A patient with long standing melanin laden macrophages in cerebrospinal fluid in Vogt-Koyanagi-Harada syndrome.
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Autoimmune Diseases↗
Biomedical subjects
M Nakazawa
Publications and source records attributed to M Nakazawa.
Expression of inducible nitric oxide synthase in rat experimental autoimmune myocarditis with special reference to changes in cardiac hemodynamics.
Excessive NO produced by an inducible NO synthase (iNOS) has been implicated in many types of immune-associated disorders of the cardiovascular system, but it remains to be determined whether NO plays a role in myocarditis. Thus, the significance of iNOS expression in the development of experimental autoimmune myocarditis (EAM), an animal model of human giant cell myocarditis, was investigated. Lewis rats were immunized with cardiac myosin and were killed 7, 14, 21, 28, and 49 days after immunization. The development of severe myocarditis was observed on days 14, 21, and 28 in association with significant deterioration of hemodynamics determined by cardiac catheterization, which peaked on day 21. In parallel with histological severity of myocarditis and deterioration of cardiac performance, iNOS activity in the heart measured by [14C]L-citrulline formation was markedly increased on days 14, 21, and 28. The expression of iNOS was confirmed by immunoblotting and was localized to the infiltrating inflammatory cells found in the vicinity of necrotic myocytes by immunohistochemical analysis. Aminoguanidine, a selective inhibitor of iNOS, significantly decreased the iNOS activity (1.04 +/- 0.37 compared with 29.1 +/- 8.62 pmol.min-1.mg protein-1 in untreated myosin-immunized rats, P < .01) and effectively attenuated histopathological changes of EAM on day 21. Hemodynamic parameters were also improved from 64 +/- 3 to 89 +/- 3 mm Hg for mean blood pressure, from 80 +/- 2 to 113 +/- 4 mm Hg for left ventricular systolic pressure, from 7.8 +/- 0.3 to 3.2 +/- 0.3 mm Hg for left ventricular end-diastolic pressure, from 2867 +/- 137 to 4180 +/- 102 mm Hg/s for +dP/dt, and from 2717 +/- 132 to 4180 +/- 184 mm Hg/s for -dP/dt (P < .01). The values after aminoguanidine treatment were not significantly different from the control values. These results suggest an important role for NO in mediating pathophysiological changes in myocarditis of autoimmune origin.
Animals↗
Inhibitory effects of talipexole and pramipexole on MPTP-induced dopamine reduction in the striatum of C57BL/6N mice.
We have investigated the effects of two novel antiparkinsonian drugs, talipexole (Domin) and pramipexole, on MPTP-induced dopamine (DA) reduction in the striatum of C57BL/6N mice in comparison with those of bromocriptine. Fifteen days after MPTP treatment (25 mg/kg, i.p., given daily for 5 days), the DA content in the striatum was decreased to 40-60% of the control value. Among the three dopamine receptor agonists, talipexole and pramipexole (1 mg/kg, i.p., once a day for 20 days) more significantly suppressed the MPTP-induced DA reduction in the striatum than bromocriptine (10 mg/kg, i.p., once a day for 20 days). Talipexole did not influence [3H]MPP+ uptake into striatal synaptosomes. These results suggest that talipexole and pramipexole have a protective effect against MPTP-induced DA reduction in the striatum of C57BL/6N mice.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
[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↗
[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↗
[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↗
[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↗
[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↗
[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↗
Seventy-eight-week dietary carcinogenicity 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 mice.
The oncogenic potential 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 assessed when it was administered in the diet of Charles River B6C3F1 mice for 78 weeks in dosages of 0, 30, 100 and 300 mg/kg/day. No drug-related effects occurred on survival, appearance or behavior, or occurrence, location or number of palpable masses. Average food consumption, food efficiency and hematologic values also were apparently unaffected. Statistically significantly low body weights were observed in the 100 and 300 mg/kg/day mice. The plasma concentrations of NS-21 and its active metabolite, RCC-36, in the treated groups were increased in a dose-dependent manner. Histopathological examinations disclosed midzonal hepatocellular vacuolization compatible with lipid vacuoles in both sexes at the 300 mg/kg/day dose level. There were no test article-related effects on the incidence or type of neoplastic lesions. In conclusion, under the conditions of this study, no oncogenic effects were evident in B6C3F1 mice when NS-21 was administered in the diet in concentrations to produce an intake of up to 300 mg/kg/day for 78 weeks.
Administration, Oral↗
Two-year dietary carcinogenicity 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.
The oncogenic potential 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 assessed when it was administered in the diet of Charles River Fischer-344 rats for 2 years in dosages of 0, 10, 30 and 100 mg/kg/day. No drug-related effects occurred on survival, appearance or behavior, or occurrence, location or number of palpable masses. Food efficiency and hematologic values also were apparently unaffected. Statistically significantly low mean weekly body weights and average food consumption values were observed in the all dose groups. The plasma concentrations of NS-21 and its active metabolite, RCC-36, in the treated groups were increased in a dose-dependent manner. Histopathological examinations disclosed test article-related increases in the incidence of periportal hypertrophy and midzonal hepatocellular vacuolization in the livers of the 100 mg/kg/day animals. There were no test article-related effects on the incidence or type of neoplastic lesions. In conclusion, under the conditions of this study, no oncogenic effects were evident in Fischer-344 rats when NS-21 was administered in the diet in concentrations to produce an intake of up to 100 mg/kg/day for 2 years.
Administration, Oral↗
DNAinsight: An Image Processing System for 2-D Gel Electrophoreisis of Genomic DNA.
