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Introduction: Gestation under chronic hypoxia causes pulmonary hypertension, cardiovascular remodeling, and increased aortic stiffness in the offspring. To mitigate the neonatal cardiovascular risk, pharmacological treatments (such as hemin and sildenafil) have been proposed to improve pulmonary vasodilation. However, little is known about the effects of these treatments on the aorta. Therefore, we studied the effect of hemin and sildenafil treatments in the aorta of lambs gestated and raised at highlands, thereby subjected to chronic hypoxia. Methods: Several biomechanical tests were conducted in the descending thoracic aorta (DTA) and the distal abdominal aorta (DAA), assessing 3 groups of study of hypoxic animals: non-treated (Control) and treated either with hemin or sildenafil. Based on them, the stiffness level has been quantified in both zones, along with the physiological strain in the unloaded aortic duct. Furthermore, a morphological study by histology was conducted in the DTA. Results: Biomechanical results indicate that treatments trigger an increment of axial pre-stress and circumferential residual stress levels in DTA and DAA of lambs exposed to high-altitude chronic hypoxia, which reveals a vasodilatation improvement along with an anti-hypertensive response under this characteristic environmental condition. In addition, histological findings do not reveal significant differences in either structure or microstructural content. Discussion: The biomechanics approach emerges as a valuable study perspective, providing insights to explain the physiological mechanisms of vascular function. According to established results, alterations in the function of the aortic wall may not necessarily be explained by morphostructural changes, but rather by the characteristic mechanical state of the microstructural components that are part of the studied tissue. In this sense, the reported biomechanical changes are beneficial in mitigating the adverse effects of hypobaric hypoxia exposure during gestation and early postnatal life.
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Drug repurposing is defined as the use of approved therapeutic drugs for indications different from those for which they were originally designed. Repositioning diminishes both the time and cost for drug development by omitting the discovery stage, the analysis of absorption, distribution, metabolism, and excretion routes, as well as the studies of the biochemical and physiological effects of a new compound. Besides, drug repurposing takes advantage of the increased bioinformatics knowledge and availability of big data biology. There are many examples of drugs with repurposed indications evaluated in in vitro studies, and in pharmacological, preclinical, or retrospective clinical analyses. Here, we briefly review some of the experimental strategies and technical advances that may improve translational research in cardiovascular diseases. We also describe exhaustive research from basic science to clinical studies that culminated in the final approval of new drugs and provide examples of successful drug repurposing in the field of cardiology.
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Background: Familial Alzheimer's disease (FAD) presenilin 1 E280A (PSEN 1 E280A) is characterized by functional impairment and the death of cholinergic neurons as a consequence of amyloid-ß (Aß) accumulation and abnormal phosphorylation of the tau protein. Currently, there are no available therapies that can cure FAD. Therefore, new therapies are urgently needed for treating this disease. Objective: To assess the effect of sildenafil (SIL) on cholinergic-like neurons (ChLNs) harboring the PSEN 1 E280A mutation. Methods: Wild-type (WT) and PSEN 1 E280A ChLNs were cultured in the presence of SIL (25µM) for 24âh. Afterward, proteinopathy, cell signaling, and apoptosis markers were evaluated via flow cytometry and fluorescence microscopy. Results: We found that SIL was innocuous toward WT PSEN 1 ChLNs but reduced the accumulation of intracellular Aß fragments by 87%, decreased the non-physiological phosphorylation of the protein tau at residue Ser202/Thr205 by 35%, reduced the phosphorylation of the proapoptotic transcription factor c-JUN at residue Ser63/Ser73 by 63%, decreased oxidized DJ-1 at Cys106-SO3 by 32%, and downregulated transcription factor TP53 (tumor protein p53), BH-3-only protein PUMA (p53 upregulated modulator of apoptosis), and cleaved caspase 3 (CC3) expression by 20%, 32%, and 22%, respectively, compared with untreated mutant ChLNs. Interestingly, SIL also ameliorated the dysregulation of acetylcholine-induced calcium ion (Ca2+) influx in PSEN 1 E280A ChLNs. Conclusions: Although SIL showed no antioxidant capacity in the oxygen radical absorbance capacity and ferric ion reducing antioxidant power assays, it might function as an anti-amyloid and antiapoptotic agent and functional neuronal enhancer in PSEN 1 E280A ChLNs. Therefore, the SIL has therapeutic potential for treating FAD.
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Doença de Alzheimer , Neurônios Colinérgicos , Mutação , Presenilina-1 , Citrato de Sildenafila , Presenilina-1/genética , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/metabolismo , Neurônios Colinérgicos/patologia , Mutação/genética , Animais , Citrato de Sildenafila/farmacologia , Peptídeos beta-Amiloides/metabolismo , Humanos , Células Cultivadas , Camundongos , Proteínas tau/metabolismo , Proteínas tau/genética , Fosforilação/efeitos dos fármacos , FenótipoRESUMO
OBJECTIVE: To test feasibility and safety of administering sildenafil in neonates with neonatal encephalopathy (NE), developing brain injury despite therapeutic hypothermia (TH). STUDY DESIGN: We performed a randomized, double-blind, placebo-controlled phase Ib clinical trial between 2016 and 2019 in neonates with moderate or severe NE, displaying brain injury on day-2 magnetic resonance imaging (MRI) despite TH. Neonates were randomized (2:1) to 7-day sildenafil or placebo (2 mg/kg/dose enterally every 12 hours, 14 doses). Outcomes included feasibility and safety (primary outcomes), pharmacokinetics (secondary), and day-30 neuroimaging and 18-month neurodevelopment assessments (exploratory). RESULTS: Of the 24 enrolled neonates, 8 were randomized to sildenafil and 3 to placebo. A mild decrease in blood pressure was reported in 2 of the 8 neonates after initial dose, but not with subsequent doses. Sildenafil plasma steady-state concentration was rapidly reached, but decreased after TH discontinuation. Twelve percent of neonates (1/8) neonates died in the sildenafil group and 0% (0/3) in the placebo group. Among surviving neonates, partial recovery of injury, fewer cystic lesions, and less brain volume loss on day-30 magnetic resonance imaging were noted in 71% (5/7) of the sildenafil group and in 0% (0/3) of the placebo group. The rate of death or survival to 18 months with severe neurodevelopmental impairment was 57% (4/7) in the sildenafil group and 100% (3/3) in the placebo group. CONCLUSIONS: Sildenafil was safe and well-absorbed in neonates with NE treated with TH. Optimal dosing needs to be established. Evaluation of a larger number of neonates through subsequent phases II and III trials is required to establish efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.govNCT02812433.
