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Patients with sickle cell disease (SCD) display priapism. Clinical studies have shown a strong positive correlation between priapism and high levels of intravascular hemolysis in men with SCD. However, there are no experimental studies that show that intravascular hemolysis promotes alterations in erectile function. Therefore, we aimed to evaluate the corpus cavernosum smooth muscle relaxant function in a murine model that displays intravascular hemolysis induced by phenylhydrazine (PHZ), as well as the role of intravascular hemolysis in increasing the stress oxidative in the penis. Corpus cavernosum strips were dissected free and placed in organ baths. Acetylcholine and electrical field stimulation (EFS)-induced corpus cavernosum relaxations in vitro were obtained. Increased corpus cavernosum relaxant responses to acetylcholine and EFS were observed in the PHZ group. Protein expression of heme oxygenase-1 increased in the corpus cavernosum of the PHZ group, but PDE5 protein expression was not modified. Preincubation with the heme oxygenase inhibitor 1 J completely reversed the increased relaxant responses to acetylcholine and EFS in PHZ mice. Protein expression of NADPH oxidase subunit gp91phox, 3-nitrotyrosine, and 4-hydroxynonenal increased in the corpus cavernosum of the PHZ group, suggesting a state of oxidative stress. Basal cGMP production was lower in the PHZ group. Our results show that intravascular hemolysis promotes increased corpus cavernosum smooth muscle relaxation associated with increased HO-1 expression, as well as increased oxidative stress associated with upregulation of gp91phox expression. Moreover, our study supports clinical studies that point to a strong positive correlation between priapism and high levels of intravascular hemolysis in men with SCD.
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Anemia de Células Falciformes , Priapismo , Acetilcolina/farmacología , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/metabolismo , Animales , Hemólisis , Humanos , Masculino , Ratones , Pene , Priapismo/complicacionesRESUMEN
Background: In sickle cell disease (SCD), reduced bioavailability of endothelial NO and cGMP results in reduced expression of phosphodiesterase type 5 (PDE5), thus impairing the penile erection control mechanism and resulting in prolonged penile erection (priapism). In SCD, reduced NO bioavailability is associated with excess plasma hemoglobin due to intravascular hemolysis and increased oxidative stress. Haptoglobin is the plasma protein responsible for reducing plasma hemoglobin levels, but in SCD, haptoglobin levels are reduced, which favors the accumulation of hemoglobin in plasma. Therefore, we aimed to evaluate the effects of haptoglobin treatment on functional and molecular alterations of erectile function, focusing on the contractile and relaxant mechanisms of corpus cavernosum (CC), as well as oxidative stress. Methods: SCD mice were treated with haptoglobin (400 mg/kg, subcutaneous) or vehicle of Monday, Wednesday and Friday for a period of 1 month. Corpus cavernosum strips were dissected free and placed in organ baths. Cumulative concentration-response curves to the acetylcholine, sodium nitroprusside, phenylephrine and KCL, as well as to electrical field stimulation (EFS), were obtained in CC. Protein expressions of eNOS, phosphorylation of eNOS at Ser-1177, nNOS, PDE5, ROCK1, ROCK2, gp91phox, 3-nitrotyrosine, and 4-HNE were measured by western blot in CC. Results: Increased CC relaxant responses to acetylcholine, sodium nitroprusside and electrical-field stimulation were reduced by haptoglobin in SCD mice. Reduced CC contractile responses to phenylephrine and KCl were increased by haptoglobin in SCD mice. Haptoglobin prevented downregulated eNOS, p-eNOS (Ser-1177), PDE5, and ROCK2 protein expressions and reduced protein expressions of reactive oxygen species markers, NADPH oxidase subunit gp91phox, 3-nitrotyrosine and 4-HNE in penises from SCD mice. Haptoglobin treatment did not affect ROCK1 and nNOS protein expressions in penises from SCD mice. Basal cGMP production was lower in the SCD group, which was normalized by haptoglobin treatment. Conclusion: Treatment with haptoglobin improved erectile function due to up-regulation of eNOS-PDE5 expression and down-regulation of the gp91phox subunit of NADPH oxidase and oxidative/nitrosative stress in the penises of SCD mice. Treatment with haptoglobin also increased contractile activity due to up-regulation of ROCK2. Therefore, haptoglobin treatment may be an additional strategy to prevent priapism in SCD.
