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Noradrenaline (NA) modulates glutamatergic and GABAergic transmission in various areas of the brain. It is reported that some alpha2-adrenoceptor subtypes are expressed in the cerebellar cortex and alpha2-adrenoceptors may play a role in motor coordination. Our previous study demonstrated that the selective alpha2-adrenoceptor agonist clonidine partially depresses spontaneous inhibitory postsynaptic currents (sIPSCs) in mouse cerebellar Purkinje cells (PCs). Here we found that the inhibitory effect of clonidine on sIPSCs was enhanced during postnatal development. The activation of alpha2-adrenoceptors by clonidine did not affect sIPSCs in PCs at postnatal days (P) 8-10, when PCs showed a few sIPSCs and interneurons in the molecular layer (MLIs) did not cause action potential (AP). In the second postnatal week, the frequency of sIPSCs increased temporarily and reached a plateau at P14. By contrast, MLIs began to fire at P11 with the firing rate gradually increasing thereafter and reaching a plateau at P21. In parallel with this rise in the rate of firing, the magnitude of the clonidine-mediated inhibition of sIPSCs increased during postnatal development. Furthermore, the magnitude of the clonidine-mediated firing suppression in MLIs, which seemed to be mediated by a reduction in amplitude of the hyperpolarization-activated nonselective cation current, I(h), was constant across development. Both alpha2A- and alpha2B-, but not alpha2C-, adrenoceptors were strongly expressed in MLIs at P13, and P31. Therefore, the developmental enhancement of the clonidine-mediated inhibition of sIPSCs is attributed to an age-dependent increase in AP-derived sIPSCs, which can be blocked by clonidine. Thus, presynaptic activation of alpha2-adrenoceptors inhibits cerebellar inhibitory synaptic transmission after the second postnatal week, leading to a restriction of NA signaling, which is mainly mediated by alpha1- and beta2-adrenoceptors in the adult cerebellar neuronal circuit.

Although no potential homologues of multicellular apoptotic genes (e.g. Bax, Bak, Bcl-2, caspases and p53) have been identified in a unicellular eukaryote, previous reports contain several implications of the apoptotic behaviour of yeasts (i.e. Saccharomyces cerevisiae and Schizosaccharomyces pombe). Therefore, whether or not yeast undergoes apoptosis has been a topic of some debate. hCCG1, which is the largest subunit of TFIID and a histone acetyltransferase, appears to be involved in the regulation of apoptosis. The factor hCIA interacts with hCCG1 and functions as a histone chaperone in mammalian cells; its homologue in yeast is Asf1p/Cia1p. Therefore, we anticipated that a yeast mutant in Asf1p/Cia1p would be a valuable tool for studying apoptosis in yeast.We established a strain of S. cerevisiae lacking the histone chaperone ASF1/CIA1. This disruptant, asf1/cia1, arrested preferentially at the G2/M-phase and died. We systematically analysed the phenotype associated with the death of this mutant yeast and identified many changes, such as fragmentation of the nuclei, condensation and fragmentation of chromatin, reduction of the mitochondrial membrane-potential, dysfunction of the mitochondrial proton pump, and a discernible release of cytochrome c to cytoplasm that resembles those in apoptotic multicellular organisms. Other changes potentially associated with the death in our mutant included a reduction in the vacuolar membrane potential, dysfunction of the vacuolar proton pump, reduction of endocytosis, and the presence of many autophagic bodies. However, these mutant yeast cells also showed cellular enlargement, which is characteristic of necrosis.Cell death in S. cerevisiae occurs with a phenotype that largely resembles apoptosis in multicellular organisms, but that has some features of necrosis. Therefore, we indicate that yeast undergoes a 'prototypal active cell death' that retains some characteristics of passive cell death (necrosis). In addition, we think that active cell death is ubiquitously the essential attribute of life. Although such an active cell death system in yeast remains open to confirmation, we speculate that deletion of the histone chaperone Asf1p/Cia1p inhibits the normal assembly/disassembly of nucleosomes in yeast and thereby initiates the active cell death system.

