part on astrocyte inactivation. Results suggest that statins could be useful in synergistically enhancing the efficacy of duloxetine in some chemotherapy-induced neuropathic conditions.
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Inibidores de Hidroximetilglutaril-CoA Redutases , Neuralgia , Camundongos , Animais , Paclitaxel/efeitos adversos , Cloridrato de Duloxetina/farmacologia , Cloridrato de Duloxetina/uso terapêutico , Rosuvastatina Cálcica/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Medição da Dor , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Neuralgia/complicações , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Analgésicos/efeitos adversosRESUMO
OBJECTIVE: To investigate the safety and efficacy of short-term (7-day) Dual Antiplatelet Therapy (DAPT) with intensive rosuvastatin in Acute Ischemic Stroke (AIS). METHODS: In this study, patients with AIS in the emergency department of the hospital from October 2016 to December 2019 were registered and divided into the control group (Single Antiplatelet Therapy [SAPT] + rosuvastatin) and the study group (7-day DAPT + intensive rosuvastatin) according to the therapy regimens. The generalized linear model was used to compare the National Institute of Health Stroke Scale (NIHSS) scores between the two groups during the 21-day treatment. A Cox regression model was used to compare recurrent ischemic stroke, bleeding events, Statin-Induced Liver Injury (SILI), and Statin-Associated Myopathy (SAM) between the two groups during the 90-day follow-up. RESULTS: Comparison of NIHSS scores after 21-day treatment: NIHSS scores in the study group decreased significantly, 0.273-times as much as that in the control group (Odds Ratio [OR] 0.273; 95% Confidence Interval [95% CI] 0.208-0.359; p < 0.001). Comparison of recurrent ischemic stroke during the 90-day follow-up: The therapy of the study group reduced the risk of recurrent stroke by 65% (7.76% vs. 22.82%, Hazard Ratio [HR] 0.350; 95% CI 0.167-0.730; p = 0.005). Comparison of bleeding events: There was no statistical difference between the two groups (7.79% vs. 6.71%, HR = 1.076; 95% CI 0.424-2.732; p = 0.878). No cases of SILI and SAM were found. CONCLUSIONS: Short-term DAPT with intensive rosuvastatin effectively relieved the clinical symptoms and significantly reduced the recurrent stroke for patients with mild-to-moderate AIS within 90 days, without increasing bleeding events, SILI and SAM.
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Inibidores de Hidroximetilglutaril-CoA Redutases , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Inibidores da Agregação Plaquetária/efeitos adversos , Rosuvastatina Cálcica/efeitos adversos , Acidente Vascular Cerebral/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hemorragia/induzido quimicamente , Hemorragia/tratamento farmacológico , Quimioterapia Combinada , Resultado do TratamentoRESUMO
Ball-milling using neat grinding (NG) or liquid-assisted grinding (LAG) by varying the polarity of the solvents allowed access to various drug-drug solid forms of pioglitazone hydrochloride (PGZ·HCl) and rosuvastatin calcium (RSV). Using NG, the coamorphous form was formed from the reaction of pioglitazone hydrochloride (PGZ·HCl) and rosuvastatin calcium (RSV) in a 2:1 molar ratio. The formation of the expected coamorphous salt could not be corroborated by FT-IR, but DSC data showed that it was indeed a single-phase amorphous mixture. By varying the molar ratios of the reactants, either keeping PGZ·HCl constant and varying RSV or vice versa, another coamorphous form was obtained when a 1:1 molar ratio was employed. In the case of the other outcomes, it was observed that they were a mixture of solid forms coexisting simultaneously with the coamorphous forms (1:1 or 2:1) together with the drug that was in excess. When RSV was in excess, it was in an amorphous form. In the case of PGZ·HCl, it was found in a semicrystalline form. The intrinsic dissolution rates (IDRs) of the solid forms of PGZ·HCl-RSV in stoichiometric ratios (1:1, 2:1, 1:4, 6:1, and 1:10) were evaluated. Interestingly, a synchronized release of both drugs in the dissolution medium was observed. In the case of the release of RSV, there were no improvements in the dissolution profiles, because the acidic media caused the formation of degradation products, limiting any probable modification in the dissolution processes. However, the coamorphous 2:1 form exhibited an improvement of 1.03 times with respect to pure PGZ·HCl. It is proposed that the modification of the dissolution process of the coamorphous 2:1 form was limited by changes in the pH of the media as RSV consumes protons from the media due to degradation processes.
