The Antidepressant- and Anxiolytic-Like Effects of the Phosphodiesterase Type-5 Inhibitor Tadalafil are Associated with the Modulation of the Gut-Brain Axis During CNS Autoimmunity.

Multiple Sclerosis (MS) is a debilitating disease that severely affects the central nervous system (CNS). Apart from neurological symptoms, it is also characterized by neuropsychiatric comorbidities, such as anxiety and depression. Phosphodiesterase-5 inhibitors (PDE5Is) such as Sildenafil and Tadalafil have been shown to possess antidepressant-like effects, but the mechanisms underpinning such effects are not fully characterized. To address this question, we used the EAE model of MS, behavioral tests, immunofluorescence, immunohistochemistry, western blot, and 16 S rRNA sequencing. Here, we showed that depressive-like behavior in Experimental Autoimmune Encephalomyelitis (EAE) mice is due to neuroinflammation, reduced synaptic plasticity, dysfunction in glutamatergic neurotransmission, glucocorticoid receptor (GR) resistance, increased blood-brain barrier (BBB) permeability, and immune cell infiltration to the CNS, as well as inflammation, increased intestinal permeability, and immune cell infiltration in the distal colon. Furthermore, 16 S rRNA sequencing revealed that behavioral dysfunction in EAE mice is associated with changes in the gut microbiota, such as an increased abundance of Firmicutes and Saccharibacteria and a reduction in Proteobacteria, Parabacteroides, and Desulfovibrio. Moreover, we detected an increased abundance of Erysipelotrichaceae and Desulfovibrionaceae and a reduced abundance of Lactobacillus johnsonii. Surprisingly, we showed that Tadalafil likely exerts antidepressant-like effects by targeting all aforementioned disease aspects. In conclusion, our work demonstrated that anxiety- and depressive-like behavior in EAE is associated with a plethora of neuroimmune and gut microbiota-mediated mechanisms and that Tadalafil exerts antidepressant-like effects probably by targeting these mechanisms. Harnessing the knowledge of these mechanisms of action of Tadalafil is important to pave the way for future clinical trials with depressed patients.

Anti-inflammatory and anti-oxidant action of tadalafil in testicular regeneration process after heat stress.

Tadalafil, a potent phosphodiesterase inhibitor 5 (PDE-5), is commonly used for the management of erectile dysfunction. However, its therapeutic potential extends beyond this indication. This study aimed to investigate the impact of tadalafil on the recovery of testicular parenchyma in male Wistar rats exposed to testicular thermal stress. Fifty-four Wistar rats were subjected to testicular thermal stress and randomly assigned to receive either tadalafil treatment (TAD) or no treatment (control). TAD was administered intraperitoneally at a dose of either 0.9 mg/kg or 1.8 mg/kg. Biometric parameters, histopathological assessment of the testis, serum testosterone levels, oxidative stress, and interleukin levels were evaluated on days 7, 15, and 30 after thermal shock. The animals were euthanized at the end of each experimental period, and samples were collected. TAD treatment maintained testicular weight and reduced the testicular degenerative process up to day 7 post-injury. However, despite TAD therapy, serum testosterone levels were decreased in the treated groups at days 7 and 15 post-thermal stress. TAD also decreased TNF-α and NO levels at different doses but had no effect on IL-6. The treatment with TAD after heat shock demonstrated anti-inflammatory and antioxidant properties but did not prevent the aggravation of testicular lesions in subsequent periods, even with the systematic reduction in TNF-α and NO levels. Therefore, this selective PDE-5 inhibitor, at the dosages used, did not have a positive impact on testosterone levels during the post-thermal stress period, which could compromise the resumption of the spermatogenic process.