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Asfixia Neonatal , Lesões Encefálicas , Hipotermia Induzida , Hipóxia-Isquemia Encefálica , Doenças do Recém-Nascido , Recém-Nascido , Humanos , Citrato de Sildenafila/efeitos adversos , Asfixia/complicações , Estudos de Viabilidade , Asfixia Neonatal/terapia , Lesões Encefálicas/complicações , Lesões Encefálicas/tratamento farmacológico , Doenças do Recém-Nascido/terapia , Hipóxia-Isquemia Encefálica/terapia , Hipotermia Induzida/métodos , Método Duplo-CegoRESUMO
Abstract Objective The purpose of this study was to analyze the available evidence regarding the efficacy of iPDE5 in the treatment of female sexual dysfunction (FSD). Methods A comprehensive literature search was conducted in March 2023 through the main scientific databases. Results A total of 53 articles were identified, out of which, 6 met the predefined inclusion criteria. All of these were randomized controlled trials. Among the included studies, 4 demonstrated the effectiveness of sildenafil in improving sexual response and addressing FSD, while 2 studies failed to establish its efficacy in this context. Conclusion Overall, the efficacy of sildenafil in the treatment of FSD remains controversial and inconclusive based on the available evidence. Further research is necessary to clarify the therapeutic potential of iPDE5 in addressing FSD and to better understand the factors that influence treatment outcomes.
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Lead (Pb) reduces NO bioavailability, impairs the antioxidant system, and increases the generation of reactive oxygen species (ROS). Pb-induced oxidative stress may be responsible for the associated endothelial dysfunction. Sildenafil has shown nitric oxide (NO)-independent action, including antioxidant effects. Therefore, we examined the effects of sildenafil on oxidative stress, reductions of NO and endothelial dysfunction in Pb-induced hypertension. Wistar rats were distributed into three groups: Pb, Pb + sildenafil and Sham. Blood pressure and endothelium-dependent vascular function were recorded. We also examined biochemical determinants of lipid peroxidation and antioxidant function. ROS levels, NO metabolites and NO levels in human umbilical vein endothelial cells (HUVECs) were also evaluated. Sildenafil prevents impairment of endothelium-dependent NO-mediated vasodilation and attenuates Pb-induced hypertension, reduces ROS formation, enhances superoxide dismutase (SOD) activity and antioxidant capacity in plasma and increases NO metabolites in plasma and HUVECs culture supernatants, while no changes were found on measurement of NO released from HUVECs incubated with plasma of the Pb and Pb + sildenafil groups compared with the sham group. In conclusion, sildenafil protects against ROS-mediated inactivation of NO, thus preventing endothelial dysfunction and attenuating Pb-induced hypertension, possibly through antioxidant effects.
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Antioxidantes , Hipertensão , Ratos , Animais , Humanos , Citrato de Sildenafila/farmacologia , Citrato de Sildenafila/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Chumbo/toxicidade , Ratos Wistar , Estresse Oxidativo , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Hipertensão/prevenção & controle , Células Endoteliais da Veia Umbilical Humana/metabolismo , Óxido Nítrico/metabolismo , Endotélio VascularRESUMO
Background: Prostaglandin F2 alpha (PGF2 α) binds to the specific receptor (PTGFR) on the corpus luteum (CL) in mammals, inducing regression of the CL structure (luteolysis) and initiating a new cycle. While PGF2 α is effective only on mature CL, the immature CL structure (early luteal phase) resists PGF2 α. In this study, sildenafil citrate, which is used to increase blood flow in the genital organs for treating specific pregnancy issues in women, was administered during the early luteal phase in a rabbit model to test the hypothesis of enhancing blood flow to the CL, thereby promoting earlier maturation and enabling a response to PGF2 α. Materials, Methods & Results: The study was conducted in 2 sub-studies: clinical and molecular. A large number of rabbits were initially included in the sub-studies to ensure a sufficient number of pseudo-pregnant rabbits. Ovulation in rabbits was induced with buserelin acetate and was considered as day 0 of the study. The sub-studies were continued with rabbits whose pseudo-pregnancies were confirmed according to progesterone (P4 ) results. As a result, the studies were continued with a total of 41 pseudo-pregnant New Zealand female rabbits, 21 of which were included in the clinical sub-study and 20 in the molecular sub-study. In both sub-studies, on day 3 of the luteal period, rabbits in the treatment group received 5 mg/kg sildenafil citrate and all rabbits received a single dose of exogenous PGF2 α on day 4 to induce luteolysis. In the clinical sub-study, echotexture and intraovarian blood flow changes in the ovaries were determined by ultrasonography (USG) examination. In the molecular sub-study, the expression changes of Hypoxia Inducible Factor 1 Alpha (HIF1A) and Vascular Endothelial Growth Factor (VEGF) related to angiogenesis, Steroidogenic Acute Regulatory Protein (StAR) related to P4 metabolism, Prostaglandin-Endoperoxide Synthase 2 (PTGS2) related to