RESUMEN
Ten POWER dietary supplements, chronologically called tabs, pills then caps, and advertised as 100% natural aphrodisiacs, were analyzed by 1H NMR from 2007 to 2022. They were all tainted by PDE-5 inhibitors. Eight different adulterants were identified (sildenafil (1), sildenafil analogues (6), and vardenafil analogue (1)). Their amounts ranged from 15 to 145 mg/capsule. Four supplements contained at least 100 mg/capsule of PDE-5 inhibitor or analogue, the maximal recommended dose of sildenafil. The nature of the adulterant has changed over time, probably to evade its detection by regulatory agencies routine screening tests. Despite several warnings and/or seizures from several European food and/or health authorities, the dietary supplement POWER is still on sale on the Internet, thus demonstrating the impossibility of controlling this market. Faced with this situation, the consumer should be better informed by establishing at the European level a public database of tainted dietary supplements on the model of that of the US Food and Drug Administration. It should indicate the product name, its photo, the adulterant name, and be easily accessible to everyone.
Asunto(s)
Suplementos Dietéticos , Inhibidores de Fosfodiesterasa 5 , Suplementos Dietéticos/análisis , Contaminación de Medicamentos/prevención & control , Espectroscopía de Resonancia Magnética , Inhibidores de Fosfodiesterasa 5/farmacología , Citrato de Sildenafil , Diclorhidrato de Vardenafil , HumanosRESUMEN
Bromodomain and extraterminal (BET) proteins are promising therapeutic targets for hematological and solid tumors. However, BET inhibitor monotherapy did not show a significant therapeutic benefit for hepatocellular carcinoma (HCC) in preclinical trials. Here, we identified YAP/TAZ genes, as determinants for sensitivity to BET inhibitors. YAP/TAZ expression, especially TAZ, promote resistance to BET inhibitor. In addition, we analyzed that the mRNA level of PDE5 was positively correlated with YAP/TAZ based on TCGA database and demonstrated tadalafil, a PDE5 inhibitor, could block YAP/TAZ protein expression by activating Hippo pathway. Cotreatment with tadalafil and JQ-1 synergistically reduced YAP/TAZ protein expression, suppressed proliferation and induced G0-G1 arrest of cultured HCC cells. JQ-1 alone does not show significant benefits in a mouse model of HCC induced by c-Myc/N-Ras plasmids. In contrast, the combination, tadalafil and JQ-1, successfully suppressed tumor progression, enhanced antitumor immunity by improving the ratio of activated CD8 and extended the survival time of mice. Our data define the key role of YAP/TAZ in mediating resistance to BET inhibitor, described the PDE5/PKG/Hippo/YAP/TAZ axis and identified a common clinical drug that can be developed as an effective combined strategy to overcome BET inhibitor resistance in MYC/Ras-driven HCC.
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Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Proteínas del Tejido Nervioso/genética , Receptores de Superficie Celular/genética , Tadalafilo/farmacología , Proteínas Señalizadoras YAP/genética , Animales , Azepinas/farmacología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/genética , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/genética , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Vía de Señalización Hippo/efectos de los fármacos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Ratones , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Inhibidores de Fosfodiesterasa 5/farmacología , Proteínas Proto-Oncogénicas c-myc/genética , Receptores de Superficie Celular/antagonistas & inhibidores , Triazoles/farmacologíaRESUMEN
Erectile dysfunction (ED) is one of the main challenges occurring among men worldwide, and is characterised by trouble getting or keeping steady erection during sexual intercourse. Various drugs like sildenafil, a phosphodiesterase-5 inhibitor (PDE-5) are freely available in the pharmacies, though normally associated with several adverse. This study was designed to assess the molecular relations obtainable between catechin, garcinal, garcinoic acid and d-tocotrienol compounds isolated from Garcinia kola and targeted receptor linked to ED. These processes include the molecular docking of catechin, garcinal, garcinoic acid, d-tocotrienol, and sildenafil to receptor: PDE-5 via AutoDock Vina. Following the docking of catechin, garcinal, garcinoic acid and d-tocotrienol with the PDE-5-receptor protein, we observed that all are protein inhibitors with garcinoic acid showing better binding affinity -10.0 kcal/mol with PDE-5 receptor relevant to ED. Hence, the results provided insights into the development of garcinoic acid as a replacement for present ED management, with further analysis worth considering.
