Regulatory effect of histamine H1 receptor antagonist on the expression of messenger RNA encoding CC chemokines in the human nasal mucosa.

BACKGROUND: Allergic rhinitis is characterized by tissue accumulation of inflammatory cells. CC chemokines, including monocyte chemotactic protein (MCP) 1, MCP-3, RANTES, and eotaxin, are thought to play an important role in inducing selective recruitment of these cells to the allergic inflammatory site. Furthermore, MCPs have been indicated as histamine-releasing factors. Histamine is an important mediator in the pathogenesis of nasal allergy. The regulation of histamine may have a role in the management of allergic inflammation. OBJECTIVE: The objectives of this study were to investigate the expression of MCP-1, MCP-3, RANTES, and eotaxin in the nasal mucosa of patients with allergic rhinitis and to clarify the effect of histamine and antihistamine on the regulation of the expression of these CC chemokines. METHODS: By using a semiquantitative reverse transcriptase PCR technique, the numbers of copies of messenger RNA encoding MCP-1, MCP-3, RANTES, and eotaxin were measured in explant cultures of human nasal mucosa. In culture medium, specific antigen or histamine was added. Furthermore, the effect of preincubation with the antihistamine carebastine was estimated. RESULTS: Mite antigen (1:2 x 10(4) dilution) and histamine (10(-4) to 10(-3) mol/L) upregulated the messenger RNA expression of these CC chemokines at 3- to 10-fold increases. Carebastine (10(-7) to 10(-6) mol/L) inhibited this upregulation. CONCLUSION: Our results suggest that histamine may induce CC chemokine production in the nasal mucosa of patients with allergic rhinitis. This indicates that there may be a prolonged inflammatory cycle in the histamine-MCP axis in allergic rhinitis. The regulation of histamine-CC chemokine interaction could lead to new therapeutic approaches in the treatment of nasal allergy.

Regional differences in homicide patterns in five areas of Japan.

This article describes regional differences in the homicide patterns which occurred in Sapporo City and the surrounding area, and in Akita, Ibaraki, Chiba and Toyama prefectures in Japan. Information collected from each case of homicide included factors such as age, sex of the victim and assailant, causes of death, disposition of the offender, relationship between assailant and victim, reasons for criminal action, et al. The statistical features of homicidal episodes among the five different regions showed considerable variation, as follows. The mean death rates for homicide (number of victims per 100,000 of population) during the period 1986-1995 were 0.44 (Sapporo), 0.8 (Akita), 0.58 (Toyama), 0.7 (Ibaraki) and 0.75 (Chiba), respectively. Close family relationship between the victim and assailant was observed in the homicidal acts which occurred in Sapporo, Akita and Toyama. Assailant's relationship to victim was commonly extra-familial in Ibaraki and Chiba-neighboring megalopolis Tokyo, where some events of murder by a foreigner occurred. Homicide by female assailant, murder by mentally abnormal killers and homicide-suicide events were closely associated with family members. And these factors contributed to the considerable number of victims in Sapporo, Akita and Toyama. But, this close family relationship of the victim to the assailant did not correspond with the elevation in the number of deaths, and it was rather inversely related to the higher death rates recognized in Ibaraki and Chiba. This comparative study suggested that rapid urbanization considerably affects regional differences in homicide patterns.

Acute cerebellar hemorrhage in a patient with Klinefelter syndrome: XXY karyotype obtained postmortem from cells from pericardial fluid.

A case of Klinefelter syndrome and a spontaneous cerebellar hemorrhage in a 12-year-old boy is presented. Autopsy revealed that the hemorrhage was due to the rupture of a dilated artery in an arteriovenous malformation in the right cerebellar hemisphere. The small, undescended testes exhibited partial atrophy of the seminiferous tubules. Postmortem chromosome analysis of cells from the pericardial fluid demonstrated a 47, XXY karyotype. He had previous surgical treatment for bilateral thumb polydactyly and patent ductus arteriosus. In juvenile cases of sudden death with overlapping morphological dysgenesis, postmortem karyotyping may provide important diagnostic information.

Giant hornet (Vespa mandarinia) venomous phospholipases. The purification, characterization and inhibitory properties by biscoclaurine alkaloids.