prostaglandin (PG) mechanism and 15-Hydroxyprostaglandin Dehydrogenase (HPGD) genes at mRNA level were determined using Real Time Polymerase Chain Reaction (RT-PCR) in CL tissues obtained with ovariohysterectomy (OVH) at 1 and 12 h after PGF2 α injection. In addition, blood samples were collected for determine P4 levels from all rabbits. In the clinical sub-study; there was no difference between the groups in mean gray values (MGV), whereas there was a significant decrease in both pulsatile index (PI) and resistance index (RI) values at 40 min after PGF2 α injection (P < 0.05). In the molecular sub-study, it was determined that sildenafil citrate had no significant effect (P > 0.05) on the expression levels 1 and 12 h after PGF2 α injection. According to the results of the molecular sub-study, no significant effect of sildenafil citrate on the mRNA expression levels in the investigated genes was detected (P > 0.05). However, within each group, differences were found according to OVH time after PGF2 α injection. It was observed that PTGS2 and HPGD mRNA expressions decreased at the 12th h compared to the 1st h, while HIF1A expression increased (P < 0.05). Discussion: According to the results obtained from clinical and molecular sub-studies, it was determined that a single dose of sildenafil citrate (5 mg/kg) applied on the 3rd day of the luteal period did not contribute to the maturation process of the CL, did not increase blood flow, and was insufficient to break the resistance of the CL against PGF2 α applied on the 4th day of the luteal period. However, a significant decrease in the PI value at the 40th min after PGF2 α injection suggests that sildenafil citrate has a supportive effect, and that this decrease is also seen in the RI value, suggesting that its effect is insufficient against the vasoconstrictive effect of PGF2 α.
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Animais , Feminino , Coelhos , Dinoprosta/administração & dosagem , Corpo Lúteo/crescimento & desenvolvimento , Citrato de Sildenafila/administração & dosagem , Luteolíticos/análiseRESUMO
Los linfangiomas orbitarios son malformaciones vasculares benignas, de crecimiento lento, abortivas y no funcionales, que se presentan principalmente en la primera década de la vida. Las opciones terapéuticas en estos casos presentan una resolutividad limitada, algunos tratamientos suelen ser agresivos y provocar daños del aparato visual. Se presenta un caso de una paciente femenina de 6 años de edad atendida por proptosis del ojo izquierdo a la que se le realizó el diagnóstico clínico-imagenológico de linfangioma de la órbita, con el objetivo de mostrar el resultado alcanzado en el manejo de la misma mediante el uso del sildenafilo por vía oral, modalidad terapéutica en estudio a nivel mundial en el tratamiento de estas afecciones. El tratamiento con sildenafilo en el linfangioma orbitario demostró ser eficaz en la mejoría del cuadro clínico y por imágenes. Durante el tratamiento no se reportaron reacciones adversas(AU)
Orbital lymphatic malformations are benign, slow-growing, abortive, nonfunctional vascular malformations that occur mainly in the first decade of life. Therapeutic options in these cases present limited resolution, some treatments are usually aggressive and cause damage to the visual apparatus. We present a case of a 6-year-old female patient treated for proptosis of the left eye. The clinical-imaging diagnosis of lymphangioma of the orbit was made to show the results achieved in its treatment through the use of oral sildenafil, a therapeutic modality under study worldwide in the treatment of these conditions. The treatment with sildenafil in orbital lymphangioma proved to be effective in the improvement of the clinical and imaging picture. No adverse reactions were reported during treatment(AU)
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Humanos , Feminino , Criança , Malformações Vasculares/terapia , Linfangioma/etiologiaRESUMO
Oral sildenafil (SDF) is used to treat pulmonary arterial hypertension (PAH), and its bioavailability is approximately 40%. Several formulations of nano and microparticles (for pulmonary delivery) are being developed because it is possible to improve characteristics such as release time, bioavailability, dose, frequency, and even directly target the drug to the lungs. This review summarizes the latest SDF drug delivery systems for PAH and explains challenges related to the development, the preclinical, and the clinical studies. A scoping review was conducted by searching electronic databases including PubMed, Scopus, and Web of Science to identify studies published between 2001 and 2021. From 300 articles found, 31 met the inclusion criteria. This review identified colloidal formulations such as polymeric, lipid, and metal-organic framework nanoparticles. Strategies were determined to reach the deep airways such as polymeric microparticles, large porous microparticles, nanocomposites, and nano in microparticles. Finally, aspects related to toxicological, pharmacokinetics, and gaps in information for potential use in humans were discussed. SDF formulations are significant candidates for the treatment of PAH by inhalation. In summation, future preclinical studies are still required in large animals, as there is no particular formulation yet submitted to clinical studies.
