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1.
Urology ; 135: 66-70, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31541647

RESUMO

OBJECTIVE: To define age-specific normal Color Doppler Duplex Ultrasound (CDDU) parameters based on a large institutional database of men referred for vascular erectile testing, but found to have normal and sustained rigidity following penile injection of alprostadil. METHODS: A retrospective review of patients who underwent CDDU from January 1, 2005 to December 31, 2014 was conducted. The indications for CDDU assessments included complaint of erectile dysfunction refractory to PDE-5 inhibitors, new-onset penile curvature, or secondary consultation for erectile dysfunction. Pearson correlation test was used to evaluate the association between ordinal age groups with peak systolic velocity (PSV) and resistive index (RI) measurements to determine the effect of age on erectile response. RESULTS: A total of 2043 patients underwent CDDU from January 1, 2005 to December 31, 2014. 259 patients (12.7%) with a mean age 53.7 and a mean BMI of 27.2 were noted to have normal erectile rigidity and normal Doppler parameters (PSV >35 cm/s, RI >0.90). Prolonged erection, defined by need to inject phenylephrine reversal agent at 1-2 hours, occurred in 93% of patients. When age was categorized by decade, a negative correlation coefficient was obtained for previsual sexual stimulation PSV (-0.09, P = .164) and postvisual sexual stimulation PSV (-0.23, P = .005). CONCLUSION: In men with normal vascular erections there appears to be a significant, age-related decline in postvisual sexual stimulation PSV without compromise to cavernous venous occlusion as measured by RI. We have used Doppler parameters in patients without vascular ED to define age-specific normalcy.


Assuntos
Envelhecimento/fisiologia , Disfunção Erétil/diagnóstico , Ereção Peniana/fisiologia , Pênis/diagnóstico por imagem , Ultrassonografia Doppler em Cores , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Ereção Peniana/efeitos dos fármacos , Pênis/irrigação sanguínea , Pênis/fisiologia , Fenilefrina/administração & dosagem , Fenilefrina/antagonistas & inibidores , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Estudos Retrospectivos , Falha de Tratamento , Agentes Urológicos/uso terapêutico , Adulto Jovem
2.
Food Chem Toxicol ; 135: 111038, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31825855

RESUMO

The aim of the study was to evaluate the potential protective role of sildenafil and tadalafil in contrast-induced nephropathy (CIN) by modulating oxidative stress. Thirty Wistar male rats were equally assigned into five groups: sham, CIN, CIN + sildenafil (10 mg/kg bw/day), CIN + tadalafil (5 mg/kg bw/day) and CIN + N-Acetyl Cysteine (NAC) (100 mg/kg bw/day) as a positive control. CIN was induced by 12 h dehydration and administration of indomethacin (10 mg/kg bw), N-ω- nitro-L-arginine methyl ester (10 mg/kg bw), and iopromide (3 g/kg bw iodine). Blood was drawn prior to and 24 h after CIN induction for evaluating renal function and oxidative stress. In the CIN group, total antioxidant capacity (TAC), reduced glutathione (GSH) and catalase (CAT) levels were significantly decreased; and protein carbonyl (PROTC) and thiobarbituric reactive species (TBARS) were significantly increased compared to the sham group. Pre- Sildenafil and tadalafil pre-treatment reduced CIN risk and reversed oxidative stress almost to the sham group levels. These results suggest that PDE5Is can be good candidates for preventing CIN based on their ability to modulate the oxidant/antioxidant balance.


