Biomedical subjects

M Yoshida

Publications and source records attributed to M Yoshida.

At least 991 records · Page 55Linked to original sources

PubMed1997

Effects of exposure to microwaves on cellular immunity and placental steroids in pregnant rats.

OBJECTIVES: Microwaves produce various detrimental changes based on actions of heat or non-specific stress, although the effects of microwaves on pregnant organisms has not been uniform. This study was designed to clarify the effect of exposure to microwaves during pregnancy on endocrine and immune functions. METHODS: Natural killer cell activity and natural killer cell subsets in the spleen were measured, as well as some endocrine indicators in blood--corticosterone and adrenocorticotrophic hormone (ACTH) as indices of the hypothalamic-pituitary-adrenal axis--beta-endorphin, oestradiol, and progesterone in six female virgin rats and six pregnant rats (nine to 11 days gestation) exposed to microwaves at 10 mW/cm2 incident power density at 2450 MHz for 90 minutes. The same measurements were performed in control rats (six virgin and six pregnant rats). RESULTS: Skin temperature in virgin and pregnant rats increased immediately after exposure to microwaves. Although splenic activity of natural killer cells and any of the subset populations identified by the monoclonal antibodies CD16 and CD57 did not differ in virgin rats with or without exposure to microwaves, pregnant rats exposed to microwaves showed a significant reduction of splenic activity of natural killer cells and CD16+CD57-. Although corticosterone and ACTH increased, and oestradiol decreased in exposed virgin and pregnant rats, microwaves produced significant increases in beta-endorphin and progesterone only in pregnant rats. CONCLUSIONS: Microwaves at the power of 10 mW/cm2 produced activation of the hypothalamic-pituitary-adrenal axis and increased oestradiol in both virgin and pregnant rats, suggesting that microwaves greatly stress pregnant organisms. These findings in pregnant rats suggest that--with exposure to microwaves--pregnancy induces immunosuppression, which could result in successful maintainance of pregnancy. This enhancement of adaptability to heat stress with pregnancy may be mediated by activation of placental progesterone and placental or pituitary beta-endorphin.

Adrenocorticotropic Hormone↗

PubMed1997

Prognostic significance of plasma D-dimer levels in patients with lung cancer.

BACKGROUND: The peripheral blood concentrations of several proteases of the clotting system have been shown to predict survival in patients with malignancy. A study was undertaken to investigate the independent value of the plasma levels of the D-dimer degradation product of fibrin before treatment for predicting prognosis in patients with lung cancer. METHODS: The study comprised 70 patients with lung cancer (49 non-small cell lung cancer and 21 small cell lung cancer). Plasma levels of D-dimer were measured using an enzyme immunoassay kit. Multivariate statistical analysis was carried out using the Cox's proportional hazards model. RESULTS: The median value of the plasma level of D-dimer differentiated two groups of patients with different outcomes: a group with a D-dimer level of < 150 ng/ml (low DD group) and those with D-dimer levels of > or = 150 ng/ml (high DD group). Survival time was significantly better in patients in the low DD group than in those in the high DD group in all patients (hazard ratio for high DD group = 4.7; 95% confidence interval (CI) 1.8 to 11.7). The plasma levels of D-dimer predicted survival independently from the clinical stage of disease, histological type, performance status, and tumour size (hazard ratio = 3.9; 95% CI 1.6 to 9.2). CONCLUSIONS: These results suggest that plasma levels of D-dimer might be useful for predicting the clinical outcome in patients with lung cancer. However, further prospective studies are needed in a larger population to confirm these findings.

Adult↗

PubMed1997

Sympathetic denervation of myocardium demonstrated by 123I-MIBG scintigraphy in pure progressive autonomic failure.