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Estruturas Metalorgânicas , Hipertensão Arterial Pulmonar , Administração por Inalação , Animais , Hipertensão Pulmonar Primária Familiar , Humanos , Lipídeos , Pulmão , Nanotecnologia , Citrato de SildenafilaRESUMO
Chronic treatment with sildenafil (SILD) is an effective protector on the development of cardiovascular complications of pulmonary hypertension (PH) and diabetes. However, to date, no studies have evaluated the effect of SILD on cardiopulmonary pathophysiology during PH secondary to type 1 diabetes. AIM: The present study aimed to evaluate the beneficial effects of chronic SILD treatment on pulmonary arterial pressure, right ventricular hypertrophy (RVH) and cardiac autonomic dysfunction in rats with PH secondary to diabetes. METODOLOGY: Male Sprague Dawley rats were randomly distributed into the control group (saline), diabetic group (60 mg/kg with streptozotocin), SILD-treated control group (20 mg/kg) and SILD-treated diabetic group. RESULTS: After 8 weeks the type 1 diabetic animals presented PH, endothelial dysfunction of the pulmonary arteries, electrocardiographic alterations, RVH and overexpression of phosphodiesterase type 5 in the heart. In type 1 diabetic animals, SILD treatment prevented the development of PH, endothelial dysfunction and RVH. SILD treatment also prevented alterations in the corrected QT period and heart rate variability and prevented overexpression of phosphodiesterase type 5. CONCLUSION: Our results indicate for the first time that SILD treatment prevents pulmonary arterial endothelial dysfunction, pulmonary hypertension, right ventricular hypertrophy and improves heart rate variability in type 1 diabetic rats.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Hipertensão Pulmonar , Ratos , Masculino , Animais , Citrato de Sildenafila/farmacologia , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/prevenção & controle , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/prevenção & controle , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Frequência Cardíaca , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Diabetes Mellitus Tipo 1/complicações , Ratos Sprague-Dawley , Modelos Animais de DoençasRESUMO
INTRODUCCIÓN Y OBJETIVO: La restricción del crecimiento intrauterino (RCIU), expresión insuficiente del potencial genético de crecimiento fetal, complica el 5-8% de los embarazos, con unas altas tasas de morbimortalidad perinatal. De origen multifactorial, puede ser causada por patologías maternas, fetales o placentarias. El tratamiento es limitado, optándose por un seguimiento riguroso con eventual interrupción del embarazo según la evolución. Se han utilizado diferentes estrategias terapéuticas para su prevención y manejo, surgiendo el citrato de sildenafil (CS), inhibidor de la fosfodiesterasa tipo 5, como fármaco que podría mejorar el flujo sanguíneo uteroplacentario y ofrecer mejores resultados perinatales en fetos con RCIU. Se propone realizar una revisión de la literatura disponible en relación al CS como tratamiento del RCIU. MÉTODO: Se realizó una búsqueda de literatura en inglés y español. De 105 artículos seleccionados, se excluyeron 94. La información obtenida fue clasificada y utilizada como soporte para la realización de esta revisión, siguiendo el modelo PRISMA. RESULTADOS: Se encontraron 11 estudios que contrastan el uso de placebo y CS en pacientes con RCIU. Respecto al aumento de peso al nacimiento, solo dos estudios demostraron evidencia significativa. Se reportaron 40 casos de muerte fetal/neonatal asociada al tratamiento con CS. CONCLUSIONES: No se encontró evidencia suficiente que justifique el uso sistemático de CS en casos de RCIU. Aún es necesario realizar estudios con muestras de mayor tamaño y posterior metaanálisis para confirmar el beneficio farmacológico en cuanto al aumento de peso de nacimiento, la prolongación del embarazo y los posibles efectos adversos a largo plazo.
INTRODUCTION AND OBJECTIVE: Intrauterine growth restriction (IUGR) is an insufficient expression of the genetic potential for fetal growth, complicates 5-8% of pregnancies and represents high rates of perinatal morbidity and mortality. Of multifactorial origin, it can be caused by pathologies at the maternal, fetal or placental level. The treatment is limited, opting for a rigorous follow-up with eventual interruption of the pregnancy according to evolution. Different therapeutic strategies have been used for its prevention and management, emerging sildenafil citrate (CS), inhibitor of phosphodiesterase type 5, as a drug that could improve the uteroplacental blood flow and offer better perinatal results in fetuses with IUGR. A review of the available literature on CS as a treatment for IUGR is proposed. METHOD: A search was conducted for literature in English and Spanish. Out of 105 selected articles, 94 were excluded. The information obtained was classified and used as support for this review, following the PRISMA model. RESULTS: We found 11 studies that contrast the use of placebo and CS in patients with IGR. Regarding birth weight gain, only two studies showed significant evidence. Forty cases of fetal/neonatal death associated with CS treatment were reported. CONCLUSIONS: Not enough evidence was found to justify the routine use of CS in IUGR cases. Studies with larger samples and subsequent meta-analysis are still necessary to confirm the benefit of this drug in terms of birth weight gain, prolongation of pregnancy and possible long-term adverse effects.