Assuntos
Antioxidantes/metabolismo , Meios de Contraste/efeitos adversos , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Oxidantes/metabolismo , Inibidores da Fosfodiesterase 5/farmacologia , Citrato de Sildenafila/farmacologia , Tadalafila/farmacologia , Acetilcisteína/administração & dosagem , Animais , Catalase/metabolismo , Modelos Animais de Doenças , Glutationa/metabolismo , Nefropatias/enzimologia , Nefropatias/metabolismo , Masculino , Camundongos , Estresse Oxidativo , Ratos , Ratos Wistar , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
3.
Acta Cir Bras ; 34(9): e201900901, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31800678

RESUMO

PURPOSE: To evaluate the effects of tadalafil (TD) in preventing histological alterations of the corpus cavernosum caused by isolated lesions of cavernous nerve (ILCN) and artery (ILCA) in rats. METHODS: Fifty male Wistar rats were randomly assigned in five groups: G1: control; G2: bilateral ILCN; G3: bilateral ILCA; G4: ILCN+TD; G5: ILCA+TD. The cavernous bodies were submitted to histomorphometry, immunohistochemistry and biochemical analysis. RESULTS: Nerve density was significantly higher in G2 and G4 compared to control (22.62±2.84 and 19.53±3.47 vs. 15.72±1.82; respectively, p<0.05). Smooth muscle density was significantly lower in G2 and G3 in comparison to G1 (12.87±1.90 and 18.93±1.51 vs. 21.78±1.81, respectively; p<0.05). A significant decrease in the sinusoidal lumen area was observed in G2 compared to controls (5.01±1.62 vs. 9.88±3.66, respectively; p<0.05) and the blood vessel density was increased in G2 and G3 (29.32±4.13 e 20.80±2.47 vs. 10.13±2.71, p<0.05). Collagen density was higher in G3 compared to G1 (93.76±15.81 vs. 64.59±19.25; p<0.05). CONCLUSIONS: Histomorphometric alterations caused by ILCN were more intense than those produced by vascular injury, but the collagen analyses showed more fibrosis in animals with ILCA. TD was effective in preventing the majority of the alterations induced by the periprostatic bundle injury.


Assuntos
Pênis/irrigação sanguínea , Pênis/inervação , Traumatismos dos Nervos Periféricos/prevenção & controle , Inibidores da Fosfodiesterase 5/farmacologia , Substâncias Protetoras/farmacologia , Tadalafila/farmacologia , Animais , Colágeno/análise , Colágeno/efeitos dos fármacos , Tecido Elástico/anatomia & histologia , Tecido Elástico/efeitos dos fármacos , Disfunção Erétil/prevenção & controle , Imuno-Histoquímica , Masculino , Pênis/efeitos dos fármacos , Pênis/patologia , Prostatectomia/efeitos adversos , Distribuição Aleatória , Ratos Wistar , Reprodutibilidade dos Testes
4.
Artigo em Inglês | MEDLINE | ID: mdl-31469654

RESUMO

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.


Assuntos
Antioxidantes/farmacologia , Fenóis/química , Inibidores da Fosfodiesterase 5/farmacologia , Extratos Vegetais/análise , Extratos Vegetais/farmacologia , Rauwolfia/química , Animais , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Ratos , Água/química
5.
Drugs Aging ; 36(11): 991-997, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31435912

RESUMO

Phosphodiesterase type 5 inhibitors (PDE5Is) may increase intraocular pressure (IOP) by increasing blood flow to the ciliary body. Although clinical studies of changes in IOP after single and multiple doses of PDE5Is show variable results, most are limited by small sample sizes, absence of control groups and blinding, and use of normal patient volunteers who have no risk factors for glaucoma. However, multiple case reports of glaucoma have been published, and one epidemiologic analysis of the National Health and Nutrition Examination Survey (NHANES) database of US respondents suggested a significant association of prolonged sildenafil use and self-reported glaucoma. With the widespread use of PDE5Is for treatment of erectile dysfunction in males with risk factors for glaucoma, and the potential of PDE5Is to worsen optic nerve damage in patients with glaucoma, we recommend a vision screening exam prior to the initiation of the PDE5I and careful follow-up thereafter, particularly if the patient is taking tadalafil, a long-acting PDE5I, if the patient is taking high doses of a PDE5I daily and persistently, and if the patient has risk factors for glaucoma or if the patient is at risk of worsening glaucoma.