Tamsulosin vs. Tadalafil as medical expulsive therapy for distal ureteral stones: a systematic review and meta-analysis

ABSTRACT Purpose: Medical expulsive therapy (MET) is recommended for distal ureteral stones from 5 to 10 mm. The best drug for MET is still uncertain. In this review, we aim to compare the effectiveness of tadalafil and tamsulosin for distal ureteral stones from 5 to 10 mm in terms of stone expulsion rate (SER), stone expulsion time (SET) and the side effect profile. Materials and methods: A comprehensive literature search was conducted on MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Scopus and Web of Science, from inception until April 2023. Only randomized controlled trials were included in the analysis. Results: Eleven publications with 1,330 patients were included. We observed that tadalafil has a higher SER (OR 0.55, CI 95% 0.38;0.80, p=0.02, I2=52%) and the same efficacy in SET (MD 1.07, CI 95% -0.25; 2.39, p=0.11, I2=84%). No differences were found when comparing side effects as headache, backache, dizziness, and orthostatic hypotension. Conclusion: Tadalafil has a higher stone expulsion rate than tamsulosin as a medical expulsive therapy for patients with distal stones from 5 to 10 mm without differences in side effects.

Tamsulosin vs. Tadalafil as medical expulsive therapy for distal ureteral stones: a systematic review and meta-analysis.

PURPOSE: Medical expulsive therapy (MET) is recommended for distal ureteral stones from 5 to 10 mm. The best drug for MET is still uncertain. In this review, we aim to compare the effectiveness of tadalafil and tamsulosin for distal ureteral stones from 5 to 10 mm in terms of stone expulsion rate (SER), stone expulsion time (SET) and the side effect profile. MATERIALS AND METHODS: A comprehensive literature search was conducted on MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Scopus and Web of Science, from inception until April 2023. Only randomized controlled trials were included in the analysis. RESULTS: Eleven publications with 1,330 patients were included. We observed that tadalafil has a higher SER (OR 0.55, CI 95% 0.38;0.80, p=0.02, I2=52%) and the same efficacy in SET (MD 1.07, CI 95% -0.25; 2.39, p=0.11, I2=84%). No differences were found when comparing side effects as headache, backache, dizziness, and orthostatic hypotension. CONCLUSION: Tadalafil has a higher stone expulsion rate than tamsulosin as a medical expulsive therapy for patients with distal stones from 5 to 10 mm without differences in side effects.

Co-administration of sodium hydrosulfide and tadalafil modulates hypoxia and oxidative stress on bladder dysfunction in a rat model of bladder outlet obstruction

ABSTRACT Purpose: This study aimed to assess the possible healing effect of combination treatment with a hydrogen sulfide (H2S) donor, sodium hydrosulfide (NaHS) plus tadalafil on partial bladder outlet obstruction (PBOO)-induced bladder dysfunction. Materials and Methods: A total of 75 male Sprague-Dawley rats aged 10-wk and 300-350g were divided into five groups; control; PBOO; PBOO+NaHS (5.6mg/kg/day, i.p., 6-wk); PBOO+tadalafil (2mg/kg/day, oral, 6-wk) and PBOO+NaHS+tadalafil. PBOO was created by partial urethral ligation. 6 weeks after obstruction, the in vitro contractile responses of the detrusor muscle and Western blotting, H2S and malondialdehyde assay were performed in bladder tissues. Results: There was an increase in bladder weight(p<0.001) and a decrease in contractile responses to KCl (p<0.001), carbachol (p<0.01), electrical field stimulation (p<0.05) and ATP (p<0.001) in the detrusor smooth muscle of obstructed rats which was normalized after the combination treatment. Cystathionine γ-lyase and cystathionine β-synthase, and nuclear factor kappa B protein levels did not significantly differ among groups. The obstruction induced decrement in 3-mercaptopyruvate sulfur transferase protein expression(p<0.001) and H2S levels(p<0.01) as well as increment in protein expressions of neuronal nitric oxide synthase (NO, p<0.001), endothelial NOS (p<0.05), inducible NOS(p<0.001), hypoxia-inducible factor 1-alpha (p<0.01), and malondialdehyde levels (p<0.01), when combined treatment entirely normalized. Conclusions: Combination therapy has beneficial effects on bladder dysfunction via regulating both H2S and nitric oxide pathways as well as downregulation of oxidative stress and hypoxia. The synergistic effect of H2S and nitric oxide is likely to modulate bladder function, which supports the combined therapy for enhancing clinical outcomes in men with BPH/LUTS.