Pyogenic sacroiliitis is an extremely rare disease in the field of obstetrics and gynecology, and especially for the cases discovered and treated during pregnancy, only five cases can be found in literature. We experienced one case of the disease in which the patient needed urgent hospitalization due to dysbasia caused by fever and pain at the left hip at the 27th week of her pregnancy. The patient was a 31-year-old primipara presenting typical clinical symptoms of pyogenic sacroiliitis along with evidence of severe infection as represented by fever of 39.7 degrees C and CRP of 12.6 mg/dl. She showed a good response to meropenem (MEPM) at 1 g twice a day for 8 days and then at 0.5 g twice a day for 2 days, followed by faropenem (FRPM) at 200 mg three times a day for 12 days, which successfully improved her subjective and objective findings as well as her laboratory test values, resulting in a complete cure. The definitive diagnosis of the disease in the patient was made on the basis of MRI findings, but no pathogen was identified. The patient was found to have marginal placenta previa as a complication, but she had an uneventful trans-vaginal delivery at the 37th week of her pregnancy and left hospital after both she and her baby showed favorable post-delivery progress. The case reported here is the first case of pyogenic sacroiliitis that has ever been discovered and treated during pregnancy in Japan.

Effectiveness and safety of cefpirome (CPR) were studied in perinatal infection and prevention of postoperative infections. 1. Enrolled in the study of perinatal infections were the total 62 cases comprising 47 of chorioamnionitis, 10 of puerperal intrauterine infections, 1 of infectious abortion and 4 of others. The effective rate of CPR 2 g/day given in drip infusion was 61/62 (98.4%). In bacteriological studies, the bacterial elimination rate was 57/61 (93.4%). Unchanged and remained were 3 strains of Gram-positive bacteria and 1 strain of Bacteroides spp. 2. Enrolled in the study of prevention of postoperative infections during perinatal period were the total 88 cases comprising 74 who underwent cesarean section and 14 others. The effective rate of CPR 2 g/day given in drip infusion was 87/88 (98.9%). 3. With respect to subjective and objective adverse affects due to the agent, drug eruption was observed in 1/150 (0.7%). No abnormal result of clinical laboratory tests was found. The above results suggested the usefulness of CPR for treatment of perinatal infections and prevention of postoperative infections.

The efficacy and the safety of meropenem (MEPM) were examined in obstetric and gynecological infections and the results shown below were obtained. 1. The subjects were patients with infectious diseases during a non-pregnant period (n = 14), a pregnant period (n = 13) and a puerperal period (n = 11). After intravenous drip infusion of MEPM at 1-2 g/day, the response rate was 38/39 (97.4%) (Excellent: 13/39 (33.3%), Effective: 25/39 (64.1%)). 2. The response rates in a group receiving 1 g/day, a group receiving 2 g/day and a group receiving a combination of both were, respectively, 25/26 (96.2%), 9/9 (100%) and 4/4 (100%). 3. In cases that did not respond to previous treatments, the response rate to MEPM was 20/20 (100%). 4. In clinical efficacy classified by causative organisms, the rate of Excellent was 10/23 (43.5%) and the rate of Effective was 13/23 (56.5%), and the bacterial eradication rate was 21/23 (91.3%). 5. No subjective and objective adverse reactions or abnormalities in clinical laboratory tests due to administration of MEPM were observed.

Clinical effects of cefoselis (CFSL) on various infections and prevention of postoperative infections in the field of obstetrics and gynecology were investigated with a total of 100 patients of 8 facilities in Yamagata and the following results were obtained: 1. For the patients (n = 70) who received the treatment with CFSL at 2 g/day for 5 days to prevent postoperative infections, the treatment was effective for such infections in 68 of 69 (98.6%) except one to whom the treatment was discontinued during the course. 2. For the patients with infections (n = 30) who were treated with CFSL at 2-4 g/day for 5-7 days, the treatment was markedly effective in 8/30 (26.7%), effective in 21/30 (70%) and not effective in 1/30 (3.3%). The overall rate of efficacy was 29/30 (96.7%). Based on the clinical effects for each isolate, the bacteriological efficacy was evaluated as 29/29 and the rate of bacterial eradication for each isolate was 23/29 (79.3%). 3. Laboratory test revealed liver functional abnormalities in one patient and eruption, a subjective/objective symptom caused by CFSL was noted in two patients. These results suggest that CFSL is effective for various infections in obstetric and gynecologic field and also the prevention of postoperative infections.

