Synthesis and antifungal activity of novel thiazole-containing triazole antifungals. II. Optically active ER-30346 and its derivatives.

A series of novel thiazole-containing triazole antifungals was synthesized and evaluated for antifungal activity against a variety of clinically isolated pathogenic fungi in vitro and against systemic candidosis in vivo. These compounds showed potent antifungal activities in vitro and in vivo. In particular, (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4- difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (12g; ER-30346) showed potent and well-balanced in vitro activities and potent in vivo efficacy, and had a good safety profile.

Synthesis and antifungal activity of novel thiazole-containing triazole antifungals.

A new series of thiazole-containing triazole antifungals was synthesized and evaluated for antifungal activity against a variety of clinically isolated pathogenic fungi in vitro and against systemic candidosis in vivo. Among these compounds, (+/-)-1-(2,4-difluorophenyl)-1-[4-(2,4-difluorophenyl) thiazol-2-yl]-2-(1H-1,2,4-triazol-1-yl)ethanol (ER24161) showed the most potent and well-balanced in vitro activities and excellent in vivo efficacy. We also achieved an enantioselective synthesis of the more potent enantiomer of ER-24161.

Antibodies to GAD in Japanese diabetic patients: a multicenter study.

We determined the prevalence of antibodies to glutamic acid decarboxylase (anti-GAD) in Japanese diabetic patients. Anti-GAD were detected by RIP Anti-GAD Hoechst, which is a new sensitive radioimmunoassay (RIA) kit using purified pig brain GAD as the antigen. One thousand nine hundred Japanese patients were collected by the Study Group for Antibodies to GAD. The prevalence of anti-GAD in the subjects of this study was: 35.4% (326/921) in all patients with IDDM, 50.3% (96/191) in patients with IDDM less than 1-year duration, 4.3% (29/680) in NIDDM, 37.9% (39/103) in slowly progressive IDDM, 10.5% (4/38) in gestational diabetes mellitus, 0% (0/27) in impaired glucose tolerance, 4.8% (6/124) in the school children with glycosuria, 2.1% (1/47) in the relatives of IDDM and 5.0% (1/20) in neurological diseases without diabetes. The prevalence in normal subjects was 2.2% (7/323). Anti-GAD are frequently detected by the RIA kit in patients with IDDM of short duration and this assay may be useful for population screening for IDDM and for better understanding of its pathogenesis.

Studies on orally active cephalosporins. I. Synthesis and structure-activity relationships of new 3-substituted carbamoyloxymethyl cephalosporins.

The synthesis and antibacterial activities of 7 beta-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-N,N - dimethylcarbamoyloxymethyl-3-cephem-4-carboxylic acid (E1100) and its analogs are described, as well as oral absorbability and in vivo activities of the 1-(isopropoxycarbonyloxy)ethyl ester (E1101) and its analogous esters. The introduction of acyclic and cyclic lower alkyl groups at the N-position of 3-carbamoyloxymethyl cephems influences antibacterial activities, especially against H. influenzae, and oral absorbability of their prodrug esters. The structure-activity relationships are also discussed.

Studies on orally active cephalosporins. II. Synthesis and structure-activity relations of new [(E) or (Z) 3-substituted carbamoyloxy]-1-propenyl cephalosporins.

In an effort to find a new oral cephalosporin with well-balanced antibacterial spectrum, good oral absorbability and long plasma half-life, a series of oxyimino aminothiazolyl 3-[(E)- or (Z)-N-substituted carbamoyloxy]propenyl cephems was synthesized and evaluated for antibacterial activity and oral absorbability. The substituents of the carbamoyloxy group affected their in vitro activity and bioavailability after oral administration of their pivaloyloxymethyl esters at the C-4 position. The compound possessing an N,N-dimethylcarbamoyloxy moiety at the C-3 position showed good oral absorption and well-balanced antibacterial activity. In this report, the structure-activity relationships and the structure-oral absorbability relationships of 3-(N-substituted carbamoyloxy)-propenyl cephems are described.

Self-monitoring of blood glucose, as a means of self-management.

In Japan, the study of the self-monitoring of blood glucose (SMBG) was started in 1976. After that, SMBG gradually became popular among the diabetes clinics, and was covered by health insurance in 1987. Although performers of SMBG constitute only 35% of all insulin-treated patients, it has been highly evaluated that 60% of patients with insulin-dependent diabetes perform SMBG. The results of this study of SMBG revealed that it was useful for the prevention of chronic complications and for the education of diabetes patients. New systems using an electrochemical technology are developing so rapidly that the newest model, with no wiping or blotting of a blood sample, will help the spread of SMBG. We must put emphasis on introducing SMBG as a means of self-management to all patients with diabetes.

Preventive effects of cyclosporin on diabetes in NOD mice.

Non-obese diabetic mice aged 30 to 60 days were treated orally with Cyclosporin at doses of 25, 15 and 2.5 mg/kg every 2 days until 160 days of age. Diabetes developed in 12 out of 18 oil-treated mice (67%), with partial to complete Langerhans' islet destruction associated with lymphocytic infiltration. The non-obese diabetic mice showed a plasma glucose concentration of 6.62 +/- 0.92 mmol/l (mean +/- SD) at 50 days of age. The plasma glucose level of oil-treated non-obese diabetic mice gradually increased after 130 days of age and reached 14.0 to 19.0 mmol/l at 160 days of age, while Cyclosporin-treated non-obese diabetic mice showed neither clear increase of plasma glucose levels nor development of insulitis. The cumulative incidence of diabetes in Cyclosporin-treated mice was significantly lower than that in oil-treated mice (p less than 0.01). Subsequently, Cyclosporin treatment was started after development of glucose intolerance. Twenty-five mg/kg of Cyclosporin was administered every 2 days for 35 days. Cyclosporin appeared to have little therapeutic effect on diabetes in non-obese diabetic mice.