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This study evaluates the influence of pregnancy and HIV infection in conjunction with the use of raltegravir, lamivudine, and tenofovir disoproxil fumarate (combined antiretroviral therapy [cART]) on intestinal P-glycoprotein (P-gp) and hepatic organic anion transporter polypeptide (OATP) 1B1/1B3 and/or breast cancer resistance protein (BCRP) drug transporter activity using rosuvastatin (OATP1B/BCRP) and fexofenadine (P-gp) probes. Single oral doses of 5-mg rosuvastatin and 60-mg fexofenadine were administered to women living with HIV under cART in the third trimester of gestation (n = 15) and postpartum period (n = 10). A control group of 12 healthy nonpregnant women also was investigated. Pharmacokinetic parameters were estimated by using a noncompartmental method and evaluated by t test (P < .05). The rosuvastatin area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC0-last ) value was higher in the third trimester of pregnancy (19.5 [95%CI, 16.8-22.3] ng ⢠h/mL] when compared to postpartum (13.3 [95%CI, 9.3-17.5] ng ⢠h/mL), while the fexofenadine AUC0-last values did not differ between the third trimester of pregnancy (738.0 [95%CI, 611.4-864.6] ng ⢠h/mL) and postpartum period (874.9 [95%CI, 408.2-1342.0] ng⢠h/mL). The rosuvastatin AUC0-last values did not differ between healthy nonpregnant women (13.8 [95%CI, 10.0-17.6] ng ⢠h/mL) and women living with HIV in the postpartum period (13.3 [95%CI, 9.3-17.5] ng ⢠h/mL), and the fexofenadine AUC0-last values did not differ between the 2 investigated groups (603.6 [95%CI, 467.5-739.7] ng ⢠h/mL vs 874.9 [95%CI, 408.2-1342.0] ng ⢠h/mL). It is suggested that gestation inhibits the hepatic OATP1B1/1B3 and/or BCRP activity but does not alter intestinal P-gp activity. The influence of HIV infection in conjunction with use of cART on OATP1B/BCRP and intestinal P-gp activity was not observed.
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Neoplasias da Mama , Infecções por HIV , Transportadores de Ânions Orgânicos , Humanos , Feminino , Gravidez , Rosuvastatina Cálcica/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Gestantes , Infecções por HIV/tratamento farmacológico , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Interações Medicamentosas , Proteínas de Neoplasias/metabolismoRESUMO
Abstract Objective: To investigate the safety and efficacy of short-term (7-day) Dual Antiplatelet Therapy (DAPT) with intensive rosuvastatin in Acute Ischemic Stroke (AIS). Methods: In this study, patients with AIS in the emergency department of the hospital from October 2016 to December 2019 were registered and divided into the control group (Single Antiplatelet Therapy [SAPT] + rosuvastatin) and the study group (7-day DAPT + intensive rosuvastatin) according to the therapy regimens. The generalized linear model was used to compare the National Institute of Health Stroke Scale (NIHSS) scores between the two groups during the 21-day treatment. A Cox regression model was used to compare recurrent ischemic stroke, bleeding events, Statin-Induced Liver Injury (SILI), and Statin-Associated Myopathy (SAM) between the two groups during the 90-day follow-up. Results: Comparison of NIHSS scores after 21-day treatment: NIHSS scores in the study group decreased significantly, 0.273-times as much as that in the control group (Odds Ratio [OR] 0.273; 95% Confidence Interval [95% CI] 0.208-0.359; p < 0.001). Comparison of recurrent ischemic stroke during the 90-day follow-up: The therapy of the study group reduced the risk of recurrent stroke by 65% (7.76% vs. 22.82%, Hazard Ratio [HR] 0.350; 95% CI 0.167-0.730; p = 0.005). Comparison of bleeding events: There was no statistical difference between the two groups (7.79% vs. 6.71%, HR = 1.076; 95% CI 0.424-2.732; p = 0.878). No cases of SILI and SAM were found. Conclusions: Short-term DAPT with intensive rosuvastatin effectively relieved the clinical symptoms and significantly reduced the recurrent stroke for patients with mild-to-moderate AIS within 90 days, without increasing bleeding events, SILI and SAM.