Asunto(s)
Disfunción Eréctil , Garcinia kola , Disfunción Eréctil/tratamiento farmacológico , Humanos , Masculino , Simulación del Acoplamiento Molecular , Inhibidores de Fosfodiesterasa 5/farmacología , Semillas , Citrato de Sildenafil/farmacologíaRESUMEN
Herbal supplements sold as 'all natural' on various markets in Accra (Ghana) and advertised as highly efficacious in treating erectile dysfunction (ED) were bought and analysed by a PDE-5 enzyme inhibition assay. The claimed efficacy of these products could be the result of inherent plant constituents, but also of intentionally added pharmaceuticals. Medically, ED is treated with potent inhibitors of the phosphodiesterase-5 (PDE-5) enzyme, as in the case of sildenafil. To test the efficacy of the Ghanaian supplements, extracts were made and tested using a PDE-Glo phosphodiesterase assay, a luminescent high-throughput screening (HTS) method. Results revealed that about 90% of the selected samples were able to inhibit PDE-5 activity to a high extent. Estimated concentrations in sildenafil equivalents ranged from traces to very high, with 25 samples (62.5%) pointing at daily doses higher than 25 mg sildenafil equivalents and 9 (22.5%) of these at doses higher than the maximal recommended daily intake of 100 mg sildenafil equivalents. Further investigations are needed to confirm if the observed effects are due to inherent plant constituents or merely the result of added synthetic PDE-5 enzyme inhibitors, especially because doses above 100 mg sildenafil equivalents per day may result in severe health risks.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Suplementos Dietéticos , Inhibidores de Fosfodiesterasa 5/farmacología , Extractos Vegetales/farmacología , Bioensayo , Disfunción Eréctil/tratamiento farmacológico , Ghana , Ensayos Analíticos de Alto Rendimiento , Humanos , MasculinoRESUMEN
Phosphodiesterase 5 (PDE5) is one of the most extensively studied phosphodiesterases that is highly specific for cyclic-GMP hydrolysis. PDE5 became a target for drug development based on its efficacy for treatment of erectile dysfunction. In the present study, we synthesized four novel analogues of the phosphodiesterase type 5 (PDE5) inhibitor-tadalafil, which differs in (i) ligand flexibility (rigid structure of tadalafil vs. conformational flexibility of newly synthesized compounds), (ii) stereochemistry associated with applied amino acid building blocks, and (iii) substitution with bromine atom in the piperonyl moiety. For both the intermediate and final compounds as well as for the parent molecule, we have established the crystal structures and performed a detailed analysis of their structural features. The initial screening of the cytotoxic effect on 16 different human cancer and non-cancer derived cell lines revealed that in most cases, the parent compound exhibited a stronger cytotoxic effect than new derivatives, except for two cell lines: HEK 293T (derived from a normal embryonic kidney, that expresses a mutant version of SV40 large T antigen) and MCF7 (breast adenocarcinoma). Two independent studies on the inhibition of PDE5 activity, based on both pure enzyme assay and modulation of the release of nitric oxide from platelets under the influence of tadalafil and its analogues revealed that, unlike a reference compound that showed strong PDE5 inhibitory activity, the newly obtained compounds did not have a noticeable effect on PDE5 activity in the range of concentrations tested. Finally, we performed an investigation of the toxicological effect of synthesized compounds on Caenorhabditis elegans in the highest applied concentration of 6a,b and 7a,b (160 µM) and did not find any effect that would suggest disturbance to the life cycle of Caenorhabditis elegans. The lack of toxicity observed in Caenorhabditis elegans and enhanced, strengthened selectivity and activity toward the MCF7 cell line made 7a,b good leading structures for further structure activity optimization and makes 7a,b a reasonable starting point for the search of new, selective cytotoxic agents.
Asunto(s)
Caenorhabditis elegans/enzimología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Inhibidores de Fosfodiesterasa 5 , Piperazinas , Tadalafilo , Animales , Evaluación Preclínica de Medicamentos , Células HEK293 , Humanos , Células MCF-7 , Inhibidores de Fosfodiesterasa 5/síntesis química , Inhibidores de Fosfodiesterasa 5/química , Inhibidores de Fosfodiesterasa 5/farmacología , Piperazinas/síntesis química , Piperazinas/química , Piperazinas/farmacología , Tadalafilo/análogos & derivados , Tadalafilo/síntesis química , Tadalafilo/química , Tadalafilo/farmacologíaRESUMEN
Phosphodiesterase 5A enzyme has been the upcoming and promising target in hypertension management. In this research, reported 270 bioactive natural products having antihypertensive potential were selected and docked against PDE5A using vLife MDS 4.6 software. Based on docking score, π-stacking, H-bond and ionic interactions with PDE5A, 82 tricyclic compounds were selected for further study. Protein residue Gln817A was associated in H-boding, Leu804A in ionic interaction whereas Val782A and Phe820A were associated in π-stacking interaction with ligand. In silico docking studies resulted in discovery of oxygen containing naphthofuran and nitrogen and oxygen containing pyrano quinolizine tricyclic lead scaffolds as novel PDE5A inhibitors. Additionally, developed pharmacophore model suggested that one centre of hydrogen bond acceptor, one aromatic centre and two aliphatic centres are minimum pharmacophoric features required in the molecule so as to show sildenafil like activity. The identified lead scaffolds would provide novel platform for drug discovery of bioactive natural products.
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Productos Biológicos/química , Productos Biológicos/farmacología , Inhibidores de Fosfodiesterasa 5/química , Inhibidores de Fosfodiesterasa 5/farmacología , Simulación por Computador , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos/métodos , Humanos , Enlace de Hidrógeno , Ligandos , Simulación del Acoplamiento Molecular , Nitrógeno/química , Oxígeno/química , Quinolizinas/química , Citrato de Sildenafil/química , Programas InformáticosRESUMEN
In 1998, sildenafil was marketed as the first FDA-approved oral drug for the treatment of erectile dysfunction (ED). During the last two decades, the commercialization of other synthetic phosphodiesterase 5 (PDE5) inhibitors has been paralleled by the rise of remedies based on natural molecules from different chemical classes (flavonoids, polyphenols and alkaloids in general). In this work, a set of in silico tools were applied to study a panel of 30 natural compounds claimed to be effective against ED in the scientific literature or in folk medicine. First, pharmacokinetic properties were analysed to exclude the compounds lacking in specific drug-like features. Estimated binding energy for PDE5 and selectivity towards other PDE isoforms were then considered to highlight some promising molecules. Finally, a detailed structural investigation of the interaction pattern with PDE in comparison with sildenafil was conducted for the best performing compound of the set.
