Xinmai 'an extract enhances the efficacy of sildenafil in the treatment of pulmonary arterial hypertension via inhibiting MAPK signalling pathway.

CONTEXT: Xinmai 'an tablet has been used to improve myocardial blood supply. Recently, some compounds from its formula have shown that they can treat pulmonary arterial hypertension (PAH). OBJECTIVE: This study investigates the effects of Xinmai 'an extract (XMA) on PAH and further tests the co-therapeutic enhancement with sildenafil (SIL). MATERIALS AND METHODS: Pulmonary artery smooth muscle cells were subjected to stimulation with SIL (12.5 µM) and XMA (250 µg/mL) for 48 h. Sprague-Dawley rats were randomly grouped into eight groups (n = 8 per group): (I) control group received saline; (II) MCT group received MCT (60 mg/kg); (III) SIL-Low group received MCT + SIL at 10 mg/kg/day; (IV) SIL-high group received MCT + SIL at 30 mg/kg/day; (V) XMA-High group received MCT + XMA at 251.6 mg/kg/day; (VI) SIL (Low)+XMA (Low) group received SIL (10 mg/kg) + XMA at 62.9 mg/kg/day; (VII) SIL (Low)+XMA (Medium) group received SIL (10 mg/kg) + XMA at 125.8 mg/kg/day; (VIII) SIL (Low)+XMA (High) group received SIL (10 mg/kg) + XMA at 251.6 mg/kg/day. Both XMA and SIL were given by gavage and were maintained daily for 2 weeks. RESULTS: XMA could improve SIL's efficacy in the treatment of PAH by decreasing cell viability more effectively at non-cytotoxic concentrations (250 µg/mL) and reducing Right Ventricular Systolic Pressure (RVSP) in PAH rat. Potential mechanisms might at least in part be through activating the MAPK signalling pathway. DISCUSSION AND CONCLUSIONS: The combination of XMA and SIL can improve the efficacy of pulmonary hypertension and reduce the dosage of SIL.

Combined Intravenous Sildenafil and L-Arginine Administration in a Porcine Animal Model: Hemodynamic Safety Profile and Effects on Coronary Blood Flow.

BACKGROUND: Endothelial dysfunction in the nitric oxide-cyclic guanosine monophosphate pathway is a potential contributor to perioperative myocardial ischemia. The nitric oxide precursor, L-arginine, and the cyclic guanosine monophosphate degradation blocker, sildenafil, have vasodilatory effects under high dosage. OBJECTIVE: This study examined the hemodynamic safety and effect profiles of the combined administration of L-arginine and sildenafil using an in-vivo pig model. METHODS: Hemodynamic safety including mean arterial pressure, central venous pressure, heart rate, coronary vascular resistance, and systemic vascular resistance, as well as effect profiles including cardiac output and left anterior descending blood flow were measured in ten female swine after administrations of L-arginine, sildenafil, as well as combined L-arginine and sildenafil. Measurements were compared using repeated-measures analysis of variance and linear mixed models. RESULTS: The combination of L-arginine and sildenafil produced a significant dose-dependent increase in left anterior descending flow and cardiac output. In contrast, mean arterial pressure, heart rate, central venous pressure, coronary vascular resistance, and systemic vascular resistance did not show any significant changes. No significant change in serum osmolality was observed after administrations of L-arginine. CONCLUSIONS: The combined intravenous administration of sildenafil and L-arginine in a porcine animal model was safe, well tolerated, and had at least additive effects on left anterior descending artery blood flow. Simultaneous application of both drugs might have dose-sparing effects leading to desired coronary effects at lower and safer sildenafil and L-arginine plasma concentrations. Hyperosmolality was only a minor factor in L-arginine hemodynamic effects.

The Effect of Sildenafil on Selenite-Induced Cataract in Rats.