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OBJECTIVE: Obesity, a major health issue worldwide, is associated with increased cardiovascular risk, endothelial dysfunction, and arterial stiffness. Tadalafil has been demonstrated to improve vascular parameters. AIM: To evaluate the effect of a single 20 mg dose of tadalafil on flow-mediated dilation and hemodynamic and arterial stiffness markers. METHODS: A randomized, double-blind, placebo-controlled study was conducted on 80 participants (41 assigned to placebo and 39 to tadalafil) with grade 1 obesity, to evaluate the acute effect of a single dose of 20 mg of tadalafil on flow-mediated dilation and hemodynamic and arterial stiffness markers. RESULTS: Tadalafil did not modify flow-mediated dilation. However, it significantly lowered systolic blood pressure (SBP) (130.6±17.1 vs. 125.0±12.7 mmHg, p=0.011), diastolic blood pressure (82.7±18.2 vs. 76.5±11.8 mmHg, p≤0.001), central systolic blood pressure (116.33±19.16 vs. 109.90±15.05 mmHg, p=0.001), the augmentation index (69.1±17.1 vs. 65.7±14.4, p=0.012), and brachial-ankle pulse wave velocity (1229.7±218.4 vs. 1164.0±181.7, p=0.001). CONCLUSION: A single dose of tadalafil did not modify flow-mediated dilation in patients with grade 1 obesity but improved blood pressure and brachial-ankle pulse wave velocity.
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Rigidez Vascular , Humanos , Análisis de la Onda del Pulso , Tadalafilo/efectos adversos , Índice Tobillo Braquial , Dilatación , Presión Sanguínea , Hemodinámica , Obesidad/diagnóstico , Obesidad/tratamiento farmacológico , Método Doble CiegoRESUMEN
Approximately 12-18% of hypertensive patients are diagnosed with resistant hypertension (RH). The risk of having worse cardiovascular outcomes is twice higher in those patients. The low effectiveness of conventional antihypertensive drugs in RH emphasizes the need to evaluate complementary drug therapies to achieve blood pressure (BP) control. Previous studies have demonstrated that phosphodiesterase 5 (PDE-5) inhibitors improve hemodynamics and reduce BP on essential hypertension. So, the authors aimed to summarize current clinical trials-based evidence published concerning the use of PDE-5 inhibitors on BP, cardiovascular function, and hemodynamics of patients with RH. We searched MEDLINE, EMBASE, LILACS, ClinicalTrials.gov, and WHO International Clinical Trials Registry databases on May 15th, 2020 using pre-defined search terms. Two independent reviewers assessed and extracted data from clinical trials that evaluated the effect of PDE-5 inhibitors on BP. We have included five articles in this systematic review. Four of them developed a single-day protocol, while one has developed a 14-day study. The main findings indicate that PDE-5 inhibitors ameliorate BP, vascular hemodynamics, and diastolic function parameters. Some data demonstrated improvement of endothelial function, but it was not a consensus. The side effects seemed to be limited and well-tolerated. In brief, our systematic review highlights the potential of PDE-5 inhibitors as a therapeutic alternative in addition to the multiple-drug regime for RH. Larger studies are still needed to determine whether the beneficial effects of PDE-5 inhibitors on RH would be maintained with chronic administration.
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Hipertensión/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 5/farmacología , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Enfermedades Cardiovasculares , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Diástole/efectos de los fármacos , Humanos , Hipertensión/fisiopatología , Inhibidores de Fosfodiesterasa 5/metabolismoRESUMEN
A previous work indicates that the red LASER (660 nm) induces vascular relaxation by nitric oxide (NO)-dependent mechanism. NO activates soluble guanylate cyclase (sGC) which produces cGMP, the main effector in the vasodilation pathway. An interesting pharmacological strategy is to control the levels of intracellular cGMP, preventing its efflux (with multidrug-resistant protein blockers, such as MK-571), or preventing its degradation (such as sildenafil, which inhibits the enzyme responsible for cGMP degradation, the phosphodiesterase-5 PDE5). This study aimed to look for pharmacological strategies to improve vasodilation LASER effect in normotensive and hypertensive rats (L-NAME model). The vascular reactivity study was performed in isolated aortic rings from normotensive and hypertensive rats, with a single LASER application and sodium nitroprusside (SNP) treatment. In aortic rings from normotensive rats, MK-571 and sildenafil potentiated the relaxation induced by LASER, compared to control. The vasodilation induced by SNP was potentiated by MK-571 and sildenafil, compared to control. In aortic rings from hypertensive rats, vasodilation effect induced by LASER and by SNP was potentiated just by MK-571, compared to control, with no potentiation by sildenafil. In addition, it was seen that the withdrawal of nitric oxide stocks carried out by L-cysteine is capable of being reversed with the use of the SNP. The results support the evidence that the vasodilation induced by red LASER is potentiated by MK-571 and sildenafil in aortic rings from normotensive rats. However, in aortic rings from L-NAME hypertensive rats, the potentiation in vasodilation was induced just by MK-571.
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Inhibidores de Fosfodiesterasa , Vasodilatadores , Animales , Óxido Nítrico/metabolismo , Nitroprusiato/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Ratas , Citrato de Sildenafil/farmacología , Vasodilatación , Vasodilatadores/farmacologíaRESUMEN
The use of already-approved drugs to treat new or alternative diseases has proved to be beneficial in medicine, because it reduces both drug development costs and timelines. Most drugs can be used to treat different illnesses, due their mechanisms of action are not restricted to one molecular target, organ or illness. Diverging from its original intent offers an opportunity to repurpose previously approved drugs to treat other ailments. This is the case of sildenafil (Viagra), a phosphodiesterase-5 (PDE5) inhibitor, which was originally designed to treat systemic hypertension and angina but is currently commercialized as erectile dysfunction treatment. Sildenafil, tadalafil, and vardenafil are PDE5 inhibitors and potent vasodilators, that extend the physiological effects of nitric oxide and cyclic guanosine monophosphate (cGMP) signaling. Although most of the biological implications of these signaling regulations remain unknown, they offer a large therapeutic potential for several diseases. In addition, some PDE5 inhibitors' molecular effects seem to play a key role in different illnesses such as kidney disease, diabetes mellitus, and cancer. In this review, we discuss the molecular effects of PDE5 inhibitors and their therapeutic repurposing in different types of cancer.
