Perspectives for a new drug candidate for Chagas disease therapy

Chagas disease (CD), a neglected tropical illness caused by the protozoan Trypanosoma cruzi, affects more than 6 million people mostly in poor areas of Latin America. CD has two phases: an acute, short phase mainly oligosymptomatic followed to the chronic phase, a long-lasting stage that may trigger cardiac and/or digestive disorders and death. Only two old drugs are available and both present low efficacy in the chronic stage, display side effects and are inactive against parasite strains naturally resistant to these nitroderivatives. These shortcomings justify the search for novel therapeutic options considering the target product profile for CD that will be presently reviewed besides briefly revisiting the data on phosphodiesterase inhibitors upon T. cruzi.

Role and Research Progress of Phosphodiesterase Inhibitor in Gastrointestinal Tract / 胃肠病学

Phosphodiesterases (PDE) are a group of enzymes that can hydrolyze cyclic nucleotides. It is composed of 11 gene related isozyme families (PDE1-PDE11). Due to the diversity of isozymes, PDE distribute in different cells and sub-cells, regulate different intracellular signals and become an important target in intracellular signal pathway. Studies have shown that PDE inhibitor plays an important role in the regulation of gastrointestinal motility and related gastrointestinal diseases. This article reviewed the role and research progress of PDE inhibitor in gastrointestinal tract.

Effect of Cilostazol-Loaded PCL/PEG Nanocapsules on Abdominal Aortic Tunics and Lipid Profile of Wistar Rats

Abstract Cilostazol (CLZ) is a phosphodiesterase III inhibitor with antiplatelet and vasodilator properties. It has been recently verified that CLZ plays a significant role in the arteries by inhibiting the proliferation and growth of muscle cells, increasing the release of nitric oxide by the endothelium and promoting angiogenesis. Considering these promising effects, the use of nanocapsules may be an interesting strategy to optimize its pharmacokinetics and pharmacodynamics at the vascular level for preventing atherosclerosis. The aim of this study was to evaluate the effect of cilostazol-loaded nanocapsules in the abdominal aortic tunics and on the lipid profile of Wistar rats in order to investigate its potential role in the prevention of atherosclerosis. Thirty-two animals were divided into four groups of eight animals, with 30-day treatment. Group 1 received nanoencapsulated CLZ; Group 2, control nanocapsules with no drug; Group 3, propylene glycol and water; and Group 4, a solution of CLZ in propylene glycol and water. After 30 days, there was no statistically significant difference between the groups regarding the cellularity and thickness of the arterial tunics of the abdominal aorta. However, the group that received nanoencapsulated CLZ (Group 1) had an improvement in HDL-c and triglyceride values compared to unloaded nanocapsules (Group 2).

Role of oral sildenafil in neonates with persistent pulmonary hypertension of newborn

Persistent pulmonary hypertension of newborn is a devastating condition and leads to morbidity and mortality. Even after the increasing use of' NO, ECMO and HFO many patients succumb to death. About 50% of the patients either have rebound hypertension or do not respond to the treatment. Hence the role of phosphodiesterase inhibitors (sildenafil) need to be evaluated. Methods is authors report a retrospective case series of 24 patients with PPHN admitted in NICU and treated with oral sildenafil. Results sildenafil was started on all patients on a mean of 1.46 days and stopped on mean of 3.8 days. Initial fio2 was 100%, which after starting sildenafil decreased gradually to 50% on mean of 10 days. Average length of stay in NICU was 20 days. 17(70.8%) patients survived whereas 7 (29%) expired No improvement in oxygen Index after 48 hours (p<0.05) was the independent predicting risk factor for PPHN related mortality in the expired patients.Conclusion are oral sildenafil can be a used in conjunction with other treatment modalities for PPHN especially in resource limited settings.