Co-administration of sodium hydrosulfide and tadalafil modulates hypoxia and oxidative stress on bladder dysfunction in a rat model of bladder outlet obstruction.

PURPOSE: This study aimed to assess the possible healing effect of combination treatment with a hydrogen sulfide (H2S) donor, sodium hydrosulfide (NaHS) plus tadalafil on partial bladder outlet obstruction (PBOO)-induced bladder dysfunction. MATERIALS AND METHODS: A total of 75 male Sprague-Dawley rats aged 10-wk and 300-350g were divided into five groups; control; PBOO; PBOO+NaHS (5.6mg/kg/day, i.p., 6-wk); PBOO+tadalafil (2mg/kg/day, oral, 6-wk) and PBOO+NaHS+tadalafil. PBOO was created by partial urethral ligation. 6 weeks after obstruction, the in vitro contractile responses of the detrusor muscle and Western blotting, H2S and malondialdehyde assay were performed in bladder tissues. RESULTS: There was an increase in bladder weight(p<0.001) and a decrease in contractile responses to KCL(p<0.001), carbachol(p<0.01), electrical field stimulation(p<0.05) and ATP (p<0.001) in the detrusor smooth muscle of obstructed rats which was normalized after the combination treatment. Cystathionine γ-lyase and cystathionine ß-synthase, and nuclear factor kappa B protein levels did not significantly differ among groups. The obstruction induced decrement in 3-mercaptopyruvate sulfur transferase protein expression(p<0.001) and H2S levels(p<0.01) as well as increment in protein expressions of neuronal nitric oxide synthase (NO, p<0.001), endothelial NOS (p<0.05), inducible NOS(p<0.001), hypoxia-inducible factor 1-alpha (p<0.01), and malondialdehyde levels (p<0.01), when combined treatment entirely normalized. CONCLUSIONS: Combination therapy has beneficial effects on bladder dysfunction via regulating both H2S and nitric oxide pathways as well as downregulation of oxidative stress and hypoxia. The synergistic effect of H2S and nitric oxide is likely to modulate bladder function, which supports the combined therapy for enhancing clinical outcomes in men with BPH/LUTS.

Tadalafil Improves Haemodynamics and Arterial Stiffness but Not Flow- Mediated Dilation in Grade 1 Obesity. A Single-dose, Placebo-controlled Clinical Trial.

OBJECTIVE: Obesity, a major health issue worldwide, is associated with increased cardiovascular risk, endothelial dysfunction, and arterial stiffness. Tadalafil has been demonstrated to improve vascular parameters. AIM: To evaluate the effect of a single 20 mg dose of tadalafil on flow-mediated dilation and hemodynamic and arterial stiffness markers. METHODS: A randomized, double-blind, placebo-controlled study was conducted on 80 participants (41 assigned to placebo and 39 to tadalafil) with grade 1 obesity, to evaluate the acute effect of a single dose of 20 mg of tadalafil on flow-mediated dilation and hemodynamic and arterial stiffness markers. RESULTS: Tadalafil did not modify flow-mediated dilation. However, it significantly lowered systolic blood pressure (SBP) (130.6±17.1 vs. 125.0±12.7 mmHg, p=0.011), diastolic blood pressure (82.7±18.2 vs. 76.5±11.8 mmHg, p≤0.001), central systolic blood pressure (116.33±19.16 vs. 109.90±15.05 mmHg, p=0.001), the augmentation index (69.1±17.1 vs. 65.7±14.4, p=0.012), and brachial-ankle pulse wave velocity (1229.7±218.4 vs. 1164.0±181.7, p=0.001). CONCLUSION: A single dose of tadalafil did not modify flow-mediated dilation in patients with grade 1 obesity but improved blood pressure and brachial-ankle pulse wave velocity.