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Obesity is recognized as an independent risk factor for cardiovascular diseases and is an important contributor to cardiac mortality. Açaí seed extract (ASE), rich in proanthocyanidins, has been shown to have potential anti-obesity effects. This study aimed to investigate the therapeutic effect of ASE in cardiovascular remodeling associated with obesity and compare it with that of rosuvastatin. Male C57BL/6 mice were fed a high-fat diet or a standard diet for 12 weeks. The ASE (300 mg/kg/day) and rosuvastatin (20 mg/kg/day) treatments started in the 8th week until the 12th week, totaling 4 weeks of treatment. Our data showed that treatment with ASE and rosuvastatin reduced body weight, ameliorated lipid profile, and improved cardiovascular remodeling. Treatment with ASE but not rosuvastatin reduced hyperglycemia and oxidative stress by reducing immunostaining of 8-isoprostane and increasing SOD-1 and GPx expression in HFD mice. ASE and rosuvastatin reduced NOX4 expression, increased SIRT-1 and Nrf2 expression and catalase and GPx activities, and improved vascular and cardiac remodeling in HFD mice. The therapeutic effect of ASE was similar to that of rosuvastatin in reducing dyslipidemia and cardiovascular remodeling but was superior in reducing oxidative damage and hyperglycemia, suggesting that ASE was a promising natural product for the treatment of cardiovascular alterations associated with obesity.
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Antioxidantes/uso terapêutico , Cardiomegalia/tratamento farmacológico , Obesidade/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Remodelação Ventricular/efeitos dos fármacos , Animais , Cardiomegalia/etiologia , Dieta Hiperlipídica , Euterpe/química , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/complicações , Proantocianidinas/uso terapêutico , Sementes/químicaRESUMO
Rosuvastatin is a well-known lipid-lowering agent generally used for hypercholesterolemia treatment and coronary artery disease prevention. There is a substantial inter-individual variability in the absorption of statins usually caused by genetic polymorphisms leading to a variation in the corresponding pharmacokinetic parameters, which may affect drug therapy safety and efficacy. Therefore, the investigation of metabolic markers associated with rosuvastatin inter-individual variability is exceedingly relevant for drug therapy optimization and minimizing side effects. This work describes the application of pharmacometabolomic strategies using liquid chromatography coupled to mass spectrometry to investigate endogenous plasma metabolites capable of predicting pharmacokinetic parameters in predose samples. First, a targeted method for the determination of plasma concentration levels of rosuvastatin was validated and applied to obtain the pharmacokinetic parameters from 40 enrolled individuals; then, predose samples were analyzed using a metabolomic approach to search for associations between endogenous metabolites and the corresponding pharmacokinetic parameters. Data processing using machine learning revealed some candidates including sterols and bile acids, carboxylated metabolites, and lipids, suggesting the approach herein described as promising for personalized drug therapy.
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Introduction: Several studies in the literature have evaluated the role of oxidative stress and adjuvant therapies for X-linked adrenoleukodystrophy (X-ALD). Here, we investigated whether n-acetyl-L-cysteine (NAC) and rosuvastatin (RSV) could influence the generation of reactive species, redox status and nitrative stress in fibroblasts from asymptomatic patients with X-ALD. Methods: Skin biopsy samples were cultured and treated for 2 hours (37 °C) with NAC and RSV. Results: X-ALD fibroblasts generated high levels of reactive oxygen species. These levels were significantly lower in fibroblasts treated with NAC and RSV relative to untreated samples. The X-ALD fibroblasts from asymptomatic patients also had higher catalase activity, and only NAC was able to increase enzyme activity in the samples. Conclusions: Our results indicated that NAC and RSV were able to improve oxidative stress parameters in fibroblasts from asymptomatic patients with X-ALD, showing that adjuvant antioxidant therapy may be a promising treatment strategy for asymptomatic patients with this disease. (AU)
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Humanos , Masculino , Feminino , Acetilcisteína , Estresse Oxidativo , Adrenoleucodistrofia/terapia , Rosuvastatina Cálcica , FibroblastosRESUMO
BACKGROUND: Ischemic heart disease is the leading cause of death in the world and is associated with dyslipidemia, high blood pressure, diabetes mellitus, and other factors. OBJECTIVE: To determine the clinical effectiveness on the lipid profile of the rosuvastatin + fenofibric acid combination in Colombian patients with high cardiovascular risk and mixed dyslipidemia. METHODS: Longitudinal observational study in a random sample of patients with a diagnosis of mixed dyslipidemia and moderate, high, or very high cardiovascular risk who were treated with rosuvastatin + fenofibric acid. Anthropometric, clinical, laboratory, comorbidity, and pharmacological variables were identified. Effectiveness on the lipid profile was determined. RESULTS: A total of 386 patients were analyzed. They had a mean age of 60.8 ± 11.4 years, 53.1% were female, and 75.6% had high/very high cardiovascular risk. The initial evaluation showed a mean LDL cholesterol of 138.4 ± 67.1 mg/dL and triglycerides of 679.7 ± 573.6 mg/dL. At the end of follow-up, mean LDL cholesterol was 87.5 ± 41.2 mg/dL (reduced by 43.3%; P < .001), and triglycerides were 243.5 ± 170.5 mg/dL (reduced by 64.2%; P < .001). Only 35.4% (n = 73) of patients with very high risk reached the goal of metabolic control, compared to 61.6% (n = 53) with high risk and 55.4% (n = 46) with moderate risk. Belonging to the very high-risk group was associated with a lower probability of achieving the control goal (OR: 0.32; 95%CI: 0.192-0.539). CONCLUSION: The combination of rosuvastatin + fenofibric acid is an effective option in patients with mixed dyslipidemia and high cardiovascular risk, providing a therapeutic alternative for those conditions that require it.