123I-MIBG myocardial scintigrams obtained in 2 cases with pure progressive autonomic failure are presented. In the less advanced case, 123I-MIBG myocardial SPECT disclosed uptake defects of radioisotopes in both the apical region and the inferior wall and a marked decrease in uptake in the lateral wall. However, residual radioactivity was demonstrated in the anterior wall. In the terminal stage, radioactivity over the whole heart was undetectable in planar images, so as to be of no use to obtain SPECT images. These scintigrams might suggest where the sympathetic denervation began and subsequently extended to the whole myocardium in the course of the disease. In addition, 123I-MIBG scintigraphy was recommended in a case with the disease, since an unequal impairment of myocardial sympathetic nervous system has been described to probably induce fatal arrhythmias which were the cause of sudden death in this case.

3-Iodobenzylguanidine↗

PubMed1997

Combined inhalation of nitric oxide and oxygen in chronic obstructive pulmonary disease.

Inhaled nitric oxide (NO) has been shown to reduce the mean pulmonary artery pressure (mPAP) and to improve PaO2 in patients with acute respiratory failure undergoing oxygen (O2) therapy. However, inhaled NO reduced pulmonary hypertension without improving PaO2 in patients with chronic obstructive pulmonary disease (COPD). This study was intended to compare the hemodynamic and gas exchange responses during inhalation of NO or O2 with those observed during the combined inhalation of NO and O2 in 10 spontaneously breathing COPD patients. Hemodynamic and blood gas parameters were measured after breathing: (1) room air; (2) NO added to room air; (3) O2 (1 L/min); or (4) NO and O2. During inhalation of 2 ppm NO added to room air, the mPAP (23.1 +/- 2.5 versus 20.6 +/- 2.2 mm Hg) and the pulmonary vascular resistance (PVR) (434 +/- 70 versus 378 +/- 50 dyne s/cm5) were significantly (p < 0.05) lower than those measured with room air. However, the values of PaO2 did not improve. The combined inhalation of NO and O2 was associated not only with a significant (p < 0.05) decrease of mPAP (21.4 +/- 2.3 versus 19.7 +/- 1.8 mm Hg) and PVR (431 +/- 72 versus 370 +/- 44 dyne s/cm5), but also with a remarkable improvement (p < 0.05) in the values of PaO2 (91.4 +/- 6.6 versus 111.5 +/- 7.8 mm Hg) as compared with values obtained during the inhalation of O2 alone. These findings suggest that combined therapy with NO and O2 may constitute an alternative approach to treating patients with COPD and pulmonary hypertension.

Administration, Inhalation↗

PubMed1997

The effect of low-dose inhalation of nitric oxide in patients with pulmonary fibrosis.

The aim of this study was to determine whether low-dose inhalation of nitric oxide (NO) improves pulmonary haemodynamics and gas exchange in patients with stable idiopathic pulmonary fibrosis (IPF). The investigation included 10 IPF patients breathing spontaneously. Haemodynamic and blood gas parameters were measured under the following conditions: 1) breathing room air; 2) during inhalation of 2 parts per million (ppm) NO with room air; 3) whilst breathing O2 alone (1 L.min-1); and 4) during combined inhalation of 2 ppm NO and O2 (1 L.min-1). During inhalation of 2 ppm NO with room air the mean pulmonary arterial pressure (Ppa 25 +/- 3 vs 30 +/- 4 mmHg) and the pulmonary vascular resistance (PVR 529 +/- 80 vs 699 +/- 110 dyn.s.cm-5) were significantly (p < 0.01) lower than levels measured whilst breathing room air alone. However the arterial oxygen tension (Pa,O2) did not improve. The combined inhalation of NO and O2 produced not only a significant (p < 0.01) decrease of Ppa (23 +/- 2 vs 28 +/- 3 mmHg) but also, a remarkable improvement (p < 0.05) in Pa,O2 (14.2 +/- 1.2 vs 11.7 +/- 1.0 kPa) (107 +/- 9 vs 88 +/- 7 mmHg)) as compared with the values observed during the inhalation of O2 alone. These findings suggest that the combined use of nitric oxide and oxygen might constitute an alternative therapeutic approach for treating idiopathic pulmonary fibrosis patients with pulmonary hypertension. However, further studies must first be carried out to demonstrate the beneficial effect of oxygen therapy on pulmonary haemodynamics and prognosis in patients with idiopathic pulmonary fibrosis and to rule out the potential toxicity of inhaled nitric oxide, particularly when used in combination with oxygen.