Assuntos
Monitoramento de Medicamentos , Glaucoma/induzido quimicamente , Pressão Intraocular/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/efeitos adversos , Disfunção Erétil/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Fatores de Risco , Seleção Visual
6.
Int Braz J Urol ; 45(5): 1033-1042, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31408283

RESUMO

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.


Assuntos
Acroleína/análogos & derivados , Cinnamomum zeylanicum/química , Relaxamento Muscular/efeitos dos fármacos , Óleos Voláteis/farmacologia , Pênis/efeitos dos fármacos , Acroleína/farmacologia , Idoso , Análise de Variância , Animais , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Relaxamento Muscular/fisiologia , Ereção Peniana/efeitos dos fármacos , Ereção Peniana/fisiologia , Pênis/fisiopatologia , Fenilefrina/farmacologia , Inibidores da Fosfodiesterase 5/farmacologia , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Citrato de Sildenafila/farmacologia , Vasoconstritores/farmacologia
7.
Fitoterapia ; 138: 104286, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31394164

RESUMO

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 µg/mL. Simplicildone K and globosuxanthone E displayed antifungal activity against Cryptococcus neoformans ATCC90113 with the same MIC values of 32 µg/mL. In addition, known botryohordine C and simplicildone A showed phosphodiesterase 5 inhibitory activity with the IC50 values of 5.69 and 9.96 µM, respectively, and were noncytotoxic toward noncancerous Vero cells.


Assuntos
Depsídeos/farmacologia , Hevea/microbiologia , Hypocreales/química , Lactonas/farmacologia , Xantonas/farmacologia , Animais , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Cryptococcus neoformans/efeitos dos fármacos , Depsídeos/isolamento & purificação , Endófitos/química , Lactonas/isolamento & purificação , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Inibidores da Fosfodiesterase 5/isolamento & purificação , Inibidores da Fosfodiesterase 5/farmacologia , Folhas de Planta/microbiologia , Tailândia , Células Vero , Xantonas/isolamento & purificação
8.
Free Radic Res ; 53(9-10): 993-1004, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31455116

RESUMO

Sildenafil is a phosphodiesterase type 5 inhibitor which confers cardioprotection against myocardial ischaemia/reperfusion (I/R) injury. The aim of this study was to determine if Trx1 participates in cardioprotection exerted by sildenafil in an acute model of I/R, and to evaluate mitochondrial bioenergetics and cellular redox status. Langendorff-perfused hearts from wild type (WT) mice and a dominant negative (DN-Trx1) mutant of Trx1 were assigned to placebo or sildenafil (0.7 mg/kg i.p.) and subjected to 30 min of ischaemia followed by 120 min of reperfusion. WT + S showed a significant reduction of infarct size (51.2 ± 3.0% vs. 30 ± 3.0%, p < .001), an effect not observed in DN-Trx. After I/R, sildenafil preserved state 3 oxygen consumption from WT, but had a milder effect in DN-Trx1 only partially protecting state 3 values. Treatment restored respiratory control (RC) after I/R, which resulted 8% (WT) and 24% (DN-Trx1) lower than in basal conditions. After I/R, a significant increase in H2O2 production was observed both for WT and DN-Trx (WT: 1.17 ± 0.13 nmol/mg protein and DN-Trx: 1.38 ± 0.12 nmol/min mg protein). With sildenafil, values were 21% lower only in WT I/R. Treatment decreased GSSG levels both in WT and DN-Trx1. In addition, GSSG/GSH2 ratio was partially restored by sildenafil. Also, an increase in p-eNOS/eNOS even before the myocardial ischaemia was observed with sildenafil, both in WT (14%, p > .05) and in DN-Trx (35%, p < .05). Active Trx1 is required for the onset of the cardioprotective effects of sildenafil on I/R injury, together with the preservation of cellular redox balance and mitochondrial function.