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Dislipidemias , Fenofibrato , Inibidores de Hidroximetilglutaril-CoA Redutases , Rosuvastatina Cálcica , Idoso , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Colômbia , Método Duplo-Cego , Quimioterapia Combinada , Dislipidemias/tratamento farmacológico , Feminino , Fenofibrato/análogos & derivados , Fenofibrato/uso terapêutico , Fluorbenzenos/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pirimidinas/uso terapêutico , Rosuvastatina Cálcica/uso terapêutico , Sulfonamidas/uso terapêuticoRESUMO
BACKGROUND: The addition of ezetimibe to statin therapy has been reported to result in increased efficacy for reduction of LDL-C levels and achievement of lipid targets, compared with monotherapy. OBJECTIVE: This study was designed to demonstrate the noninferiority of therapy with fixed-dose rosuvastatin plus ezetimibe formulations versus fixed dose simvastatin and ezetimibe formulations for reduction of LDL-C levels in Brazilian patients with hypercholesterolemia or mixed dyslipidemia. METHODS: Phase III, multicenter, randomized, parallel, open-label, noninferiority study that included male and female participants (aged 21-80 years) with hypercholesterolemia or mixed dyslipidemia. After a 1-week screening period with washout of lipid-lowering medications when needed, patients were treated with simvastatin 20 mg/d for 5 weeks. Participants with LDL-C levels ≥100 mg/dL after the initial treatment were submitted to a 1-week washout period, and then randomized 1:1 to receive either combined rosuvastatin 10 mgâ¯+â¯ezetimibe 10 mg (R/E) or simvastatin 20 mgâ¯+â¯ezetimibe 10 mg (S/E) for 4 weeks and, if they still did not achieve the stipulated target, doses were readjusted to rosuvastatin 20 mgâ¯+â¯ezetimibe 10 mg or simvastatin 40 mgâ¯+â¯ezetimibe 10 mg, respectively, for 4 weeks. RESULTS: One hundred twenty-nine participants were enrolled, including 66 in R/E and 63 in S/E. At the end of simvastatin 20 mg treatment period, mean LDL-C values were 124.79 mg/dL and 121.27 mg/dL for participants randomized to R/E and S/E arms, respectively. After 4 weeks of R/E 10 mgâ¯+â¯10 mg or S/E 20 mgâ¯+â¯10 mg combined treatments, adjusted mean LDL-C values were 74.21 mg/dL and 85.58 mg/dL, respectively (Pâ¯=â¯0.0005), and after 9 weeks, with dose adjustment to R/E 20 mgâ¯+â¯10 mg in 6 patients and to S/E 40 mg +10 mg in 19 patients, LDL-C adjusted mean values were 75.29 mg/dL and 86.62 mg/dL, respectively (Pâ¯=â¯0.0006). There was a statistically significant difference between the association R/E and S/E (Pâ¯=â¯0.0013) in percentage change of LDL-C after 9 weeks of combined treatments. The adjusted mean difference was estimated at -10.32% (95% CI, -16.94% to -3.70%). The LDL-C <100 mg/dL target was achieved in a significantly greater proportion of participants at week 4 in the R/E compared with the S/E arm (84.8% vs 68.2%; Pâ¯=â¯.0257), and at week 9, the proportion was 81.2% versus 73.0%, respectively (Pâ¯=â¯0.23). LDL-C <70 mg/dL was achieved at a significantly greater proportion in the R/E arm, both at week 4 (45.4% vs 15.9%; Pâ¯=â¯0.003) and week 9 (40.9% vs 15.9%; Pâ¯=â¯0.0017). A statistically significant difference at week 9 (Pâ¯=â¯0.0106) was observed in fasting blood glucose in the R/E arm, but the overall incidence of adverse events was not significantly different between groups. CONCLUSIONS: Rosuvastatin and ezetimibe fixed dose combination in both 10 mg/10 mg and 20 mg/10 mg doses, respectively, provided significantly lower levels of LDL-C compared with simvastatin and ezetimibe in doses of 20 mg/10 mg and 40 mg/10 mg, respectively. The fixed-dose combinations were both effective and well tolerated in this Brazilian study population. ClinicalTrials.gov identifier: NCT01420549. (Curr Ther Res Clin Exp. 2020; 81:XXX-XXX).
