The use of antimuscarinics,phosphodiesterase type Ⅴ inhibitors and phytotherapy for lower urinary tract symptoms in men

Besides the mainstay of α-blockers and 5α-reductase inhibitors,other forms of medical therapy complete the armamentarium in the treatment of lower urinary tract symptoms(LUTS)in men.These treatments can target specific symptoms as well as associated symptoms that would affect the quality of life of the patients.Many patients are bothered by storage symptoms,more so than the voiding symptoms.Antimuscarinics are efficacious and safe,provided the patients do not have high post void residual urine.Many patients with LUTS also have erectile dysfunction,and phosphodiesterase type Ⅴ inhibitors are effective in relieving both LUTS as well as erectile dysfunction for such patients.Phytotherapy provides a popular and safe treatment for LUTS,however,the efficacy of the treatment has not been proven in well conducted prospective randomized controlled studies.

Mechanisms mediating cholinergic antral circular smooth muscle contraction in rats

AIM:To investigate the pathway(s)mediating rat antral circular smooth muscle contractile responses to the cholinomimetic agent,bethanechol and the subtypes of muscarinic receptors mediating the cholinergic contraction. METHODS:Circular smooth muscle strips from the antrum of Sprague-Dawley rats were mounted in muscle baths in Krebs buffer.Isometric tension was recorded.Cumulative concentration-response curves were obtained for(+)-cis- dioxolane(cD),a nonspecific muscarinic agonist,at 10^(-8)- 10^(-4)mol/L,in the presence of tetrodotoxin(TTX,10^(-7)mol/L). Results were normalized to cross sectional area.A repeat concentration-response curve was obtained after incubation of the muscle for 90 min with antagonists for M1(pirenzepine), M2(methoctramine)and M3(darifenadn)muscarinic receptor subtypes.The sensitivity to PTX was tested by the ip injection of 100 mg/kg of PTX 5 d before the experiment.The antral circular smooth muscles were removed from PTX-treated and non-treated rats as strips and dispersed smooth muscle cells to identify whether PTX-linked pathway mediated the contractility to bethanechol. RESULTS:A dose-dependent contractile response observed with bethanechol,was not affected by TTx.The pretreatment of rats with pertussis toxin decreased the contraction induced by bethanechol.Lack of calcium as well as the presence of the L-type calcium channel blocker,nifedipine,also inhibited the cholinergic contraction,with a reduction in response from 2.5±0.4 g/mm^2 to 1.2±0.4 g/mm^2(P<0.05).The dose- response curves were shifted to the right by muscarinic antagonists in the following order of affinity:darifenacin (M_3)>methocramine(M_2)>pirenzepine(M_1). CONCLUSION:The muscarinic receptors-dependent contraction of rat antral circular smooth muscles was linked to the signal transduction pathway(s)involving pertussis-toxin sensitive GTP-binding proteins and to extracellular calcium via L-type voltage gated calcium channels.The presence of the residual contractile response after the treatment with nifedipine,suggests that an additional pathway could mediate the cholinergic contraction.The involvement of more than one muscarinic receptor(functionally predominant type 3 over type 2)also suggests more than one pathway mediating the cholinergic contraction in rat antrum.

Resolution and Crystal Structure of 9α-(3-Azabicyclo[3,3,1]nonanyl)- 2′-cyclopentyl-2′-hydroxyl-2′-thienylacetate

The crystal structure of 9α-（3-azabicyclo[3,3,1]nonanyl）-2′-cyclopentyl-2′-hydro- xyl-2′-thienylacetate （C16H27NO3S, Mr = 349.48） has been determined by single-crystal X-ray diffraction analysis. The crystal belongs to orthorhombic, space group P212121 with a = 14.937（3）, b = 8.1673（16）, c = 15.423（3） ,A, V = 1881.5（6） ,A^3, Z = 4, Dc =1.234 g/cm^3, μ = 0.188 mm^-1, F（000） = 752, the final R = 0.0468 and wR = 0.1251. The bicyclo[3,3,1]nonane ring system adopts the most favored twin-chair conformation. The crystal structure shows the existence of intramolecular O-H…O hydrogen bonds by which a one-dimensional chain structure is formed.