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The cardiac Na+/H+ exchanger (NHE1) is a membrane glycoprotein fundamental for proper cell functioning due its multiple housekeeping tasks, including regulation of intracellular pH, Na+ concentration, and cell volume. In the heart, hyperactivation of NHE1 has been linked to the development of different pathologies. Several studies in animal models that reproduce the deleterious effects of ischemia/reperfusion injury or cardiac hypertrophy have conclusively demonstrated that NHE1 inhibition provides cardioprotection. Unfortunately, NHE1 inhibitors failed to reproduce these effects in the clinical arena. The reasons for those discrepancies are not apparent yet. However, a reasonable clue to consider would be that drugs that completely abolish the exchanger activity, including that its essential housekeeping function may not be the best therapeutic approach. Therefore, interventions tending to specifically reduce its hyperactive state without affecting its basal activity emerge as a novel potential gold standard. In this regard, a promising goal seems to be the modulation of the phosphorylation state of the cytosolic tail of the exchanger. Recent own experiments demonstrated that Sildenafil, a phosphodiesterase 5A inhibitor drug that has been widely used for the treatment of erectile dysfunction is able to decrease NHE1 phosphorylation, and hence reduce its hyperactivity. In connection, growing evidence demonstrates cardioprotective properties of Sildenafil against different cardiac pathologies, with the distinctive characteristic of directly affecting cardiac tissue without altering blood pressure. This mini-review was aimed to focus on the regulation of NHE1 activity by Sildenafil. For this purpose, experimental data reporting Sildenafil effects in different animal models of heart disease will be discussed.
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Sildenafil (SIL) has potential as an interesting gastroprotective drug. However, the pathways of its protective effect still needs to be clarified, and its use as a potential gastroprotective agent validated. This study aims to evaluate the effects of SIL via modulation of oxidative stress in a NSAID-induced gastric lesion model. Male Swiss mice were divided into six groups: control (CON, water), nonsteroidal anti-inflammatory drug (NSAID, water), proton pump inhibitor (PPI, 30 mg/kg of lansoprazole), SIL 5 (5 mg/kg), SIL 25 (25 mg/kg) and SIL 50 (50 mg/kg). The animals were treated by gavage (a single dose) after 24 hours of fasting, and gastric lesions were performed after 30 minutes, with indomethacin (40 mg/kg, by gavage). After 6h, the animals were killed and the stomach was removed to evaluate reactive oxygen species (ROS) production, oxidation of macromolecules, quantification of antioxidant enzymes, DNA fragmentation, apoptosis and macroscopic and histologic analysis of gastric lesions. SIL exerts a dose-dependent gastroprotective effect against NSAID-induced mucosal injury, also reducing cytoplasmic levels of ROS and consequent oxidative damage to macromolecules. In addition, SIL increases nitric oxide bioavailability, antioxidant enzymes and gastric cellular viability, as well as restoring important factors involved in gastroprotection. Our results demonstrate that different doses of SIL prevent indomethacin-induced gastric ulcer in mice via different, but complementary antioxidant, antigenotoxic and antiapoptotic mechanisms.
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Antioxidantes , Úlcera Gástrica , Animales , Antiinflamatorios no Esteroideos , Masculino , Ratones , Citrato de SildenafilRESUMEN
Pulmonary arterial hypertension (PAH) is characterized by the remodeling of pulmonary arteries, with an increased pulmonary arterial pressure and right ventricle (RV) overload. This work investigated the benefit of the association of human umbilical cord mesenchymal stem cells (hMSCs) with lodenafil, a phosphodiesterase-5 inhibitor, in an animal model of PAH. Male Wistar rats were exposed to hypoxia (10% O2) for three weeks plus a weekly i.p. injection of a vascular endothelial growth factor receptor inhibitor (SU5416, 20 mg/kg, SuHx). After confirmation of PAH, animals received intravenous injection of 5.105 hMSCs or vehicle, followed by oral treatment with lodenafil carbonate (10 mg/kg/day) for 14 days. The ratio between pulmonary artery acceleration time and RV ejection time reduced from 0.42 ± 0.01 (control) to 0.24 ± 0.01 in the SuHx group, which was not altered by lodenafil alone but was recovered to 0.31 ± 0.01 when administered in association with hMSCs. RV afterload was confirmed in the SuHx group with an increased RV systolic pressure (mmHg) of 52.1 ± 8.8 normalized to 29.6 ± 2.2 after treatment with the association. Treatment with hMSCs + lodenafil reversed RV hypertrophy, fibrosis and interstitial cell infiltration in the SuHx group. Combined therapy of lodenafil and hMSCs may be a strategy for PAH treatment.