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OBJECTIVES: Obesity is considered a risk factor for the development of non-alcoholic fatty liver disease (NAFLD). The hydroalcoholic extract obtained from the açai seed (ASE), rich in proanthocyanidins, has been shown a potential body weight regulator with antioxidant properties. This study aimed to investigate the therapeutic effect of ASE in obesity-associated NAFLD and compare it with Rosuvastatin. METHODS: Male C57BL/6 mice received a high-fat diet or standard diet for 12 weeks. The treatments with ASE (300 mg/kg per day) or rosuvastatin (20 mg/kg per day) began in the eighth week until the 12th week. KEY FINDINGS: Our data show that the treatments with ASE and rosuvastatin reduced body weight and hyperglycaemia, improved lipid profile and attenuated hepatic steatosis in HFD mice. ASE and Rosuvastatin reduced HMGCoA-Reductase and SREBP-1C and increased ABGC8 and pAMPK expressions in the liver. Additionally, ASE, but not Rosuvastatin, reduced NPC1L1 and increased ABCG5 and PPAR-α expressions. ASE and rosuvastatin increased SIRT-1 expression and antioxidant defence, although only ASE was able to decrease the oxidative damage in hepatic tissue. CONCLUSIONS: The therapeutic effect of ASE was similar to that of rosuvastatin in reducing dyslipidemia and hepatic steatosis but was better in reducing oxidative damage and hyperglycaemia.
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Euterpe , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipolipemiantes/farmacologia , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Obesidade/tratamento farmacológico , Extratos Vegetais/farmacologia , Rosuvastatina Cálcica/farmacologia , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Dislipidemias/metabolismo , Dislipidemias/prevenção & controle , Euterpe/química , Hiperglicemia/metabolismo , Hiperglicemia/prevenção & controle , Hipolipemiantes/isolamento & purificação , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , SementesRESUMO
Rosuvastatin, is a widely-used statin for the treatment of hypercholesterolemia and the prevention of cardiovascular diseases. Although rosuvastatin is well tolerated, about 3/10.000 patients can suffer severe myopathy. Rhabdomyolysis is a severe medical condition that causes injury to the skeletal muscle, electrolyte imbalances, acute renal failure and extreme creatine kinase (CK) elevation. Little is known regarding the molecular involvement of rosuvastatin-induced rhabdomyolysis (RIR). It has been demonstrated that genomic variants associated with decreased enzymatic activity of proteins are important determinants in plasmatic and skeletal muscle distribution of rosuvastatin and its toxicity. Until now, no interactions of ticagrelor, ezetimibe and rosuvastatin have been described with the consideration of pharmacogenomics predisposition. The present report involves a whole-exome sequencing (WES), in a patient affected by rosuvastatin-induced rhabdomyolysis. A pharmacogenomic dissection was performed by analyzing a comprehensive subset of candidate genes (n=160) potentially related to RIR. The genes were selected according to their implication in drug metabolism or inherited myopathies. Using an innovative approach of bioinformatics analysis, considering rare and common variants, we identified 19 genomic variations potentially related to the pharmacokinetic/pharmacodynamic modifications of rosuvastatin, ezetimibe and ticagrelor. The affected genes are involved in Phase I metabolism (CYP2C19, CYP2E1, CYP1A1, CYP2D6 and CYP2C9), Phase II metabolism (UGT2B15 and UGT2B7), influx transportation (SLCO1B3 and SLCO2B1), efflux transportation (ABCG8, ABCB11, ABCC4 and ABCB1), drug targeting (NPC1L1) and inherited myopathy etiology (OBSCN). We report three rare, potentially pathogenic molecular variants in CYP2C19, NPC1L1 and OBSCN genes. Pharmacogenetic analysis indicated that the patient was a carrier of inactivating alleles in several pharmacogenes involved in drug toxicity. The whole-exome sequencing and bioinformatics analysis presented here represents an innovative way to identify genomic variants contributing with RIR´s origin and evokes the polygenic nature of adverse drug reactions.