PURPOSE: To investigate the effect of sildenafil on an experimental sodium selenite-induced cataract model in rats. MATERIALS AND METHODS: Twenty-six young Wistar rats were separated into four groups. On postpartum day 10, six rats received only selenite (group 1, selenite-induced cataract), seven rats received selenite and high dose oral sildenafil (group 2, high-dose sildenafil-treated), seven rats received selenite and low dose oral sildenafil (group 3, low-dose sildenafil-treated), and six rats received only saline (group 4, controls). On postpartum day 30, cataract formation was graded and recorded using an operating microscope. The rats were sacrificed, lens tissues were isolated, and serum samples were collected. Nitrite oxide metabolites (NOx), advanced oxidative protein products (AOPP), and total sulfhydryl (TSH) levels were assessed in both serum and lenticular samples. RESULTS: The rats treated with low-dose sildenafil showed lower levels of AOPP and NOx, and the higher levels of TSH than the rats in other experimental groups. Otherwise, the rats treated with high-dose sildenafil, similar to the selenite-induced cataract group, showed higher levels of AOPP and serum NOx than rats in the low-dose sildenafil-treated group. The rats treated with low-dose sildenafil also showed less cataract development than rats in the other experimental groups. CONCLUSION: Low doses (0.7 mg/kg) of oral sildenafil might show a protective effect on cataract development by lowering oxidative stress.

Addition of sildenafil citrate for treatment of severe intrauterine growth restriction: a double blind randomized placebo controlled trial.

Background: Severe intrauterine growth restriction complicates approximately 0.4% of the pregnancies. It increases the risk of perinatal morbidity and mortality.Subjects and methods: A double blind placebo controlled trial was conducted in Beni Suef University hospitals during 2017. It included 46 pregnant women with severe intrauterine growth restriction. Women were randomly allocated into two groups each included 23 patients. Intervention group received sildenafil citrate 20 mg orally three times a day, in addition to fish oil and zinc supplementation. Control group received tablets similar to sildenafil and the same treatment as intervention group. Primary outcomes included improvement in umbilical and middle cerebral arteries pulsatility indices and abdominal circumference.Results: Umbilical and middle cerebral arteries Doppler indices showed significant difference between groups after intake of sildenafil. Umbilical artery pulsatility index decreased significantly (p value = .001) while middle cerebral artery pulsatility index increased significantly in intervention group (p value0.001). Moreover, abdominal circumference growth velocity improved after two weeks of sildenafil intake (p value = .001).Conclusions: Sildenafil citrate may improve uteroplacental and fetal cerebral perfusion in pregnancies complicated by severe intrauterine growth restriction. It also improves abdominal circumference growth velocity. A wide scale randomized trials are needed for evaluation of neonatal and long term morbidity and mortality outcomes of pregnancies treated by sildenafil citrate.

In vivo effects of Rauvolfia vomitoria (Apocynaceae) ethanolic extract on sexual performance and reproductive activity in male rats.

Plants and plant-derived products have a long history in the treatment of sexual disorders. Rauvolfia vomitoria is one of such plant used traditionally for the enhancement of male sexual and reproductive activity. This study was carried out to elucidate the potential activity of R. vomitoria ethanolic extract on sexual behaviour and male reproductive function. Twenty-five male rats were assigned to five groups and orally treated with distilled water (control), sildenafil citrate (standard) and R. vomitoria ethanolic extract (50, 100 and 200 mg/kg BW) for 22 days. Sexual behaviour parameters such as mount latency (ML), intromission latency (IL), ejaculation latency (EL), mount frequency (MF), intromission frequency (IF), ejaculation frequency (IF) and post-ejaculatory interval (PEI) were recorded at day 0, 1, 8, 15 and 22. The reproductive function including reproductive organ weights, testicular histology and sperm parameters was also assessed. Results showed enhancement in sexual behaviour through significant reduction (p < .01) in ML, IL and PEI and significant increase (p < .01) in EL, MF IF and EF. The extract also caused an increase in sperm count, motility and transit. Present findings demonstrate the ability of R. vomitoria ethanolic extract to improve male sexual behaviour and reproductive activity in rats.

Orange peels modulate antioxidant markers and key enzymes relevant to erection in the penile tissue of paroxetine-treated rats.