Asunto(s)
Inhibidores de Fosfodiesterasa 5/química , Inhibidores de Fosfodiesterasa 5/farmacología , Sitios de Unión , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Simulación por Computador , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Disfunción Eréctil/tratamiento farmacológico , Humanos , Masculino , Medicina Tradicional , Inhibidores de Fosfodiesterasa 5/farmacocinética , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Citrato de Sildenafil/farmacologíaRESUMEN
Hypoxic coronary vasospasm may lead to myocardial ischaemia and cardiac dysfunction. Inosine 3',5'-cyclic monophosphate (cIMP) is a putative second messenger to mediate this pathological process. Nevertheless, it remains unclear as to whether levels of cIMP can be regulated in living tissue such as coronary artery and if so, what is the consequence of this regulation on hypoxia-induced vasoconstriction. In the present study, we found that cIMP was a key determinant of hypoxia-induced constriction but not that of the subsequent relaxation response in porcine coronary arteries. Subsequently, coronary arteries were treated with various phosphodiesterase (PDE) inhibitors to identify PDE types that are capable of regulating cIMP levels. We found that inhibition of PDE1 and PDE5 substantially elevated cIMP content in endothelium-denuded coronary artery supplemented with exogenous purified cIMP. However, cGMP levels were far lower than their levels in intact coronary arteries and lower than cIMP levels measured in endothelium-denuded coronary arteries supplemented with exogenous cIMP. The increased cIMP levels induced by PDE1 or PDE5 inhibition further led to augmented hypoxic constriction without apparently affecting the relaxation response. In intact coronary artery, PDE1 or PDE5 inhibition up-regulated cIMP levels under hypoxic condition. Concomitantly, cGMP level increased to a comparable level. Nevertheless, the hypoxia-mediated constriction was enhanced in this situation that was largely compromised by an even stronger inhibition of PDEs. Taken together, these data suggest that cIMP levels in coronary arteries are regulated by PDE1 and PDE5, whose inhibition at a certain level leads to increased cIMP content and enhanced hypoxic constriction.
Asunto(s)
Vasos Coronarios/metabolismo , IMP Cíclico/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 1/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Óxido Nítrico/metabolismo , Animales , Cromatografía Líquida de Alta Presión , Vasos Coronarios/efectos de los fármacos , GMP Cíclico/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 1/antagonistas & inhibidores , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Hipoxia/metabolismo , Metabolómica/métodos , Inhibidores de Fosfodiesterasa 5/farmacología , Porcinos , Espectrometría de Masas en Tándem , VasoconstricciónRESUMEN
Diabetic nephropathy (DN) is a leading cause of end-stage renal disease (ESRD). Hypertension increases kidney stress, which deteriorates function, and leads to peripheral renal vascular resistance. Long-term hypoperfusion promotes interstitial fibrosis and glomerular sclerosis, resulting in nephrosclerosis. Although hypertension and DN are frequent ESRD complications, relevant animal models remain unavailable. We generated a deoxycorticosterone acetate (DOCA)-salt hypertensive uni-nephrectomized (UNx) KKAy mouse model demonstrating hypertension, hyperglycemia, cardiac hypertrophy, kidney failure, increased urinary albumin creatinine ratio (UACR), and increased renal PDE4D and cardiac PDE5A mRNA levels. We hypothesized that the novel PDE4 selective inhibitor, compound A, and PDE5 inhibitor, sildenafil, exhibit nephroprotective, and cardioprotective effects in this new model. Compound A, sildenafil, and the angiotensin II receptor blocker, irbesartan, significantly reduced ventricular hypertrophy and pleural effusion volume. Meanwhile, compound A and sildenafil significantly suppressed the UACR, urinary kidney injury molecule-1, and monocyte chemoattractant protein-1 levels, as well as that of renal pro-fibrotic marker mRNAs, including collagen 1A1, fibronectin, and transforming growth factor-beta (TGF-ß). Moreover, compound A significantly suppressed TGF-ß-induced pro-fibrotic mRNA expression in vitro in all major kidney lesions, including within the glomerular mesangial region, podocytes, and epithelial region. Hence, PDE4 and PDE5 inhibitors may be promising treatments, in combination with irbesartan, for DN with hypertension as they demonstrate complementary mechanisms.
