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Biomedical subjects

M Yoshida

Publications and source records attributed to M Yoshida.

At least 1,009 records · Page 56Linked to original sources
PubMed1997

[A 13-week oral repeated dose toxicity study 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 dogs followed by a 5-week recovery test].

A 13-week oral repeated dose toxicity study 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, was conducted in beagle dogs. Male and female dogs were given the drug orally for 13 weeks at doses of 0 (control), 5, 25 and 125 mg/kg. After discontinuation of the treatment, a 5-week recovery test was also conducted. No effects related to the treatment were observed on survival. Mydriasis and a decrease in body weight or a suppression of its weight gain were seen in the 25 and 125 mg/kg groups. Vomiting, salivation and a decrease in food consumption were seen in the 125 mg/kg group. Ophthalmologic examination confirmed the mydriasis in the 125 mg/kg group. Electrocardiographic examination and urinalysis showed no abnormalities attributable to the treatment. Hematological examination showed an increase in number of platelets in the 125 mg/kg group. Blood chemical examination revealed increases in GPT and ALP and a decrease in albumin in the 25 and 125 mg/kg groups, and an increase in triglyceride in the 125 mg/kg group. Pathological examination disclosed hepatocellular hypertrophy in the 125 mg/kg group, hyperplasia of smooth-ER and concentric lamellar bodies derived from the smooth-ER, and bile pigments in the bile capillary, hepatocyte and stellate cells of Kupffer in the 25 and 125 mg/kg groups. Megakaryocytes in mesenteric lymph node were observed in the 25 and 125 mg/kg groups. The recovery test showed that the above-mentioned changes were satisfactorily reversible or the degree and frequency of these changes were lowered. No treatment-related effects were seen in the 5 mg/kg group. These results show that the NOAEL (no observed adverse effect level) of NS-21 is 5 mg/kg for 13-week oral toxicity in dogs.

Administration, Oral↗
PubMed1997

[A 12-month oral repeated dose toxicity study 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 dogs followed by a 2-month recovery test].

A 12-month oral repeated dose toxicity study 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, was conducted in beagle dogs. Male and female dogs were given the drug orally for 12 months at doses of 0 (control), 3, 17.5 and 100 mg/kg. After discontinuation of the treatment, a 2-month recovery test was also conducted. No effects related to the treatment were observed on survival and water consumption. Mydriasis, vomiting and a decrease in body weight or a suppression of its weight gain were seen in the 17.5 and 100 mg/kg groups. Salivation and a decrease in food consumption were seen in the 100 mg/kg group. Ophthalmologic examination confirmed the mydriasis in the 17.5 and 100 mg/kg groups. Electrocardiographic and hematological examinations and urinalysis showed no abnormalities attributable to the treatment. Blood chemical examination revealed increases in GPT and ALP in the 17.5 and 100 mg/kg groups, increases in GOT and triglyceride and a decrease in total protein in the 100 mg/kg group. Pathological examination disclosed hepatocellular hypertrophy and concentric lamellar bodies derived from the smooth-ER in the 100 mg/kg group, and hyperplasia of smooth-ER, an increase in number of lysosomes and bile pigments in the bile capillary, hepatocyte and stellate cells of Kupffer in the 17.5 and 100 mg/kg groups. The recovery test showed that the above-mentioned changes were satisfactorily reversible or the degree and frequency of these changes were lowered. The serum concentrations of NS-21 and its active metabolite. RCC-36, in the treated groups were increased in a dose-dependent manner. No treatment-related effects were seen in the 3 mg/kg group. These results show that the NOAEL (no observed adverse effect level) of NS-21 is 3 mg/kg for 12-month oral toxicity in dogs.

Administration, Oral↗
PubMed1997

[Toxicokinetics 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 and rats during 13-week dietary administration].