Two species of giant hornet phospholipase B (PLB), alpha and beta, were purified from the venom of Vespa mandarinia. The purification procedure was simplified by two steps of column chromatographies, Sephadex G-100 and SP-Sepharose. The molecular sizes of PLB alpha and beta were 29.5 and 26.0 kDa, respectively. The isoelectric point of alpha and beta enzymes were pH 10.6 and 10.7, respectively. The temperature optimum for egg yolk lecithin was a broad peak at 40-60 degrees C for both enzymes. Amino acid compositions of both enzymes were high contents of aspartic acid, glycine, leucine, lysine and other aliphatic amino acids. Cystine was similar amounts to other species of phospholipases (PLs). The K(m) values of alpha and beta enzymes were 8.29 and 7.53 mg/ml for egg yolk lecithin, respectively. In the catalytic specificity for L-alpha-phosphatidylcholine-beta-oleoil-gamma-palmitoil, the K(m) values of alpha enzyme for gamma-palmitoil and beta-oleoil residues were 0.528 and 1.392 mM, respectively. While the K(m) values of beta enzyme for gamma-palmitoil and beta-oleoil residues were 7.91 and 2. 68 mM, respectively. Both alpha and beta enzymes were inhibited strongly by cepharanthine. The lecithin hydrolysis of alpha enzyme was competitively inhibited, but beta enzyme was uncompetitive. Cepharanthine also inhibited noncompetitively PLA(2)s of bovine pancreas, bee venom and Naja mossambica mossambica.

YM116, 2-(1H-imidazol-4-ylmethyl)-9H-carbazole, decreases adrenal androgen synthesis by inhibiting C17-20 lyase activity in NCI-H295 human adrenocortical carcinoma cells.

The concentrations of androstenedione and dehydroepiandrosterone, products of C17-20 lyase, in the medium after a 6-hr incubation of NCI-H295 cells were decreased by YM116 (2-(1H-imidazol-4-ylmethyl)-9H-carbazole) (IC50: 3.6 and 2.1 nM) and ketoconazole (IC50: 54.9 and 54.2 nM). 17Alpha-hydroxyprogesterone, a product of 17alpha-hydroxylase, was increased by YM116 (1-30 nM) and by ketoconazole (10-300 nM) and then was decreased at higher concentrations of both agents (IC50: 180 nM for YM116, 906 nM for ketoconazole), indicating that YM116 and ketoconazole were 50- and 16.5-fold more specific inhibitors of C17-20 lyase, respectively, than 17alpha-hydroxylase. Compatible with these findings, progesterone, a substrate of 17alpha-hydroxylase, was increased by these agents. Cortisol production was inhibited by YM116 and ketoconazole (IC50: 50.4 and 80.9 nM, respectively). YM116 was a 14-fold more potent inhibitor of androstenedione production than cortisol production, whereas ketoconazole was a nonselective inhibitor of the production of both steroids. YM116 and ketoconazole inhibited the C17-20 lyase activity in human testicular microsomes (IC50: 4.2 and 17 nM, respectively). These results demonstrate that YM116 reduces the synthesis of adrenal androgens by preferentially inhibiting C17-20 lyase activity.

Monocyte chemotactic and activating factor/monocyte chemoattractant protein-1-mediated histamine release from human nasal mucosa.

OBJECTIVES: To demonstrate the existence and localization of monocyte chemotactic and activating factor or monocyte chemoattractant protein-1 (MCAF/MCP-1) in human nasal mucosa and to verify its activity as a histamine-releasing factor. DESIGN: Detection of MCAF/MCP-1 in culture supernatants of nasal mucosa using Western blot analysis and assay of histamine release from basophils induced by these culture supernatants. Detection of MCAF/MCP-1 expression in nasal mucosa of patients with perennial allergic rhinitis using immunohistochemistry. PATIENTS: Twenty-one patients with house dust mite allergy, 7 nonallergic patients, and 5 patients with chronic inflammatory sinusitis participated in the study. All the allergic patients had positive test results for mite nasal allergy, detected by a clinical history, a nasal provocation test, and determination of specific mite IgE antibodies by a radioallergosorbent test. RESULTS: In Western blot analysis of supernatants of explant culture of human nasal mucosa, the band corresponding to approximately 13 to 15 kd was observed. This band was considered to be MCAF/MCP-1. These supernatants induced histamine release from basophils (approximately 3%-5% in net histamine release), and anti-MCAF/MCP-1 antibody inhibited this histamine-releasing activity. Immunoreactivity of MCAF/MCP-1 was observed in the nasal submucosa but not in the epithelium. Immunoreactive cells of MCAF/MCP-1 were also stained with the antibody, which recognizes monocytes and macrophages. CONCLUSIONS: These results suggest that MCAF/MCP-1, which is produced constantly by monocytes and macrophages and is stored in human nasal mucosa, possibly participates in the protracted histamine release from basophils and in the pathogenesis of perennial allergic rhinitis.