We have developed a powerful image processing system DNAinsight, which performs automated detection of several thousands of spots found on autoradiogram images obtained with 2-D gel electrophoresis of genomic DNA. Algorithms and parameters for detecting spot locations and intensities are carefully chosen so as to enable reliable and rapid processing of 2-D gel electrophoretograms based on the RLGS (restriction landmark genomic scanning) method. In DNAinsight, matching of several related spot patterns, such as those from tumor-cell and normal-cell, can be accomplished rapidly with easy operations, being solved by comparing the Delaunay net and relative neighborhood graph. The automated and accurate image processing system strongly supports the rapid identification and analysis of genetic variation in the DNA of humans and other animals.
Journal Article↗
[Analysis of the profile of CD4+ cells in Behçet's disease].
The cell-mediated immune response and disorders of the cytokine-producing cells play an important role in the pathogenic mechanisms of Behçet's disease. Recently, CD4+ T helper cells have been categorized into at least two distinct subsets based on their profiles of cytokine production. We analyzed the number of interleukin (IL)-2 producing type 1 helper T (Th1) cells and IL-4 producing Th2 cells from 22 patients (male: 12, female: 10) with Behçet's disease and 19 normal controls (male: 9) by flow cytometric analysis. The patients with Behçet's disease were categorized into two groups by the activity of ocular inflammation; one group comprised the active cases (13 patients) and the other the inactive cases (9 patients). Peripheral blood mononuclear cells (PBMCs) from patients and normal controls were stimulated with immobilized anti-CD3 mAb for 6 hours and immunostained with anti IL-2 and anti IL-4 mAbs followed by fluorescein isothiocyanate (FITC) conjugated 2nd Abs. The number of IL-2 producing CD4+ cells in Behçet's disease patients with active uveoretinitis was significantly higher than that from both inactive cases (p < 0.005) and controls (p < 0.01). In contrast, the number of IL-4 producing CD4+ cells showed no significant difference among the groups. These results may indicate that Th1 cells play an important role in the immunopathogenesis of ocular inflammation of Behçet's disease. Thus, analysis of Th subsets in Behçet's disease may be useful for management of the disease.
Adult↗
[Two-peak monoclonal protein (IgA kappa and IgG kappa) in non-Hodgkin lymphoma].
A 72-year-old man was admitted because of general weakness. On physical examination, marked splenomegaly was found. Blood tests revealed anemia, thrombocytopenia and two-peak hypergammaglobulinemia composed of kappa type IgG and IgA monoclonal proteins. Peripheral blood and bone marrow (BM) contained abnormal lymphocytes including plasmacytoid lymphocytes and/or plasma cells. Pathological examination of the biopsied BM showed non-Hodgkin lymphoma consistent with the lymphoplasmacytoid type. Immunohistochemical staining revealed two different populations of cells, one with IgG and the other with IgA; no cell stained both and no solitary cluster of either IgG or IgA positive cell was seen. The surface phenotype of the lymphoma cells was CD19+, CD20+, HLADR+. Double immunofluorescence staining of the BM smear showed IgG or IgA positive plasma cells, whereas small lymphocytes were negative for IgG and IgA. Analysis of immunoglobulin genes in the BM cells showed 2 rearranged bands in each of heavy chain genes and kappa light chain genes. The patient was treated with modified MVCP therapy and the two monoclonal proteins decreased in parallel with the improvement of splenomegaly. These findings strongly suggest that the two-peak monoclonal protein was produced by monoclonal lymphoma cells. The patients has been disease-free without any therapy since August, 1995.
Aged↗
[A successful mitral valve replacement for a 13-year-old girl with mitral stenosis and pulmonary hypertension after renal transplantation].
Mitral valve replacement was successfully performed in a 13-year-old girl due to severely calcified mitral valve stenosis and pulmonary hypertension who had undergone renal transplantation from her father at the age of 8 years old. Although, percutaneous transluminal mitral commissurotomy had been performed for four times until January 1996, severe mitral stenosis could be relieved and she was transported to our hospital in emergency for respiratory failure caused by pulmonary edema. Then we decided to perform mitral valve replacement. The operation was done successfully using trans-septal superior approach with SJMHP 19 mmM. the blood cyclosporin levels were monitored and controlled within normal limits. This is the first successful case of pediatric open heart surgery after renal transplantation to our knowledge.
Adolescent↗
[Cardiovascular pharmacology--present and future].
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Animals↗
[Diet training of diabetics with mental disease].
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Diabetes Mellitus↗
[An analysis of type 2 helper T cells in patients with atopic dermatitis].
In order to know the role of type 2 helper T (Th2) cells on patients with atopic dermatitis (AD), peripheral blood mononuclear cells were taken from the patients, stimulated with immobilized anti CD3 monoclonal antibody in the presence of monensin, and stained with fluorescein isothiocyanate-labeled anti IL-2 or IL-4 monoclonal antibody, followed by phycoerythrin labeled-anti CD4 monoclonal antibody. The fluorescent intensity was detected by FACScan. The results showed that the frequency of IL-4 producing CD4+ cells from AD patients was significantly higher than that from the healthy controls, whereas that of IL-2 producing CD4+ cells from patients were the same as healthy controls. The frequency of IL-4 producing cells was well correlated to the clinical severity of the disease, but that of IL-2 producing cells did not show any significance. Neither IL-2 nor IL-4 producing CD4+ cells had any relation to the serum IgE levels and the number of eosinophils in the patients. Our results indicate dominance of IL-4 producing CD4+ cells, which means Th2 cells in the peripheral mononuclear cells in the patients with AD, especially severe cases.
Adult↗