Assuntos
Mitocôndrias/efeitos dos fármacos , Isquemia Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Inibidores da Fosfodiesterase 5/uso terapêutico , Citrato de Sildenafila/uso terapêutico , Animais , Masculino , Camundongos , Camundongos Transgênicos , Inibidores da Fosfodiesterase 5/farmacologia , Citrato de Sildenafila/farmacologia
9.
Andrologia ; 51(9): e13364, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31304987

RESUMO

A cross-sectional survey was conducted in Egypt from November 2015 to June 2016. Sexually active adult men were interviewed by a questionnaire designed by the authors. All the participants were evaluated by the abridged 5-item version of the International Index of Erectile Function (IIEF). A total of 3,000 sexually active Egyptian males participated in this study, 946 (31.53%) reported using PDE5Is at least once, and 2054 (68.47%) have never used them. The majority of those who used PDE5Is obtained them for recreational purposes mainly for pleasure (58.35%) and to increase duration/frequency of the intercourse (15.6%). Only 26.05% used PDE5Is to treat ED. The main source of obtaining PDE5Is was friends, relatives and colleagues (62.79%); 25.16% of users obtained the drug by themselves, and 6.66% were prescribed the drug by a pharmacist. Only 5.39% of users obtained the drug after a specialist physician consultation. Sildenafil was the most commonly used PDE5I (90.6%), and most of the users (88.05%) used them in an occasional manner even in the presence of erectile dysfunction, while 11.95% used the drug in a regular manner for every intercourse. PDE5Is are frequently used by the Egyptian male population, and most of them seemed to take them as recreational medications.


Assuntos
Coito/psicologia , Disfunção Erétil/epidemiologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Prazer , Adulto , Estudos Transversais , Egito/epidemiologia , Disfunção Erétil/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente/estatística & dados numéricos , Ereção Peniana/efeitos dos fármacos , Ereção Peniana/psicologia , Inibidores da Fosfodiesterase 5/farmacologia , Prevalência , Citrato de Sildenafila/farmacologia , Citrato de Sildenafila/uso terapêutico , Inquéritos e Questionários/estatística & dados numéricos
10.
Basic Clin Pharmacol Toxicol ; 125(3): 202-214, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31206240

RESUMO

Current treatment of pulmonary arterial hypertension (PAH) targets three signalling pathways: the nitric oxide (NO) pathway, the endothelin pathway and the prostacyclin pathway. Riociguat is a soluble guanylate cyclase stimulator, acting via the NO pathway in a new way: unlike other common drugs targeting this pathway (eg tadalafil and sildenafil), riociguat acts independently of endogenous NO. This MiniReview focuses on PAH treatment with riociguat and on its advantages and disadvantages compared with other drugs targeting the NO pathway. In the PATENT-1 trial (NCT00810693), riociguat improved significantly the 6-minute walking distance in patients suffering from PAH, with a mean difference (MD) of 36 m compared with a placebo group. The results are comparable to those found for its competitors tadalafil (MD of 33 m) and sildenafil (MD of 50 m) in the PHIRST-1 trial (NCT00125918) and the SUPER-1 trial (NCT00644605). No obvious advantages were found regarding pharmacokinetic features and adverse events. In the RESPITE study (NCT02007629), patients with PAH with insufficient response to treatment with tadalafil or sildenafil were switched to riociguat. These results indicate that riociguat might be superior regarding efficacy to PDE-5 inhibitors in a patient group, where endogenous NO production might be insufficient. This finding was further examined in the REPLACE study (NCT02891850). Moreover, riociguat has shown promising anti-proliferative, anti-inflammatory and anti-fibrotic effects in animal models. Further investigations are needed to determine whether this applies also to human beings. Taken together, riociguat induces vasodilation of the pulmonary arteries and leads to an improvement in the ability to carry out physical activity.