The Effect of Daily Low Dose Tadalafil on Cerebral Perfusion and Cognition in Patients with Erectile Dysfunction and Mild Cognitive Impairment

OBJECTIVE: The aims of this study were to investigate the effects of daily low-dose tadalafil on cognitive function and to examine whether there was a change in cerebral blood flow (CBF) in patients with erectile dysfunction (ED) and mild cognitive impairment. METHODS: Male patients aged 50 to 75 years with at least three months of ED (International Index of Erectile Function [IIEF]-5 score ≤ 21) and mild cognitive impairment (Montreal Cognitive Assessment [MoCA] score ≤ 22) were included in the study. The subjects were prescribed a low-dose PDE5 inhibitor (tadalafil 5 mg) to be taken once daily for eight weeks. Changes in MoCA score and single-photon emission computed tomography (SPECT) study between the two time-points were assessed by paired t tests. RESULTS: Overall, 30 male patients were assigned to the treatment group in this study and 25 patients completed the eight-week treatment course. Five patients were withdrawn due to adverse events such as myalgia and dizziness. Mean baseline IIEF and MoCA scores were 7.52 ± 4.84 and 18.92 ± 1.78. After the eight-week treatment, mean IIEF and MoCA scores were increased to 12.92 ± 7.27 (p < 0.05) and 21.8 ± 1.71 (p < 0.05), respectively. Patients showed increased relative regional CBF in the postcentral gyrus, precuneus, and brainstem after tadalafil administration versus at baseline (p < 0.001). CONCLUSION: The results of this prospective clinical study suggest that daily use of tadalafil 5 mg increases some regional CBF and improves cognitive function in patients with ED and mild cognitive impairment.

A comparative study of efficacy of tadalafil and alfuzosin regimens in patients of benign prostate hyperplasia

Background: Aim of the study was to compare efficacy of Tadalafil and Alfuzosin regimens in patients of Benign Prostate Hyperplasia.Methods: It was a comparative, prospective, observational, non-invasive, parallel and randomised study conducted at the Outpatient Department of Urology, Rajindra Hospital, Patiala. 60 patients diagnosed with Benign Prostate Hyperplasia along with Lower Urinary Tract Symptoms, out which, 30 patients, consuming Tadalafil and 30 patients consuming Alfuzosin were considered. History regarding the concerned disease and the compliance of treatment was taken. Symptom scores were assessed with the help of International Prostate Symptom Score, Quality of Lifestyle Score and Erectile Dysfunction Score. Physical examination consisting of Focused Neurological Examination along with Digital Rectal Examination were conducted. Parameters like Renal Function Test, Urine analysis, Ultrasound of Prostate and uroflowmetry were also considered.Results: The mean age selected for study was 64 years for Tadalafil and Alfuzosin group. The mean level of IPS Score, Qol Score and ED Score at the first day of inclusion of patients were 23.96±4.49, 4±0.78, and 25.33±4.02 respectively for Tadalafil group and regarding Alfuzosin group they were 25.23±4.84, 3.56±0.81, and 26.1±4.04 respectively. Follow ups were conducted at 15 days, 1 month and 3 months for both the groups which were found to be statistically significant after 3 months and Alfuzosin showed a favourable result.Conclusions: Alfuzosin 10mg given at daily dose was found to have higher efficacy than Tadalafil (5mg).

New and developing therapies for atopic dermatitis

Abstract: Atopic dermatitis is a common inflammatory skin disease. New understanding in disease pathogenesis has led to a considerable number of promising new drugs in development. New topical agents can be especially helpful for children, providing an alternative to the need for chronic topical corticosteroid use. While many patients with mild or moderate disease can be managed with topical treatments, there are unmet needs for recalcitrant and severe cases. New and developing therapies hold promise for real advances in management of this complex disease.

Tadalafil: protective action against the development of multiple organ failure syndrome