Administration, Inhalation↗

PubMed1997

Arterial endothelin-1 level in pulmonary emphysema and interstitial lung disease. Relation with pulmonary hypertension during exercise.

This study was undertaken to assess the arterial plasma levels of endothelin-1 (ET-1) and their relationship with pulmonary haemodynamic and gas exchange variables during exercise in patients with emphysema and interstitial lung disease (ILD). Incremental cycle ergometry was performed in all patients up to maximal capacity. At rest, arterial ET-1 levels were higher in emphysema (1.86 +/- 0.35 pg.mL-1; p < 0.02) and ILD (1.75 +/- 0.25 pg.mL-1; p < 0.03) patients than in controls (1.35 +/- 0.18 pg.mL-1). Emphysema (2.08 +/- 0.26 versus 1.70 +/- 0.40 pg.mL-1) and ILD (1.98 +/- 0.21 versus 1.67 +/- 0.02 pg.mL-1) patients with pulmonary hypertension (PH) presented significantly (p < 0.05) higher arterial ET-1 levels than those without. At rest, arterial ET-1 levels were significantly correlated with mean pulmonary arterial pressure (Ppa) in both ILD (r = 0.8, p = 0.01) and emphysema (r = 0.5, p = 0.03) patients. During exercise, the arterial ET-1 levels were significantly correlated with arterial oxygen (Pa,O2) (r = -0.6, p = 0.04), alveolar-arterial oxygen difference (r = 0.8, p = 0.01), and Ppa (r = 0.6, p = 0.04) in ILD patients, but not in those with emphysema. In brief, the results of this study suggest that arterial endothelin-1 is markedly increased in interstitial lung disease and emphysema patients, and that, it is related to the exercise-induced exacerbation of pulmonary hypertension in patients with interstitial lung disease, but not in those with emphysema.

Aged↗

PubMed1997

Emx1 and Emx2 functions in development of dorsal telencephalon.

The genes Emx1 and Emx2 are mouse cognates of a Drosophila head gap gene, empty spiracles, and their expression patterns have suggested their involvement in regional patterning of the forebrain. To define their functions we introduced mutations into these loci. The newborn Emx2 mutants displayed defects in archipallium structures that are believed to play essential roles in learning, memory and behavior: the dentate gyrus was missing, and the hippocampus and medial limbic cortex were greatly reduced in size. In contrast, defects were subtle in adult Emx1 mutant brain. In the early developing Emx2 mutant forebrain, the evagination of cerebral hemispheres was reduced and the roof between the hemispheres was expanded, suggesting the lateral shift of its boundary. Defects were not apparent, however, in the region where Emx1 expression overlaps that of Emx2, nor was any defect found in the early embryonic forebrain caused by mutation of the Emx1 gene, of which expression principally occurs within the Emx2-positive region. Emx2 most likely delineates the palliochoroidal boundary in the absence of Emx1 expression during early dorsal forebrain patterning. In the more lateral region of telencephalon, Emx2-deficiency may be compensated for by Emx1 and vice versa. Phenotypes of newborn brains also suggest that these genes function in neurogenesis corresponding to their later expressions.

Animals↗

PubMed1997

Defects of urogenital development in mice lacking Emx2.