In comparison to other antidepressant drugs, erectile dysfunction (ED) is more pronounced in paroxetine use. On the other hand, orange (Citrus sinensis) peels commonly consumed in various forms are used in folkloric medicine for ED management. Thus, this study evaluated the effect of orange peels infusion on sexual behaviour, nitric oxide (NO) level and some enzymes (arginase, phosphodiesterase-5 [PDE-5], acetylcholinesterase [AChE] and adenosine deaminase [ADA]) in paroxetine-treated rats. Erectile dysfunction was induced with paroxetine (10 mg/kg body weight). The animals were grouped into five (n = 6): normal rats; paroxetine-induced rats; paroxetine-induced rats treated with sildenafil citrate (5 mg/kg); paroxetine-induced rats treated with orange peels infusion (50 mg/kg); Paroxetine induced rats treated with orange peel infusions (100 mg/kg). The results revealed a significant decrease in sexual behaviour, NO level and the activities of antioxidant enzymes, while there was a significant increase in arginase, PDE-5, AChE and ADA activities in paroxetine-induced rats. However, orange peel infusions ameliorated erectile dysfunction in paroxetine-treated rats. This study showed some possible biochemical basis underlying the use of orange peels infusion in erectile dysfunction management.

Systematic Review of Oral Combination Therapy for Erectile Dysfunction When Phosphodiesterase Type 5 Inhibitor Monotherapy Fails.

INTRODUCTION: On-demand phosphodiesterase type 5 inhibitor (PDE5i) monotherapy is a first-line treatment for erectile dysfunction (ED), but 30%-40% of patients exhibit little or no response. The success rate of alprostadil therapy is high in these patients, but this treatment requires painful intracavernosal injection. AIM: To systematically review the efficacy and safety of second-line oral pharmacologic combination therapies of ED when PDE5i monotherapy fails. METHODS: PubMed and Embase were searched to identify reports providing quantitative data on the treatment of ED in patients failing PDE5i monotherapy. MAIN OUTCOME MEASURES: The measures of erectile function were the International Index of Erectile Function (IIEF) and the Erectile Function Domain (EFD). RESULTS: Chronic treatment with the PDE5i tadalafil alone or in combination with sildenafil on demand showed similar IIEF-5 score improvements. None of the 3 randomized controlled trials (RCTs) in patients who had failed PDE5i monotherapy found a superior effect on IIEF scores from the combination of androgen plus PDE5i compared with PDE5i monotherapy. Combination therapy with androgen supplementation and PDE5i appears safe. In 1 RCT, combination therapy with PDE5i and an α1-adrenoceptor antagonist was not superior to PDE5i monotherapy. Six other studies, each with a different combination of PDE5i and another drug (eg, metformin, folic acid, 5-alpha-reductase inhibitors), were identified, but further research is required to investigate their efficacy in treating ED. CONCLUSION: For ED, chronic treatment with low-dose PDE5i can be attempted when standard on-demand regimens fail. Combination therapy with androgen supplementation and a PDE5i appears to be safe. The combination of an α1-adrenoceptor antagonist and PDE5i shows no advantageous effect on ED compared with PDE5i monotherapy. The efficacy of combining PDE5i with metformin, folic acid, or 5-alpha-reductase inhibitors is uncertain and requires further research. There is an unmet need for oral treatment of ED in nonresponders to PDE5i treatment. Munk NE, Knudsen JS, Comerma-Steffensen S, et al. Systematic Review of Oral Combination Therapy for Erectile Dysfunction When Phosphodiesterase Type 5 Inhibitor Monotherapy Fails. Sex Med Rev 2019;7:430-441.

Investigation of Interactive Activity of Electro-Acupuncture on Pharmacokinetics of Sildenafil and Their Synergistic Effect on Penile Blood Flow in Rats.

Erectile dysfunction (ED) is a disorder found in males throughout the world, which negatively affects relationships with partners with advancing age. Hence, in this study, we tested a combined novel treatment of electro-acupuncture (EA) and sildenafil citrate against ED. In addition to EA therapy, the sildenafil citrate, a phosphodiesterase 5 inhibitor, is a widely recognized drug that has achieved considerable success in the treatment of ED. However, the combined effect of both the EA and sildenafil has not yet been investigated. Hence, we aimed to examine the effect of EA on the pharmacokinetics and pharmacodynamics of sildenafil in rat plasma. The pharmacokinetic parameters were determined using ultra performance liquid chromatography (UPLC) after EA and sildenafil administration (10 mg/Kg). Following this, the pharmacodynamics was studied via blood flow pattern using developing Doppler images of the lower body and penis. The pharmacokinetic studies demonstrated that sildenafil significantly increases by administration of low-frequency EA. Further, the pharmacodynamic studies using Doppler imaging revealed an elevated blood flow in rat penis compared with lower body during combined treatment of sildenafil and low-frequency EA. These data indicate a synergistic therapeutic effect of EA and sildenafil for the treatment of ED.