Tadalafil treatment improves cardiac, renal and lower urinary tract dysfunctions in rats with heart failure.

Tadalafil, a phosphodiesterase-5 (PDE5) inhibitor, shown to exert a protection to heart failure (HF) associated damage or lower urinary tract symptoms (LUTS). Thus, we investigated the contribution of tadalafil chronic treatment in the alterations of LUTS in HF rats. Male rats were subjected to aortocaval fistula model for HF induction. Echocardiography, cystometric, renal function and redox cell balance, as well as concentration-response curves to carbachol, KCl, ATP and frequency-response curves to electrical field stimulation (EFS) were evaluated in Sham, HF, Tadalafil and HF-Tadalafil (12 weeks endpoint) groups. HF group to present increased in left-ventricle (LV) mass and in LV end-diastolic- and LV end-systolic volume, with a decreased ejection fraction. Tadalafil treatment was able to decrease in hypertrophy and improve the LV function restoring cardiac function. For micturition function (in vivo), HF animals shown an increase in basal pressure, threshold pressure, no-voiding contractions and decreased bladder capacity, being that the tadalafil treatment restored the cystometric parameters. Contractile mechanism response (in vitro) to carbachol, KCl, ATP and EFS in the detrusor muscles (DM) were increased in the HF group, when compared to Sham group. However, tadalafil treatment restored the DM hypercontractility in the HF animals. Moreover, renal function as well as the oxidative mechanism was impaired in the HF animals, and the tadalafil treatment improved all renal and oxidative parameters in HF group. Our data shown that tadalafil has potential as multi-therapeutic drug and may be used as a pharmacological strategy for the treatment of cardiovascular, renal and urinary dysfunctions associated with HF.

Tadalafil and Sildenafil illicit association: Stability- indicating HPLC method, photodegradation kinetic and toxicological studies

Abstract The illicit market of counterfeit medicines containing sildenafil and tadalafil has been causing serious public health problems. Thus, further studies on this illicit association are needed. A stability-indicating HPLC method was developed for simultaneous determination of tadalafil (TAD) and sildenafil (SIL) using a C18 column (250 x 4.6 mm, 5 µm). Detection was achieved at 284 nm, for TAD, and 292 nm, for SIL. The method was considered to be specific, linear, precise, accurate, robust, and sensitive. In the photodegradation kinetic studies, the drugs showed a first-order reaction rate when isolated, and zero-order when associated. Toxicological assays demonstrated that the photodegraded drugs decreased cell viability in compared to non- degraded drugs, suggesting cytotoxic activity. Additional, mutagenic activity was not observed under the tested conditions. Photodegraded drugs, in association, depicted DNA damage index, suggesting genotoxic effects. The obtained results will be able to support the forensic intelligence laboratories, as well as to alert the population about the risk inherent to consuming counterfeit products.

Tratamiento farmacológico en la restricción del crecimiento fetal: revisión de la bibliografía / Pharmacological management for fetal growth restriction: literature review

Resumen OBJETIVO: Explorar las diferentes estrategias de tratamiento farmacológico de la restricción del crecimiento fetal propuestas a lo largo del tiempo. METODOLOGÍA: Revisión cuasi-sistemática de la evidencia científica histórica disponible acerca del tratamiento médico descrito para la atención de mujeres embarazadas con restricción del crecimiento fetal. RESULTADOS: Entre los tratamientos médicos descritos para tratar la restricción del crecimiento fetal, los donadores de óxido nítrico, las estatinas y la aspirina asociada con omega 3, han tenido desenlaces no consistentes en estudios con limitado tamaño de muestra. Por lo que se refiere a los inhibidores de la 5-fosfodiesterasa, el sildenafilo no se ha asociado con un aumento de la velocidad de crecimiento fetal pero sí con alarmas respecto de su seguridad debidas al incremento de los casos de hipertensión pulmonar fetal y mortalidad perinatal. Por su parte, el tadalafilo ha mostrado desenlaces iniciales favorables y se esperan estudios con mayor tamaño de muestra que permitan emitir recomendaciones claras con respecto a su indicación. También se esperan los desenlaces de estudios clínicos en curso, para definir la indicación de la heparina de bajo peso molecular en este escenario en virtud de sus prometedores resultados iniciales. Los procedimientos más invasivos, como la inyección de factor de crecimiento endotelial vascular y la plasmaféresis, permanecen en estudio como propuestas terapéuticas por los resultados de estudios preclínicos y clínicos con pocos pacientes. CONCLUSIÓN: Por ahora, ninguna estrategia farmacológica propuesta ha conseguido generar recomendaciones fuertes para su indicación; sin embargo, se esperan nuevos estudios con alta calidad metodológica que generen evidencia científica lo suficientemente contundente para recomendar su indicación.