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Many obese patients are exposed to hypolipidemic and serotonin-norepinephrine reuptake inhibitor (SNRI) drugs. Statins are one of the most marketed drugs in the world to treat dyslipidemia, while sibutramine, a SNRI drug, is prescribed in some countries to treat obesity and is detected as an additive in many adulterated weight loss supplements marketed worldwide. Previous studies reported adverse effects of isolated exposure to these drugs on male rat reproductive parameters. In the present work, we further investigated male reproductive toxicity of these drugs, administered in isolation or combination in adult rats for a longer period of treatment. Adult male rats (90 days) were treated (gavage) for 70 days with saline and dimethyl sulfoxide (control), sibutramine (10 mg/kg), rosuvastatin (5 mg/kg), or rosuvastatin combined with sibutramine. Sibutramine alone or with rosuvastatin, promoted a reduction in food intake and body weight gain, weight of the epididymis, ventral prostate and seminal vesicle; as well as decreased sperm reserves and transit time through the epididymis; androgen depletion; and increased index of cytoplasmic droplet. The rosuvastatin-treated group showed reduced frequency of ejaculation. Exposure to this drug alone or combined with sibutramine impaired epididymal morphology. Co-exposed rats had altered epididymal morphometry, and seminal vesicle and testis weights. The rats also showed decreased fertility after natural mating and a trend toward a delay in ejaculation, suggesting a small synergistic effect of these drugs. Given the greater reproductive efficiency of rodents, the results obtained in the present study raise concern regarding possible fertility impairment in men taking statins and SNRI drugs.
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Ciclobutanos/toxicidade , Ciclobutanos/uso terapêutico , Obesidade/tratamento farmacológico , Fenômenos Reprodutivos Fisiológicos/efeitos dos fármacos , Rosuvastatina Cálcica/toxicidade , Rosuvastatina Cálcica/uso terapêutico , Testículo/efeitos dos fármacos , Adulto , Animais , Humanos , Masculino , Modelos Animais , Ratos , Ratos WistarRESUMO
In this work, it is shown the development and validation of innovative analytical methodology based on solid-phase extraction (SPE) with molecularly imprinted polymers (MIP) as a sorbent associated to UV-Vis spectroscopy to isolate and quantify, respectively, rosuvastatin (RSV) in water samples. For this purpose, porogenic solvent in MIP synthesis and SPE extraction parameters for MIP and non-imprinted polymers (NIP) were evaluated univariately for comparison purposes. The sorptive capacity and characterization studies by infrared spectroscopy and atomic force microscopy showed difference between MIP and NIP. The selectivity study of the MIP-RSV against other statins (simvastatin and atorvastatin) showed that the synthesized MIP can also be applied as a solid phase for isolation and quantitative pre-concentration of RSV and atorvastatin. The conjugation of SPE and UV-Vis spectroscopy in the determination of RSV in aqueous matrices led to large factor of pre-concentration (125 times), limit of detection (LOD) of 3 µg L-1, limit of quantification (LOQ) of 10 µg L-1, precision of 2.87% (n = 10), and accuracy of 83.1% (n = 4).
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Impressão Molecular , Polímeros , Cromatografia Líquida de Alta Pressão , Rosuvastatina Cálcica , Extração em Fase Sólida , Abastecimento de ÁguaRESUMO
The cardioprotective activity of rosuvastatin (R) is yet to be known. The objective of this study was to research whether R perfusion before global ischemia can mitigate myocardial ischemia-reperfusion damage, considering the metabolic condition in which these effects occur, and to contemplate potential mitochondrial benefits. Protein kinase B (Akt)/glycogen synthase kinase-3ß (GSK-3ß) and mitochondrial permeability transition pore (MPTP) are key elements in myocardial injury produced by ischemia-reperfusion. Isolated rat hearts were subjected to 25-min ischemia and 1-h reperfusion in the presence or absence of R, with or without Wortmannin (W), a phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor. Akt and GSK-3ß were measured by Western blot analysis; lactate, glycogen, and G6PDH were determined; and Ca2+-induced MPTP opening was evaluated using a spectrophotometric method. Contractility was assessed by left ventricular developed pressure (LVDP), and rate-pressure product (RPP), peak rate of contraction and peak rate of relaxation (± dP/dt), and left ventricular end-diastolic pressure (LVEDP) were determined. Tissue samples were extracted to evaluate mitochondrial damage by electron microscopy and to assess infarct size. Statistical analysis employed ANOVA (n = 6/per group). Myocardial infarct size was significantly reduced by R, which also improved cardiac function. MPTP opening was delayed to 300 µM CaCl2, while use of W resulted in MPTP opening at 200 µM CaCl2. Electron microscopy showed better mitochondrial preservation with R, which reduced lactic acid production, increased glycogen consumption and G6PDH activity, as well as phosphorylation of Akt and GSK-3ß. R before ischemia is cardioprotective against ischemic and reperfusion damage, activating Akt and regulating GSK-3ß negatively and attenuating the MPTP opening.