Abstract Introduction: Multiple organ failure syndrome (MOFS) is a pathology associated to unspecified and severe trauma, characterized by elevated morbidity and mortality. The complex inflammatory MOFS-related reactions generate important ischemia-reperfusion responses in the induction of this syndrome. Nitric oxide elevation, through the activation of cyclic guanosine monophosphate (cGMP), has the potential of counteracting the typical systemic vasoconstriction, and platelet-induced hypercoagulation. Tadalafil would possibly act protectively by reducing cGMP degradation with consequent diffuse vasodilatation, besides reduction of platelet-induced hypercoagulation, thus, preventing multiple organ failure syndrome development. Methods: The experimental protocol was previously approved by an institution animal research committee. Experimental MOFS was induced through the stereotaxic micro-neurosurgical bilateral anterior hypothalamic lesions model. Groups of 10 Wistar rats were divided into: a) Non-operated control; b) Operated control group; c) 2 hours after tadalafil-treated operated group; d) 4 hours after tadalafil-treated operated group; e) 8 hours after post-treated operated group. The animals were sacrificed 24 hours after the neurosurgical procedure and submitted to histopathologic examination of five organs: brain, lungs, stomach, kidneys, and liver. Results: The electrolytic hypothalamic lesions resulted in a full picture of MOFS with disseminated multiple-organs lesions, provoked primarily by diffusely spread micro-thrombi. The treatment with tadalafil 2 hours after the micro-neurosurgical lesions reduced the experimental MOFS lesions development, in a highly significant level (P<0.01) of 58.75%. The treatment with tadalafil, 4 hours after the micro-neurosurgically-induced MOFS lesions, also reduced in 49.71%, in a highly significant level (P<0.01). Finally, the treatment with tadalafil 8 hours after the neurosurgical procedure resulted in a statistically significant reduction of 30.50% (P<0.05) of the experimentally-induced MOFS gravity scores. Conclusion: The phosphodiesterase 5 inhibitor, tadalafil, in the doses and timing utilized, showed to protect against the experimentally-induced MOFS.

Inhaled therapy for the management of perioperative pulmonary hypertension.

Patients with pulmonary hypertension (PH) are at high risk for complications in the perioperative setting and often receive vasodilators to control elevated pulmonary artery pressure (PAP). Administration of vasodilators via inhalation is an effective strategy for reducing PAP while avoiding systemic side effects, chiefly hypotension. The prototypical inhaled pulmonary‑specific vasodilator, nitric oxide (NO), has a proven track record but is expensive and cumbersome to implement. Alternatives to NO, including prostanoids (such as epoprostenol, iloprost, and treprostinil), NO‑donating drugs (sodium nitroprusside, nitroglycerin, and nitrite), and phosphodiesterase inhibitors (milrinone, sildenafil) may be given via inhalation for the purpose of treating elevated PAP. This review will focus on the perioperative therapy of PH using inhaled vasodilators.

Effect of cilostazol on neointimal hyperplasia in iliac arteries of pigs after transluminal angioplasty / Efeito do cilostazol na hiperplasia neointimal em artérias ilíacas de suínos submetidas à angioplastia transluminal

OBJECTIVE: To evaluate whether systemic administration of cilostazol reduces neointimal hyperplasia in iliac arteries of pigs submitted to balloon catheter angioplasty. METHODS:Twenty pigs underwent angioplasty with a 6x40 mm balloon catheter in the right common iliac artery, guided by Doppler ultrasound. The animals were randomized into two groups: group 1 (n=10), which received 50mg cilostazol twice a day, and group 2 (n=10), control. After 30 days, the animals were killed and the iliac arteries prepared for histological analysis. The histological sections were digitized and analyzed by digital morphometry. Statistical analysis was performed using the Student t and Mann-Whitney tests. RESULTS:When comparing the iliac arteries submitted to angioplasty with those not subjected to angioplasty, there was significant neointimal hyperplasia (0.228 versus 0.119 mm2; p=0.0001). In arteries undergoing angioplasty, there was no difference between group 1 (cilostazol) and group 2 (control) as for the lumen area (2.277 versus 2.575 mm2; p=0.08), the tunica intima (0.219 versus 0.237 mm2; p=0.64), the tunica media (2.262 vs. 2.393 mm2; p=0.53) and the neointimal occlusion percentage (8.857 vs. 9.257 %; p=0.82). CONCLUSION:The use of cilostazol 50mg administered in two daily doses did not reduce neointimal hyperplasia in iliac arteries of pigs submitted to balloon angioplasty catheter.