Abstract OBJECTIVE: To explore the different pharmacological treatment strategies for fetal growth restriction proposed over time. METHODOLOGY: Quasi-systematic review of the available historical scientific evidence on the medical treatment described for the care of pregnant women with fetal growth restriction. RESULTS: Among the medical treatments described to treat fetal growth restriction, nitric oxide donors, statins, and aspirin associated with omega-3 have had inconsistent outcomes in studies with limited sample size. As for 5-phosphodiesterase inhibitors, sildenafil has not been associated with an increase in fetal growth velocity, but there have been alarms regarding its safety due to the increase in cases of fetal pulmonary hypertension and perinatal mortality. On the other hand, tadalafil has shown favorable initial outcomes and studies with a larger sample size are awaited to issue clear recommendations regarding its indication. The results of ongoing clinical studies are also awaited to define the indication of low molecular weight heparin in this setting, given its promising initial results. More invasive procedures, such as vascular endothelial growth factor injection and plasmapheresis, remain under study as therapeutic proposals due to the results of preclinical and clinical studies with few patients. CONCLUSION: For now, no proposed pharmacological strategy has managed to generate strong recommendations for its indication; however, new studies with high methodological quality are expected to generate scientific evidence strong enough to recommend its indication.

Spray-dried co-amorphous Tadalafil ternary mixtures: a promising platform towards the enhancement of solubility and bioavailability

Abstract Tadalafil (Tad) is a poorly water-soluble drug (BCS class II) that is used for the treatment of erectile dysfunction. An enhancement of aqueous solubility is vital to accelerate its onset of action and subsequently enhance its therapeutic effect. Binary and ternary mixtures of Tad with different amino acids (histidine, valine, alanine or arginine) and other excipients (mannitol and SLS) were prepared and then spray dried. The solubilizing efficiency and physicochemical characterization of all spray dried mixtures of Tad were studied. The optimum formulation was investigated in male rats to determine the onset of erection and the pharmacokinetic parameters of Tad. In general terms, the drug solubility of spray-dried formulae was enhanced compared to the crystalline form of the drug as a result of the formation of co-amorphous structures. The final result revealed that the Tad/alanine/mannitol spray-dried mixture (F10) showed the highest solubility and an improvement in its physicochemical characteristics. Moreover, F10 showed a significantly faster erection in rats with an improvement in Tad pharmacokinetic parameters when compared to the crystalline drug. Thus, F10 is selected as a promising formulation that successfully enhanced the bioavailability and the therapeutic efficacy of Tad.

Efficacy of tamsulosin versus tadalafil as medical expulsive therapy on stone expulsion in patients with distal ureteral stones: A randomized double-blind clinical trial