Assuntos
Ativadores de Enzimas/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Substituição de Medicamentos , Endotelinas/metabolismo , Ativadores de Enzimas/uso terapêutico , Epoprostenol/metabolismo , Guanilato Ciclase/metabolismo , Humanos , Óxido Nítrico/metabolismo , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiopatologia , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Vasodilatação/efeitos dos fármacos
11.
Pharm Dev Technol ; 24(9): 1083-1094, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31215307

RESUMO

This study aims at improving the bioavailability of a poorly soluble phosphodiesterase-5 inhibitor; tadalafil (TD) via developing intranasal (IN) nanoemulsions (NEs). Optimum NE ingredients were selected based on solubility studies, emulsification tests, and phase diagram construction. Both o/w and w/o NEs were selected based on their drug loading capacity. Optimum formulations were subjected to physicochemical characterization and were assessed for nasal toxicity through biochemical analysis of tumor necrosis factor-α (TNF-α) and caspase-3 in rat nasal tissues. Pharmacodynamic study was performed via biochemical analysis of cyclic guanosine monophosphate (cGMP) in rat penis 2-h post-treatment and compared with oral suspension of Cialis® tablets. Optimum o/w and w/o NEs were successfully prepared using different ratios of Capmul-MCM-EP, Labrasol:Transcutol-HP (1:1) and water. Optimized formulations exhibited more than 4000-fold increase in TD solubility compared with its aqueous solubility. Both formulations were optically isotropic with the majority of globules in the nanometric-size range. Nasal toxicity study revealed no significant difference in values of TNF-α and caspase-3 between the NE-treated groups and the control group. Both TD-NEs succeeded to achieve a significant enhancement in cGMP levels. Our findings suggested that IN administration of the developed TD-NEs could provide a safe and effective alternative to TD oral delivery.


Assuntos
Inibidores da Fosfodiesterase 5/administração & dosagem , Tadalafila/administração & dosagem , Vasodilatadores/administração & dosagem , Administração Intranasal , Animais , GMP Cíclico/metabolismo , Emulsões/química , Masculino , Transição de Fase , Inibidores da Fosfodiesterase 5/química , Inibidores da Fosfodiesterase 5/farmacocinética , Inibidores da Fosfodiesterase 5/farmacologia , Ratos , Ratos Sprague-Dawley , Solubilidade , Tadalafila/química , Tadalafila/farmacocinética , Tadalafila/farmacologia , Vasodilatadores/química , Vasodilatadores/farmacocinética , Vasodilatadores/farmacologia
12.
Acta Cir Bras ; 34(4): e201900407, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31038585

RESUMO

PURPOSE: To evaluate the functional and structural response of tadalafil effects in the intestinal mucosa, using an experimental model of hypoxia and reoxygenation injury in rats. METHODS: The animals were divided into 4 groups: CTL, H/R, H/R+Td and M+Td. The newborn rats allocated in groups H/R, H/R+Td and M+Td were submitted twice a day, to a gas chamber with CO2 at 100% for 10 minutes and afterward reoxygenation with O2 at 98% for 10 minutes, in the three first days of life. Tadalafil dose was given to newborn of group H/R+Td and to the pregnant rat of group M+Td. Histological analysis was made with hematoxylin-eosin technique and oxidative stress through nitrite and nitrate levels and lipid peroxidation. RESULTS: The histological analysis showed a reduction of mucosa alterations in the groups that received tadalafil. In the oxidative stress evaluation, occurred an increase of NO levels and less lipidic peroxidation in the ileum segments that received tadalafil. CONCLUSION: Tadalafil provides tissue protection when administered independently to both, pregnant or newborns.


Assuntos
Hipóxia/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxigênio/metabolismo , Inibidores da Fosfodiesterase 5/farmacologia , Tadalafila/farmacologia , Animais , Animais Recém-Nascidos , Feminino , Humanos , Mucosa Intestinal/patologia , Peroxidação de Lipídeos , Malondialdeído/análise , Nitratos/análise , Nitritos/análise , Gravidez , Distribuição Aleatória , Ratos Wistar , Reprodutibilidade dos Testes , Fatores de Tempo
13.
Rev Assoc Med Bras (1992) ; 65(3): 388-393, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30994838