Toxicokinetics 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 studied in mice and rats during a 13-week dietary administration to determine the toxicokinetic profiles of NS-21 and its active metabolite (+/-)-4-ethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride (RCC-36) in dietary carcinogenicity studies. Male and female mice were given the drug in the diet at doses of 0(control), 30, 100 and 300 mg/kg/day, and male and female rats were given the drug at doses of 0(control), 10, 30 and 100 mg/kg/day. The chosen doses and means of administration were identical to those of a 78-week dietary carcinogenicity study in mice and 2-year dietary carcinogenicity study in rats. The plasma concentrations were measured on the first and the last day of the administration. For every treatment period, the plasma concentrations of NS-21 and RCC-36 increased with dose in mice and rats. The sum of the area under the concentration-time curve(AUC) of NS-21 and RCC-36 was 2694 to 8614 ng.hr/ml in the maximum dose of mice, and 2232 to 3593 ng.hr/ml in the maximum dose of rats through the administration period. These results show that, when compared with therapeutic dose in humans(682 ng.hr/ml at 10 mg/body/day), the total maximal exposure to NS-21 and RCC-36 in the earlier dietary carcinogenicity studies were estimated to be 4 to 13 times higher in mice, and 3 to 5 times higher in rats.

Administration, Oral↗
PubMed1997

[The mechanism of increased thyroidal function caused by (+/-)-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, administration in rats].

A study was conducted to elucidate the mechanism of the increased thyroidal function caused by oral administration 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, in rats. Rats were given 500 mg/kg of NS-21 orally for 13 weeks. Rats were also given 500 mg/kg of the drug and 15 micrograms/animal of thyroxine (T4) in order to assess the influence of T4 treatment. NS-21 caused decreases in both total and free T4 and increases in TSH and thyroxine uridine diphosphate glucuronyltransferase (T4UDP-GT). Morphological examination of thyroid gland revealed stimulated follicles indicating heightened thyroidal function. The treatment of T4 inhibited the stimulating effect of NS-21 on thyroid gland. These results show that the administration of NS-21 caused induction of T4UDP-GT, which resulted in a compensatory stimulation of the thyroidal function by the increased secretion of pituitary TSH in response to increased blood thyroid hormone metabolism.

Animals↗
PubMed1997

[A 13-week oral repeated dose toxicity study 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 rats followed by a 5-week recovery test].

A 13-week oral repeated dose toxicity study 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, was conducted in Sprague-Dawley rats. Male and female rats were given the drug orally for 13 weeks at doses of 0 (control), 6, 30, 150 and 750 mg/kg. After discontinuation of the treatment, a 5-week recovery test was also conducted at doses of 0, 30, 150 and 750 mg/kg. Nine cases of death occurred in the 750 mg/kg group. Main pathological findings in these cases were congestion and edema in lung. Mydriasis, salivation, lacrimation and a decrease in body weight or a suppression of its weight gain were seen in the 30 mg/kg group and over. Piloerection and an increase in water consumption were seen in the 150 and 750 mg/kg groups. In addition, a decrease in spontaneous locomotor activity, abdominal distention, unkempt fur, soft stool, diarrhea and decreases in feces and food consumption were seen in the 750 mg/kg group. Ophthalmologic examination confirmed mydriasis and lacrimation in the 30 mg/kg group and over. Urinalysis showed decreases in Na+ and K+ excretions in the 30 mg/kg group and over, an increase in urinary protein in the 150 and 750 mg/kg groups, and a decrease in urine volume in the 750 mg/kg group. Hematological examination showed decreases in hemoglobin and hematocrit in the 150 and 750 mg/kg groups, and a decrease in lymphocytes in the 750 mg/kg group. Blood chemical examination showed an increase in total protein in the 30 mg/kg group and over, a decrease in triglyceride in the 150 and 750 mg/kg groups, and an increase in BUN in the 750 mg/kg group. Pathological examination disclosed hepatocellular hypertrophy caused by hyperplasia of smooth-ER in the 30 mg/kg group and over, and a decrease in number of glycogen granules in the 150 and 750 mg/kg groups. Stimulated thyroid follicles were seen in the 30 mg/kg group and over. Increases in incidence and severity of chronic progressive nephropathy were observed in the 150 and 750 mg/kg groups. Ultrastructual features of the renal lesions were swelling and foot process loss of the glomerular epithelial cells, absorption droplets in the glomerular epithelial cells, increase of lysosomes in the proximal tubular cells and hyaline casts in the tubular lumen. Adrenocortical hypertrophy was seen in the 150 and 750 mg/kg groups. In the 750 mg/kg group, a decrease of hematopoietic tissue in bone marrow and thymic and testicular tubular atrophy were observed. The recovery test showed that the above-mentioned changes were satisfactorily reversible or the degree and frequency of these changes were lowered. No treatment-related effects were seen in the 6 mg/kg group. These results show that the NOAEL (no observed adverse effect level) of NS-21 is 6 mg/kg for 13-week oral toxicity in rats.