Cellular hypersensitivity to human pancreatic B-cell clone in diabetes mellitus and its relationship to the presence of islet cell antibodies.

A leukocyte migration inhibition test on the human pancreatic B-cell clone (JHPI-1) was performed in 13 IDDM patients with islet cell cytoplasmic antibody (ICCA) and/or islet cell surface antibody (ICSA), 15 IDDM patients without ICCA or ICSA, 34 NIDDM patients and 17 healthy controls. The mean values for the migration index (M.I. %) in each group were 85.4 +/- 6.9, 89.1 +/- 10.9, 98.3 +/- 7.9 and 100.0 +/- 8.5. The M.I. values were significantly decreased in IDDM patients than in NIDDM patients and controls irrespective of whether or not there were islet cell antibodies in the patients' sera. When M.I. values less than 0.83 (Mean-2 S.D.) were taken as indicative of inhibition, the percentage of IDDM and NIDDM patients with migration inhibition were 32% and 0% respectively. And the decreased M.I. values in IDDM patients proved not to be due to non-specific migration inhibition by normal M.I. values, with the human fetal lung fibroblast cells (W 138) as antigen. Our data suggested that the lymphocytes of IDDM patients might be sensitized by pancreatic B-cell antigen(s) present in the JHPI-1 cells, which promoted leukocyte migration inhibition. No correlation between the migration indices and duration of diabetes mellitus in IDDM patients was observed (r = 0.254, Y = 84.9 + 0.49 X). LMT to JHPI-1 seems to be useful in detecting the abnormal cell-mediated immunity even in patients with longstanding IDDM.

[The effect of methyleneblue on insulin and glucagon release stimulated by glucose and arginine in the isolated perfused rat pancreas].

To examine the role of NADPH in the release of insulin and glucagon, isolated rat pancreata were perfused with methyleneblue, which is known to oxidize NADPH. Hormonal release was stimulated by changes in arginine or glucose concentrations as follows. After establishing the basal secretion state during perfusion at various glucose levels for 10 min., pancreata were stimulated by the addition of arginine or a change in glucose concentration of the perfusate for 15 min. Conditions for the stimulation were: (A) addition of 10 mM arginine at constant 4 mM glucose concentration; (B) increase in glucose concentration from 2.8 mM to 11.1 mM, or (C) decrease in glucose concentration from 11.1 mM to 2.8 mM. In some experiments, methyleneblue was added throughout the perfusion period at 1 or 3 micrograms/ml. The effluent from the portal vein was collected over 1 minute intervals: Insulin and glucagon concentrations in the effluent were determined by radioimmunoassay. Insulin release. Stimulation by the addition of arginine and increased glucose concentration produced a typical biphasic insulin response. In both cases, 1 microgram/ml methyleneblue reduced the second phase, and 3 micrograms/ml methyleneblue inhibited both phases almost completely. Glucagon release: Stimulation by arginine and inhibition by increasing glucose concentration were not influenced by methyleneblue; however, glucagon release induced by lowering of glucose concentration was suppressed by 3 micrograms/ml of methyleneblue. Thus, methyleneblue specifically inhibits glucose- and arginine-induced insulin release while it has no effect on arginine-induced glucagon release.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell-mediated cytotoxic islet cell surface antibodies to human pancreatic beta cells.

Sera containing islet cell surface antibodies show a complement-dependent cytotoxic reaction against islet cells, but it has not yet been clarified whether islet cell surface antibodies exhibit cell-mediated cytotoxicity to these cells. By 51Cr release assay we investigated whether islet cell surface antibodies showed a cytotoxic reaction to human pancreatic B cells (JHPI-1 clone) in the presence of normal human lymphocytes. The sera from 14 islet cell surface antibody-positive, 16 islet cell surface antibody-negative Type 1 (insulin-dependent) diabetic patients and 18 islet cell surface antibody-negative healthy subjects were studied. Four sera containing islet cell surface antibodies showed specific cytotoxicity above the mean +3SD value of healthy subjects, and the mean specific cytotoxicity of islet cell surface antibody-positive sera differed significantly from that of both islet cell surface antibody-negative groups. These results suggest that this cell-mediated cytotoxic mechanism may play an important role in the pathogenesis of Type 1 diabetes.

[Hyperglycemia and inhibition of glucose-induced insulin release in 6-aminonicotinamide treated rats].

The effects of 6-aminonicotinamide (6-AN) on blood glucose and insulin release were studied in rats. 6-AN at 4mg/100g body weight slowly raised blood glucose concentrations to a significantly higher level than the control values 6 hours after an intraperitoneal injection. At this time severe glucose intolerance and low IRI response were noticed during an intravenous glucose tolerance test. Adrenalectomized rats replaced by hydrocortisone also presented hyperglycemia, glucose intolerance and low IRI response during IVGTT under treatment with 6-AN but to a lesser extent than in the intact rats. In in vitro experiments, decreased insulin release from the perfused pancreata of rats pretreated with 6-AN was found both in the 1st and 2nd phases of response to glucose stimulation. These data indicate that 6-AN-induced hyperglycemia is attributed to the inhibition of insulin release in adrenalectomized rats except for the hypothetical effect of 6-AN which diminishes an action of insulin on cellular glucose transport.