The clinical effect of faropenem was evaluated in 165 ambulatory patients with various infections in the field of obstetrics and gynecology at 10 institutions in Yamagata Prefecture. The results obtained are summarized below. 1. The rate of efficacy, as determined from the clinical effect following 3- to 7-day repeated administration at a dose of 600 mg/day, was 97.9% (46/47) for intrauterine infections, 92.0% (23/25) for adnexitis, 93.8% (15/16) for external genital infections, 88.9% (8/9) for mastitis, 94.0% (63/67) for cystitis, and 100% (1/1) for cervicitis. The overall efficacy rate was estimated to be 94.5% (156/165). 2. The rate of clinical efficacy, as classified by isolate, was high, 95.1% for Gram-positive bacteria, 100% for Gram-negative bacteria, and 100% for anaerobes. As for bacteriological response classified by isolate, the eradication rate was high, 91.4% (74/81) for Gram-positive bacteria, 98.4% (62/63) for Gram-negative bacteria, 89.5% (17/19) for anaerobes, and 93.9% (153/163) in all. 3. No adverse reactions or laboratory abnormalities were observed in any patient. The results presented suggest that faropenem is a highly safe and effective antibiotic for the treatment of obstetric or gynecological infections of various kinds in an ambulatory setting.

An investigation was made on the concentration of levofloxacin (LVFX) in cervical mucus and its clinical effects on cervicitis. The results were as follows: 1) The concentrations of orally administered LVFX in the cervical mucus of 110 subjects were determined by HPLC. During 1-4 hour after the administration the mean concentration of LVFX in the cervical mucus reached a level of 2 micrograms/g, which was higher than the serum level. The transfer of LVFX to the cervical mucus was almost the same as that to other genital organs. 2) When LVFX was given to 102 patients at a dose of 100-200 mg, t.i.d for 4-5 days and the efficacy was evaluated with clinical improvement, the clinical efficacy rate of LVFX was 72/102 (70.6%). Significant bacteriological effects were observed in 70/73 (95.9%), especially, the disappearance rate of C. trachomatis was 18/18 (100%). 3) The administration LVFX did not cause any subjective or objective side effects and any abnormalities were not detected in the laboratory test done in this study. These results demonstrate that LVFX can be sufficiently transferred to the cervical mucus for the treatment of cervicitis due to the infection of C. trachomatis etc.

Efficacy and safety of panipenem/betamipron (PAPM/BP) in treatment of obstetric and gynecological infections, and change of interleukin-6 (IL-6) and interleukin-8 (IL-8) levels in blood, as markers of infection, were investigated. The results were as follows; 1) Clinical efficacy of PAPM/BP by drip infusion of 1-2 g/day for 3-14 days against 52 patients with intrauterine infection (n = 29), pelveoperitonitis (n = 19), and other infections were 14 "Excellent" in 14 cases, "Good" in 35 cases, and efficacy rate was 94.2% (49/52). Both efficacy rate analy by causative organisms and eradication rate were 35/37 (94.6%). No subjective or objective side effects and no abnormal labolatory findings were observed. 2) Changes of IL-6 (4 pg/ml) levels in serum, as an infection marker, were observed in 8 cases out of 14 cases (57.1%), and correlation between CRP and IL-6 in the treatment process was noticed. However, changes of serum IL-8 (12.5 pg/ml) were observed in only 2 cases of those 14 cases (14.3%), indicative that IL-8 has no significance as a marker of infection.

Generally, clinical symptoms such as abnormal leukorrhea are caused by C. trachomatis, an ordinary bacteria in cervical infection. The effects of levofloxacin administration at a dose of 300 mg/day for 5-14 days were investigated in the subjects (n = 66) after the discussion of cystic cervicitis. The treatment was made in combination with chloramphenicol-solcoseryl tablet for vaginal use. And it was demonstrated that treatment was effective in all subjects. Then, Sero IPALISA, an examination of IgA/IgG antibody was conducted for the screening of Chlamydia infection (n = 258). The rate of antibody-positive case was 48/160 (30.0%) for the non-pregnant women and 26/98 (26.5%) for the pregnant. The occurrence rates for the women singing in 15-24 and 35-39 years of age were 50 and 41%, respectively. The results from the measurement of the antibody titer were as follows: the rate of IgA/IgG positive care was 61/87 for IgA and 56/87 for IgG when the cut-off index was 1.11 or more. The rates for both antibody were 11/87 (12.6%) and 24/87 (27.6%) for the indexes of 1.11-3.00 and 3.01 or more, respectively. Next, one to three courses levofloxacin at 300 mg/day for 14 days were given to 48 non-pregnant subjects infected with Chlamydia and one to two courses of clarithromycin at 400 mg/day for 14 days were given to 26 pregnant subjects. Side effects have not been noted in any care and there was no changes in the IgA/IgG antibody titer depending on these treatments.