Inhibitory effects of YM175, a bisphosphonate, on the progression of experimental periodontitis in beagle dogs.

This study examined the efficacy of YM175 [disodium dihydrogen (cycloheptylamino) methylene-1, 1-bisphosphonate] in reducing alveolar bone loss caused by experimental periodontitis in beagle dogs. Thirty-six dogs were used and divided into 6 groups. Periodontitis was induced in 30 dogs (groups 2-6) by ligating the bilateral mandibular third and fourth premolar teeth with silk ligatures and by feeding a soft diet. Six dogs were sham-operated (group 1). Saline (placebo), flurbiprofen (0.02 mg/kg) and YM175 (0.01, 0.1 and 1.0 mg/kg) were administered to the dogs (groups 2-6) 5 d/wk for 25 wk. Radiographic and morphometric analyses were performed. In placebo-treated animals (group 2), the ligation caused a significant decrease in the alveolar bone height by 0.57 and 1.91 mm at 2 and 25 wk, respectively. YM175 (1.0 mg/kg) prevented the decrease in bone height by 47 and 31% at 2 and 25 wk. YM175 (0.1 mg/kg) and flurbiprofen tended to prevent bone loss after 15 wk. Although the ligation elicited no significant change in bone mineral density, it significantly decreased bone volume. YM175 (1.0 mg/kg) and flurbiprofen tended to increase the bone volume. The number of formative or resorptive Haversian canals and the bone turnover through the periosteal bone surface were increased by the ligation, indicating the increased turnover of the cortical bone. YM175 (1.0 mg/kg) reduced the increased bone turnover. The gingival index was maximally increased at 2 wk and was suppressed by YM175. These results suggest that YM175 prevents alveolar bone loss by reducing the increased alveolar bone turnover in dogs with periodontitis.

Novel nonsteroidal inhibitor of cytochrome P450(17alpha) (17alpha-hydroxylase/C17-20 lyase), YM116, decreased prostatic weights by reducing serum concentrations of testosterone and adrenal androgens in rats.

BACKGROUND: The purpose of this study was to determine the effects of a nonsteroidal C17-20 lyase inhibitor, 2-(1H-imidazol-4-ylmethyl)-9H-carbazole (YM116), on serum concentrations of androgens and ventral prostatic weight in rats. METHODS: Serum concentrations of testosterone and of dehydroepiandrosterone sulfate and prostatic weights were measured in rats treated with YM116. RESULTS: YM116 inhibited testicular C17-20 lyase competitively (Ki, 0.38 nM), and decreased the serum testosterone concentration in gonadotropin-releasing hormone-treated rats (ED50, 0.7 mg/kg), indicating that YM116 was about 21-24 times more potent than other C17-20 lyase inhibitors such as ketoconazole and liarozole, and was twice as potent as CB7630. YM116 also reduced dehydroepiandrosterone sulfate levels in ACTH-treated castrated rats (ED50, 11 mg/kg). YM116 (40 mg/kg, p.o., for 2 weeks) was almost comparable to bilateral orchiectomy with respect to the time course and magnitude of the reduction in prostatic weight. Each of these two treatments decreased the prostatic weight 3 days following the treatment. Contrarily, leuprolide transiently increased the prostatic weight and then decreased it. YM116 (100 mg/kg) had no effect on the serum cortisol level in guinea pigs, and slightly decreased the serum aldosterone level in rats. CONCLUSIONS: YM116 is a selective C17-20 lyase inhibitor which decreases rat prostatic weight by reducing androgen production in the testes and adrenal glands.

Zoonotic tuberculosis due to Mycobacterium bovis in developing countries.