ABSTRACT Purpose: To compare the effects of tadalafil, tamsulosin, and placebo as a medical expulsive therapy (MET) for distal ureteral calculi. Materials and Methods: This prospective randomized double-blind clinical trial was conducted on 132 renal colic patients with distal ureteric stones (≤10mm) over a period of 12 months. Patients were randomly divided into three groups. Patients in group A received tamsulosin 0.4mg, in group B received tadalafil 10mg, and in group C received placebo. Therapy was given for a maximum of 4 weeks. The rate of stone expulsion, duration of stone expulsion, the dose and the duration of nonsteroidal anti-inflammatory drugs (NSAIDs), analgesic use, and adverse effects of drugs were recorded. Results: Demographic profiles were comparable between the 3 groups. Although the stone expulsion rate in group A (72.7%) was higher in comparison to group B(63.6%) and group C(56.8%), it was not considered statistically significant (P=0.294). Shorter mean time to stone expulsion was significantly observed in group A (17.75±75), than group B(21.13±1.17) and group C(22.25±1.18) (P=0.47). The mean number of analgesic use was 9.8±5.09 days in group A, 14.6±7.9 days in group B, and 12.6±22.25 days in group C, this difference was significant (P=0.004). The analgesic requirement (doses of NSAIDs and pethidine) in group A was significantly lower than other groups (P<0.05). Also, patients in group A reported fewer headaches compared to other groups (P=0.011). Conclusion: Tamsulosin as medical expulsive therapy is more effective for distal ureteric stones with less need for analgesics and less stone expulsion time than tadalafil.

Efficacy of tamsulosin versus tadalafil as medical expulsive therapy on stone expulsion in patients with distal ureteral stones: A randomized double-blind clinical trial.

PURPOSE: To compare the effects of tadalafil, tamsulosin, and placebo as a medical expulsive therapy (MET) for distal ureteral calculi. MATERIALS AND METHODS: This prospective randomized double-blind clinical trial was conducted on 132 renal colic patients with distal ureteric stones (≤10mm) over a period of 12 months. Patients were randomly divided into three groups. Patients in group A received tamsulosin 0.4mg, in group B received tadalafil 10mg, and in group C received placebo. Therapy was given for a maximum of 4 weeks. The rate of stone expulsion, duration of stone expulsion, the dose and the duration of nonsteroidal anti-inflammatory drugs (NSAIDs), analgesic use, and adverse effects of drugs were recorded. RESULTS: Demographic profiles were comparable between the 3 groups. Although the stone expulsion rate in group A (72.7%) was higher in comparison to group B(63.6%) and group C(56.8%), it was not considered statistically significant (P=0.294). Shorter mean time to stone expulsion was significantly observed in group A (17.75±75), than group B(21.13±1.17) and group C(22.25±1.18) (P=0.47). The mean number of analgesic use was 9.8±5.09 days in group A, 14.6±7.9 days in group B, and 12.6±22.25 days in group C, this difference was significant (P=0.004). The analgesic requirement (doses of NSAIDs and pethidine) in group A was significantly lower than other groups (P< 0.05). Also, patients in group A reported fewer headaches compared to other groups (P=0.011). CONCLUSION: Tamsulosin as medical expulsive therapy is more effective for distal ureteric stones with less need for analgesics and less stone expulsion time than tadalafil.

Nonablative transurethral Erbium:YAG laser treatment for chronic prostatitis/chronic pelvic pain syndrome: A prospective comparative study.

AIMS: This prospective study aimed to compare the clinical outcomes between the use of Erbium:YAG (Er:YAG) laser in a nonablative mode, to the use of the pharmacological treatment of oral tadalafil for the treatment of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). METHODS: The laser group received two sessions of Erbium:YAG laser, administered intraurethrally in a long, nonablative train of long pulses (SMOOTH™ mode), applied at the level of the male prostatic urethra. Tadalafil group received oral tadalafil at a dose of 5 mg/day, consecutively for 2 months. Effectiveness was assessed using the International Prostate Symptom Score (IPSS) questionnaire, VAS (visual analogue scale) pain score, and maximum urethral flow at follow-up visits up to 12 months after initiating treatment. Adverse effects were recorded after each treatment and follow-up sessions. RESULTS: The results show a significant decrease in the IPSS score in both groups up to the 12-month follow-up. The increase in Q-max was evident up to 3-months follow-up in the tadalafil group and up to 6 months in the laser group. The decrease in the VAS pain score was also significant in both treatment groups, lasting up to 3 months in the tadalafil group and up to 6 months in the laser group. CONCLUSIONS: The nonablative Er:YAG SMOOTH™ laser seems to be a promising treatment for this widely occurring condition. More studies are needed to confirm its safety and efficacy.