Sildenafil normalizes bowel transit in preclinical models of constipation.

Guanylyl cyclase-C (GC-C) agonists increase cGMP levels in the intestinal epithelium to promote secretion. This process underlies the utility of exogenous GC-C agonists such as linaclotide for the treatment of chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C). Because GC-C agonists have limited use in pediatric patients, there is a need for alternative cGMP-elevating agents that are effective in the intestine. The present study aimed to determine whether the PDE-5 inhibitor sildenafil has similar effects as linaclotide on preclinical models of constipation. Oral administration of sildenafil caused increased cGMP levels in mouse intestinal epithelium demonstrating that blocking cGMP-breakdown is an alternative approach to increase cGMP in the gut. Both linaclotide and sildenafil reduced proliferation and increased differentiation in colon mucosa, indicating common target pathways. The homeostatic effects of cGMP required gut turnover since maximal effects were observed after 3 days of treatment. Neither linaclotide nor sildenafil treatment affected intestinal transit or water content of fecal pellets in healthy mice. To test the effectiveness of cGMP elevation in a functional motility disorder model, mice were treated with dextran sulfate sodium (DSS) to induce colitis and were allowed to recover for several weeks. The recovered animals exhibited slower transit, but increased fecal water content. An acute dose of sildenafil was able to normalize transit and fecal water content in the DSS-recovery animal model, and also in loperamide-induced constipation. The higher fecal water content in the recovered animals was due to a compromised epithelial barrier, which was normalized by sildenafil treatment. Taken together our results show that sildenafil can have similar effects as linaclotide on the intestine, and may have therapeutic benefit to patients with CIC, IBS-C, and post-infectious IBS.

Possible Role of Sildenafil Citrate in the Recurrence of Neovascularization in Laser-regressed Aggressive Posterior ROP.

BACKGROUND: Systemic diseases and their treatment influence aggressive posterior retinopathy of prematurity. CASE CHARACTERISTICS: A premature infant with aggressive posterior retinopathy of prematurity underwent laser treatment with a favourable outcome. She was started on oral sidenafil citrate for pulmonary hypertension. Ten days later she developed neovascularization within the lasered retina. INTERVENTION/OUTCOME: Considering the possible role of sildenafil in this unusual development, the drug was withdrawn resulting in regression of the neovascularization. MESSAGE: The clinician should be aware of this retinal adverse effect of sildanefil in neonates with aggressive posterior retinopathy of prematurity.

Off-Target Effect of Sildenafil on Postsurgical Erectile Dysfunction: Alternate Pathways and Localized Delivery System.

INTRODUCTION: There is no consensus on the best oral phosphodiesterase type 5 inhibitor (PDE5I) for patients undergoing penile rehabilitation after surgical nerve injury. AIM: To determine the mechanism of PDE5I on cultured neuronal cells and the effectiveness of local drug delivery using nanospheres (NSPs) to sites of nerve injury in a rat model of bilateral cavernous nerve injury (BCNI). METHODS: The effects of sildenafil, tadalafil, and vardenafil on cyclic adenosine monophosphate, cyclic guanosine monophosphate, and cell survival after exposure to hypoxia and H2O2 were measured in PC12, SH-SY5Y, and NTERA-2 (NT2) cell cultures. The effects of phosphodiesterase type 4 inhibitor (PDE4I) and PDE5I on neuronal cell survival were evaluated. Male rats underwent BCNI and were untreated (BCNI), immediately treated with application of empty NSPs (BCNI + NSP), NSPs containing sildenafil (Sild + NSP), or NSPs containing rolipram (Rol + NSP). MAIN OUTCOME MEASURES: Viability of neuronal cells was measured. Intracavernous pressure changes after cavernous nerve electrostimulation and expression of neurofilament, nitric oxide synthase, and actin in mid-shaft of penis were analyzed 14 days after injury. RESULTS: Sildenafil and rolipram significantly decreased cell death after exposure to H2O2 and hypoxia in PC12, SH-SY5Y, and NT2 cells. PC12 cells did not express PDE5 and knockdown of PDE4 significantly increased cell viability in PC12, SH-SY5Y, and NT2 cells exposed to hypoxia. The ratio of intracavernous pressure to mean arterial pressure and expression of penile neurofilament, nitric oxide synthase, and actin were significantly higher in the Sild + NSP and Rol + NSP groups than in the BCNI and BCNI + NSP groups. Limitations included analysis in only two PDE families using only a single dose. CONCLUSION: Sildenafil showed the most profound neuroprotective effect compared with tadalafil and vardenafil. Sildenafil- or rolipram-loaded NSP delivery to the site of nerve injury prevented erectile dysfunction and led to increased neurofilament, nitric oxide synthase, smooth muscle content in rat penile tissue after BCNI.