The homeobox gene Emx2 is a mouse homologue of a Drosophila head gap gene empty spiracles (ems) and is essential for the development of dorsal telencephalon (Yoshida, M., Suda, Y., Matsuo, I., Miyamoto, N., Takeda, N., Kuratani, S. and Aizawa, S. (1997) Development 124, 101-111). At the same time, Emx2 is expressed in the epithelial components of the developing urogenital system and, in Emx2 mutant mice, the kidneys, ureters, gonads and genital tracts were completely missing. Pax-2 and c-ret expressions in the Wolffian duct and WT-1 and GDNF expressions in the metanephric blastema were initially normal in the mutant. The ureteric bud grew and invaded the metanephric mesenchyme where Pax-2 expression was normally induced. Subsequently, however, Pax-2, c-ret and Lim1 expressions in the ureteric bud and GDNF expression in the mesenchyme were greatly reduced. Wnt-4 expression was never found in the mesenchyme. The tip of the ureteric bud never dilated and branching of the bud did not occur. Neither pretubular cell aggregates nor epithelialization were found in the mesenchyme. Instead the ureteric bud soon degenerated and apoptotic figures were prominent in mesenchymal cells. In explant culture, the mutant ureteric bud did not induce the epithelial transformation of the wild-type mesenchyme, and branching of the mutant ureteric bud was not induced by wild-type mesenchyme. In contrast, defects were not apparent in the mutant mesenchyme by co-culture with wild-type ureteric bud or spinal cord. These results suggest that, in metanephrogenesis, Emx2 is essential for the ureteric bud functions subsequent to Pax-2 induction in the metanephric mesenchyme. Degeneration of the Wolffian duct and mesonephric tubules was also abnormally accelerated without the formation of the Mullerian duct.

Animals↗

PubMed1997

Tableting of coated particles. I. Small particle size chitosan as an agent protecting coating membrane from mechanical damage of compression force.

Formulation of sustained release tablets containing coated particles whose coating membrane is not damaged during compression was studied and several kinds of chitosan of different particle size were evaluated as protective agents for the membrane. Comparison was made with the dissolution rate of the coated particles. Ethylcellulose or ethylcellulose/hydroxypropylcellulose was chosen as a coating agent. When the coated particles were compressed with the small particle size chitosan (Marine Chito), the coating membrane was not ruptured, and the protective effect was not influenced by the compression pressure. Both the Eudragit RS-coated particles and the tablets manufactured by compressing the coated particles with Marine Chito were orally administered to dogs, and the plasma theophylline levels of the two dosage forms were compared to determine the drug release characteristics in the gastrointestinal tract. It was found that the plasma concentration-time curve of the tablets coincided with that of the coated particles, and the compressed tablet would disintegrate instantly and redisperse into many particles in the body after oral administration.

Animals↗

PubMed1997

Incidence of ischemic strokes in hypertrophic cardiomyopathy is markedly increased if complicated by atrial fibrillation.

The clinical outcome and the incidence of ischemic strokes in patients with hypertrophic cardiomyopathy (HCM) with and without atrial fibrillation (AF) were examined. Eighty-three patients with HCM, complicated by AF in 19 patients, and 131 patients with AF but without HCM were studied retrospectively. Primary endpoints (ischemic strokes or cardiac death, whichever occurred first) and ischemic strokes were examined by Kaplan-Meier curves. In the patients with HCM, the primary endpoints occurred more frequently in those with AF than in those without AF (event rate at 5 year 23.0% vs 12.3%, p < 0.01). Similarly, the frequency of ischemic strokes in HCM was also much higher with AF than without AF (23.0% vs 5.9% at 5 years, p < 0.01). According to multivariate Cox analysis, the strong independent risk factor for ischemic strokes in HCM was AF (p < 0.01), whereas in patients with AF they were HCM (p < 0.01) and age (p < 0.01). These results suggest that incidence of ischemic strokes in HCM is markedly increased if complicated by AF as compared with that in patients with AF alone.

Adult↗

PubMed1997

Effects of a novel potent aldose reductase inhibitor, GP-1447, on aldose reductase activity in vitro and on diabetic neuropathy and cataract formation in rats.