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Humanos , Feminino , Gravidez , Inibidores da Fosfodiesterase 5/uso terapêutico , Retardo do Crescimento Fetal/tratamento farmacológico , Citrato de Sildenafila/uso terapêuticoRESUMO
BACKGROUND: SARS-CoV-2 seems to affect the regulation of pulmonary perfusion. Hypoperfusion in areas of well-aerated lung parenchyma results in a ventilation-perfusion mismatch that can be characterized using subtraction computed tomography angiography (sCTA). This study aims to evaluate the efficacy of oral sildenafil in treating COVID-19 inpatients showing perfusion abnormalities in sCTA. METHODS: Triple-blinded, randomized, placebo-controlled trial was conducted in Chile in a tertiary-care hospital able to provide on-site sCTA scans and ventilatory support when needed between August 2020 and March 2021. In total, 82 eligible adults were admitted to the ED with RT-PCR-confirmed or highly probable SARS-COV-2 infection and sCTA performed within 24 h of admission showing perfusion abnormalities in areas of well-aerated lung parenchyma; 42 were excluded and 40 participants were enrolled and randomized (1:1 ratio) once hospitalized. The active intervention group received sildenafil (25 mg orally three times a day for seven days), and the control group received identical placebo capsules in the same way. Primary outcomes were differences in oxygenation parameters measured daily during follow-up (PaO2/FiO2 ratio and A-a gradient). Secondary outcomes included admission to the ICU, requirement of non-invasive ventilation, invasive mechanical ventilation (IMV), and mortality rates. Analysis was performed on an intention-to-treat basis. RESULTS: Totally, 40 participants were enrolled (20 in the placebo group and 20 in the sildenafil group); 33 [82.5%] were male; and median age was 57 [IQR 41-68] years. No significant differences in mean PaO2/FiO2 ratios and A-a gradients were found between groups (repeated-measures ANOVA p = 0.67 and p = 0.69). IMV was required in 4 patients who received placebo and none in the sildenafil arm (logrank p = 0.04). Patients in the sildenafil arm showed a significantly shorter median length of hospital stay than the placebo group (9 IQR 7-12 days vs. 12 IQR 9-21 days, p = 0.04). CONCLUSIONS: No statistically significant differences were found in the oxygenation parameters. Sildenafil treatment could have a potential therapeutic role regarding the need for IMV in COVID-19 patients with specific perfusion patterns in sCTA. A large-scale study is needed to confirm these results. TRIAL REGISTRATION: Sildenafil for treating patients with COVID-19 and perfusion mismatch: a pilot randomized trial, NCT04489446, Registered 28 July 2020, https://clinicaltrials.gov/ct2/show/NCT04489446 .
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Tratamento Farmacológico da COVID-19 , COVID-19 , Citrato de Sildenafila , Vasodilatadores , Administração Oral , Adulto , Idoso , COVID-19/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Citrato de Sildenafila/administração & dosagem , Resultado do Tratamento , Vasodilatadores/administração & dosagem , Relação Ventilação-PerfusãoRESUMO
INTRODUCTION: Intra-abdominal adhesions' main etiology is surgical procedures that commonly require reintervention. Oral treatments with sildenafil, zafirlukast, and pirfenidone have yielded decreased severity of fibrotic phenomena secondary to the introduction of foreign material. This study aimed to evaluate the efficacy of oral zafirlukast, sildenafil, or pirfenidone treatment on reducing or preventing intra-abdominal adhesions in an experimental rat model. METHODS: Four groups, each of 10 male Wistar rats weighing 250-300 g, were used. A midline laparotomy was used to excise an area of 1.5 × 1.5 cm and reconstructed with polypropylene mesh fixed to the abdominal wall. After 12 h, oral doses of zafirlukast (1.25 mg/kg, group B), sildenafil (15 mg/kg, group C), or pirfenidone (500 mg/kg, group D) were given every day for 8 days. The control group, A, received no treatment. At day 9, animals were reoperated. The implant was resected after ethically approved euthanasia, and specimens were fixed in 10% formaldehyde for histopathology. RESULTS: Control group A yielded adhesions with greater fibrovascular density and neighboring organ involvement than the other groups (p = 0.001), as well as intense inflammatory infiltrates and numerous granulomas (p = 0.04). Adhesions in group C had less fibrovascular density (p = 0.03) with decreased serosal injuries (p = 0.001) and less organ involvement. Group D had reduced adhesions without organ involvement (p < 0.01) and less inflammatory infiltrates, collagen fibers, and foreign body granulomas than group B or C (p < 0.01). CONCLUSIONS: Oral administration of these agents did not prevent adhesions but ameliorated them. Oral pirfenidone offered the best performance and could be recommended for human use.
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Telas Cirúrgicas , Animais , Humanos , Indóis , Masculino , Fenilcarbamatos , Piridonas , Ratos , Ratos Wistar , Citrato de Sildenafila , Sulfonamidas , Telas Cirúrgicas/efeitos adversos , Aderências Teciduais/prevenção & controleRESUMO
Abstract The illicit market of counterfeit medicines containing sildenafil and tadalafil has been causing serious public health problems. Thus, further studies on this illicit association are needed. A stability-indicating HPLC method was developed for simultaneous determination of tadalafil (TAD) and sildenafil (SIL) using a C18 column (250 x 4.6 mm, 5 µm). Detection was achieved at 284 nm, for TAD, and 292 nm, for SIL. The method was considered to be specific, linear, precise, accurate, robust, and sensitive. In the photodegradation kinetic studies, the drugs showed a first-order reaction rate when isolated, and zero-order when associated. Toxicological assays demonstrated that the photodegraded drugs decreased cell viability in compared to non- degraded drugs, suggesting cytotoxic activity. Additional, mutagenic activity was not observed under the tested conditions. Photodegraded drugs, in association, depicted DNA damage index, suggesting genotoxic effects. The obtained results will be able to support the forensic intelligence laboratories, as well as to alert the population about the risk inherent to consuming counterfeit products.