In 95 patients with abnormal vaginal and cervical secreta (49 pregnant women and 46 non-pregnant women), the relation between intravaginal flora and intravaginal granulocyte elastase (Elastase) and pH was investigated. The results were as follows. 1) Gram-positive bacteria were detected in the vaginal secreta at a high rate (87/144, 60.4%), and it mainly consisted of Lactobacillus sp. (67/142, 46.5%). It was followed anaerobia (26/144, 18.1%) and fungi (26/144, 18.1%). 2) The patients with cervicitis or vaginitis had higher elastase value (6.65-6.69 micrograms/ml) than the ones with vaginal erosion, and the patients who showed an intravaginal pH value not lower than 5.0 had significantly increased elastase value (6.44 +/- 1.40 micrograms/ml) than the patients who showed the values 4.5 or higher. 3) Regarding the relation between the detected bacteria and elastase values, elastase values were higher in the patients infected by anaerobia (6.58 +/- 1.40 micrograms/ml), Gram-negative bacteria (6.01 +/- 3.61 micrograms/ml), Gram-positive bacteria (5.02 +/- 0.94 micrograms/ml) and fungi (5.14 +/- 1.08 micrograms/ml) than the values in patients with Lactobacillus sp. (pH4.5). Further, the intravaginal pH value was higher than 4.5 in all of these groups, which was higher compared with the one in the patients infected with Lactobacillus sp. (4.04 +/- 0.04).

A clinical study was carried out to investigate clinical efficacy and safety of tazobactam/piperacillin (TAZ/PIPC), a newly developed antibiotic agent for injections. The obtained results are as follows: 1. In 10 patients with obstetrics and gynecological infections (7 patients with endometrial infections, one patient with pelvic peritonitis, one patient with ovarian abscess and one patient with Bartholins's abscess) intravenous drip infusion of TAZ/PIPC, 5.0 g/day, was administered for 5 to 10 days. The total doses were 2550 g/body. 2. Clinical efficacy was evaluated in the above cases. As a result, an excellent result was obtained in one patient and good efficacies in 9 patients. The efficacy rate was 100% (10/10). Concerning the clinical bacteriological effect, eradication ratio was 83.3% (5/6). Concerning the bacteriological effect against 11 strains of clinical isolates, 4 strains were eradicated, 6 strains were replaced and one strain was unchanged. 3. Neither subjective/objective side effects nor abnormal laboratory test results were observed upon administration of TAZ/PIPC. These results suggested the usefulness of tazobactam/piperacillin in obstetrics and gynecological infections.

Ecological treatment of bacterial vaginosis with a Lactobacillus (yoghurt) was studied, and the following results were obtained. 1. A total of 11 women aged 20 to 60 with bacterial vaginosis were treated with intravaginal application of 5 ml of commercial yoghurt (pH 4.3 +/- 0.2). The effect of the treatment was evaluated 3 days after administration by monitoring the vaginal discharge and bacteriological assessment. 2. The clinical improvement was evaluated and the decreases of vaginal discharge and vaginal redness were significant and vaginal pH was lowered significantly also (P0.05). In the vaginal discharge 29 strains of bacteria were detected, but 3 days after administration, all 14 strains of Gram-negative bacteria disappeared. As for the overall bacteriological effects, 6/11 cases (54.5%) were eradicated. 3 cases were partly eradicated, 2 cases were replaced. These findings indicated that the Lactobacillus therapy was effective in both clinical and bacteriological responses.

Effects of imipenem/cilastatin (IPM/CS) therapy, flomoxef (FMOX) therapy and combined ceftazidime + aspoxicillin (CAZ/ASPC) therapy as initial therapies for chorioamnionitis were assessed clinically. 1. The subjects were 49 women with threatened abortion and 29 with premature rupture of membranes (PROM), complicated in all cases by chorioamnionitis. The inflammation was treated with IPM/CS in 19 patients, FMOX in 39, CAZ in 11, and CAZ/ASPC in 9. 2. The response rate to therapy for chorioamnionitis was 95.9% (47/49) in the threatened abortion group. Of the 49 patients in this group, 16 (32.7%) underwent premature labor. Of the therapies administered, IPM/CS tended to prevent premature labor more frequently than did any other therapy. The latent period (from rupture of membranes to delivery) was equal to or longer than 7 days in the PROM group. The percent prolongation of the latent period in these patients (55.5%) was significantly greater than that previously obtained with penicillin therapy. 3. The bacterial elimination rate was 50.9% (29/57). Of the 36 bacterial isolates, 66.7% were Gram-positive bacteria. The bacteriological efficacy rate was 89.7% (26/29). These results suggest that antibacterial agents effective against Gram-positive bacteria should be selected for treatment of chorioamnionitis, and that IPM/CS therapy is particularly useful considering the drug's good transfer into amniotic fluid and its antibacterial spectrum.