Effects of tadalafil to prevent injury on corpus cavernosum after vascular or nervous peri-prostatic bundle injury. Experimental model in rats

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.(AU)

Penile calciphyilaxis treated with daily Tadalafil: Case report.

Calciphylaxis is a rare vascular disorder, characterized by a progresive systemic calcification of dermo-hypodermic arterioles. We present a case of end-stage renal disease (ESRD) patient on Hemodialysis, with calciphyilaxis, whose clinical manifestation were ulcerated lesions on the penis, treated with phosphodiesterae-5 (PDE5) inhibitors, with good clinical response.

The Effect of Tadalafil on Renal Fibrosis Induced by Ureteral Obstruction / Efecto del Tadalafil en la Fibrosis Renal Inducida por Obstrucción Uretral

ABSTRACT Objective: It has been reported that phosphodiesterase-5 (PDE-5) inhibitors improve kidney function during acute and chronic renal failure. This study aimed to determine the possible therapeutic effects of tadalafil, a specific PDE-5 inhibitor, on renal fibrosis induced by unilateral ureteral obstruction (UUO). Methods: Male Sprague-Dawley rats were used and randomly divided into three groups (n = 6) as sham-operated, UUO and tadalafil-treated (10 mg/72 hours, ig) UUO (UUO+T) groups. Unilateral ureteral obstruction was induced by complete ligation of the left ureter and 14 days after surgery creatinine clearance, urinary cyclic guanosine monophosphate (cGMP), renal alpha-smooth muscle actin (α-sma) and transforming growth factor βeta (TGF-β) levels, as well as histologic changes, were observed in all the animals. Results: Unilateral ureteral obstruction-induced renal fibrosis was confirmed by increased α-sma level, collagen deposition, tubular dilation, inflammatory cell infiltration and necrosis. An increased renal TGF-β level and decreased urinary cGMP level was also observed in obstructed animals in addition to reduced creatinine clearance. Tadalafil treatment, which restored the animals 'urinary cGMP level, significantly attenuated the fibrotic changes and TGF-β increase in their kidneys. Conclusion: This study suggests that tadalafil treatment ameliorates renal fibrosis by reducing TGF-β expression and may have important clinical relevance since tadalafil is currently used clinically to treat erectile dysfunction and pulmonary hypertension.

RESUMEN Objetivo: Se ha reportado que los inhibidores de la fosfodiesterasa-5 (PDE-5) mejoran las funciones renales durante la insuficiencia renal aguda y crónica. Este estudio tuvo por objetivo determinar los posibles efectos terapéuticos del tadalafil - un inhibidor específico de la PDE-5 - sobre la fibrosis renal inducida por una obstrucción ureteral unilateral (OUU). Métodos: Se utilizaron ratas machos Sprague-Dawley, divididas de manera aleatoria en tres grupos (n = 6): operación simulada, OUU y tratamiento con tadalafil (10 mg/72 horas, IG), y OUU (OUU+T). La obstrucción uretral unilateral fue inducida por una ligadura completa del uréter izquierdo y 14 días después de la cirugía, se observaron niveles de monofosfato de guanosina cíclico (GMP) urinario, alfa-actina de músculo liso (α-SMA), y factor de crecimiento transformante βeta (FCT-β), así como cambios histológicos en todos los animales. Resultados: La fibrosis renal inducida por obstrucción uretral unilateral fue confirmada por un aumento del nivel de α-SMA, deposición de colágeno, dilatación tubular, infiltración de células inflamatorias y necrosis. También se observó un aumento del nivel de FCT-β renal y una disminución del nivel de GMP urinario en los animales con obstrucción, además de una reducción del aclaramiento de la creatinina. El tratamiento con tadalafil, que restauró el nivel de GMP urinario de los animales, atenuó significativamente los cambios fibróticos y el aumento de FCT-β en los riñones. Conclusión: Este estudio sugiere que el tratamiento con tadalafil mejora la fibrosis renal al reducir la expresión de FCT-β y puede tener una importante relevancia clínica por cuanto el tadalafil se usa hoy día clínicamente para tratar la disfunción eréctil y la hipertensión pulmonar.