Asunto(s)
Cardiomegalia/tratamiento farmacológico , Desoxicorticosterona/toxicidad , Hiperglucemia/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 5/farmacología , Insuficiencia Renal/tratamiento farmacológico , Citrato de Sildenafil/farmacología , Acetatos/farmacología , Animales , Antiinflamatorios no Esteroideos/farmacología , Cardiomegalia/inducido químicamente , Cardiomegalia/enzimología , Cardiomegalia/patología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/química , Femenino , Hiperglucemia/inducido químicamente , Hiperglucemia/enzimología , Hiperglucemia/patología , Hipertensión/inducido químicamente , Hipertensión/enzimología , Hipertensión/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mineralocorticoides/toxicidad , Insuficiencia Renal/inducido químicamente , Insuficiencia Renal/enzimología , Insuficiencia Renal/patología , Cloruro de Sodio/toxicidad , Tiramina/análogos & derivados , Tiramina/farmacologíaRESUMEN
BACKGROUND: In cirrhosis, the nitric oxide-soluble guanylyl cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway is impaired, which contributes to increased intrahepatic vascular resistance (IHVR) and fibrogenesis. We investigated if sGC stimulation (riociguat (RIO)), sGC activation (cinaciguat (CINA)) or phosphodiesterase (PDE)-5 inhibition (tadalafil (TADA)) improves portal hypertension (PHT) and liver fibrosis. METHODS: Fifty male Sprague-Dawley rats underwent bile-duct ligation (BDL) or sham operation. RIO (0.5 mg/kg), CINA (1 mg/kg), TADA (1.5 mg/kg) or vehicle (VEH) was administered from weeks 2 to 4 after BDL. At week 4, invasive haemodynamic measurements were performed, and liver fibrosis was assessed by histology (chromotrope-aniline blue (CAB), Picro-Sirius red (PSR)) and hepatic hydroxyproline content. RESULTS: Cirrhotic bile duct-ligated rats presented with PHT (13.1 ± 1.0 mmHg) and increased IHVR (4.9 ± 0.5 mmHgâ min/mL). Both RIO (10.0 ± 0.7 mmHg, p = 0.021) and TADA (10.3 ± 0.9 mmHg, p = 0.050) decreased portal pressure by reducing IHVR (RIO: -41%, p = 0.005; TADA: -21%, p = 0.199) while not impacting heart rate, mean arterial pressure and portosystemic shunting. Hepatic cGMP levels increased upon RIO (+239%, p = 0.006) and TADA (+32%, p = 0.073) therapy. In contrast, CINA dosed at 1 mg/kg caused weight loss, arterial hypotension and hyperlactataemia in bile duct-ligated rats. Liver fibrosis area was significantly decreased by RIO (CAB: -48%, p = 0.011; PSR: -27%, p = 0.121) and TADA (CAB: -21%, p = 0.342; PSR: -52%, p = 0.013) compared to VEH-treated bile duct-ligated rats. Hepatic hydroxyproline content was reduced by RIO (from 503 ± 20 to 350 ± 30 µg/g, p = 0.003) and TADA (282 ± 50 µg/g, p = 0.003), in line with a reduction of the hepatic stellate cell activation markers smooth-muscle actin and phosphorylated moesin. Liver transaminases decreased under RIO (AST: -36%; ALT: -32%) and TADA (AST: -24%; ALT: -27%) treatment. Hepatic interleukin 6 gene expression was reduced in the RIO group (-56%, p = 0.053). CONCLUSION: In a rodent model of biliary cirrhosis, the sGC stimulator RIO and the PDE-5 inhibitor TADA improved PHT. The decrease of sinusoidal vascular resistance was paralleled by a reduction in liver fibrosis and hepatic inflammation, while systemic haemodynamics were not affected.
Asunto(s)
Hipertensión Portal/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Guanilil Ciclasa Soluble/antagonistas & inhibidores , Animales , Benzoatos/farmacología , Benzoatos/uso terapéutico , Conductos Biliares/cirugía , Modelos Animales de Enfermedad , Humanos , Hipertensión Portal/diagnóstico , Hipertensión Portal/etiología , Hipertensión Portal/fisiopatología , Ligadura/efectos adversos , Cirrosis Hepática/etiología , Masculino , Inhibidores de Fosfodiesterasa 5/farmacología , Presión Portal/efectos de los fármacos , Presión Portal/fisiología , Sistema Porta/efectos de los fármacos , Sistema Porta/fisiopatología , Pirazoles/farmacología , Pirazoles/uso terapéutico , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Guanilil Ciclasa Soluble/metabolismo , Tadalafilo/farmacología , Tadalafilo/uso terapéutico , Resistencia Vascular/efectos de los fármacos , Resistencia Vascular/fisiologíaRESUMEN
INTRODUCTION: Preeclampsia (PE) is a serious maternal inflammatory disease with endothelial cell dysfunction, and there is a lack of effective treatment and prevention. Tadalafil is considered to be a promising drug for PE. This study aimed to determine whether and how tadalafil use during early pregnancy alleviates PE induced by N-nitro-l-arginine-methyl-ester (l-NAME), an antagonist of nitric oxide synthase, in rats. METHODS: Twenty-eight Sprague-Dawley (SD) rats were randomly divided into 4 equal groups on gestational day 0 (GD0): a pregnant control group, an l-NAME-treated PE group and two prophylactic low-dose and high-dose tadalafil groups. Blood pressure was measured on GD0, 5, 10, 15 and 20. Proteinuria was assessed on GD0 and 18. Femoral artery ultrasound was performed on GD19. Tissue sampling was performed on GD20. The perinatal outcomes, placenta and kidney tissue morphology, and endothelial and inflammatory markers were examined. RESULTS: Prophylactic administration of low and high doses of tadalafil improved l-NAME induced hypertension, proteinuria, maternal weight loss during pregnancy, fetal growth restriction and flow-mediated dilatation, balanced endothelial-relative factors, and alleviated inflammation activation in placenta and kidney tissue. What's more, in some results, the HT group performed better than the LT group. DISCUSSION: Our results indicate that prophylactic use of tadalafil in l-NAME-induced PE-like rat models alleviates PE symptoms, promotes fetal growth, protects endothelial function and reduces inflammation, suggesting that tadalafil may be a potential drug for the prevention of PE.