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Antihipertensivos/farmacología , Carbonatos/farmacología , Hipertensión Pulmonar/terapia , Hipertrofia Ventricular Derecha/terapia , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Inhibidores de Fosfodiesterasa 5/farmacología , Piperazinas/farmacología , Pirimidinas/farmacología , Administración Oral , Animales , Terapia Combinada/métodos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Modelos Animales de Enfermedad , Humanos , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/genética , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/fisiopatología , Hipoxia/genética , Hipoxia/metabolismo , Hipoxia/fisiopatología , Hipoxia/terapia , Indoles/farmacología , Masculino , Células Madre Mesenquimatosas/fisiología , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/metabolismo , Arteria Pulmonar/fisiopatología , Pirroles/farmacología , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Resultado del Tratamiento , Cordón Umbilical/citología , Cordón Umbilical/fisiología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Multiple sclerosis (MS) is a chronic immuno-inflammatory disease of the central nervous system characterized by demyelination and axonal damage. Cognitive changes are common in individuals with MS since inflammatory molecules secreted by microglia interfere with the physiological mechanisms of synaptic plasticity. According to previous data, inhibition of PDE5 promotes the accumulation of cGMP, which inhibits neuroinflammation and seems to improve synaptic plasticity and memory. The present study aimed to evaluate the effect of sildenafil on the signaling pathways of neuroinflammation and synaptic plasticity in experimental autoimmune encephalomyelitis (EAE). C57BL/6 mice were divided into three experimental groups (n = 10/group): (a) Control; (b) EAE; (c) EAE + sild (25 mg/kg/21 days). Sildenafil was able to delay the onset and attenuate the severity of the clinical symptoms of EAE. The drug also reduced the infiltration of CD4+ T lymphocytes and their respective IL-17 and TNF-α cytokines. Moreover, sildenafil reduced neuroinflammation in the hippocampus (assessed by the reduction of inflammatory markers IL-1ß, pIKBα and pNFkB and reactive gliosis, as well as elevating the inhibitory cytokines TGF-ß and IL-10). Moreover, sildenafil induced increased levels of NeuN, BDNF and pCREB, protein kinases (PKA, PKG, and pERK) and synaptophysin, and modulated the expression of the glutamate receptors AMPA and NMDA. The present findings demonstrated that sildenafil has therapeutic potential for cognitive deficit associated with multiple sclerosis.
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Antiinflamatorios/uso terapéutico , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Plasticidad Neuronal/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Citrato de Sildenafil/uso terapéutico , Animales , Antiinflamatorios/farmacología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Citocinas/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/inmunología , Hipocampo/patología , Ratones Endogámicos C57BL , Neuroglía/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Citrato de Sildenafil/farmacologíaRESUMEN
Arterial hypertension is a condition associated with endothelial dysfunction, accompanied by an imbalance in the production of reactive oxygen species (ROS) and NO. The aim of this study was to investigate and elucidate the possible mechanisms of sildenafil, a selective phosphodiesterase-5 inhibitor, actions on endothelial function in aortas from spontaneously hypertensive rats (SHR). SHR treated with sildenafil (40â¯mg/kg/day, p.o., 3â¯weeks) were compared to untreated SHR and Wistar-Kyoto (WKY) rats. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography and vascular reactivity was determined in isolated rat aortic rings. Circulating endothelial progenitor cells and systemic ROS were measured by flow cytometry. Plasmatic total antioxidant capacity, NO production and aorta lipid peroxidation were determined by spectrophotometry. Scanning electron microscopy was used for structural analysis of the endothelial surface. Sildenafil reduced high SBP and partially restored the vasodilator response to acetylcholine and sodium nitroprusside in SHR aortic rings. Using selective inhibitors, our experiments revealed an augmented participation of NO, with a simultaneous decrease of oxidative stress and of cyclooxygenase-1 (COX-1)-derived prostanoids contribution in the endothelium-dependent vasodilation in sildenafil-treated SHR compared to non-treated SHR. Also, the relaxant responses to sildenafil and 8-Br-cGMP were normalized in sildenafil-treated SHR and sildenafil restored the pro-oxidant/antioxidant balance and the endothelial architecture. In conclusion, sildenafil reverses endothelial dysfunction in SHR by improving vascular relaxation to acetylcholine with increased NO bioavailability, reducing the oxidative stress and COX-1 prostanoids, and improving cGMP/PKG signaling. Also, sildenafil reduces structural endothelial damage. Thus, sildenafil is a promising novel pharmacologic strategy to treat endothelial dysfunction in hypertensive states reinforcing its potential role as adjuvant in the pharmacotherapy of cardiovascular diseases.