The World Health Organization (WHO) estimates that human tuberculosis (TB) incidence and deaths for 1990 to 1999 will be 88 million and 30 million, respectively, with most cases in developing countries. Zoonotic TB (caused by Mycobacterium bovis) is present in animals in most developing countries where surveillance and control activities are often inadequate or unavailable; therefore, many epidemiologic and public health aspects of infection remain largely unknown. We review available information on zoonotic TB in developing countries, analyze risk factors that may play a role in the disease, review recent WHO activities, and recommend actions to assess the magnitude of the problem and control the disease in humans and animals.

Placental cavities.

OBJECTIVE: To study placental cavities by gross and microscopic examination and ultrasonography and their frequency with various epidemiologic factors and intervillous thrombosis. METHODS: After formalin fixation, interval sections of 567 placentas were prepared to search for cavities and intervillous thrombosis. Cavities were subjected to histologic and ultrasonographic examinations. RESULTS: Frequency of cavities with diameter of 1 cm or more was 34.9% in 567 mature placentas. Frequency of cavities was significantly higher in heavy, thick placentas associated with male fetuses. Histologic examination revealed villus laceration in cavities and syncytial cells, isolated chorionic villi, or air bubbles in placental fetal veins. All 82 placentas with cavities showed villus lacerations in the cavities and air bubbles in the fetal veins. Intervillous thromboses in fetal lobules were located only in the cavities. Cavities were first found by ultrasonography at a mean gestational age of 30.9 +/- 3.8 weeks. Ultrasonography did not always differentiate accurately between intervillous thrombosis and cavities. CONCLUSION: Placental cavities were found significantly more often in heavy, thick placentas associated with male fetuses. Strong uterine contractions during placental detachment could produce villus laceration in cavities, following contamination by air bubbles and isolated villus tissue in the fetal veins. Placental cavities are vulnerable to villus laceration. Intervillous thrombosis occurred only in cavities.

Increase of bone mass and mechanical strength in rats after treatment with a novel bisphosphonate, YM175, for two years.

We have evaluated the relationship between bone mass and mechanical properties of bone from male and female rats treated with YM175, a novel bisphosphonate, for 104 weeks. YM175 [disodium (cycloheptylamino) methylenediphosphonate monohydrate] was given via the drinking water at a concentration of 0, 0.005, 0.015, 0.05, or 0.15%. Since the mortality in the male 0.15% group exceeded the exclusion criteria (75%) at week 88, this-group was omitted from the study. Mean daily intake of YM175 was 2.2-22.1 mg/kg for males and 3.6-104 mg/kg for females. After the treatment, mechanical properties and ash weight of the humerus were determined. In males, 0.015 and 0.05% of YM175 (6.6-22.1 mg/kg) significantly increased failure load of the midshaft. In females, failure load and stiffness of the midshaft tended to be increased by YM175 (up to 104 mg/kg). Furthermore, ultimate compressive load at the humeral metaphysis treated with the highest dose of YM175 was 2- or 3.5-fold greater than that of untreated male or female control. Ash weight of the humerus was increased dose-dependently and was positively correlated with failure load of the midshaft. These findings indicate that treatment for 2 years with YM175 increased bone mass and mechanical strength without blocking bone mineralization.

Homicide patterns in the Toyama Prefecture, Japan.

Homicides occurring in the Toyama prefecture, Japan, during the past 10 years were reviewed. Between 1985 and 1994, 56 offenders committed 63 homicides. The mean death rate for homicide was 0.55 per 100,000. The ratio of male to female victims was 1:1, while 82% of the assailants were male and 18% were female. The victim and the assailant had a close family relationship in 58.7% of the cases. Dyadic death (homicide followed by suicide) accounted for 27% of all victims. Twenty-nine per cent of the victims were murdered by mentally unstable offenders, and in almost half (44%) of the cases the offender was convicted. Homicides during robbery were rare (only two cases), and there was only one homicide during sexual assault. Death was caused by blunt instrument injury in 38.1% of cases, asphyxia in 31.7%, stabbing in 17.5%, burns in 9.5% and shooting in 3.2% (only two cases). The majority (80%) of homicides occurred at the residence of the victim(s). None of the victims had a history of drug abuse. Social conditions in Toyama prefecture, and their possible relevance to local homicide patterns, are discussed briefly.

