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Aim: Activation of protein kinase C (PKC) is thought to play an important role in the pathogenesis of diabetic microvascular complications. PKC-β is elevated in hyperglycaemic conditions, both in vivo and in vitro. In this study, pharmacological effects of a novel PKC-β isoform selective inhibitor, JTT-010 ((2R)-3-(2-aminomethyl-2,3-dihydro-1H-3a-azacyclopenta(a)inden-8-yl)-4-phenylaminopyrrole-2,5-dione monomethanesulphonate), on diabetic neuropathy were examined. Methods: PKC inhibitory activity of JTT-010 was evaluated with an enzyme assay. For the in vivo study, streptozotocin (STZ)-induced diabetic rats were treated with JTT-010 for 12 weeks and tail/sciatic nerve conduction velocity (NCV) evaluated. Hyper/hypoalgesia was evaluated using tail-flick and formalin tests. Results: JTT-010 inhibited PKC-βI and -βII with IC50 values of 4.0 and 2.3 nm respectively. For other PKC isoforms, IC50 values were 54 nm or greater. In STZ-induced diabetic rats showing a reduction in tail/sciatic nerve conduction velocities, JTT-010 (0.3–3 mg/kg) ameliorated the reduction of these velocities. In a formalin test, STZ-induced diabetic rats had hyperalgesia in the first phase. JTT-010 reduced nociceptive response at doses of 0.1 mg/kg or higher. Furthermore, STZ-induced diabetic rats showed hypoalgesia in the second phase of the formalin test and tail-flick test. JTT-010 also ameliorates these symptoms at doses of 0.1 mg/kg or higher. Conclusions: These observations suggest that PKC-β contributes not only to diabetic hyperalgesia, but also to hypoalgesia and also contributes to defects in NCV. PKC-β inhibitor, JTT-010, may be beneficial in suppressing the development of diabetic nerve dysfunction, including hyperalgesia and hypoalgesia.

This paper proposes a new spectrum estimation method for speech signals which are uttered with a short pitch period. This method is one of the excellent spectrum estimators in which an exact spectrum of a linear model can be obtained even if quite high frequency pitch pulses are fed into the model as an input. This method consists of two-stage analyses. The troughs of harmonics are removed by using cepstrum analysis repeatedly in the first stage. After that, the spectral envelope is estimated by using the autocorrelation method in the second stage. This report shows that the proposed method can estimate the formant frequencies of speech signals uttered by children quite accurately, more so than the conventional linear prediction method.

PTP-BAS is a membrane-associated protein tyrosine phosphatase containing a band-4.1 homology region and five PDZ (PSD-95 Dlg ZO-1) [discs-large homology region ('DHR')/Gly-Leu-Gly-Phe ('GLGF')] domains. The second and fourth PDZ domains were reported to associate with Fas/CD95. By using the first PDZ domain as a bait in yeast two-hybrid screening, we have identified IkappaBalpha as a binding protein. IkappaBalpha associated with PDZ1 through the stretch of the N-terminal three ankyrin repeats. The association was also confirmed in HeLa cells by co-immunoprecipitation experiments. Inhibition of PTP-BAS by expression of dominant-negative PTP-BAS mutant resulted in tyrosine-phosphorylation of IkappaBalpha. Tyrosine-phosphorylation of IkappaBalpha is a key event in activation of nuclear factor (NF)-kappaB during reoxygenation. PTP-BAS may thus play a regulatory role in activation of NF-kappaB under high oxidative stress.

Imipenem/cilastatin sodium (MK-0787/MK-0791) was studied for its penetration into the adnexa uteri and uterine tissue, as well as for its clinical efficacy in the treatment of patients with obstetric and gynecologic infections. The following results were obtained. When 500 mg/500 mg of MK-0787/MK-0791 was administered by an intravenous drip infusion, peak levels of MK-0787 in tissues of adnexa uteri and uterus ranged from 14.6 micrograms/g to 25.8 micrograms/g, Tmax ranged from 0.55 hour to 0.98 hour, and the AUC ranged from 25.6 micrograms X hr/g to 45.2 micrograms X hr/g. Thus, the penetration of the drug into these tissues was good. Clinical efficacy of MK-0787 was evaluated in 30 patients in the field of obstetrics and gynecology. The clinical efficacy was excellent or good in all patients. Bacteriological effects of MK-0787/MK-0791 were very good, and 90% of the organisms detected before the treatment were eradicated. The antimicrobial activity of MK-0787 was tested against pathogens isolated before, during and after the treatment. Mean MIC80 values of MK-0787 were 0.39-0.78 micrograms/ml against all Gram-positive bacteria, 0.20-0.39 micrograms/ml against all Gram-negative bacteria, and less than or equal to 0.10-0.20 micrograms/ml against all anaerobic bacteria. The antimicrobial activity of MK-0787 appeared very good. No side effects or abnormal laboratory findings were observed except a slight elevation of S-GPT in 1 patient.