Administration, Oral↗
PubMed1997

Circulating intercellular adhesion molecule-1 in patients with lung cancer.

Recently, abnormal expression of a great variety of adhesion molecules has been reported in malignancy. Of these adhesion molecules, intercellular adhesion molecule-1 (ICAM-1) has been suggested to play an important role in the process of tumor invasion and distant metastasis. The purpose of this investigation was to assess the peripheral blood levels of soluble ICAM-1 and the effect of cytotoxic therapy upon these circulating molecules in a cohort of patients with lung cancer. This study comprised 19 lung cancer patients hospitalized in our institution (males 16 and females 3, mean age 60 years old). Serum concentration of soluble ICAM-1 was measured using a commercially available enzyme immunoassay test kit. These measurements were done before the initiation of any therapy and on day 5 of chemotherapy. Samples taken from healthy volunteers were available for comparison. Soluble ICAM-1 serum concentration was significantly higher (p < 0.0001) in the cancer patients as compared to that of the control group. Serum levels of ICAM-1 were more significantly (p < 0.02) elevated in patients with advanced stages of disease. This study suggests the presence of an increased expression of circulating adhesion molecules in lung cancer. The concentration of this adhesion molecule was correlated with the clinical stage of the malignant disease, but did not change significantly after multidrug cytotoxic therapy.

Adenocarcinoma↗
PubMed1997

Left ventricular hypertrophic patterns and wall motion dynamics in hypertrophic cardiomyopathy: an electron beam computed tomographic study.

To investigate the left ventricular hypertrophic patterns and wall motion dynamics in hypertrophic cardiomyopathy, 51 patients were studied using electron beam computed tomography. The subject consisted of 26 asymmetrical hypertrophy, 9 diffuse hypertrophy, 14 apical hypertrophy and 2 papillary muscle hypertrophy. Concerning the wall motion dynamics in hypertrophic wall, 7 demonstrated homogeneous wall thickening involving the non-hypertrophic wall, 36 showed decrease wall thickening, 6 showed normal wall thickening, and 2 cases of papillary muscle hypertrophy had increased wall thickening in the apical wall. The percent wall thickening in hypertrophic wall was significantly reduced in relation to the increase of wall thickness; 14 +/- 8% in the wall over 20 mm, 23 +/- 12% in 16-9 mm and 56 +/- 36% in 13-15 mm. The reduced wall motion dynamics in hypertrophic wall were clearly observed by electron beam computed tomography.

Adult↗
PubMed1997

Long-term continuous intravenous infusion of prostacyclin for severe primary pulmonary hypertension.

A patient suffering from severe symptomatic primary pulmonary hypertension (PPH) underwent long-term intravenous prostacyclin therapy; the first time for such treatment in Japan. A 26-year-old male had experienced gradually progressive dyspnea for about one year. Despite conventional therapy he suffered repeated syncopal attacks. However, after receiving a permanent central venous access device and a portable infusion pump, he recovered fully and was discharged. This remedy seems to be promising for PPH as has already been proven in Europe and North Americas, although in Japan it is not as yet commercially available and some problems still need to be resolved.

Adult↗
PubMed1997

[Quantitative flow cytometric determination of cytoplasmic bcl-2 oncoprotein in peripheral blood lymphocyte subsets].