Chorioamnionitis as a complication of threatened abortion and preterm labor and preterm PROM were treated with ceftazidime (CAZ) and aspoxicillin (ASPC) as a primary therapy. The following results were obtained. 1. Cases of threatened abortion and preterm labor (n = 25) and preterm PROM (n = 5) were treated with 2-4 g CAZ/day alone (n = 14) or in combination with 4 g ASPC/day (n = 16) along with a uterine contraction inhibitor (ritodrine hydrochloride etc. n = 28) and clinical evaluation was made. 2. In the cases of threatened abortion and preterm labor the efficacy ratio was 24/25 (96%). In the cases of preterm PROM, the latent period-delaying effect was observed in five out of the five patients. Upon analysis of the tocolysis index in the group of threatened abortion and preterm labor, the index valuesor = 5 were observed in 12 out of 25 (60%), and the delivery incidence before the 35th week of gestation was 4/25 (16%). In all patients, the incidence of delivery after the 36th week of gestation was 24/30 (80%). 3. Bacteriological examinations showed a high detection rate for Gram-positive bacteria, and the combination effect between ASPC and CAZ was demonstrated against all 9 isolates examined. The above results indicated a high efficacy as well as safety of the combination of CAZ and ASPC as a primary therapeutic means against chorioamnionitis.

We evaluated the effectiveness and safety of imipenem/cilastatin sodium (IPM/CS) in gynecological infections at gynecological departments at multiple institutions in Yamagata Prefecture. The subjects consisted of 64 patients with gynecological infections, 9 with urinary tract infections, and 21 with other infections. IPM/CS was intravenously drip infused at a dose of 1-2 g/day. The overall response rate was 97.9% (92/94); 96.9% (62/64) for gynecological infections, 100% (9/9) for urinary tract infections, and 100% (21/21) for other infections. Bacteriologically the response rate was 97.3% (36/37), and the eradication rate was 97% (32/33). As for subjective and objective side effects, only diarrhea was observed in 1 patient. Clinical laboratory examinations showed no abnormal values. These results suggest the usefulness of IPM/CS for gynecological infections.

We administered imipenem/cilastatin sodium (IPM/CS) to patients with gynecological infections as initial treatment and evaluated changes in blood interleukin 6 (IL-6) as an infection marker. 1. The subjects consisted of 7 patients with chorioamnionitis, 4 with intrauterine infections, and 1 with subcutaneous abscess. IPM/CS (1-2 g/day) was intravenously drip infused. This therapy was markedly effective in 1 patient and effective in 11; the response rate was 100%. 2. IL-6 generally began to decrease earlier than CRP. Before drug administration, correlations were observed between IL-6 and CRP (r = 0.946) between IL-6 and elastase (r = 0.355), and between elastase and CRP (r = 0.579). During the entire course, correlations were observed between IL-6 and CRP (r = 0.581), between IL-6 and elastase (r = 0.303), and between elastase and CRP (r = 0.776). These results suggest that blood IL-6 reflects early the pathologic state and treatment effects, and is a useful infection marker in gynecological infections.

Clinical effects of combined use of Shouhu-san and mequitazine in 8 cases with recurrent vaginal candidiasis in obstetrics and gynecology were studied, and the following results were obtained. Shouhu-san was orally administered to 8 patients, with recurrent vaginal candidiasis, using a daily dose of 7.5 g. The duration of treatment was between 14 to 28 days. Also mequitazine was used in combination, with a daily dose of 6 mg. The clinical responses were good in all 8 and the efficacy rate was 100%. The microbiological eradication was obtained in all 8 cases of Candida albicans. Neither subjective nor objective side effects were observed. These results suggest that a combination of Shouhu-san and mequitazine appears to be useful of immunologic aspects against recurrent vaginal candidiasis.