Effects of chronic l-DOPA administration on neurogenic and endothelium-dependent relaxation responses in rabbit corpus cavernosum.

BACKGROUND: Dopamine is a crucial central neurotransmitter that plays a fundamental role in the autonomic and somatic components of penile reflexes in animals and humans. Similar to the erectile responses of dopamine, systemic administration of l-DOPA induces yawning and penile erection in some species. The possible effects of l-DOPA on nitric oxide (NO)-dependent and -independent non-adrenergic non-cholinergic (NANC) relaxation responses mediated by electrical field stimulation (EFS) and endothelium-dependent relaxation were investigated in this study. METHODS: Thirty-two adult albino male rabbits, in two- and four-week-treatment groups, were divided into three subgroups: control group (saline-injected) (n=4), 3mg/kg/day (low dose) l-DOPA-injected groups (n=6) and 12mg/kg/day (high dose) l-DOPA-injected groups (n=6). After the intraperitoneal injection treatments, the corpus cavernosum tissues were placed in organ bath chambers. The EFS-mediated responses, and the concentration-response curve to carbachol, sodium nitroprusside (SNP), sildenafil were assessed. RESULTS: The two-week treatment with high-dose l-DOPA decreased the NO-dependent NANC relaxation responses, while there was no change in the low-dose two- and four-week treatment groups. The NO-independent NANC relaxation responses in the two-week groups decreased, and the responses in the four-week groups were unchanged when compared to the controls. The relaxation responses to carbachol showed no differences among all groups except for the high-dose four-week l-DOPA group. The relaxation responses of SNP and sildenafil were increased in all of the treatment groups when compared to the controls. CONCLUSIONS: The observed increases in SNP- and sildenafil-induced responses, along with the decreased EFS-mediated responses, suggest increased sensitivity in the NO-signalling pathway following l-DOPA administration.

Evaluación de efectividad y seguridad comparativas del sildenafilo para el tratamiento de pacientes con hipertensión arterial pulmonar / Comparative effectiveness and safety assessment of sildenafil for the treatment of patients with pulmonary arterial hypertension