We measured serial changes of cytoplasmic bcl-2 oncoprotein in peripheral blood lymphocyte subsets after preparation of cell samples or cultivation with mitogen or interleukin-2 (IL-2) by two-color flow cytometry using monoclonal antibodies to lymphocyte subsets and human bcl-2. The bcl-2 levels determined by mean fluorescence intensity were diminished in most lymphocyte subsets when the samples were preserved at 4 degrees C for 6 hours or more without 1% paraformaldehyde (PFA) fixation. However, the bcl-2 levels were kept constant for a week or more in the samples preserved at 4 degrees C after immediate staining of cell surface markers and subsequent fixation with PFA. The percentages of CD4+ cells, CD8+, CD19+ cells and Fas+ cells became high when lymphocytes were cultured with concanavalin-A, and bcl-2 levels were also enhanced in these subsets. In addition, the bcl-2 levels were compared between lymphocytes cultured with and those without recombinant IL-2. IL-2 inhibited spontaneous decrease of bcl-2 in cultured lymphocytes. Apoptosis of the cultured lymphocytes was also determined by a flow cytometric method. IL-2 seemed to diminish apoptosis of cultured lymphocytes.

Adult↗
PubMed1997

[Otoacoustic emissions evoked by electrical stimulation].

Otoacoustic emissions evoked by electrical stimulation of the cochlea were measured in guinea pigs. Alternating current with acoustic frequencies was delivered directly to the scala tympani and the vestibuli of the basal turn by using a constant current stimulator made in our laboratory. The amplitude of the electrically evoked otoacoustic emmisson (EEOAE), which was 21.0 dB SPL in response to 2 kHz electrical stimuli of 120 microArms, was decreased gradually with anoxia of the animal and was reduced to below the noise level by extirpation of the ossiculum. The EEOAEs rose with a delay of 100 microseconds from the beginning of the stimulus, and reached maximum amplitude within three cycles. The output of EEOAE was magnified in a linear manner as the stimulus current increased from 10 to 200 microArms. The averages and standard deviations of the EEOAE output at the stimulus level of 170 microArms in six animals were 20.5 +/- 4.1 dB SPL for 1 kHz, 23.3 +/- 4.8 dB SPL for 2 kHz, 10.5 +/- 6.0 dB SPL for 3 kHz, 17.1 +/- 4.7 dB SPL for 4 kHz, 13.6 +/- 4.4 dB for 5 kHz and 18.3 +/- 4.8 dB SPL for 6 kHz. Measurement of EEOAE, in which stable responses could be obtained with simple and easy preparation, was considered a potential procedure for assessing the electromotility of the cochlear outer hair cells in vivo.

Animals↗
PubMed1997

[Suppression tuning characteristics of the 2f1-f2 distortion product in cochlear microphonics and otoacoustic emissions].

Suppression of the 2f1-f2 distortion product (DP) by the third tone was measured in cochlear microphonics (CM) and otoacoustic emissions (OAEs) in guinea pigs to clarify the generation site of the DPs. The DPs were elicited by the primary tones with frequencies of 4.62 kHz (f1) and 6 kHz (f2). Five dB-iso-suppression tuning curves (STCs) of the DPs were obtained by plotting the suppressor level as a function of its frequencies. The STCs in both CM DP and DPOAE had the shape of the letter "V" with the tip centering around the frequency of f2. The slopes of the STC on the higher frequency side were steeper than those on the lower side. As the intensity of the primary tones was decreased, the turning of the STC became sharper. These suppression properties indicate that the 2f1-f2 DPs were generated in the area on the basilar membrane where the characteristic frequency corresponded to those of primary tones, especially for the primaries at lower intensities. Because the suppression properties in CM DP and DPOAE were similar to each other, we concluded that these two phenomena had a common generation site.

Acoustic Stimulation↗
PubMed1997

Lymphostin (LK6-A), a novel immunosuppressant from Streptomyces sp. KY11783: taxonomy of the producing organism, fermentation, isolation and biological activities.