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Antihipertensivos/farmacología , Aorta/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Ciclooxigenasa 1/metabolismo , Endotelio Vascular/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Proteínas de la Membrana/metabolismo , NADP/metabolismo , Óxido Nítrico/metabolismo , Citrato de Sildenafil/farmacología , Vasodilatadores/farmacología , Animales , Aorta/enzimología , Aorta/fisiopatología , Aorta/ultraestructura , GMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Células Progenitoras Endoteliales/efectos de los fármacos , Células Progenitoras Endoteliales/metabolismo , Células Progenitoras Endoteliales/ultraestructura , Endotelio Vascular/enzimología , Endotelio Vascular/fisiopatología , Endotelio Vascular/ultraestructura , Hipertensión/enzimología , Hipertensión/patología , Hipertensión/fisiopatología , Peroxidación de Lípido/efectos de los fármacos , Masculino , Estrés Oxidativo/efectos de los fármacos , Inhibidores de Fosfodiesterasa 5/farmacología , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Transducción de Señal , Vasodilatación/efectos de los fármacosRESUMEN
ABSTRACT Objective: It has been reported that phosphodiesterase-5 (PDE-5) inhibitors improve kidney function during acute and chronic renal failure. This study aimed to determine the possible therapeutic effects of tadalafil, a specific PDE-5 inhibitor, on renal fibrosis induced by unilateral ureteral obstruction (UUO). Methods: Male Sprague-Dawley rats were used and randomly divided into three groups (n = 6) as sham-operated, UUO and tadalafil-treated (10 mg/72 hours, ig) UUO (UUO+T) groups. Unilateral ureteral obstruction was induced by complete ligation of the left ureter and 14 days after surgery creatinine clearance, urinary cyclic guanosine monophosphate (cGMP), renal alpha-smooth muscle actin (α-sma) and transforming growth factor βeta (TGF-β) levels, as well as histologic changes, were observed in all the animals. Results: Unilateral ureteral obstruction-induced renal fibrosis was confirmed by increased α-sma level, collagen deposition, tubular dilation, inflammatory cell infiltration and necrosis. An increased renal TGF-β level and decreased urinary cGMP level was also observed in obstructed animals in addition to reduced creatinine clearance. Tadalafil treatment, which restored the animals 'urinary cGMP level, significantly attenuated the fibrotic changes and TGF-β increase in their kidneys. Conclusion: This study suggests that tadalafil treatment ameliorates renal fibrosis by reducing TGF-β expression and may have important clinical relevance since tadalafil is currently used clinically to treat erectile dysfunction and pulmonary hypertension.
RESUMEN Objetivo: Se ha reportado que los inhibidores de la fosfodiesterasa-5 (PDE-5) mejoran las funciones renales durante la insuficiencia renal aguda y crónica. Este estudio tuvo por objetivo determinar los posibles efectos terapéuticos del tadalafil - un inhibidor específico de la PDE-5 - sobre la fibrosis renal inducida por una obstrucción ureteral unilateral (OUU). Métodos: Se utilizaron ratas machos Sprague-Dawley, divididas de manera aleatoria en tres grupos (n = 6): operación simulada, OUU y tratamiento con tadalafil (10 mg/72 horas, IG), y OUU (OUU+T). La obstrucción uretral unilateral fue inducida por una ligadura completa del uréter izquierdo y 14 días después de la cirugía, se observaron niveles de monofosfato de guanosina cíclico (GMP) urinario, alfa-actina de músculo liso (α-SMA), y factor de crecimiento transformante βeta (FCT-β), así como cambios histológicos en todos los animales. Resultados: La fibrosis renal inducida por obstrucción uretral unilateral fue confirmada por un aumento del nivel de α-SMA, deposición de colágeno, dilatación tubular, infiltración de células inflamatorias y necrosis. También se observó un aumento del nivel de FCT-β renal y una disminución del nivel de GMP urinario en los animales con obstrucción, además de una reducción del aclaramiento de la creatinina. El tratamiento con tadalafil, que restauró el nivel de GMP urinario de los animales, atenuó significativamente los cambios fibróticos y el aumento de FCT-β en los riñones. Conclusión: Este estudio sugiere que el tratamiento con tadalafil mejora la fibrosis renal al reducir la expresión de FCT-β y puede tener una importante relevancia clínica por cuanto el tadalafil se usa hoy día clínicamente para tratar la disfunción eréctil y la hipertensión pulmonar.