OBJETIVO: Avaliar se a administração sistêmica de cilostazol reduz a hiperplasia neointimal nas artérias ilíacas de suínos submetidas à angioplastia com cateter balão. MÉTODOS:Vinte suínos foram submetidos à angioplastia com cateter balão 6x40 mm na artéria ilíaca comum direita, guiada por ultrassonografia com Doppler. Os animais foram randomizados em dois grupos: grupo 1 (n=10), no qual foi administrado cilostazol 50mg em duas doses diárias, e grupo 2 (n=10), considerado controle. Após 30 dias, os animais foram mortos, e as artérias ilíacas preparadas para análise histológica. Os cortes histológicos foram digitalizados e analisados por morfometria digital. A análise estatística foi realizada com o teste t de Student e o de Mann-Whitney. RESULTADOS: Comparando as artérias ilíacas submetidas à angioplastia com as artérias não submetidas à angioplastia, houve hiperplasia neointimal significativa (0,228 versus 0,119 mm2; p=0,0001). Nas artérias submetidas à angioplastia, não houve diferença entre o grupo 1 (cilostazol) e o grupo 2 (controle) na área do lúmen (2,277 versus 2,575 mm2; p=0,08), área da íntima (0,219 versus 0,237 mm2; p=0,64), área da média (2,262 versus 2,393 mm2; p=0,53) e no percentual de obstrução neointimal (8,857 versus 9,257 %; p=0,82).CONCLUSÃO: O uso de cilostazol 50mg administrado em duas doses diárias durante 30 dias não reduziu a hiperplasia neointimal em artérias ilíacas de suínos submetidas à angioplastia com cateter balão.

Study of Angiogenesis-Related Phosphodiesterase Inhibitors.

Angiogenesis is the process through which new capillaries form from pre-existing capillaries and venules. Its occurrence depends on the migration of vascular endothelial cells which is inhibited by high levels of cAMP. Such levels can be regulated by the degradation caused by the phosphodiesterases (PDEs). Therefore, by inhibiting the action of PDEs it is assumed that angiogenesis can be inhibited with the prevention of migration of these cells. The aim of this study was to evaluate the effect PDE inhibitors on angiogenesis in mice by using nonspecific inhibitors (aminophylline) and selective inhibitors of PDE4 (roflumilast) and PDE5 (sildenafil). BALB/c mice were used as a model; under anesthesia, the mice had a sponge of 0.5 x 0.5 cm introduced into their dorsal subcutaneous tissue; they were then divided into 4 groups and daily gavage treated: 1) control group (n=13) – treated with 0.3 mL of saline solution; 2) aminophylline group (n=16) – 50 mg/kg; 3) roflumilast group (n=14) – 5mg/kg; 3) sildenafil group (n=12) –100 mg/kg. After 7 days, with the animals anesthetized, a blood sample was drawn for hemoglobin (Hb) measurement, the sponge implant was removed, and its content was obtained in 2 mL of saline solution for hemoglobin measurement. Absorbance levels (A), the amount of Hb from the sponge (S) and the total blood Hb concentration levels from each mouse were evaluated. According to the results obtained, we concluded that aminophylline, roflumilast and sildenafil (phosphodiesterase inhibitors) did not cause any alteration in the angiogenesis evaluated by the sponge-implantation method.

Effects of Ro20-1724 on cognitive dysfunction induced by repetitive ketamine anesthesia in immature rats / 中华麻醉学杂志

Objective To evaluate the effects of Ro20?1724 on cognitive dysfunction induced by repetitive ketamine anesthesia in immature rats. Methods Thirty?two Sprague?Dawley rats of both sex, aged 21 days, weighing 45-55 g, were randomly divided into 4 groups ( n=8 each ) using a random number table: control group ( group C ) , ketamine group ( group K ) , ketamine+Ro20?1724 group ( group K+R) , and ketamine+anhydrous alcohol group ( group K+A) . In K, K+R and K+E groups, 70 mg∕kg ketamine was intraperitoneally injected once a day for 7 consecutive days. The equal volume of normal saline was given instead in group C. Two days after the rats were fed a common diet, 0.5 mg∕kg Ro20?1724 and the equal volume of anhydrous alcohol were injected in K+R and K+E groups, respectively, and the equal volume of normal saline was given instead in K and C groups, once a day for 7 consecutive days. Morris water maze test was used to test cognitive function, and the escape latency and frequency of crossing the original platform were recorded. The rats were sacrificed after the end of behavior tests, and hippocampi were removed to detect the content of brain?derived neurotrophic factor ( BDNF) in CA1 region using enzyme?linked immunosorbent assay. Results Compared with group C, the escape latency was significantly prolonged on 1st-4th days in K and K+E groups, the escape latency was prolonged on 3rd-4th days in K+R group, and the frequency of crossing the original platform and content of BDNF in CA1 region were decreased in K, K+R and K+E groups. Compared with K group, the escape latency was significantly shortened, and the frequency of crossing the original platform was increased on 3rd-4th days, and the content of BDNF in CA1 region was increased in K+R group, and no significant changes were found in the parameters mentioned above in K+E group. Conclusion Ro20?1724 can improve cognitive dysfunction induced by repetitive ketamine anesthesia in immature rats, and enhanced production of BDNF is involved in the mechanism.