Assuntos
Cardiotônicos/uso terapêutico , Glicogênio Sintase Quinase 3 beta/metabolismo , Mitocôndrias Cardíacas/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rosuvastatina Cálcica/uso terapêutico , Animais , Feminino , Coração/efeitos dos fármacos , Técnicas In Vitro , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , Infarto do Miocárdio/patologia , Ratos , Ratos WistarRESUMO
Statins are a class of drugs that act lowering lipid levels by inhibiting cholesterol biosynthesis. Additionally, statins can act by "pleiotropic effects", related to the inhibition of synthesis of the other mevalonate pathway products. Rosuvastatin is a third-generation statin and has shown better results in reducing cholesterol concentrations when compared to other statins. Recent studies suggest that rosuvastatin may act as an endocrine disruptor that potentially damages the hormonal axis and, consequently reproductive development and function of male rats. However, the effects of rosuvastatin exposure on rat female reproductive parameters remain unknown. In this study female rats were exposed to rosuvastatin at the doses of 0 (control), 3, or 10 mg/Kg.bw-1/day from pre-puberty to adulthood. No alterations in the female reproductive parameters were observed at a dose of 3 mg/Kg.bw-1. However, females exposed to 10 mg/Kg.bw-1 exhibited shorter estrous cycles, altered copulatory behavior, decreased serum prolactin level, and alterations in the liver, pituitary and placental weights, parameters to some extent influenced by the reproductive hormonal axis signaling pathway. On the other hand, pubertal onset, reproductive hormone levels, fertility, and histological parameters of the ovary, uterus, and placenta were unaltered by exposure to both doses of this statin. Thus, rosuvastatin exposure, at the higher dose, altered the reproductive function of female rats, probably due to the pleiotropic effects of this statin. Additional studies on the effects of this statin on female reproductive function and development are encouraged to better characterize its mode of action.
RESUMO
Statins are prescribed to prevent and treat atherosclerotic cardiovascular and metabolic diseases but have controversial effects on skeletal muscles. While statins are a reported cause of myopathy, some studies have suggested that statins could potentially ameliorate dystrophy due to their pleiotropic effects on inflammation, myonecrosis, and autophagy. In the present study, we evaluated the potential benefit of rosuvastatin treatment on heart, limb, and diaphragm muscles in dystrophin-deficient mdx mice at an early stage (45 days of age) of disease. Mdx mice received rosuvastatin (10 mg/kg) by gavage for 30 days beginning at 15 days of age. Normal C57BL/10 mice received rosuvastatin by the same route over the same interval. In the mdx group, rosuvastatin significantly increased IgG-positive fibers (myonecrosis) and the inflammatory areas in the biceps brachii and diaphragm muscles and decreased the anterior limb muscle force (grip strength). Molecular markers of inflammation (TNF-α and NF-kB) and fibrosis (fibronectin) were not altered by rosuvastatin in mdx mice skeletal and cardiac muscles. In normal mice, rosuvastatin increased CK, TNF-α (heart), NF-kB (diaphragm), and fibronectin (heart and diaphragm). Inflammatory areas were seen in all normal muscles of rosuvastatin-treated mice. Rosuvastatin did not benefit dystrophy in the mdx mice and was associated with inflammation in normal cardiac and skeletal muscles.