Effect of ipratropium bromide on airway and pulmonary muscarinic receptors in a rat model of chronic obstructive pulmonary disease

OBJECTIVE: To observe the level of muscarinic receptors in airway and lung tissues, and the effect of inhaled ipratropium bromide on these receptors in a rat model of chronic obstructive pulmonary disease (COPD). METHODS: This model was developed by exposure of rats to 250 ppm SO2 gas, 5 h/d, 5 d/wk, for a period of 7 wk. The COPD rats inhaled 0.025% aerosolized iratropium bromide for 20 min, 2 times daily, in an airtight chamber. Muscarinic receptors in airway and lung tissues of normal rats, ipratropium bromide-treated COPD rats and the recovering COPD rats were measured by the radio-ligand binding assay. RESULTS: Airway/lung pathology and pulmonary function tests showed that chronic SO2 exposure caused pathophysiologic changes similar to those observed in human COPD. The density (0.038 +/- 0.011, pmol/mg protein) and affinity (Kd, 23 +/- 11 pmol/L) of muscarinic receptors in airway and lung tissues of COPD rats were not changed compared with those of normal control rats (0.030 +/- 0.008 and 29 +/- 19, respectively, P > 0.05). Densities of the muscarinic receptors were not changed after inhalation of ipratropium bromide for 5 days, but increased significantly after inhalation for 30 days, as compared with those of the untreated COPD rats. The muscarinic receptors returned the normal levels at day 6 after cessation of ipratropium bromide treatment. There were no differences among different groups of rats in equilibrium dissociation constants (Kd). CONCLUSION: A rat model of COPD with pathophysiologic changes similar to the human counterpart was developed using chronic SO2 exposure. There was no significant change in the number and function of muscarinic receptors in airway and lung tissues of the COPD rats, but upregulation of the muscarinic receptors was observed after long-term inhalation of ipratropium bromide.

Overactive bladder symptom score to evaluate efficacy of solifenacin for the treatment of overactive bladder symptoms

Background Overactive bladder （OAB） is a series of symptoms with high prevalence in elderly people.This study was conducted using the overactive bladder symptom score （OABSS） to evaluate the efficacy of solifenacin succinate for the treatment of OAB.Methods This was a prospective,multicenter,single-arm,12-week study that enrolled 241 OAB patients.The patients received 5-10 mg/day solifenacin.Changes in OABSS,symptoms from voiding diary,perception of bladder condition （PPBC） score,international prostate symptom score （IPSS） and quality of life （QOL） were evaluated at weeks 0,4,and 12.The relationship between OABSS and PPBC score or parameters of voiding diary was also evaluated.Results At baseline,the mean OABSS for all patients was 9.41±2.40,and was reduced significantly at week 12 （-3.76 points; 61.21％,P ＜0.0001）.The OABSS subscore,PPBC score,IPSS,and QOL were also significantly reduced during the study （P ＜0.0001）.The overall incidence of adverse events was 19.91％ （44 cases）.The gastrointestinal system was the most commonly affected （11.31％）.Around 5.88％ of the cases had adverse events related to the genitourinary system.There was a strong correlation between OABSS and urinary symptoms that was recorded in the 3-day voiding dairy.Conclusions We showed that solifenacin was clinically effective for relieving OAB symptoms,considering the balance between efficacy,patients＇ well-being,and tolerability.OABSS integrates four OAB symptoms into a single score and can be a useful tool for research and clinical practice.

Clemastine rescues behavioral changes and enhances remyelination in the cuprizone mouse model of demyelination

Increasing evidence suggests that white matter disorders based on myelin sheath impairment may underlie the neuropathological changes in schizophrenia.But it is unknown whether enhancing remyelination is a beneficial approach to schizophrenia.To investigate this hypothesis,we used clemastine,an FDA-approved drug with high potency in promoting oligodendroglial differentiation and myelination,on a cuprizone-induced mouse model of demyelination.The mice exposed to cuprizone（0.2%in chow） for 6 weeks displayed schizophrenia-like behavioral changes,including decreased exploration of the center in the open field test and increased entries into the arms of the Y-maze,as well as evident demyelination in the cortex and corpus callosum.Clemastine treatment was initiated upon cuprizone withdrawal at 10 mg/kg per day for3 weeks.As expected,myelin repair was greatly enhanced in the demyelinated regions with increased mature oligodendrocytes（APC-positive） and myelin basic protein.More importantly,the clemastine treatment rescued the schizophrenia-like behavioral changes in the open field test and the Y-maze compared to vehicle,suggesting a beneficial effect via promoting myelin repair.Our findings indicate that enhancing remyelination may be a potential therapy for schizophrenia.