Asunto(s)
Inhibidores de Fosfodiesterasa 5/uso terapéutico , Placenta/efectos de los fármacos , Preeclampsia/tratamiento farmacológico , Tadalafilo/uso terapéutico , Animales , Presión Sanguínea/efectos de los fármacos , Citocinas/metabolismo , Femenino , Arteria Femoral/diagnóstico por imagen , Arteria Femoral/efectos de los fármacos , Arteria Femoral/metabolismo , Riñón/diagnóstico por imagen , Riñón/efectos de los fármacos , Riñón/metabolismo , NG-Nitroarginina Metil Éster , Inhibidores de Fosfodiesterasa 5/farmacología , Placenta/diagnóstico por imagen , Placenta/metabolismo , Preeclampsia/inducido químicamente , Preeclampsia/diagnóstico por imagen , Preeclampsia/metabolismo , Embarazo , Ratas , Ratas Sprague-Dawley , Tadalafilo/farmacología , UltrasonografíaRESUMEN
Aging leads to a loss of vasomotor control. Both vasodilation and vasoconstriction are affected. Decreased nitric oxide-cGMP-mediated relaxation is a hallmark of aging. It contributes to vascular disease, notably hypertension, infarction, and dementia. Decreased vasodilation can be caused by aging independently from cardiovascular risk factors. This process that can be mimicked in mice in an accelerated way by activation of the DNA damage response. Genetic deletion of the DNA repair enzyme ERCC1 endonuclease in mice, as in the case of Ercc1Δ/- mice, can be used as a tool to accelerate aging. Ercc1Δ/- mice develop age-dependent vasomotor dysfunction from two months after birth. In the present study we tested if chronic treatment with sildenafil, a phosphodiesterase 5 inhibitor that augments NO-cGMP signaling, can reduce the development of vasomotor dysfunction in Ercc1Δ/- mice. Ercc1Δ/- mice and wild-type littermates were treated with 10 mg/kg/d of sildenafil from the age of 6 to the age of 14 weeks. Blood pressure and in vivo and ex vivo vasomotor responses were measured at the end of the treatment period. Ercc1Δ/- mice developed decreased reactive hyperemia, and diminished NO-cGMP-dependent acetylcholine responses. The diminished acetylcholine response involved both endothelial and vascular smooth muscle cell signaling. Chronic sildenafil exclusively improved NO-cGMP signaling in VSMC, and had no effect on endothelium-derived hyperpolarization. Sildenafil also improved KCl hypocontractility in Ercc1Δ/- mice. All effects were blood pressure-independent. The findings might be of clinical importance for prevention of morbidities related to vascular aging as well as for progeria patients with a high risk of cardiovascular disease.
Asunto(s)
Envejecimiento/efectos de los fármacos , Inhibidores de Fosfodiesterasa 5/farmacología , Citrato de Sildenafil/farmacología , Sistema Vasomotor/efectos de los fármacos , Animales , Evaluación Preclínica de Medicamentos , Endotelio Vascular/efectos de los fármacos , Femenino , Masculino , Ratones Endogámicos C57BL , Modelos Animales , Vasoconstricción/efectos de los fármacosRESUMEN
BACKGROUND: The possible role of phosphodiesterase 5 inhibitors (PDE5Is) in prevention of negative effect of diabetes mellitus (DM) on erectile function is not well settled. OBJECTIVES: To investigate the effect of early administration of vardenafil on erectile function, cavernosal structure, and genes expression in a rat model of DM. MATERIALS AND METHODS: This experimental study was carried out at Suez Canal University's research laboratory. This study was conducted on a total of 60 adult male Albino Wistar rats, aged 60-80 days and weighing an average of 200 g. Rats were equally divided into six groups of 10 rats each: Group I (sham); Group II (DM with no treatment); Groups III, IV, V, and VI received vardenafil started at day 1, week 4, week 8, and week 12 after induction of DM, respectively. Functional study assessment of all groups was performed before euthanization, and then tissues were harvested for histopathological, ultrastructural, and molecular examinations. RESULTS: There was a significant difference of intracavernosal pressure between early (94 ± 2.18) and late (40.5 ± 1.94) treatment groups (p = 0.011). Histopathological and ultrastructural changes of DM with no treatment and late treatment groups showed distorted cavernous architecture and extensive fibrosis. There was significant difference of smooth muscle to collagen ratio between early and late treatment groups (p = 0.035). There was significant upregulation of nNOS(p = 0.021) and iNOS (p = 0.047) in early vs. late treatment group. The difference was insignificant in eNOS (p = 0.386) or TGF-ß1(p = 0.149). DISCUSSION AND CONCLUSION: Early treated rats with vardenafil had preserved erection and normal cavernosal structure, ultrastructure and gene expression of iNOS, nNOS, eNOS, and TGF-ß1. Quantification of gene expression would improve our knowledge regarding cytokines expression and molecular background of DM-associated ED. Clinical application of this result may encourage early administration of PDE5I to prevent deleterious effects of DM on erectile function in newly diagnosed DM patients with probable uncontrolled blood glucose.