The effects of vardenafil on high altitude pulmonary hypertension in rats / 天津医药

Objective To investigate the effect of vardenafil on high altitude pulmonary hypertension in rats, and the possible mechanism thereof. Methods Thirty rats were randomly divided into three groups:control group with normal-pres?sure and normal-oxygen (group C), pulmonary hypertension group with low-pressure and low-oxygen (group P), and the group treated by vardenafil in low-pressure and low-oxygen condition (group V). The rats of group P and group V were ex?posed to low-pressure and low-oxygen condition in an auto-modulating hypobaric and hypoxic cabin to simulate 5 000 m high altitude environment (air pressure 50 kPa, oxygen concentration 10%) for 8 hours daily. Vardenafil (1 mg/kg) was given by gastrogavage to rats in group V once daily for 4 weeks, while the isodose distilled water was given by gastrogavage to rats in group C and group P. The mean pulmonary arterial pressure and right ventricular mass index were measured respectively after 4-week treatment. Morphologic changes of peripheral pulmonary artery were detected by light microscope. The serum levels of nitric oxide (NO) and endothelin-1 (ET-1) were detected as well. Results The pulmonary arterial pressure and right ventricular mass index were significantly higher in group P than those of group C and group V (P<0.05). The ratio of vascular medial wall thickness to external diameter (WT%) and the ratio of pulmonary artery wall area to tube area (WA%) were significantly increased in group P than those of group C and group V (P<0.05). Furthermore, the serum level of NO was significantly lower in group P than that of group C and group V, but the serum level of ET-1 was significantly increased compared with that of group C and group V (P<0.05). Conclusion Vardenafil can effectively reduce the pulmonary arteri?al pressure, and attenuate pulmonary vessels and right ventricle remodeling induced by high altitude pulmonary hypertension.

Effect of sildenafil on expression of tumor necrosis factor-alpha in lung tissues of rats with pulmonary hypertension / 中华麻醉学杂志

Objective To evaluate the effect of sildenafil on the expression of tumor necrosis factor-alpha (TNF-α) in lung tissues of rats with pulmonary hypertension.Methods Twenty-four male Sprague-Dawley rats,aged 8 weeks,weighing 180-220 g,were randomly divided into 3 groups (n =8 each) using a random number table:control group (group C),pulmonary hypertension group (group PH),and sildenafil group (group S).Sildenafil 50 mg/kg was injected through a gastric tube into stomach once a day for 35 consecutive days starting from 1 day after lelf pneumonectomy in group S.Pulmonary hypertension was induced by left pneumonectomy and subcutaneous monocrotaline injected at 7 days after operation in PH and S groups.At 35 days after operation,mean pulmonary arterial pressure (mPAP),relative medial thickness of pulmonary artery (RMT),right ventricular systolic pressure (RVSP),and muscularization of small pulmonary arteries were measured in the lung.The ratio of the right ventricular weight to the sum of the weights of the left ventricle and septum (RV/(LV + S)) was calculated.The expression of TNF-α mRNA and protein was determined using RT-PCR and Western blot analysis,respectively.Results Compared with group C,mPAP,RVSP,muscularization of small pulmonary arteries,RMT and RV/(LV + S) ratio were significantly increased,and the expression of TNF-α mRNA and protein was upregulated in group PH,and RVSP,muscularization of small pulmonary arteries and RV/(LV + S) ratio were increased in group S.Compared with group PH,mPAP,RVSP,muscularization of small pulmonary arteries,RMT and RV/(LV + S) ratio were significantly decreased,and the expression of TNF-α mRNA and protein was downregulated in group S.Conclusion Sildenafil can down-regulate the expression of TNF-α in lung tissues of rats with pulmonary hypertension,inhibit reconstruction of pulmonary artery,and decrease the pulmonary arterial pressure.