4-(3,4-Dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline derivatives. II. Their renal vasodilation activity and structure-activity relationship.

A series of 4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline derivatives showed potent DA1 agonistic activities. We investigated the structure-activity relationship of the racemic compounds of this series. 4-(3,4-Dihydroxyphenyl)-7-methanesulfonamido-1,2,3,4-tetrahydroiso quinoline (43) was identified as a potent renal vasodilator with activity almost equal to that of YM435 (1).

Studies on aromatase inhibitors. I. Synthesis and biological evaluation of 4-amino-4H-1,2,4-triazole derivatives.

Various 4-N-substituted amino-4H-1,2,4-triazole derivatives were synthesized and evaluated for aromatase-inhibitory activity (in vitro) and for pregnant mare serum gonadotropin (PMSG)-induced estrogen synthesis-inhibitory activity (in vivo). The 4-(4-cyanophenyl) amino derivative and 4-(4-nitrophenyl)amino derivative, each possessing a strong electron-withdrawing group on the phenyl moiety, showed potent aromatase-inhibitory activity. Structure-activity relationship studies indicated that 4-[(4-bromobenzyl)(4-cyanophenyl)amino]-4H-1,2,4-triazole (5k, YM511) is a highly potent aromatase inhibitor with IC50 values of 0.4 and 0.12 nM in in vitro experiments using rat ovary and human placenta, respectively, and an in vivo ED50 of 0.002 mg/kg in rats on oral administration. YM511 was also a weak inhibitor of other steroid hormone synthesis enzymes. These data suggest that YM511 is a highly selective aromatase inhibitor and may be a useful agent for the treatment of estrogen-dependent diseases such as breast cancer.

Prevention of bone loss by bisphosphonate YM175 in ovariectomized dogs with dietary calcium restriction.

We have evaluated the effects of YM175 (disodium dihydrogen (cycloheptylamino) methylenebisphosphonate monohydrate), a novel bisphosphonate, on bone mineral densities (BMD) at the lumbar spine and forelimb in ovariectomized beagles with dietary calcium restriction. Groups 1 and 2 were given a sham operation and Groups 3-6 were ovariectomized. One month later (month 0), a low calcium diet was given to Groups 2-6. Groups 4-6 were orally treated with YM175 at doses of 0.01, 0.1 and 1.0 mg/kg, respectively, for 18 months. Changes in BMD at the lumbar spine and left forelimb were determined serially by dual energy X-ray absorptiometry. Calcium restriction decreased lumbar BMD by 19% at month 2 and by up to 30% at month 17 compared to its baseline value, but ovariectomy itself had a minimal effect on bone mass in dogs with restricted calcium intake. YM175 (1 mg/kg) prevented the bone loss at month 2 and YM175 at 0.1 mg/kg or more inhibited the BMD reduction at month 17. The magnitude of BMD reduction of the forelimb was less remarkable as compared to that of the lumbar spine. Urinary hydroxyproline excretion and plasma osteocalcin levels were increased by calcium restriction, indicating a high turnover of bone. YM175 reduced hydroxyproline excretion but not osteocalcin levels. These results indicate that YM175 prevents bone loss induced by calcium restriction and ovariectomy through partially normalizing high bone turnover.

Inhibitory effect of a novel non-steroidal aromatase inhibitor, YM511 on the proliferation of MCF-7 human breast cancer cell.

The proliferation of MCF-7, human breast cancer cell line, was stimulated by testosterone and estradiol. The aromatase activity in MCF-7 cells, which catalysed the conversion of testosterone to estradiol, was inhibited by a novel non-steroidal aromatase inhibitor, YM5111, with the IC50 of 0.2 nM, indicating that its inhibitory activity was 5.5 times more potent than that of CGS 16949A. YM511 inhibited the proliferation of MCF-7 stimulated by testosterone but did not inhibit the cell proliferation stimulated by estradiol. The IC50 values of YM511 for cell growth and DNA synthesis were 0.13 nM and 0.18 nM, respectively, demonstrating that YM511 was about 3-5 times more potent than CGS 16949A and had no anti-estrogenic or cytotoxic activity. YM511 significantly inhibited testosterone-stimulated transcriptional activation of estrogen-responsive element (ERE) in MCF-7 cells transfected transiently with ERE-luciferase reporter plasmid. The IC50 of YM511 for transactivation was 0.36 nM, suggesting that its inhibitory potency was comparable to the inhibition of aromatase activity of MCF-7 cells. These data may indicate that the inhibition by YM511 of cell proliferation of MCF-7 is attributed to the decreased production of estrogen due to the inhibition of aromatase activity. YM511 may be useful in the treatment of estrogen-dependent cancers.