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Diabetes Mellitus Experimental/complicaciones , Disfunción Eréctil/prevención & control , Pene/efectos de los fármacos , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Diclorhidrato de Vardenafil/uso terapéutico , Animales , Evaluación Preclínica de Medicamentos , Disfunción Eréctil/etiología , Disfunción Eréctil/patología , Masculino , Pene/ultraestructura , Inhibidores de Fosfodiesterasa 5/farmacología , Ratas Wistar , Diclorhidrato de Vardenafil/farmacologíaRESUMEN
ABSTRACT Cinnamomum cassia (Cinnamon) is a well-known traditional medicine with therapeutic benefits for centuries. We evaluated the effects of cinnamon essential oil (CEO) and its main component cinnamaldehyde (CA) on human corpus cavernosum (HCC) and rat CC. The essential oil of cinnamon was analyzed for the confirmation of the oil profile. HCC specimens from patients undergoing penile prosthesis surgery (age 48-69 years) were utilized for functional studies. In addition, erectile responses in anesthetized control and diabetic rats were evaluated in vivo after intracavernosal injection of CEO and CA, and rat CC strips were placed in organ baths. After precontraction with phenylephrine (10µM), relaxant responses to CEO and CA were investigated. CA (96.9%) was found as the major component. The maximum relaxation responses to CEO and CA were 96.4±3.5% and 96.0±5.0% in HCC and 97.5±5.5% and 96.8±4.8% in rat CC, respectively. There was no difference between control and diabetic rats in relaxation responses to CEO and CA. The relaxant responses obtained with essential oil and CA were not attenuated in the presence of nitric oxide synthase (NOS) inhibitor, and soluble guanylate cyclase inhibitor (sGS) in CC. In vivo, erectile responses in diabetic rats were lower than in control rats, which was restored after intracavernosal injection of CEO and CA. CEO and CA improved erectile function and relaxation of isolated strips of rat CC and HCC by a NO/cGMP-independent mechanism. Further investigations are warranted to fully elucidate the restorative effects of CEO and CA on diabetic erectile dysfunction.
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Humanos , Animales , Masculino , Anciano , Pene/efectos de los fármacos , Acroleína/análogos & derivados , Aceites Volátiles/farmacología , Cinnamomum zeylanicum/química , Relajación Muscular/efectos de los fármacos , Pene/fisiopatología , Fenilefrina/farmacología , Vasoconstrictores/farmacología , Acroleína/farmacología , Erección Peniana/efectos de los fármacos , Erección Peniana/fisiología , Reproducibilidad de los Resultados , Análisis de Varianza , Ratas Sprague-Dawley , Inhibidores de Fosfodiesterasa 5/farmacología , Citrato de Sildenafil/farmacología , Disfunción Eréctil/fisiopatología , Disfunción Eréctil/tratamiento farmacológico , Persona de Mediana Edad , Relajación Muscular/fisiologíaRESUMEN
Background In Nigerian traditional medicine, Rauwolfia vomitoria has been reported to be useful in the management of various human diseases, but there is no relevant information to substantiate its involvement in managing diseases arising from vascular dysfunction and oxidative stress. However, this study sought to investigate the antioxidant property of R. vomitoria and its effect on phophodiesterase-5 activity in vitro. Methods The antioxidant property was assessed through ferric-reducing antioxidant power (FRAP), copper chelation, and ABTS radical-scavenging activity. In addition, the effect of R. vomitoria on phosphodiesterase-5 (PDE-5) activity was assessed in vitro. Furthermore, analysis of phenolic compounds present in R. vomitoria was carried out using high-performance liquid chromatography (HPLC). Results The findings in this study revealed that R. vomitoria inhibited PDE-5 in a dose-dependent manner (IC50 = 252.42 µg/mL). Furthermore, the antioxidant activity of R. vomitoria was established through FRAP (19.68 mg AAE/g), ABTS radical-scavenging ability (74.25 mmol TEAC/g), and Cu2+-chelating ability (IC50 = 0.13 mg/mL). Conclusions The antioxidant property of R. vomitoria and its inhibitory effect on PDE-5 could be useful in the management of diseases arising from vascular dysfunction and oxidative stress.