Assuntos
Coração/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Músculo Esquelético/efeitos dos fármacos , Distrofia Muscular Animal/metabolismo , Rosuvastatina Cálcica/farmacologia , Animais , Diafragma/efeitos dos fármacos , Diafragma/metabolismo , Modelos Animais de Doenças , Fibronectinas/metabolismo , Camundongos , Camundongos Endogâmicos mdx , Miocárdio/metabolismo , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Metabolic syndrome is a multifaceted condition associated with a greater risk of various disorders (e.g., diabetes and heart disease). In a rat model of metabolic syndrome, an acute in vitro application of rosuvastatin causes relaxation of aortic rings. Since the outcome of a subchronic rosuvastatin treatment is unknown, the present study explored its effect on acetylcholine-induced vasorelaxation of aortic rings from rats with metabolic syndrome. Animals were submitted to a 16-week treatment, including a standard diet, a cafeteria-style diet (CAF-diet), or a CAF-diet with daily rosuvastatin treatment (10 mg/kg). After confirming the development of metabolic syndrome in rats, aortic segments were extracted from these animals (those treated with rosuvastatin and untreated) and the acetylcholine-induced relaxant effect on the corresponding rings was evaluated. Concentration-response curves were constructed for this effect in the presence/absence of L-NAME, ODQ, KT 5823, 4-aminopyridine (4-AP), tetraethylammonium (TEA), apamin plus charybdotoxin, glibenclamide, indomethacin, clotrimazole, and cycloheximide pretreatment. Compared to rings from control rats, acetylcholine-induced vasorelaxation decreased in rings from animals with metabolic syndrome, and was maintained at a normal level in animals with metabolic syndrome plus rosuvastatin treatment. The effect of rosuvastatin was inhibited by L-NAME, ODQ, KT 5823, TEA, apamin plus charybdotoxin, but unaffected by 4-AP, glibenclamide, indomethacin, clotrimazole, or cycloheximide. In conclusion, the subchronic administration of rosuvastatin to rats with metabolic syndrome improved the acetylcholine-induced relaxant response, involving stimulation of the NO/cGMP/PKG/Ca2+-activated K+ channel pathway.
Assuntos
Animais , Masculino , Ratos , Aorta/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Acetilcolina/farmacologia , Síndrome Metabólica/fisiopatologia , Rosuvastatina Cálcica/farmacologia , Vasodilatadores , Endotélio Vascular/fisiopatologia , Ratos Wistar , Modelos Animais de DoençasRESUMO
Abstract This study aimed to investigate the cardioprotection of rosuvastatin pre-conditioning (R-Pre) in a rat model of myocardial ischemia / reperfusion (I/R). Male SD rats were assigned into three groups: sham group, I/R group and R-Pre group. Rats in I/R group and R-Pre group received ischemia for 30 min and reperfusion for 2 h. In R-Pre group, rats received intragastrical administration with rosuvastatin at 5 mg/kg once daily for 1 week. After 2-h reperfusion, the cardiac function was detected by ultrasonography; the blood was collected for biochemical analysis; the heart was collected for the TUNEL staining and immunohistochemistry for Bcl-2 and Bax. Our results showed rosuvastatin pre-conditioning for 1 week could significantly reduce the infarct ratio and improve the cardiac function after myocardial I/R injury, in which attenuation of oxidative stress and cell apoptosis played an important role. Our study provides evidence on the cardioprotection of rosuvastatin pre-conditioning and highlight the use of rosuvastatin before cardiopulmonary bypass.
Assuntos
Animais , Ratos , Reperfusão Miocárdica , Isquemia/terapia , Cardiotônicos/administração & dosagem , Apoptose , Estresse Oxidativo , Modelos Animais , Rosuvastatina Cálcica/administração & dosagemRESUMO
X-linked adrenoleukodystrophy (X-ALD) is an inherited neurometabolic disorder caused by disfunction of the ABCD1 gene, which encodes a peroxisomal protein responsible for the transport of the very long-chain fatty acids from the cytosol into the peroxisome, to undergo ß-oxidation. The mainly accumulated saturated fatty acids are hexacosanoic acid (C26:0) and tetracosanoic acid (C24:0) in tissues and body fluids. This peroxisomal disorder occurs in at least 1 out of 20,000 births. Considering that pathophysiology of this disease is not well characterized yet, and glial cells are widely used in studies of protective mechanisms against neuronal oxidative stress, we investigated oxidative damages and inflammatory effects of vesicles containing lecithin and C26:0, as well as the protection conferred by N-acetyl-L-cysteine (NAC), trolox (TRO), and rosuvastatin (RSV) was assessed. It was verified that glial cells exposed to C26:0 presented oxidative DNA damage (measured by comet assay and endonuclease III repair enzyme), enzymatic oxidative imbalance (high catalase activity), nitrative stress [increased nitric oxide (NO) levels], inflammation [high Interleukin-1beta (IL-1ß) levels], and induced lipid peroxidation (increased isoprostane levels) compared to native glial cells without C26:0 exposure. Furthermore, NAC, TRO, and RSV were capable to mitigate some damages caused by the C26:0 in glial cells. The present work yields experimental evidence that inflammation, oxidative, and nitrative stress may be induced by hexacosanoic acid, the main accumulated metabolite in X-ALD, and that antioxidants might be considered as an adjuvant therapy for this severe neurometabolic disease.