GP-1447 {3-[(4,5,7-trifluorobenzothiazol-2-yl) methyl]-5-methylphenylacetic acid}, a novel aldose reductase (AR) inhibitor, exhibited highly potent and specific inhibition of AR activity from human placenta, human muscle, porcine and rat lens with IC50 values ranging from 3 to 10 nM. Lineweaver-Burk plots revealed non-competitive inhibition between DL-glyceraldehyde or beta-NADPH and inhibition of AR by GP-1447. In contrast to epalrestat, AR activity inhibited by GP-1447 did not recover after dialysis for 24 hr. Administration of GP-1447 to streptozotocin (STZ)-induced diabetic rats for 5 days beginning 1 week after STZ injection effectively inhibited the accumulation of sorbitol in the sciatic nerve, lens and retina with ED50 values of 0.25, 1.6 and 2.9 mg/kg/day, respectively. The motor nerve conduction velocity (MCV) in STZ-induced diabetic rats was significantly decreased 4 weeks after the induction of diabetes. Treatment with GP-1447 for the following 2 weeks dose-dependently restored the decreased MCV with an ED50 value of 0.28 mg/kg/day. Administration of GP-1447 (3 and 15 mg/kg/day for 12 weeks beginning 3 days after STZ injection) completely prevented cataract formation and was accompanied by marked inhibition of sorbitol accumulation in the lens. Furthermore, partial reversibility of cataract formation and morphological changes of the lens was observed in diabetic rats treated with 15 mg/kg/day of GP-1447 for 5 weeks beginning 8 weeks after the induction of diabetes. From these results, GP-1447 would be expected to exert potent ameliorating effects on some diabetic complications. Potent inhibition of cataract formation will be one of the characteristics of this compound.

Aldehyde Reductase↗

PubMed1997

Isolation of virulent Rhodococcus equi from transtracheal aspirates of foals serodiagnosed by enzyme-linked immunosorbent assay.

Although isolation of Rhodococcus equi from tracheobronchial aspirates is thought to be a definitive diagnosis of R. equi pneumonia in foals, virulence of isolates from the aspirates of infected foals remains obscure. In the present study, transtracheal aspirates were collected from thirty-one 1- to 6-month-old foals, which showed clinical signs of respiratory tract infection, and R. equi isolates were analyzed for the presence of virulence plasmids and virulence-associated antigens. Moreover, this method was compared with a serodiagnosis by an enzyme-linked immunosorbent assay (ELISA) to evaluate the sensitivity of the ELISA. Of the 31 foals, 21 revealed positive cultures for R. equi. Of the 21 foals, 20 (95%) had an ELISA OD value of 0.3 (positive limit of this test) or higher at the initial medical examination. All of the isolates from the aspirates were virulent R. equi, which contained virulence plasmids and expressed virulence-associated antigens. In the remaining 10 foals showing a negative culture for R. equi, 3 foals had positive ELISA titers. Six foals died during the treatment, and necropsy revealed that 5 of the 6 foals had R. equi infection characterized by large abscesses in the lungs, and 3 of the 5 foals also had intestinal lesions. All clinical isolates from the lesions of the foals were virulent R. equi. These results support the assumption that isolates from the transtracheal aspirates of infected foals are virulent R. equi and the sensitivity of ELISA might demonstrate a serodiagnostic value for early diagnosis of R. equi infection in foals.

Actinomycetales Infections↗

PubMed1997

Immunologic protection against canine heartworm infection.

This study was conducted to evaluate protective efficiency of three different protocols for vaccination in canine heartworm infection. To evaluate the three protocols of immunization, dogs were separately immunized with living larvae; 1) immunization with gamma-attenuated infective larvae, 2) with 50 micrograms/kg ivermectin-abbreviation, and 3) with chemical abbreviation plus Freund's complete adjuvant (FCA). Each group was composed of two dogs. All dogs used for this study were subcutaneously challenged with 100 intact third-stage larvae (L3) various days after the last immunization, and the worms in the pulmonary arteries and the right ventricle of the heart were recovered 17 to 25 weeks post-infection. The numbers and the sexes of the worms were determined. A mean of 38 worms was burdened in the group immunized with irradiated L3, 36 worms in the chemically-abbreviated group, but 15.5 worms in the group with chemical abbreviation plus FCA. The percentages of the protection in the former two groups were nearly 50%, but 72.3% in the group with ivermectin plus FCA. The adjuvant enhanced the protective immunity against L3 challenge. Obvious eosinophilia was observed in both immunized and control dogs except for two dogs. There was no correlation between the suppression of eosinophilia and the protective immunity in the present study.