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Cromatografia Líquida de Alta Pressão/métodos , Fotodegradação/efeitos dos fármacos , Citrato de Sildenafila/análise , Tadalafila/análise , Medicamentos Falsificados/classificaçãoRESUMO
Resumen OBJETIVO: Explorar las diferentes estrategias de tratamiento farmacológico de la restricción del crecimiento fetal propuestas a lo largo del tiempo. METODOLOGÍA: Revisión cuasi-sistemática de la evidencia científica histórica disponible acerca del tratamiento médico descrito para la atención de mujeres embarazadas con restricción del crecimiento fetal. RESULTADOS: Entre los tratamientos médicos descritos para tratar la restricción del crecimiento fetal, los donadores de óxido nítrico, las estatinas y la aspirina asociada con omega 3, han tenido desenlaces no consistentes en estudios con limitado tamaño de muestra. Por lo que se refiere a los inhibidores de la 5-fosfodiesterasa, el sildenafilo no se ha asociado con un aumento de la velocidad de crecimiento fetal pero sí con alarmas respecto de su seguridad debidas al incremento de los casos de hipertensión pulmonar fetal y mortalidad perinatal. Por su parte, el tadalafilo ha mostrado desenlaces iniciales favorables y se esperan estudios con mayor tamaño de muestra que permitan emitir recomendaciones claras con respecto a su indicación. También se esperan los desenlaces de estudios clínicos en curso, para definir la indicación de la heparina de bajo peso molecular en este escenario en virtud de sus prometedores resultados iniciales. Los procedimientos más invasivos, como la inyección de factor de crecimiento endotelial vascular y la plasmaféresis, permanecen en estudio como propuestas terapéuticas por los resultados de estudios preclínicos y clínicos con pocos pacientes. CONCLUSIÓN: Por ahora, ninguna estrategia farmacológica propuesta ha conseguido generar recomendaciones fuertes para su indicación; sin embargo, se esperan nuevos estudios con alta calidad metodológica que generen evidencia científica lo suficientemente contundente para recomendar su indicación.
Abstract OBJECTIVE: To explore the different pharmacological treatment strategies for fetal growth restriction proposed over time. METHODOLOGY: Quasi-systematic review of the available historical scientific evidence on the medical treatment described for the care of pregnant women with fetal growth restriction. RESULTS: Among the medical treatments described to treat fetal growth restriction, nitric oxide donors, statins, and aspirin associated with omega-3 have had inconsistent outcomes in studies with limited sample size. As for 5-phosphodiesterase inhibitors, sildenafil has not been associated with an increase in fetal growth velocity, but there have been alarms regarding its safety due to the increase in cases of fetal pulmonary hypertension and perinatal mortality. On the other hand, tadalafil has shown favorable initial outcomes and studies with a larger sample size are awaited to issue clear recommendations regarding its indication. The results of ongoing clinical studies are also awaited to define the indication of low molecular weight heparin in this setting, given its promising initial results. More invasive procedures, such as vascular endothelial growth factor injection and plasmapheresis, remain under study as therapeutic proposals due to the results of preclinical and clinical studies with few patients. CONCLUSION: For now, no proposed pharmacological strategy has managed to generate strong recommendations for its indication; however, new studies with high methodological quality are expected to generate scientific evidence strong enough to recommend its indication.
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RESUMEN Introducción: la hipertensión pulmonar es un hallazgo frecuente en la insuficiencia cardíaca. El uso del sildenafilo en estos casos es una práctica habitual, pero aún controversial por lo limitado de los estudios realizados. Objetivo: comparar las variables ecocardiográficas de hemodinamia pulmonar, en pacientes con disfunción sistólica ventricular izquierda e hipertensión pulmonar secundaria severa, antes y después del uso del sildenafilo. Materiales y métodos: se realizó un estudio de cohorte, donde se incluyeron 19 pacientes; se realizó un seguimiento de dos años. Se analizaron variables clínicas, de laboratorio y ecocardiográficas. Se evaluaron las principales variables de hemodinamia pulmonar antes del uso del sildenafilo y a las doce semanas de su indicación. Se realizó una curva de supervivencia al concluir el seguimiento. El nivel de significación estadístico empleado fue de p < 0,05. Resultados: la edad promedio fue de 56,16 ± 15,77 años y predominó el sexo masculino, con un 73,7 %. La supervivencia al término del seguimiento fue de 78,9 %. Las principales variables ecocardiográficas de hemodinamia pulmonar mostraron una reducción significativa a las doce semanas del tratamiento con sildenafilo. La supervivencia de los pacientes con una reducción del 25 % de las presiones pulmonares en el ecocardiograma realizado a las doce semanas del tratamiento, fue mayor al terminar el estudio (100 % vs 33 %, log-rank test p = 0,001). Conclusiones: posterior al uso del sildenafilo se encontró una reducción significativa de las variables de hemodinamia pulmonar en el ecocardiograma evolutivo. La sobrevida fue mayor en los pacientes que presentaron dicha reducción (AU).
ABSTRACT Introduction: pulmonary hypertension is a common finding in heart failure. The use of sildenafil in these cases is a common practice, but still controversial due to the limited number of studies carried out. Objective: to compare echocardiographic variables of pulmonary hemodynamics, in patients with left ventricular systolic dysfunction and severe secondary pulmonary hypertension, before and after the use of sildenafil. Materials and methods: a cohort study was led, including 19 patients; a two-year follow-up was carried out. Clinical, laboratory and echocardiographic variables were analyzed. The main pulmonary hemodynamics variables were evaluated before the use of sildenafil and 12 weeks after its indication. A survival curve was performed at the end of the follow-up. The statistical significance level used was p < 0.05. Results: the average age was 56.16 ± 15.77 years, and male sex predominated with 73.3 %. Survival at the end of the follow up was 78.9 %. The main echocardiographic variables of pulmonary hemodinamics showed a significant reduction at 12 weeks of treatment with sildenafil. The survival of patients with a 25 % reduction in pulmonary pressures in the echocardiogram performed at 12 weeks of treatment was greater at the end of the study (100 % vs 33 %, log-rank test p = 0.001). Conclusions: after using sildenafil, a significant reduction of pulmonary hemodynamics variables was found in the evolutionary echocardiogram. Survival was higher in patients who had this reduction (AU).