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Animales , Ratas , Fármacos Renales/farmacología , Fibromialgia/tratamiento farmacológico , Tadalafilo/farmacología , Enfermedades Renales/tratamiento farmacológico , Obstrucción Ureteral/complicaciones , Fibromialgia/etiología , Ratas Sprague-Dawley , Modelos Animales de Enfermedad , Enfermedades Renales/etiologíaRESUMEN
Phosphodiesterase type 5 (PDE-5) is an important enzyme involved in the hydrolysis of cyclic guanosine monophosphate (cGMP) to guanosine monophosphate (GMP). The inhibition of this protein leads to the accumulation of cGMP in cells with various biological and therapeutic effects. Several PDE-5 inhibitors exist, with Tadalafil being one of the most commonly studied and used in clinical therapy. In this study, we applied Molecular Dynamics simulations coupled to the ABF (Adaptive Biasing Force) method to study the effect of the mutation on the Gln817 residue (Q817G). The results of the free energy profiles made clear that the affinity of the inhibitor for PDE-5 is dependent on the amino acid residue Gln817. The hydrogen bond made between the side chain of glutamine and the indole ring of Tadalafil results in the stabilization of the ligand in the catalytic site. Despite the prominent role of this interaction, it is important to highlight the contribution of other residues of the catalytic domain for the stabilization of the compound, due to the set of polar, hydrophobic and electrostatic interactions performed by specific amino acid residues.
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Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Inhibidores de Fosfodiesterasa 5/química , Tadalafilo/química , Sitios de Unión , Dominio Catalítico , GMP Cíclico/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/genética , Humanos , Enlace de Hidrógeno , Ligandos , Simulación de Dinámica Molecular , Mutagénesis Sitio-Dirigida , Inhibidores de Fosfodiesterasa 5/metabolismo , Tadalafilo/metabolismo , TermodinámicaRESUMEN
AIM: This work evaluates a possible causative role for germline copy number variants (CNVs) in melanoma predisposition. PATIENTS & METHODS: A total of 41 melanoma-prone Brazilian patients were investigated for CNVs using 850K single nucleotide polymorphism arrays. RESULTS: Ten rare CNVs were identified in nine patients, comprising 54 known genes, mostly related to cancer. In silico analyses revealed gene enrichment for cellular development and growth, and proliferation, highlighting five genes directly associated with the melanoma phenotype (ANGPT1, IDH1, PDE5A, HIST1H1B and GCNT2). CONCLUSION: Patients harboring rare CNVs exhibited a decreased age of disease onset, in addition to an overall higher skin cancer predisposition. Our findings suggest that rare CNVs contribute to melanoma susceptibility, and should be taken into account when investigating cancer risk factors.
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Variaciones en el Número de Copia de ADN/genética , Predisposición Genética a la Enfermedad/genética , Melanoma/genética , Neoplasias Cutáneas/genética , Adulto , Femenino , Mutación de Línea Germinal , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Reacción en Cadena en Tiempo Real de la Polimerasa , Estudios RetrospectivosRESUMEN
BACKGROUND: Phosphodiesterase type 5 (PDE5) inhibitors have discontinuation rates as high as 60% in men with erectile dysfunction. Treatment satisfaction has been significantly associated with treatment continuation. Understanding key characteristics in terms of treatment preference, relationship, and lifestyle issues could provide direction on how to improve compliance with PDE5 inhibitor treatment globally. OBJECTIVE: The objective was to identify subgroups of interest in the pooled database of two observational studies conducted in Latin America (LA) and Middle East/North Africa (MENA) exploring patient characteristics and prescription of either a long- or short-acting PDE5 inhibitor at baseline. METHODS: Two identical prospective, non-interventional, observational, studies in MENA (N = 493) and LA (N = 511) treated men with an 'on demand' (pro re nata, PRN) PDE5 inhibitor (sildenafil, tadalafil, vardenafil, or lodenafil) during 6 months. In this post-hoc meta-analysis of two observational studies with equal design, pooled data were analyzed to determine patient characteristics and PDE5 inhibitor prescribed/used most likely to be associated with patient expectations, satisfaction, self-esteem, and patient-partner relationships. Decision tree analyses, with and without weighting, were used to identify and describe key features. RESULTS: In each analysis of patient expectations, patient-partner relationship, and self-esteem, we describe the two major subgroups at baseline for each decision tree. Analyses of patient expectations and sexual self-esteem revealed that patients prescribed long-acting PDE5 inhibitors (59%) highlighted the importance of treatment effect duration, second to partner satisfaction with treatment, while patients prescribed short-acting PDE5 inhibitors (32%) placed less importance on treatment effect duration but considerable importance on treatment effect lasting until intercourse completion. Further insights regarding patients, partner relationship characteristics, and treatment expectations were identified. CONCLUSION: Our analyses have described key characteristics, such as self- and partner perceptions, sexual attitudes, and treatment expectations in relation to the patients' country and prescribed treatment, which might guide treatment decisions in MENA and LA men with ED.