Animals↗

PubMed1997

Characteristics of nucleotide sequences flanking the trans-spliced leader SL1 exon in Dirofilaria immitis, Brugia malayi, and Brugia pahangi.

Nucleotide sequences surrounding the trans-spliced leader SL1 exon in the 5S rRNA gene spacer regions of Dirofilaria immitis, Brugia malayi, and B. pahangi were determined after PCR amplification, aligned with the genus Onchocerca for comparison, and used for the prediction of secondary structures. The nucleotide sequence of this region in B. pahangi was first shown in the present study. Hypothetical secondary structures of the spacer region suggested that the SL1 transcript is capable to form a stable stem-loop structure which may render transposition of the SL1 sequence to mRNA molecules. A homologous sequence to Sm-binding site was assigned on a bulge loop. No significant difference was observed in adult worms of D. immitis irrespective of sex or location. No difference was apparent between the two species in genus Brugia.

Animals↗

PubMed1997

Acute mercury poisoning by intentional ingestion of mercuric chloride.

A 26-year-old woman ingested 0.9 g of mercuric chloride in a suicide attempt and developed hematemesis, melena and acute renal failure. Anuria persisted for 14 days. She was treated by plasma exchange, hemodialysis and peritoneal dialysis in combination with continued dimercaprol chelation. While hemodialysis was ineffective in removing the mercury, plasma exchange effectively eliminated mercury. After two plasma exchange therapies, mercury concentration in the blood decreased linearly on a log scale with half-lives of 23.1 days for whole blood and 19.1 days for plasma, using first-order kinetics. One month after ingestion, renal function recovered to normal as judged by serum creatine and blood urea nitrogen levels, although the beta 2-microglobulin level in urine was still elevated. At a follow-up examination four months later, renal function was found to be completely normal. This indicates that the renal damage caused by acute mercuric chloride poisoning may not be permanent.

Adult↗

PubMed1997

Drinking habit as a base for blood pressure elevation--difference in epidemiological significance by beverage type.

To investigate whether blood pressure differs by taking preferred alcoholic beverage among habitual drinkers, systolic and diastolic blood pressure (SBP, DBP) were compared among groups with different beverage types in 563 middle-aged Japanese males using data from a cross-sectional health survey conducted from February, 1989 through March, 1991 in five areas of Japan. Mean values of SBP and DBP, adjusted for residence, age and body mass index (BMI), were significantly greater in 'exclusively sake' drinkers (adjusted SBP: 127.2 mmHg, adjusted DBP: 83.0 mmHg) and in 'exclusively shochu' drinkers (adjusted SBP: 127.5 mmHg, adjusted DBP: 84.2 mmHg) than in non-drinkers (adjusted SBP: 120.9 mmHg, adjusted DBP: 77.3 mmHg). Adjusted SBP and DBP of 'exclusively beer' drinkers (adjusted SBP: 121.9 mmHg, adjusted DBP: 79.1 mmHg) were significantly (for SBP: p = 0.016, for DBP: p = 0.008) lower than those of 'exclusively sake' drinkers. Similar patterns of blood pressure differences between five beverage types of habitual drinkers were found especially in the group with less than 150 g of weekly ethyl-alcohol consumption. Even after adding ethyl-alcohol consumption as a covariate among 479 habitual drinkers, the significant differences in adjusted SBP and DBP between 'exclusively beer' drinkers and 'exclusively sake' drinkers (for SBP: p = 0.032, for DBP: p = 0.044) were noted. These results may suggest that the effects of drinking on blood pressure differ by beverage type in middle-aged Japanese males.