Assuntos
Humanos , Masculino , Feminino , Disfunção Ventricular Esquerda/tratamento farmacológico , Hipertensão Pulmonar/tratamento farmacológico , Pacientes , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/terapia , Citrato de Sildenafila/provisão & distribuição , Citrato de Sildenafila/uso terapêutico , Citrato de Sildenafila/farmacologia , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/terapiaRESUMO
Acute kidney injury pathogenesis in envenoming by snakes is multifactorial and involves immunologic reactions, hemodynamic disturbances, and direct nephrotoxicity. Sildenafil (SFC), a phosphodiesterase 5 inhibitor, has been reported to protect against pathological kidney changes. OBJECTIVE: This study aimed to investigate the protective effect of sildenafil against Bothrops alternatus snake venom (BaV)-induced nephrotoxicity. METHODS: Kidneys from Wistar rats (n = 6, weighing 260-300 g) were isolated and divided into four groups: (1) perfused with a modified Krebs-Henseleit solution (MKHS) containing 6 g% of bovine serum albumin; (2) administered 3 µg/mL SFC; (3) perfused with 3 µg/mL BaV; and (4) administered SFC + BaV, both at 3 µg/mL. Subsequently, the perfusion pressure (PP), renal vascular resistance (RVR), urinary flow (UF), glomerular filtration rate (GFR), and percentage of electrolyte tubular sodium and chloride transport (%TNa+, %TCl-, respectively) were evaluated. The cyclic guanosine monophosphate (cGMP) levels were analyzed in the perfusate, and the kidneys were removed to perform oxidative stress and histopathological analyses. RESULTS: All renal parameters evaluated were reduced with BaV. In the SFC + BaV group, SFC restored PP to normal values and promoted a significant increase in %TNa+ and %TCl-. cGMP levels were increased in the SFC + BaV group. The oxidative stress biomarkers, malondialdehyde (MDA) and glutathione (GSH), were reduced by BaV. In the SFC + BaV group, a decrease in MDA without an increase in GSH was observed. These findings were confirmed by histological analysis, which showed improvement mainly in tubulis. CONCLUSION: Our data suggest the involvement of phosphodiesterase-5 and cGMP in BaV-induced nephrotoxicity since its effects were attenuated by the administration of SFC.
Assuntos
Bothrops , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Rim , Inibidores da Fosfodiesterase 5/uso terapêutico , Ratos , Ratos Wistar , Citrato de Sildenafila/uso terapêutico , Venenos de Serpentes/toxicidadeRESUMO
ABSTRACT Introduction: The use of substances to enhance sports performance among professional and amateur athletes is increasing. Such substances may either be included in the group of dietary supplements or fall into pharmacological classes. Every substance used for this purpose is called an ergogenic agent. The number of ergogenic options available increases every day, favoring overuse and use without proper guidance. Among the dietary supplements, we highlight the use of creatine, a substance widespread in sports. Among the pharmacological groups, many drugs are used. Recently the use of sildenafil citrate by professional athletes from various predominantly aerobic sports modalities was reported in the media. Objective: To compare and demonstrate the responses caused by physical training associated with the use of creatine and sildenafil citrate in mice. Methods: A swim training protocol was applied and then an electrophysiograph was used in order to obtain parameters related to contraction intensity, the area under the curve and the percentage drop. Results: The responses obtained demonstrated the ergogenic action of creatine because it altered the parameters used for measurement. The use of sildenafil citrate did not yield satisfactory results to frame the drug as an ergogenic agent. Conclusion: Creatine has an ergogenic effect, reducing the percentage drop after 10 seconds, while sildenafil demonstrated no ergogenic potential and, interestingly, resulted in weaker responses when compared to the exercise groups. Evidence level II; Comparative prospective study .
RESUMEN Introducción: El uso de sustancias con el objetivo de aumentar el rendimiento deportivo entre atletas profesionales y amateurs es creciente. Tales sustancias pueden formar parte del grupo de suplementos alimentarios o integrar clases farmacológicas. Toda sustancia empleada para ese fin es denominada agente ergogénico. El número de opciones entre los agentes ergogénicos aumenta cada día, favoreciendo así su uso excesivo y sin la debida orientación. Entre los suplementos alimentarios, se destaca el uso de creatina, sustancia muy difundida en el medio deportivo. Ya entre los grupos farmacológicos, muchas sustancias son usadas. Recientemente, fue divulgado entre los medios de comunicación el uso de citrato de sildenafil por atletas profesionales, de varias modalidades deportivas, predominantemente las aeróbicas. Objetivos: Comparar y demostrar las respuestas ocasionadas por el entrenamiento físico, asociadas al uso de creatina y citrato de sildenafil en ratones. Métodos: Se aplicó un protocolo de entrenamiento de natación y, a continuación, se usó un electrofisiógrafo con el objetivo de obtener parámetros referentes a la intensidad de contracción, al área bajo la curva y a la caída porcentual. Resultados: Las respuestas obtenidas demuestran acción ergogénica de la creatina, visto que alteraron los parámetros empleados para la medición. Ya el uso de citrato de sildenafil no presentó resultados satisfactorios para encuadrar al fármaco como agente ergogénico. Conclusión: La creatina presenta efecto ergogénico porque reduce la caída porcentual después de 10 segundos, mientras que el sildenafil no presentó potencial ergogénico y, curiosamente, demostró respuestas inferiores cuando comparado a los grupos de ejercicio. Nivel de evidencia II; Estudio prospectivo comparativo .