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Disfunción Eréctil , Relaciones Interpersonales , Inhibidores de Fosfodiesterasa 5 , Autoimagen , Adulto , África del Norte/epidemiología , Árboles de Decisión , Preparaciones de Acción Retardada/clasificación , Preparaciones de Acción Retardada/farmacología , Preparaciones de Acción Retardada/uso terapéutico , Disfunción Eréctil/tratamiento farmacológico , Disfunción Eréctil/epidemiología , Disfunción Eréctil/psicología , Humanos , América Latina/epidemiología , Estilo de Vida , Masculino , Persona de Mediana Edad , Medio Oriente/epidemiología , Cooperación del Paciente , Prioridad del Paciente , Inhibidores de Fosfodiesterasa 5/clasificación , Inhibidores de Fosfodiesterasa 5/farmacocinética , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Pautas de la Práctica en Medicina , Estudios Prospectivos , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
INTRODUCTION: Several cases of adulteration of dietary supplements with tadalafil, sildenafil, and vardenafil, or their unapproved analogues have been reported worldwide. Mainly, the presence of the latter represents a serious health risk to consumers as their efficacy and toxic effects have not been assessed and may result in unpredictable adverse effects. AIM: To investigate the suspected adulteration with synthetic phosphodiesterase type 5 (PDE-5) inhibitors in a dietary supplement marketed in Argentina for the treatment of erectile dysfunction (ED). METHODS: The content of the capsules of the dietary supplement (sample A) was analyzed by thin layer chromatography (TLC) and high-performance liquid chromatography (HPLC) diode-array detection. From the organic extract of sample A, a major compound was purified by column chromatography (CC). The isolated compound was identified by proton nuclear magnetic resonance (1H NMR) and carbon NMR (13C NMR), heteronuclear single quantum coherence, distortionless enhancement by polarization transfer (DEPT 135), electrospray ionization mass spectrometry, and ultraviolet, and infrared (Fourier transform infrared spectroscopy) spectroscopy. MAIN OUTCOME MEASURE: Proof of adulteration of herbal products with synthetic PDE-5 inhibitors. RESULTS: By TLC and HPLC analysis, a major compound was detected in sample A organic extract. The purification of this extract by CC led to the isolation of a pure compound which was identified according to its spectral data as (6R,12aR)-2-amino-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydropyrazino [1',2':1,6] pyrido [3,4-b] indole-1,4-dione or aminotadalafil. CONCLUSIONS: An unapproved PDE-5 inhibitor analogue, which was identified as aminotadalafil, has been detected in a dietary supplement. This study represents the first report in Latin America and one of the few independent studies of an adulteration with an unapproved PDE-5 inhibitor of an herbal product for ED treatment.
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Carbolinas/efectos adversos , Suplementos Dietéticos/efectos adversos , Contaminación de Medicamentos , Disfunción Eréctil/tratamiento farmacológico , Preparaciones Farmacéuticas/análisis , Inhibidores de Fosfodiesterasa 5/efectos adversos , Preparaciones de Plantas/efectos adversos , Argentina , Benzodioxoles , Carbolinas/administración & dosificación , Cromatografía Líquida de Alta Presión , Suplementos Dietéticos/análisis , Contaminación de Medicamentos/prevención & control , Humanos , Masculino , Inhibidores de Fosfodiesterasa 5/administración & dosificación , Preparaciones de Plantas/química , Espectrometría de Masa por Ionización de Electrospray , TadalafiloRESUMEN
OBJECTIVES: Vardenafil enhances dilatation of vascular smooth muscle and inhibits platelet aggregation. The purpose of this study was to evaluate the clinical effects of vardenafil and pentoxifylline administration in an experimental model of ischemic colitis. METHODS: Forty female Wistar albino rats weighing 250-300 g were randomized into five experimental groups (each with n = 8) as follows:1) a sham group subjected to a sham surgical procedure and administered only tap water; 2) a control group subjected to a standardized surgical procedure to induce ischemic colitis and administered only tap water; 3) and 4) treatment groups subjected to surgical induction of ischemic colitis followed by the postoperative administration of 5 mg/kg or 10 mg/kg vardenafil, respectively; and 5) a treatment group subjected to surgical induction of ischemic colitis followed by postoperative administration of pentoxifylline at 50 mg/kg/day per day as a single dose for a 3-day period. All animals were sacrificed at 72 h post-surgery and subjected to relaparotomy. We scored the macroscopically visible damage, measured the ischemic area and scored histopathology to determine the severity of ischemia. Tissue malondialdehyde levels were also quantified. RESULTS: The mean Gomella ischemic areas were 63.3 mm2 in the control group; 3.4 and 9.6 mm2 in the vardenafil 5 and vardenafil 10 groups, respectively; and 3.4 mm2 in the pentoxifylline group (p = 0.0001). The mean malondialdehyde values were 63.7 nmol/g in the control group; 25.3 and 25.6 nmol/g in the vardenafil 5 and vardenafil 10 groups, respectively; and 22.8 nmol/g in the pentoxifylline group (p = 0.0001). CONCLUSION: Our findings indicate that vardenafil and pentoxifylline are effective treatment options in an animal model of ischemic colitis. The positive clinical effects produced by these drugs are likely due to their influence on the hemodynamics associated ...