Introducción: la hipertensión arterial pulmonar es una enfermedad grave y progresiva. Si la enfermedad no es tratada, la sobrecarga de presión del ventrículo derecho lleva a dilatación, hipertrofia, falla cardíaca en estado final entre dos a tres años y a muerte. El sildenafilo, un inhibidor de la Fosfodiesterasa tipo 5, es una alternativa para su tratamiento actualmente en uso clínico. Esta evaluación de tecnología se desarrolló para informar la toma de decisiones en el marco de la actualización integral del Plan Obligatorio de Salud para Colombia. Objetivo: examinar la efectividad y seguridad comparativas del sildenafilo para el tratamiento de pacientes con hipertensión arterial pulmonar. Metodología: se realizó una búsqueda sistemática en MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects y LILACS. La tamización de referencias se realizó por dos revisores de forma independiente y la selección de estudios fue hecha por un revisor, aplicando los criterios de elegibilidad predefinidos en el protocolo de la evaluación. La calidad de las revisiones sistemáticas se valoró con la herramienta AMSTAR. Se realizó una síntesis narrativa de las estimaciones del efecto para las comparaciones y desenlaces de interés. Resultados: los hallazgos de efectividad y seguridad de la presente evaluación se basan en cuatro revisiones sistemáticas, dos de calidad alta y dos de calidad media, y cuatro ensayos controlados aleatorizados cabeza a cabeza, en general de buena calidad, para un total aproximado de 658 pacientes. Se identificó evidencia de los efectos del sildenafilo en monoterapia comparado con bosentán, y en terapia combinada más bosentán o epoprostenol, para una variedad de desenlaces incluyendo el tiempo al primer evento de morbilidad/mortalidad, capacidad de ejercicio, mortalidad, hospitalización, cambio en la clase funcional (OMS), empeoramiento de la hipertensión, trasplante de pulmón, disnea, parámetros hemodinámicos, calidad de vida, eventos adversos globales, serios y específicos. La evidencia disponible corresponde a adultos con hipertensión arterial pulmonar, de clase funcional (OMS) I, II, III y IV. También se presentan los eventos adversos reportados en la etapa post-clínica con el uso del sildenafilo. Conclusiones: la evidencia identificada en esta evaluación de tecnología, muestra efectos mixtos en la efectividad y seguridad del sildenafilo para el tratamiento de adultos con hipertensión arterial pulmonar: en cuanto a la monoterapia con sildenafilo, los resultados de efectividad demuestran que este medicamento es similar a sus comparadores; respecto a su seguridad, hay incertidumbre. En terapia combinada, algunos hallazgos de efectividad muestran superioridad del sildenafilo frente a sus comparadores, otros datos indican que esta tecnología es similar respecto a sus alternativas y para algunos desenlaces existe incertidumbre. La seguridad comparada del sildenafilo en terapia combinada puede ser mayor, similar, menor o incierta. A juicio de los expertos clínicos y representantes de los pacientes, el sildenafilo en monoterapia y en terapia combinada, tiene una relación favorable entre los beneficios y riesgos, esto sugiere que los efectos deseables con el uso de esta tecnología superan a los efectos indeseables.(AU)

Comparison of the Effects of Elaeagnus angustifolia Flower Capsule and Sildenafil Citrate Tablet on Anxiety Resulting From Sexual Dysfunction in Women Referring to the Selected Clinics of Shiraz University of Medical Sciences.

Dissatisfaction from sexual relationships can result in deprivation as well as problems, such as depression, anxiety, and destruction of family's mental health. One hundred twenty-five women (18 to 40 years) who suffered from hypoactive sexual desire disorder were divided into Elaeagnus angustifolia flower (4.5 g g daily for 35 days), sildenafil citrate tablet (50 mg for 4 weeks), and control groups. The study data were collected using the Female Sexual Function Index and Spielberger's questionnaire and measurement of thyroid-stimulating hormone and prolactin hormone. In the Elaeagnus angustifolia group, the mean score of state and trait anxiety decreased after the intervention. In the sildenafil citrate group also, the mean score of state anxiety decreased from 22.15 ± 4.98 to 20.1 ± 5.15 (P = .001) and that of trait anxiety decreased from 23.07 ± 4.44 to 21.55 ± 4.82 (P = .002) after the intervention. Consumption of sildenafil citrate tablet was effective in reduction of the mean score of anxiety resulting from sexual dysfunction.

[TREATMENT OF ERECTILE DYSFUNCTION FOLLOWING TRANSVESICAL PROSTATECTOMY].

This study examines the efficacy and safety of phosphodiesterase type 5 (PDE-5) inhibitors in treating erectile dysfunction after transvesical prostatectomy. The study involved 63 men aged 55 to 68 years, divided into two groups--29 and 34 patients, respectively. Patients in group 1 received 50 mg of sildenafil citrate (Ereksezil®) on a daily basis, in group 2--100 mg of sildenafil citrate (Ereksezil®) on demand. Postoperative visits were scheduled at the stage of screening, then after a month of treatment and on day 14 after treatment completion (3 visits altogether). Changes of patients' complaints according to IIEF-15 questionnaire showed a significant improvement in erectile function and its components of sexual life satisfaction in both groups of patients, but more significantly with regular medication intake, which has a positive impact on patients' quality of life. At the same time, treatment by PDE-5 inhibitors did not affect the maximum urinary flow rate and residual urine volume. Given the high incidence of the postoperative erectile dysfunction, postoperative administration of PDE-5 inhibitors is relevant and promising.