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Antioxidantes/farmacología , Fenoles/química , Inhibidores de Fosfodiesterasa 5/farmacología , Extractos Vegetales/análisis , Extractos Vegetales/farmacología , Rauwolfia/química , Animales , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Ratas , Agua/químicaRESUMEN
Cinnamomum cassia (Cinnamon) is a well-known traditional medicine with therapeutic benefits for centuries. We evaluated the effects of cinnamon essential oil (CEO) and its main component cinnamaldehyde (CA) on human corpus cavernosum (HCC) and rat CC. The essential oil of cinnamon was analyzed for the confirmation of the oil profile. HCC specimens from patients undergoing penile prosthesis surgery (age 48-69 years) were utilized for functional studies. In addition, erectile responses in anesthetized control and diabetic rats were evaluated in vivo after intracavernosal injection of CEO and CA, and rat CC strips were placed in organ baths. After precontraction with phenylephrine (10µM), relaxant responses to CEO and CA were investigated. CA (96.9%) was found as the major component. The maximum relaxation responses to CEO and CA were 96.4±3.5% and 96.0±5.0% in HCC and 97.5±5.5% and 96.8±4.8% in rat CC, respectively. There was no difference between control and diabetic rats in relaxation responses to CEO and CA. The relaxant responses obtained with essential oil and CA were not attenuated in the presence of nitric oxide synthase (NOS) inhibitor, and soluble guanylate cyclase inhibitor (sGS) in CC. In vivo, erectile responses in diabetic rats were lower than in control rats, which was restored after intracavernosal injection of CEO and CA. CEO and CA improved erectile function and relaxation of isolated strips of rat CC and HCC by a NO/cGMP-independent mechanism. Further investigations are warranted to fully elucidate the restorative effects of CEO and CA on diabetic erectile dysfunction.
Asunto(s)
Acroleína/análogos & derivados , Cinnamomum zeylanicum/química , Relajación Muscular/efectos de los fármacos , Aceites Volátiles/farmacología , Pene/efectos de los fármacos , Acroleína/farmacología , Anciano , Análisis de Varianza , Animales , Disfunción Eréctil/tratamiento farmacológico , Disfunción Eréctil/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Relajación Muscular/fisiología , Erección Peniana/efectos de los fármacos , Erección Peniana/fisiología , Pene/fisiopatología , Fenilefrina/farmacología , Inhibidores de Fosfodiesterasa 5/farmacología , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Citrato de Sildenafil/farmacología , Vasoconstrictores/farmacologíaRESUMEN
Three new compounds including two depsidones (simplicildones J and K) and one dihydroxanthenone (globosuxanthone E) together with nine known compounds were obtained from the crude extracts of two endophytic fungi Simplicillium lanosoniveum (J.F.H. Beyma) Zare & W. Gams PSU-H168 and PSU-H261 which were isolated from the leaves of Hevea brasiliensis. The structures were elucidated by spectroscopic evidence. The absolute configuration of globosuxanthone E was established by means of experimental and calculated TDDFT ECD data. Simplicildone K exhibited antibacterial activity against Staphylococcus aureus and methicillin-resistant S. aureus with equal MIC values of 128⯵g/mL. Simplicildone K and globosuxanthone E displayed antifungal activity against Cryptococcus neoformans ATCC90113 with the same MIC values of 32⯵g/mL. In addition, known botryohordine C and simplicildone A showed phosphodiesterase 5 inhibitory activity with the IC50 values of 5.69 and 9.96⯵M, respectively, and were noncytotoxic toward noncancerous Vero cells.
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Depsidos/farmacología , Hevea/microbiología , Hypocreales/química , Lactonas/farmacología , Xantonas/farmacología , Animales , Antibacterianos/aislamiento & purificación , Antibacterianos/farmacología , Antifúngicos/aislamiento & purificación , Antifúngicos/farmacología , Chlorocebus aethiops , Cryptococcus neoformans/efectos de los fármacos , Depsidos/aislamiento & purificación , Endófitos/química , Lactonas/aislamiento & purificación , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Inhibidores de Fosfodiesterasa 5/aislamiento & purificación , Inhibidores de Fosfodiesterasa 5/farmacología , Hojas de la Planta/microbiología , Tailandia , Células Vero , Xantonas/aislamiento & purificaciónRESUMEN
BACKGROUND: Ocimum gratissimum L. is a medicinal plant widely grown in tropical and subtropical regions with the leaf decoction usually taken in folk medicine to enhance erectile performance in men although the probable mechanism of actions remains undetermined. This study examined the inhibitory potentials of Ocimum gratissimum leaves on some key enzymes associated with erectile dysfunction in penile and testicular tissues of the rat. METHODS: Inhibitory effect of aqueous extract (1:10 w/v) of O. gratissimum leaves on the activities of phosphodiesterase-5 (PDE-5), arginase, angiotensin I -converting enzyme (ACE), and acetylcholinesterase (AChE) in penile and testicular tissues were assessed. Also, the extract was investigated for ferric reducing antioxidant property(FRAP) and 1,1-diphenyl-2-picryl-hydrazil (DPPH) radical scavenging abilities. RESULTS: The extract showed higher PDE-5 (IC50 = 43.19 µg/mL), ACE (IC50 = 44.23 µg/mL), AChE (IC50 = 55.51 µg/mL) and arginase (IC50 = 46.12 µg/mL) inhibitory activity in the penile tissue than PDE-5 (IC50 = 44.67 µg/mL), ACE (IC50 = 53.99 µg/mL), AChE (IC50 = 60.03 µg/mL) and arginase (IC50 = 49.12 µg/mL) inhibitory activity in the testicular tissue homogenate. Furthermore, the extract scavenged free radicals and in a dose-dependent manner. CONCLUSION: The enzyme activities displayed might be associated with the bioactive compounds present in the extract which could possibly explain its use in the management of erectile dysfunction (ED).