RESUMO

OBJECTIVES: We examined the effects of tadalafil, one of the phosphodiesterase type 5 (PDE5) inhibitors, in a rat model of with partial and complete unilateral ureteral obstruction (UUO). METHODS: The rats were divided into 5 groups: sham (n=6), partial unilateral ureteral obstruction (PUUO, n=6), PUUO with tadalafil treatment (PUUO+T; Cialis, 10 mg/72 h, intragastric; Lilly, Indianapolis, Indiana, USA), complete unilateral ureteral obstruction (CUUO, n=6), and CUUO with tadalafil treatment (CUUO+T). RESULTS: Fifteen days after the UUO, the ureter presented changes in the layers of urothelium and significant infiltration of inflammatory cells in the PUUO and CUUO groups. Compared with the sham, PUUO and CUUO groups had severe increased inflammatory cell infiltration. The urothelial epithelium exhibited cell degeneration and loss because of the swollen, atrophic, and denuded epithelial cells in the PUUO and CUUO groups. In the PUUO+T and CUUO+T groups, the urothelium revealed less epithelial cell degeneration and loss.The expressions of α-smooth muscle actin (α-SMA) and transforming growth factor-ß (TGF-ß) exhibited up-regulation in the PUUO and CUUO groups. The expression of TGF-ß decreased positively correlated with that of α-SMA in the tadalafil therapy groups, PUUO+T and CUUO+T. CONCLUSION: The phosphodiesterase type 5 inhibitor's tadalafil reduced expressions of α-SMA and TGF-ß in the obstructed ureters, measured by biochemical examinations. In addition, tadalafil decreased urothelium degeneration due to the decreased epithelial cell loss and inflammatory cell infiltration. Our results show that tadalafil prevents or slows down the onset of ureter inflammation and urothelial degeneration in rats with UUO.


Assuntos
Inibidores da Fosfodiesterase 5/farmacologia , Tadalafila/farmacologia , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/patologia , Actinas/análise , Animais , Ensaio de Imunoadsorção Enzimática , Inflamação/patologia , Inflamação/prevenção & controle , Masculino , Ratos Sprague-Dawley , Valores de Referência , Reprodutibilidade dos Testes , Fator de Crescimento Transformador beta/análise , Regulação para Cima , Ureter/efeitos dos fármacos , Ureter/patologia
14.
Acta Biochim Pol ; 66(1): 115-117, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30816368

RESUMO

Sildenafil is used in the treatment of erectile dysfunction and pulmonary arterial hypertension. Numerous  studies revealed beneficial effects of its use in renal, liver, heart and bone marrow transplant recipients. Some reports suggested that the drug modulates the function of the immune system, however, its influence on antigen-induced proliferation of lymphocytes remains unknown. Thus, the aim of the study was to investigate the effects of sildenafil on human peripheral blood mononuclear cells (PBMCs) proliferation in a mixed lymphocyte reaction. It was demonstrated that the drug did not affect auto- and alloantigen-induced proliferation of PBMCs and showed no cytotoxic effect.


Assuntos
Proliferação de Células/efeitos dos fármacos , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Citrato de Sildenafila/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/farmacologia
15.
BMC Complement Altern Med ; 19(1): 71, 2019 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-30890127

RESUMO

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).


Assuntos
Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/enzimologia , Ocimum/química , Pênis/enzimologia , Extratos Vegetais/uso terapêutico , Testículo/enzimologia , Animais , Arginase/antagonistas & inibidores , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Modelos Animais de Doenças , Masculino , Pênis/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Extratos Vegetais/farmacologia , Folhas de Planta/química , Ratos , Ratos Wistar , Testículo/efeitos dos fármacos
16.
Biosci Biotechnol Biochem ; 83(6): 1000-1010, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30835622