RESUMO Introdução: O uso de substâncias com o objetivo de aumentar o rendimento esportivo entre atletas profissionais e amadores é crescente. Tais substâncias podem fazer parte do grupo de suplementos alimentares ou integrar classes farmacológicas. Toda substância empregada para esse fim é denominada de agente ergogênico. O número de opções entre os agentes ergogênicos aumenta a cada dia, favorecendo assim o uso em demasia e sem a devida orientação. Entre os suplementos alimentares, salientamos a utilização de creatina, substância muito difundida no meio esportivo. Já entre os grupos farmacológicos, muitas substâncias são utilizadas. Recentemente, foi divulgado entre os meios de comunicação o uso de citrato de sildenafila por atletas profissionais de várias modalidades esportivas, predominantemente as aeróbicas. Objetivos: Comparar e demonstrar as repostas ocasionadas pelo treinamento físico, associadas ao uso de creatina e citrato de sildenafila em camundongos. Métodos: Aplicou-se um protocolo de treinamento de natação e, a seguir, empregou-se um eletrofisiógrafo com objetivo de obter parâmetros referentes à intensidade de contração, à área sob a curva e à queda percentual. Resultados: As respostas obtidas demonstram ação ergogênica da creatina, visto que alteraram os parâmetros empregados para a mensuração. Já a utilização de citrato de sildenafila não apresentou resultados satisfatórios para enquadrar o fármaco como agente ergogênico. Conclusão: A creatina apresenta efeito ergogênico porque reduz a queda percentual após 10 segundos, já a sildenafila não apresentou potencial ergogênico e, curiosamente, demonstrou respostas inferiores quando comparado aos grupos de exercício. Nível de evidência II; Estudo prospectivo comparativo .
Assuntos
Animais , Masculino , Camundongos , Natação , Vasodilatadores/farmacologia , Fadiga Muscular/efeitos dos fármacos , Creatina/farmacologia , Citrato de Sildenafila/farmacologia , Desempenho Físico Funcional , Nervo Isquiático/cirurgia , Tendões/cirurgia , Modelos Animais , Eletrofisiologia/instrumentaçãoRESUMO
Multiple Sclerosis (MS) is a neuroinflammatory and chronic Central Nervous System (CNS) disease that affects millions of people worldwide. The search for more promising drugs for the treatment of MS has led to studies on Sildenafil, a phosphodiesterase type 5 Inhibitor (PDE5I) that has been shown to possess neuroprotective effects in the Experimental Autoimmune Encephalomyelitis (EAE), an animal model of MS. We have previously shown that Sildenafil improves the clinical score of EAE mice via modulation of apoptotic pathways, but other signaling pathways were not previously covered. Therefore, the aim of the present study was to further investigate the effects of Sildenafil treatment on autophagy and nitrosative stress signaling pathways in EAE. 24 female C57BL/6 mice were divided into the following groups: (A) Control - received only water; (B) EAE - EAE untreated mice; (C) SILD - EAE mice treated with 25mg/kg of Sildenafil s.c. The results showed that EAE mice presented a pro-nitrosative profile characterized by high tissue nitrite levels, lowered levels of p-eNOS and high levels of iNOS. Furthermore, decreased levels of LC3, beclin-1 and ATG5, suggests impaired autophagy, and decreased levels of AMPK in the spinal cord were also detected in EAE mice. Surprisingly, treatment with Sildenafil inhibited nitrosative stress and augmented the levels of LC3, beclin-1, ATG5, p-CREB and BDNF and decreased mTOR levels, as well as augmented p-AMPK. In conclusion, we propose that Sildenafil alleviates EAE by activating autophagy via the eNOS-NO-AMPK-mTOR-LC3-beclin1-ATG5 and eNOS-NO-AMPK-mTOR-CREB-BDNF pathways in the spinal cord.
Assuntos
Autofagia/efeitos dos fármacos , Encefalomielite Autoimune Experimental/patologia , Inibidores da Fosfodiesterase 5/farmacologia , Citrato de Sildenafila/farmacologia , Medula Espinal/efeitos dos fármacos , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Estresse Nitrosativo/efeitos dos fármacosRESUMO
Phosphodiesterase type 5 inhibitors such as sildenafil citrate and tadalafil are well known for the treatment of erectile dysfunction. However, their use in the presence of pulmonary hypertension can cause ophthalmologic side effects, including non-arteritic optic ischemic neuropathy, chorioretinopathy, glaucoma, and optic atrophy. The present review aimed to identify these visual side effects and provide recommendations. We identified articles published from January 2000 to March 2019 on diseases arising from the management of sexual dysfunction in urology or pulmonary hypertension in pneumonia that could cause pathologic alterations in eye structure based on a literature search of the MEDLINE electronic database using keywords for the most common adverse effects and different kinds of phosphodiesterase 5 inhibitors. After applying the exclusion criteria, we selected 36 of the 77 articles initially identified to write the narrative review and added 20 additional articles to completely describe the pathological entities. Phosphodiesterase type 5 inhibitors can cause side effects in the eye including ocular surface abnormalities, increased intraocular pressure and glaucoma, uveitis, non-arteritic ischemic neuropathy, chorioretinopathy, retinal occlusion, and visual field changes. There is an increased need for well-performed studies to better understand these side effects, which are common due to the wide use of sildenafil.