In the course of screening for inhibitors of the lymphocyte kinase, Lck (p56lck), aiming at novel immunosuppressants, we isolated a novel alkaloid, lymphostin (LK6-A), from the culture broth of Streptomyces sp. KY11783. Lymphostin was produced in a fermentation medium supplemented with a highly porous polymer resin, which prevented the degradation of this compound in the culture broth. Lymphostin inhibited the kinase activity of Lck with an IC50 value of 0.05 microM, and exhibited potent inhibitory activity against the mixed lymphocyte reaction (MLR) with an IC50 value of 0.009 microM.

Chromatography, High Pressure Liquid↗
PubMed1997

Lymphostin (LK6-A), a novel immunosuppressant from Streptomyces sp. KY11783: structural elucidation.

Lymphostin (LK6-A), a novel immunosuppressant, was isolated from the culture broth of Streptomyces sp. KY11783. Lymphostin showed potent inhibitory activity against the lymphocyte kinase, Lck (p56lck). The structure of lymphostin was determined by spectroscopic methods to be a novel tricyclic aromatic alkaloid. A key feature of the structure is the pyrrolo[4,3,2-de]quinoline moiety which is rare among natural products.

Carbon Isotopes↗
PubMed1997

MS-681a, b, c and d, new inhibitors of myosin light chain kinase from Myrothecium sp. KY6568. I. Characterization of producing strain and production, isolation and biological activities.

Novel compounds MS-681a, b, c and d were isolated from the culture broth of a fungal strain KY6568. The strain was identified as Myrothecium sp. from its morphological characteristics. MS-681a, b, c and d inhibited the activity of purified smooth muscle myosin light chain kinase with IC50 values of 0.11, 0.29, 0.095 and 0.26 microM, respectively. Cyclic AMP-dependent protein kinase, cyclic GMP-dependent protein kinase and protein kinase C were not inhibited at 100 microM by MS-681 compounds.

Aminoisobutyric Acids↗
PubMed1997

MS-681a, b, c and d, new inhibitors of myosin light chain kinase from Myrothecium sp. II. Physico-chemical properties and structure elucidation.

MS-681a, b, c and d are new inhibitors of myosin light chain kinase produced by Myrothecium sp. They are novel octapeptides containing alpha-alkyl-alpha-amino acids and a polyamine moiety. The structures were determined by NMR and FAB-MS/MS spectral analyses of the intact peptides. Their absolute configurations were elucidated by GC analysis on a chiral column of the constituent amino acids and by chemical synthesis of the polyamine moieties.

Enzyme Inhibitors↗
PubMed1997

Epileptic activity prevents synapse formation of hippocampal mossy fibers via L-type calcium channel activation in vitro.

Hippocampal slice from early postnatal rat was used to elucidate the influence of epileptic activity elicited by picrotoxin on synapse formation of mossy fibers. Neurite reelongation and synaptogenesis of mossy fibers transected at 8 days in vitro were confirmed by staining with Dil, a fluorescent membrane dye used as a neuronal tracer, and by recording field excitatory postsynaptic potentials (fEPSP) in the CA3 region evoked by stimulation of the dentate gyrus. Picrotoxin (50 microM), which evoked spontaneous epileptiform firing in the CA3 region that was occluded by tetrodotoxin (1 microM), hindered development of fEPSP amplitude after a lesion of mossy fibers. Furthermore, observations using a Timm method, a histochemical technique that preferentially labels synaptic terminals of mossy fibers, revealed that picrotoxin prevented synaptogenesis in the CA3 region. This inhibitory effect of picrotoxin was completely abolished by tetrodotoxin or nicardipine (10 microM), a L-type calcium channel blocker, but not by 2-amino-5-phosphonopentanoic acid (50 microM), a N-methyl-D-aspartate receptor antagonist, suggesting that influx of calcium ion via L-type calcium channels during epileptic bursts mediated the disturbance of appropriate synapse formation of mossy fibers.

Animals↗