Inibidores da fosfodiesterase do tipo 5 e perda auditiva neurossensorial subita / Phosphodiesterase Type 5 Inhibitors and sudden sensorineural hearing loss

O uso de inibidores da fosfodiesterase do tipo 5 como sildenafil, vardenafil e tadalafil tem aumentado atualmente e alguns destes pacientes vêm apresentando perda auditiva neurossensorial súbita. OBJETIVO: Apresentar dois casos de pacientes que apresentaram surdez súbita em uso eventual do medicamento e revisar estudos sobre o uso de inibidores da fosfodiesterase do tipo 5 e surdez súbita. MÉTODO: Estudo analítico de dois casos e revisão sobre o tema no banco de dados da Pubmed/ MedLine e Bireme utilizando as palavras-chave inibidores da fosfodiesterase e surdez súbita e seus correlatos na língua inglesa. RESULTADOS: Os pacientes analisados são jovens, sem comorbidades, em uso de inibidores da fosfodiesterase do tipo 5 e após terapia combinada para o tratamento da surdez súbita, apenas um deles obteve melhora auditiva. Nove estudos científicos foram encontrados. Estudos pré-clínicos e clínicos, transversais e prospectivos foram revisados. CONCLUSÃO: O aumento da ocorrência na prática clínica e relatos científicos na literatura sugerem que o uso de inibidores da fosfodiesterase do tipo 5 seja encarado como fator de risco para surdez súbita. Novos estudos com amostras maiores e grupo controle são necessários para investigar esta associação. .

Phosphodiesterase type 5 Inhibitors, such as sildenafil, vardenafil and tadalafil have been increasingly used today and some of the users have developed sudden sensorineural hearing loss. OBJECTIVE: To present two patients with sudden deafness developed after an occasional use of the drug and review studies on the use of phosphodiesterase type 5 inhibitors and sudden hearing loss. METHOD: Analytical study of two cases and review of the subject matter in the Pubmed/Medline and Bireme databases using the keywords: phosphodiesterase type 5 inhibitors and sudden deafness and its correlates in the English language. RESULTS: The patients analyzed are young without additional disorders, using phosphodiesterase type 5 inhibitors, and after combination treatment for sudden hearing loss only one had hearing improvement. We found nine scientific studies and reviewed preclinical studies, clinical trials, prospective and cross-sectional investigations. CONCLUSION: Increased occurrence in clinical practice and scientific reports in the literature suggest that the phosphodiesterase type 5 inhibitors are considered a risk factor for sudden deafness. Further studies with larger samples and control groups are needed for better assessing this association. .

Benign Prostatic Hyperplasia: Current and Future Therapeutics.

Benign prostatic hyperplasia (BPH) is one of the most common diseases of old-aged men affecting >90% of men in their 70s and 80s. Although the exact cause is not known, most people agree that dihydrotestosterone plays a strong role in pathogenesis. BPH can be a progressive disease. Severe BPH can cause serious problems including renal insufficiency. Surprisingly the risk factors for BPH are found to be the same as for cardiovascular diseases. Management of BPH has changed significantly in the last decade. α-blockers and 5α-reductase inhibitors are the most commonly used drugs. A number of other drugs belonging to newer groups like phosphodiesterase inhibitors, hexokinase inhibitors like lonidamine, antagonists of endothelin, vanilloid and purine receptors and modulators of JM-27 expression are also showing promise. These are in different stages of clinical trials. The surgical counterpart of treatment has also witnessed recent advancements. Newer techniques like potassium-titanylphosphate (KTP) laser and photo selective vaporization of prostate have been shown to have nearly equal efficacy as that of transurethral resection of prostate (TURP) with less side effects.