Adult↗

PubMed1997

Current status of conducting function tests in repeated dose toxicity studies in Japan.

It seems desirable to conduct as many function tests as possible in repeated dose toxicity studies, but is it practicable? The current status of conducting function tests in repeated dose toxicity studies in Japan was investigated by a literature survey of more than one thousand papers published in seven Japanese toxicology journals during the past 10 years and by a questionnaire survey directed to toxicologists among the Japan Pharmaceutical Manufacturers Association (JPMA) member companies. The function tests often carried out in repeated dose toxicity studies were, for example: 1) electro-retinography (ERG) and visually evoked potential (VEP) for visual test and tonometer for intraocular pressure; 2) auricular reflex, evoked response audiometry (ERA) and auditory brainstem response (ABR) to sound stimuli; 3) respiration and heart rate, electrocardiogram (ECG) and blood pressure by noninvasive cuff methods or using electronic devices such as telemetry; 4) body temperature, spontaneous motility and some adaptation tests (using rotarod and sloped plate in rats); 5) indocyanin (ICG) or bromosulfophtalein (BSP) for hepatic test; 6) phenolsulfonphtalein (PSP) and creatinine clearance for renal test; and 7) immunoglobulin, leukocyte phagocytosis, lymphocyte blastgenesis and natural killer cell (NK) for immuno-reaction test. Limitations to conducting function tests in repeated dose toxicity studies and issues to be resolved were discussed, based on questions and suggestions given by the respondents to the questionnaire. Although it certainly seemed desirable to conduct as many function tests as possible in repeated dose toxicity studies, most of the function tests so far introduced into toxicity studies were not satisfactory, because those tests could not be carried out under the restricted conditions of repeated dose toxicity studies, and not much reliable data from function tests were obtainable. A variety of function tests should firstly be incorporated into single dose toxicity studies together with development of a new concept for methodology in safety pharmacology.

Animals↗

PubMed1997

[Single-dose toxicity studies of (+/-)-4-diethylamino-1, 1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate(NS-21), a novel drug for urinary frequency and incontinence, in mice, rats and dogs].

Comparative single-dose toxicity studies of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate(NS-21), a new drug for the treatment of urinary frequency and incontinence, were conducted in ddY mice and Sprague-Dawley rats after oral(p.o.),intraperitoneal(i.p.) and subcutaneous(s.c.) administration, and in Beagle dogs after p.o. administration. The p.o. LD50 values of NS-21 were 852 and 1167 mg/kg for male and female mice, 2839 and 1739 mg/kg for male and female rats, respectively. The i.p. LD50 values were 324 and 390 mg/kg for male and female mice, and 423 and 359 mg/kg for male and female rats, respectively. No death occurred in mice and rats at doses up to s.c. 5000 mg/kg. Minimum lethal dose for dogs could not be determined because of vomiting. Mydriasis was noted in all three species tested without regard to administration route. In addition, decreased spontaneous locomotor activity, prone or lateral position, hypopnea, hypothemia, ataxic gait, twitch and clonic convulsion were observed in mice and rats after p.o. and i.p. administration. In rats, salivation was observed after p.o. administration and lacrimation was observed after p.o. and i.p. administration. After s.c. administration, scab formation at the site of injection was observed in mice and rats. In dogs, vomiting, hyperemia of both conjunctiva and oral mucosa, prone position, tremor and clonic convulsion were observed after p.o. administration. Body weight was decreased or its gain was suppressed in mice and rats without regard to administration route. Body weight and food consumption were decreased in dogs after p.o. administration. Pathological examination showed congestion of lung in dead mice and rats after p.o. and i.p. administration. Distention of small intestine was observed in dead mice and rats after p.o. administration and in sacrificed rats after p.o. administration. Adhesion between the abdominal organs was observed in sacrificed mice and rats after i.p. administration. Thymic atrophy associated with a decrease in its organ weight was observed in dogs after p.o. administration.

Animals↗