Penetration of aztreonam (AZT) into the uterus and the adnexal tissues and usefulness and safety of AZT for obstetric and gynecologic infections were studied with the following results. By one shot intravenous injection of AZT 1 g, the uterus and the adnexal tissues showed favorable penetration with Cmax 27.0-48.5 micrograms/g, AUC 29.4-84.9 micrograms X hr/g and Tmax 0.10-0.44 hours. MIC50, MIC80 and MIC90 of AZT for Gram-negative bacteria measured prior to administration were very low being 0.10 micrograms/ml, 0.20 micrograms/ml and 1.56 micrograms/ml, respectively. Clinical effect of AZT for 30 infection cases in obstetrics and gynecology was evaluated according to an overall efficacy criteria resulting in "good" for all the cases. With regard to microbiological effect, 90.9% of the pathogens isolated prior to the administration were eliminated by AZT. During and after the administration of AZT, side effect due seemingly to AZT was not observed in subjective and objective symptoms and laboratory values.

Efficacy and safety of sulbactam/cefoperazone (SBT/CPZ) was studied on gynecological infections. The results obtained are as follows: In the treatment of 31 cases of gynecological infections, the clinical efficacy of SBT/CPZ was assessed as excellent in 9 cases and effective in 22 cases. As for the bacteriological effects of SBT/CPZ, clinically isolated organisms were completely (100%) eradicated. In comparison with MICs of CPZ, SBT/CPZ was found to show a combined effect on Gram-negative and Gram-positive organisms in the order mentioned, but this effect was not observed against anaerobes. The combined effect of SBT/CPZ on beta-lactamase producing bacteria was also investigated in the same manner. As a result, SBT/CPZ was found to exert a combined effect on beta-lactamase strains of S. aureus, S. epidermidis, E. coli, B. catarrhalis and B. fragilis. The laboratory tests performed before and after administration of SBT/CPZ revealed rise in GOT and GPT values in 1 case, GPT values in 2 cases and eosinophil in 1 case. However, these rises were all mild and required no particular measures.

A new cephamycin antibiotic, cefotetan, was administered intramuscularly to 45 patients with female genital infections including 2 cases with abscess of Bartholin's gland, 14 cases with endometritis, 23 cases with adnexitis and 6 cases with pelvic peritonitis. The daily doses of the drug were 1 to 3 g, with 2 g daily being the most frequent regimen. The treatment was given twice daily in most patients. All cases responded to the drug, and marked response was seen in 22 cases and moderate response in 23. The eradication rate for causative organisms was 64.3%. In 16 cases of S. faecalis, it was rather low at 37.5%. Neither side effects nor abnormalities in clinical laboratory findings attributable to the drug were seen.

Cefpiramide (CPM) was administrated intramuscularly to 27 cases of gynecological infections to evaluate its clinical efficacy and safety and the following results wee obtained. CPM was effective to all the cases of gynecological infections, and excellent was seen in 14 cases and good was seen in 13 cases. CPM eliminated 75% of clinical isolates. Laboratory tests were performed to blood samples and functions of liver and kidney before and after CPM treatment. Elevation of GPT was observed in 2 cases but required no treatment.

Cefpimizole (AC-1370) was studied for its transference into adnexa uteri and uterine tissues as well as for its effects and safety on gynecological infections. The results obtained are as follows: Peak levels of AC-1370 were obtained in the antecubital vein and uterine artery at 10 minutes, in the tissues of adnexa uteri and uteri about 30 minutes after one shot intravenous injection of AC-1370 1 g, and relatively high concentrations were maintained for several hours. In the treatment of 30 cases of gynecological infections, the clinical efficacy of AC-1370 was assessed as effective in all cases. As for the bacteriological effects of AC-1370, 77.6% of isolated organisms were eradicated and 90% of all cases were effective. Side effects and abnormal laboratory findings due to AC-1370 were not observed during and after administration.