Blood gas analysis of placental and uterine blood during cesarean delivery.

OBJECTIVE: To measure blood gases in uterine venous blood and maternal and fetal blood from the placenta, and to characterize gas exchange in the intervillous space. METHODS: Blood gas measurements were performed immediately after collecting placental and uterine blood from the subchorial and marginal lakes, from the chorionic vein and artery in the placenta in utero, and from the uterine vein during 12 cesarean deliveries. RESULTS: The mean oxygen pressure (PO2) values of the chorionic vein and subchorial lake were 28.7 +/- 6.0 and 29.9 +/- 7.5 mmHg, respectively, with a difference of 1.2 mmHg. The individual data for PO2 of the chorionic vein exceeded those of the subchorial lake in five subjects and were almost equal in two of the 12 subjects. The mean values of carbon dioxide pressure (PCO2) and bicarbonate were greater in the chorionic vein than in the subchorial lake, but the mean pH values were the same in the two groups. The mean values of blood gas analysis were not different between subchorial and marginal lakes with similar blood composition. The mean PO2 of the uterine vein in ten subjects was 45.9 mmHg, significantly higher than that of the subchorial lake. CONCLUSIONS: The human placenta may be defined as a multivillous model with a high degree of oxygen transfer. Arteriovenous anastomoses are suspected in the pregnant uterus beyond 37 weeks' gestation. Subchorial and marginal lakes contain similar admixed blood, which circulates and performs gas exchange.

Novel potassium channel activators: synthesis and structure-activity relationship studies of 3,4-dihydro-2H-1,4-benzoxazine derivatives.

Strong potassium channel-activating effects were found among a series of novel 4-substituted 3,4-dihydro-2H-1,4-benzoxazine derivatives. The key step in preparation was the nucleophilic substitution of 3,4-dihydro-2H-1,4-benzoxazine (3) with activated halogenopyridines, such as halogenopyridine N-oxides (15a--c) and the borane adduct (15d) of 4-bromopyridine. Structure-activity relationship studies identified 2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl)pyridin e-1-oxide (16a: YM934) as the optimal compound. This compound (16a) showed a more potent oral antihypertensive effect than cromakalim in conscious spontaneously hypertensive rats.

[Discovery and development of tamsulosin hydrochloride, a new alpha 1-adrenoceptor antagonist].

Benign prostatic hyperplasia (BPH) is an age-related disorder characterized by urinary outlet obstruction. This obstruction is due to both mechanical compression of the urethra by the hypertrophied prostate and to functional contraction of the prostate and urethra by sympathetic stimulation. We invented a novel compound tamsulosin hydrochloride, a sulphamoylphenethylamine derivative which possesses potent and selective alpha a-antagonism, and showed that this compound selectively reduced the intra-urethral pressure in the prostatic segment of the urethra in vivo. We also found that the alpha 1-adrenoceptor plays an important functional role in the prostate and urethra. For clinical use, a control release formulation was developed. This formulation did not induce orthostatic hypotension and could be administered at a fixed dose. A placebo-controlled double-blind dose finding study resulted in 0.2 mg/d as the optimal dose. This formulation significantly improved urinary outlet obstruction without affecting blood pressure as compared with placebo in P-III study, and was approved in 1993 for use in the treatment of bladder outlet obstruction associated with BPH. Tamsulosin hydrochloride is the first alpha 1-antagonist which improves bladder outlet obstruction associated with BPH without affecting blood pressure, and the treatment can be initiated and maintained at a fixed dose. Recently, the alpha 1-adrenoceptor subtypes alpha 1A, alpha 1B and alpha 1C were identified. The alpha 1C subtype is predominant and plays an important role in the human prostate. Tamsulosin hydrochloride shows high selectivity for this subtype, further supporting the clinical findings that tamsulosin hydrochloride improves bladder outlet obstruction associated with BPH with no effect on the cardiovascular system.