RESUMO

Pulmonary hypertension (PH) is a life-threatening lung disease. PH with concomitant lung diseases, e.g., idiopathic pulmonary fibrosis, is associated with poor prognosis. Development of novel therapeutic vasodilators for treatment of these patients is a key imperative. We evaluated the efficacy of dual activation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) using an active, small-molecule phosphodiesterase (PDE4)/PDE5 dual inhibitor (Compound A). Compound A increased both cAMP and cGMP levels in WI-38 lung fibroblasts and suppressed the expressions of type-1 collagen α1 chain and fibronectin. Additionally, compound A reduced right ventricular weight/left ventricular weight+septal weight ratio, brain natriuretic peptide expression levels in right ventricle, C─C motif chemokine ligand 2 expression levels in lung, and plasma surfactant protein D. Our data indicate that dual activation of cAMP/cGMP pathways may be a novel treatment strategy for PH.


Assuntos
AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/tratamento farmacológico , Inflamação/terapia , Pulmão/efeitos dos fármacos , Monocrotalina/toxicidade , Inibidores da Fosfodiesterase 5/uso terapêutico , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Células Cultivadas , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Epitélio/lesões , Fibronectinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Humanos , Pulmão/metabolismo , Pulmão/patologia , Inibidores da Fosfodiesterase 5/farmacologia , Ratos Wistar , Fator de Crescimento Transformador beta/fisiologia
17.
Curr Comput Aided Drug Des ; 15(4): 318-333, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30767749

RESUMO

OBJECTIVE: To screen the phytochemicals for phosphodiesterase 5A (PDE5A) inhibitory potential and identify lead scaffolds of antihypertensive phytochemicals using in silico docking studies. METHODS: In this perspective, reported 269 antihypertensive phytochemicals were selected. Sildenafil, a PDE5A inhibitor was used as the standard. In silico docking study was carried out to screen and identify the inhibiting potential of the selected phytochemicals against PDE5A enzyme using vLife MDS 4.4 software. RESULTS: Based on docking score, π-stacking, H-bond and ionic interactions, 237 out of 269 molecules were selected which have shown one or more interactions. Protein residue Gln817A was involved in H-boding whereas Val782A, Phe820A and Leu804A were involved in π-stacking interaction with ligand. The selected 237 phytochemicals were structurally diverse, therefore 82 out of 237 molecules with one or more tricycles were filtered out for further analysis. Amongst tricyclic molecules, 14 molecules containing nitrogen heteroatom were selected for lead scaffold identification which finally resulted in three different basic chemical backbones like pyridoindole, tetrahydro-pyridonaphthyridine and dihydro-pyridoquinazoline as lead scaffolds. CONCLUSION: In silico docking studies revealed that nitrogen-containing tetrahydro-pyridonaphthyridine and dihydro-pyridoquinazoline tricyclic lead scaffolds have emerged as novel PDE5A inhibitors for antihypertensive activity. The identified lead scaffolds may provide antihypertensive lead molecules after its optimization.


Assuntos
Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Inibidores da Fosfodiesterase 5/química , Inibidores da Fosfodiesterase 5/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/química , Desenho de Fármacos , Descoberta de Drogas , Humanos , Ligantes , Simulação de Acoplamento Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Software
18.
Curr Top Med Chem ; 19(4): 305-315, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30747070

RESUMO

BACKGROUND: PDE5A is a phosphodiesterase which specifically hydrolyzes the cGMP to GMP. It takes part in several physiological and pathological pathways and is considered an important drug target. Currently, PDE5 inhibitors (ex; Sildenafil, Tadalafil) available in the market are not only being used for the treatment of erectile dysfunction but at the same time, they are also in clinical trials being investigated as anticancer agents. MATERIALS & METHODS: In this work, we have examined pyrazolo [4,3-c]quinolin-3-ones as PDE5A inhibitors. Pyrazolo [4,3-c]quinolin-3-ones are the class of tricyclic heterocyclic derivatives having a variety of therapeutically interesting drug candidates known for their anti-inflammatory, anti-viral, anti-anxiety and anti-cancer activity. Therefore, synthetic methods providing access to pyrazolo [4, 3-c] quinolin-3-ones are immensely valuable. Here, we are reporting a simple but efficient route for the synthesis of novel 8-morpholino-2-aryl - 2, 5-dihydro-3H-pyrazolo [4, 3-c] quinolin-3-one derivatives. RESULTS: Further, molecular docking studies of synthesized compounds with human PDE5A protein showed that all the compounds exhibited good docking score in comparison with known inhibitors. In addition, all the synthesized molecules were evaluated against HCT116 cell lines for their antitumor activity. CONCLUSION: Among all the synthesized compounds, compound 5a, 5d, and 6e showed better cytotoxicity. Thus, these derivatives can be studied as potential inhibitors of PDE5A.