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Animales , Femenino , Colitis Isquémica/tratamiento farmacológico , Imidazoles/administración & dosificación , Pentoxifilina/administración & dosificación , /administración & dosificación , Piperazinas/administración & dosificación , Colitis Isquémica/patología , Colitis Isquémica/cirugía , Colon/patología , Colon/cirugía , Modelos Animales de Enfermedad , Hemodinámica/efectos de los fármacos , Malondialdehído/análisis , Distribución Aleatoria , Ratas Wistar , Reproducibilidad de los Resultados , Sulfonas/administración & dosificación , Factores de Tiempo , Resultado del Tratamiento , Triazinas/administración & dosificaciónRESUMEN
Sildenafil and other PDE-5 inhibitors have revolutionized erectile dysfunction (ED) treatment. However, a significant number of patients do not respond or present adverse reactions to these drugs. While genetic polymorphisms may underlie this phenomenon, very little research has been undertaken in this research field. Most of the current knowledge is based on sildenafil, thus almost completely ignoring other important pharmacological therapies. Currently, the most promising genes with pharmacogenetic implications in ED are related to the nitric oxide and cGMP pathway, although other genes are likely to affect the responsiveness to treatment of ED. Nevertheless, the small number of studies available opens the possibility of further exploring other genes and phenotypes related to ED. This article provides a comprehensive overview of the genes being tested for their pharmacogenetic relevance in the therapy of ED.
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Disfunción Eréctil/tratamiento farmacológico , Disfunción Eréctil/genética , Inhibidores de Fosfodiesterasa 5/farmacología , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Piperazinas/farmacología , Piperazinas/uso terapéutico , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Animales , GMP Cíclico/genética , Humanos , Masculino , Óxido Nítrico/genética , Farmacogenética/métodos , Inhibidores de Fosfodiesterasa 5/efectos adversos , Piperazinas/efectos adversos , Polimorfismo Genético/genética , Purinas/efectos adversos , Purinas/farmacología , Purinas/uso terapéutico , Citrato de Sildenafil , Sulfonamidas/efectos adversosRESUMEN
Carbonato de Lodenafila é um novo tipo de inibidor de fosfodiesterase 5 (PDE5) utilizado no tratamento da disfunção erétil. O presente estudo foi realizado para avaliar a segurança, tolerabilidade e farmacocinética do carbonato de lodenafila após a administração de doses orais únicas ascendentes (de 1 a 100 mg) a voluntários saudáveis do sexo masculino (n = 33). O estudo foi um estudo clínico fase I, aberto, de escalonamento de dose, utilizando a administração de doses orais únicas de carbonato de lodenafila. Carbonato de Lodenafila foi administrado sequencialmente escalonado em doses únicas de 1 mg a 100 mg com um período sem uso do medicamento (washout) de pelo menos 1 semana, entre cada dose. A progressão para a próxima dose foi permitida se após a avaliação dos exames clínicos, laboratoriais e Monitorização Ambulatorial da Pressão Arterial (MAPA), não demonstrassem alterações e eventos adversos sem relevância clínica. As amostras de sangue foram coletadas na pré-dose e em intervalos determinados e 24 horas após a administração. As amostras de plasma para a mensuração de carbonato lodenafila e lodenafila foram analisadas por cromatografia líquida acoplada à espectrometria de massa. Não foram observados eventos adversos graves, e nenhum dos voluntários abandonou o estudo devido à intolerância. As medições do MAPA, exames clínicos e laboratoriais e ECG não revelaram alterações significativas mesmo em doses mais elevadas. Carbonato Lodenafila não foi detectado em qualquer amostra, indicando que ele atua como um pró-droga. Os parâmetros farmacocinéticos médios de lodenafila para tmax e t1 / 2 foram 1,6 (± 0,4) horas e 3,3 (± 1,1) horas, respectivamente. Este estudo demonstrou que o carbonato de lodenafila é bem tolerado e apresentou um bom perfil de segurança em voluntários saudáveis do sexo masculino.
Lodenafil carbonate is a new phosphodiesterase type 5 (PDE5) inhibitor used in treatment of erectile dysfunction. The present study was conducted to evaluate the safety, tolerability, and pharmacokinetics of lodenafil carbonate after administering ascending (1 to 100 mg) single oral doses to healthy male volunteers (n=33). The study was an open-label, dose-escalation, phase I clinical trial involving the administration of single oral doses of lodenafil carbonate. Lodenafil carbonate was administered sequentially, escalating in single doses of 1 mg to 100 mg with a washout period of at least 1 week between each dose. The progression to the next dose was allowed after clinical and laboratory exams, Ambulatory Monitoring of Arterial Pressure (AMAP) without relevant clinical modifications and adverse events without clinical relevancy. Blood samples were collected at pre-dose, determined intervals and 24h postdosing. Plasma samples for measurement of lodenafil carbonate and lodenafil were analyzed by liquid chromatography coupled to tandem mass spectrometry. No serious adverse events were observed, and none of the subjects discontinued the study due to intolerance. The AMAP measurements, clinical and laboratory exams and ECG revealed no significant changes even at higher doses. Lodenafil carbonate was not detected in any samples, indicating that it acts as a pro-drug. The mean lodenafil pharmacokinetic parameters for tmax and t1/2 were 1.6 (±0.4) hr and 3.3 (±1.1) hr, respectively. This study demonstrated that lodenafil carbonate was well tolerated and showed a good safety profile in healthy male volunteers.