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Disfunción Eréctil/tratamiento farmacológico , Disfunción Eréctil/enzimología , Ocimum/química , Pene/enzimología , Extractos Vegetales/uso terapéutico , Testículo/enzimología , Animales , Arginasa/antagonistas & inhibidores , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/uso terapéutico , Modelos Animales de Enfermedad , Masculino , Pene/efectos de los fármacos , Inhibidores de Fosfodiesterasa 5/farmacología , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Extractos Vegetales/farmacología , Hojas de la Planta/química , Ratas , Ratas Wistar , Testículo/efectos de los fármacosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Selected Peruvian Amazon plants are macerated into sugar cane distillates to prepare alcoholic beverages used to improve male sexual performance. The tree bark from Campsiandra angustifolia Spruce ex Benth (Fabaceae), Swartzia polyphylla DC (Fabaceae), Minquartia guianensis Aubl. (Olacaceae) and Thynantus panurensis (Bureau) Sandwith (Bignoniaceae) usually are used as crude drugs in mixtures of several ingredients. AIM OF STUDY: Describe the chemical composition of the most traded traditional male enhancer beverages, namely "Levántate Lazaro" and "Siete veces sin sacarla", and their single crude drug constituents, as well as their inhibitory activity towards the enzyme phosphodiesterase-5. The presence of pro-sexual drugs such as Sildenafil® and derivatives was assessed in the samples. MATERIALS AND METHODS: Single plant constituents and the preparation mixtures were purchased in the Mercado Belen (Iquitos, Peru). Chemical profiling was carried out by HPLC-DAD-ESI-MS/MS. The extracts were assessed for phosphodiesterase-5 inhibition. The occurrence of pro-sexual drugs was determined by HPLC-DAD-ESI-MS/MS. RESULTS: Chemical profiling allowed the identification of condensed tannins as the main constituents of C. angustifolia and S. polyphylla, hydrolysable tannins for M. guianensis, and C-glycosides for T. panurensis. The traditional preparations showed similar composition compared to the crude drugs. At 200⯵g/mL, the traditional preparation "Levántate Lázaro" and "Siete veces sin sacarla" inhibited the phosphodiesterase-5 by 49.88% and 27.90%, respectively. No adulterations with pro-sexual drugs were found in the samples. From the crude drugs, low effect was found for the extracts of S. polyphylla and T. panurensis and high activity for C. angustifolia which inhibited the enzyme by 89.37% and 81.32% at 200 and 100⯵g/mL, respectively. CONCLUSION: The traditional preparations used to improve sexual performance in the Peruvian Amazon showed activity as phosphodiesterase-5 inhibitors. The most active ingredient of the traditional preparations was C. angustifolia, with some contribution from T. panurensis. These results encourage additional studies, including animal models to confirm the male enhancer effect of the preparations.
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Afrodisíacos/farmacología , Magnoliopsida , Inhibidores de Fosfodiesterasa 5/farmacología , Preparaciones de Plantas/farmacología , Afrodisíacos/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Etanol/farmacología , Humanos , Masculino , Perú , Inhibidores de Fosfodiesterasa 5/química , Fitoquímicos/análisis , Fitoquímicos/farmacología , Corteza de la Planta , Preparaciones de Plantas/químicaRESUMEN
The FDA approval of Viagra (sildenafil) for the on demand treatment of erectile dysfunction (ED) through relaxation of the corporal and cavernosal vascular smooth muscle that results in an increase in blood flow to the corporal tissues stemmed from 2 decades of research, mainly at academic centers. This culminated in the finding of the nitric oxide/cGMP pathway as the mediator of penile erection, followed by some years of basic studies and clinical validation at Pfizer. Further on, new translational laboratory and animal research from our group initiated a second phase when we proposed an alternative therapeutic schedule and mechanism of action for PDE5 inhibitors (PDE5i) in both corporal veno-occlusive dysfunction (CVOD) and Peyronie's disease (PD), specifically, continuous long-term administration (CLTA) to achieve sustained levels of cGMP within the penis. Due to the extended half-life of the long-acting PDE5i, tadalafil, this new alternative encompasses preferentially daily administration, although shorter half-life PDE5i, like sildenafil and vardenafil work too, depending on the duration, dose, and frequency of their administration This novel use was initially supported by showing the antifibrotic/antioxidant effects of nitric oxide and cGMP, produced by the induction of iNOS, as a mechanism of defense against collagen deposition in the localized fibrotic plaque of PD in an avascular tissue, the tunica albuginea. Our studies on iNOS and the progressive diffuse fibrosis occurring in the smooth muscle in CVOD, led to proposing the CLTA of PDE5i for maintaining sustained cGMP levels both in PD and in CVOD in order to halt or regress the penile fibrosis. In CVOD, we showed that PDE5i protect the corporal smooth muscle and reduce myofibroblast activation and number, counteracting the underlying corporal tissue pathology that causes CVOD, and potentially ameliorating long-term CVOD or even curing it. This review is focused on this novel PDE5i anti-fibrotic therapeutic concept.