Assuntos
Antineoplásicos/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Inibidores da Fosfodiesterase 5/química , Inibidores da Fosfodiesterase 5/farmacologia , Pirazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores da Fosfodiesterase 5/síntese química , Pirazóis/síntese química , Pirazóis/química , Quinolonas/síntese química , Quinolonas/química , Quinolonas/farmacologia , Relação Estrutura-Atividade
19.
BJU Int ; 124(1): 163-173, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30636087

RESUMO

OBJECTIVES: To investigate the influence of low-dose sildenafil, a phosphodiesterase type 5 inhibitor (PDE5-I), on the function of the mouse lower urinary tract (LUT). MATERIALS AND METHODS: Adult male mice were decerebrated and arterially perfused with a carbogenated Ringer's solution to establish the decerebrate arterially perfused mouse (DAPM). To allow distinction between central neural and peripheral actions of sildenafil, experiments were conducted in both the DAPM and in a 'pithed' DAPM, which has no functional brainstem or spinal cord. The action of systemic and intrathecal sildenafil on micturition was assessed in urethane-anaesthetised mice. RESULTS: In the DAPM, systemic perfusion of sildenafil (30 pm) decreased the voiding threshold pressure [to a mean (sem) 84.7 (3.8)% of control] and increased bladder compliance [to a mean (sem) 140.2 (8.3)% of control, an effect replicated in the pithed DAPM]. Sildenafil was without effect on most voiding variables but significantly increased the number of bursts of the external urethral sphincter (EUS) per void in DAPM [to a mean (sem) 130.1 (6.9)% of control at 30 pm] and in urethane-anaesthetised mice [to a mean (sem) 117.5 (5.8)% of control at 14 ng/kg]. Sildenafil (10 and 30 pm) increased pelvic afferent activity during both bladder filling and the isovolumetric phase [to a mean (sem) 205.4 (30.2)% of control at 30 pm]. Intrathecal application of sildenafil (5 µL of either 150 pm or 1.5 nm) did not alter cystometry and EUS-electromyography variables in urethane-anaesthetised mice. CONCLUSIONS: Low-dose sildenafil increases bladder compliance, increases pelvic nerve afferent activity, and augments the bursting activity of the EUS. We propose that the novel actions on afferent traffic and sphincter control may contribute to its beneficial actions to restore storage and voiding efficiency in LUT dysfunction.


Assuntos
Inibidores da Fosfodiesterase 5/farmacologia , Citrato de Sildenafila/farmacologia , Uretra/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Micção/efeitos dos fármacos , Vias Aferentes/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Estimulação Elétrica , Masculino , Camundongos , Contração Muscular/fisiologia , Músculo Liso/fisiologia , Inibidores da Fosfodiesterase 5/administração & dosagem , Pressão , Citrato de Sildenafila/administração & dosagem , Bexiga Urinária/fisiologia
20.
Int J Impot Res ; 31(2): 57-60, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30258189

RESUMO

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.


Assuntos
Arteriopatias Oclusivas/complicações , Disfunção Erétil/tratamento farmacológico , Induração Peniana/complicações , Inibidores da Fosfodiesterase 5/farmacologia , Citrato de Sildenafila/farmacologia , Animais , GMP Cíclico/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Disfunção Erétil/etiologia , Humanos , Masculino , Músculo Liso/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , Pesquisa Médica Translacional
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