Effects of Mirodenafil, a Phosphodiesterase-5 Inhibitor, on Female Rat Bladder in a Partial Bladder Outlet Obstruction Model: Physiological and Immunohistochemical Aspects

PURPOSE: We investigated the effects of mirodenafil, a phosphodiesterase-5 inhibitor developed in South Korea, on the female rat bladder in a partial bladder outlet obstruction (BOO) model. MATERIALS AND METHODS: Thirty-six female Sprague-Dawley rats were divided into four groups: the control group, BOO without medication group, BOO with mirodenafil 1 mg/kg group, and BOO with mirodenafil 4 mg/kg group. Mirodenafil was administered orally for 2 weeks after the induction of BOO. Two weeks after BOO, the rats in each group underwent cystometry under urethane anesthesia. After cystometry, the bladder was excised to perform immunohistochemical staining for connexin 43. RESULTS: The three BOO groups showed significant increases in mean bladder weight compared with the control group. Baseline pressure, threshold pressure, and maximum contraction pressure were not significantly different between the four groups. Although the contraction interval was decreased in all BOO groups compared with the control group, it was prolonged in the two groups treated with mirodenafil compared with the untreated BOO group. In the immunohistochemical examination, connexin 43 staining intensity in the lamina propria increased in the three BOO groups compared with the control group. The two groups treated with mirodenafil, however, showed decreased connexin 43 staining compared with the untreated BOO group. CONCLUSIONS: Mirodenafil may increase the contraction intervals of female rat bladders in a partial BOO model. Decreasing bladder overactivity by mirodenafil may be related to intracellular communication mechanisms involving connexin 43.

Effects of RO20-1724 on repetitive ketamine administration-induced learning and memory impairment in immature rats / 中华麻醉学杂志

Objective To investigate the effects of RO20-1724 on repetitive ketamine administration-induced learning and memory impairment in immature rats.Methods Forty-eight 21-day-old SD rats of both sexes weighing 45-55 g were randomly divided into 4 groups (n =12 each):control group(group C); ketamine group (group K); ketamine + RO20-1724 group (group K+ R) and ketamine + vehicle (ethanol) group (group K+ A).Ketamine 70 mg/kg was injected intraperitoneally (IP) once a day for 7 consecutive days in groups K,K+ R and K+ A.RO20-1724 0.5 mg/kg and equal volume of ethanol were injected IP at 30 min after IP ketamine once a day for 7 consecutive day in groups K + R and K + A respectively.Morris water maze test was used to assess learning and memory ability.The escape latency and the number of times of passing the safe zone were recorded.The animals were killed after water maze test and their brains removed for microscopic examination of hippocampus and determination of p-CREB protein expression in hippocampus (by Western blot).Results Repetitive ketamine administration significantly prolonged the escape latency,decreased the number of times of passing the safe zone and down-regulated the expression of p-CREB protein in hippocampus on the 3rd and 4th day in group K as compared with group C.RO20-1724 significantly attenuated the above changes induced by repetitive ketamine administration in group K + R as compared with group K.Electron microscopic examination showed that RO20-1724 significantly ameliorated repetitive ketamine administration-induced hippocampal neuronal damage.Conclusion RO20-1724 can ameliorate cognitive dysfunction induced by repetitive ketamine administration.Up-regulation of cAMP /CREB signaling pathway is involved in the mechanism.

The expressions of endothelin-1 and endothelin A/B receptors mRNA in tissue of benign prostatic hyperplasia treated by daily low-dose sildenafil / 中华老年医学杂志

Objective To observe the mRNA expressions of endothelin-1(ET-1) and endothelin A/B receptors (ETA/B) in tissue of benign prostatic hyperplasia treated by daily low-dose sildenafil.Methods A total of 32 patients with benign prostatic hyperplasia were randomly divided into two groups:treatment(25 mg sildenafi for 12 weeks,n=16) and control (no drug,n=16) groups.Immunohistochemical staining,ELISA and RT-PCR were used to detect the expression levels of ET-1 protein and ET A/B mRNA,respectively.Results The expressions of ET-1 protein and ET A/B mRNA in prostatic tissue were significantly lower in treatment group than in control group[(53.31±18.56) ng/kg vs.(83.34±31.38) ng/kg,0.356±0.056 vs.0.624±0.083,0.721±0.083 vs.0.933±0.905,t=-3.295,10.715,6.937,all P＜0.001].Conclusions Daily low-dose sildenafil can reduce the expressions of ET-1 and ET A/B receptors mRNA in benign prostatic hyperplasia.