Oxidative stress assessment in intestine of newborn rats submitted to hypoxia and reoxygenation with tadalafil

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.(AU)

Tadalafil for the treatment of benign prostatic hyperplasia.

INTRODUCTION: In men, lower urinary tract symptoms (LUTS) are primarily attributed to benign prostatic hyperplasia (BPH). Therapeutic options are targeted to relax prostate smooth muscle and/or reduce prostate enlargement. Areas covered: This article reviews the major preclinical and clinical data on PDE5 inhibitors with a specific focus on tadalafil. It includes details of the role of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) - PDE5 pathway in the LUT organs (bladder and prostate) in addition to the available data on tadalafil in patients with LUTS secondary to BPH with or without erectile dysfunction (ED). Expert opinion: Preclinical and clinical data have clearly demonstrated that PDE5 inhibitors induce bladder and prostate relaxation, which contributes to the improvement seen in storage symptoms in both animal models of bladder and prostate hypercontractility. Tadalafil is effective both as a monotherapy and add-on therapy in patients with LUTS secondary to BPH. Furthermore, as LUTS-BPH and ED are urological disorders that commonly coexist in aging men, tadalafil is more advantageous than α1-adrenoceptors and should be used as the first option. Tadalafil is a safe and tolerable therapy and unlike α1- adrenoceptors and 5-alpha reductase inhibitors, which can cause sexual dysfunctions, tadalafil improves sexual function.

Positive outcomes of phosphodiesterase type 5 inhibitor on histopathologic and biochemical changes induced by ureteral obstruction

SUMMARY 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-β (TGF-β) exhibited up-regulation in the PUUO and CUUO groups. The expression of TGF-β 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-β 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.

RESUMO OBJETIVOS: Examinamos os efeitos do tadalafil em um dos inibidores da fosfodiesterase tipo 5 (PDE5) em um modelo de rato com obstrução ureteral unilateral parcial e completa (UUO). MÉTODOS: Os ratos foram divididos em cinco grupos: sham (n = 6), obstrução ureteral unilateral parcial (PUUO, n = 6), PUUO com tadalafil (PUUO T; Cialis, 10 mg/72 h, intragástrica; Lilly, Indianapolis, Indiana, EUA), completa obstrução ureteral unilateral (CUUO, n = 6) e CUUO com tratamento com tadalafil (CUUO T). RESULTADOS: Quinze dias após a UUO, o ureter apresentou alterações nas camadas de urotélio e infiltração significativa de células inflamatórias nos grupos PUUO e CUUO. Em comparação com os grupos sham, PUUO e CUUO, houve um aumento grave da infiltração de células inflamatórias. O epitélio urotelial exibiu degeneração e perda celular devido às células epiteliais inchadas, atróficas e desnudas nos grupos PUUO e CUUO. Nos grupos PUUO T e CUUO T, o urotélio revelou menor degeneração e perda de células epiteliais. Nós mostramos que a expressão da actina do músculo liso-α (α-SMA) e do fator de crescimento transformador-β (TGF-β) foram exibidas como sub-regulação nos grupos PUUO e CUUO. A expressão do TGF-β foi diminuída positivamente correlacionada com a da α-SMA nos grupos de terapia com tadalafil, PUUO T e CUUO T. CONCLUSÃO: O tadalafil do inibidor da fosfodiesterase tipo 5 reduziu as expressões α-SMA e TGF-β nos ureteres obstruídos, medidos por exames bioquímicos. Além disso, o tadalafil diminuiu a degeneração do urotélio devido à diminuição da perda de células epiteliais e da infiltração de células inflamatórias. Nossos resultados mostram que o tadalafil previne ou retarda o início da inflamação do ureter e degeneração urotelial em ratos com UUO.