A combined therapy using miconazole (MCZ) and G-CSF was evaluated in clinical patients who developed deep-seated mycoses and fever of unknown etiology following chemotherapy for malignant gyneco-obstetrical tumors. 1. Combined administration of 100 to 250 micrograms/day of G-CSF, 400 to 800 mg/day of MCZ, and various antibiotics (Group I) was evaluated in 7 patients with mycoses (fungemia and fungal infections of the digestive and respiratory systems). The efficacy of the treatment was found to be 3/3. When 200 to 1,200 mg/day of MCZ was combined with various antibiotics (Group III), the therapy was found to be slightly effective (2/4). The rate of fungal eradication was 3/5. 2. The efficacy of combined administration of 400 to 800 mg/day of MCZ, 100 to 250 micrograms/day of G-CSF, and various antibiotics (Group II) in patients with fever of unknown etiology (n = 8) was 4/4. The efficacy of combined administration of 400 to 800 mg/day of MCZ and various antibiotics (Group III) was 3/4. 3. Leukocyte counts were recorded in the 7 patients who had received G-CSF (Groups I and II). The counts rose from1,000/microliters before the chemotherapy to5,000/microliters in 6 patients (6/7) in 5 to 8 days following drug administration. The favorable clinical efficacy was recorded in all who received MCZ and antibiotics. 4. The objective or subjective adverse effects of this therapeutic modality were limited to mild nausea in a single case. No deviations from norm were noted in clinical or other tests.

We studied clinical effects of ceftazidime (CAZ) alone or in combination with aspoxicillin (ASPC) against various infections in obstetric and gynecological patients. 1. Obstetric and gynecological patients (n = 91) with various infectious diseases were treated with CAZ alone (1-2 g x 2/day, n = 54) or in combination with ASPC (1-2 g x 2/day, n = 37) administered via drip infusion. 2. CAZ alone or in combination with ASPC was efficacious in 50 out of 54 (92.6%) or 33 out of 36 (91.7%) patients, respectively. Overall, the efficacy ratios were 46/49 (93.9%) against gynecological infections, 21/25 (84.0%) against perinatal infections and 16/16 (100%) against other infections. The bacteriological efficacy ratio was 21/21 (100%) while clinical effectiveness in cases in which causative agents were known was observed in 20 out of 21 (95.2%) patients. In patients who had not respond to other treatments, CAZ alone, and in combination with ASPC were effective in 15 out of 16 (93.8%) and 6 out of 8 (75.0%) patients, respectively, hence the overall efficacy ratio was 21/24 (87.5%). 3. Abnormal values in clinical laboratory tests were obtained in 3 out of 91 (3.3%) patients. No other adverse side effects were observed in any of the patients.

Clinical efficacy of cefodizime (CDZM) in obstetric and gynecologic infections and in their prevention, and fluctuations in cervical mucus elastase in gynecologic infections and during pregnancy were studied, and the following results were obtained: 1. Cervical mucus elastase showed high values ofor = 5,001 micrograms/L in 68.2% of non-pregnant patients and in 25.9% of pregnant patients (gestational age of 24-42 weeks). Patients with concomitant chorioamnionitis showed a significantly higher rate of elastase elevation than those without this complication (63.2% vs. 25.9%, P0.005). 2. Cervical mucus elastase in uterine and pelvic infections showed high values before administration of CDZM but tended to decline with the progress of cure (15/19 cases, 78.9%). 3. The efficacy rate of 2-4 g/day of CDZM drip infusion against infections was 53/56 (94.6%) while the bacterial eradication rate was 36/38 (94.7%). The efficacy rate of 2 g/day of CDZM drip infusion for the prevention of postoperative infections was 429/431 (99.8%). Diarrhea occurred in 3/489 (0.6%) as subjective and objective side effects. Slight rises in GOT and GPT were noted in 13/486 (2.7%) as abnormal laboratory values. These results suggested the usefulness of CDZM in the obstetric and gynecologic fields.

Lysozyme and lactoferrin, antimicrobial substances present in cervical mucus, play an important role in defense mechanisms against ascending infections in development of chorioamnionitis (CAM). In this study, we measured the concentration of lysozyme in cervical mucus, and studied its relationship with other factors, and obtained following results. The concentration of lysozyme in cervical mucus decreased more significantly in positive CAM in preterm labor than in negative CAM and control subjects (P0.001). A direct correlation between the concentrations of lysozyme and lactoferrin was observed (r = 0.709). In positive CAM, the concentration of elastase in cervical mucus reached a significantly high level (more than 8,000 micrograms/L), and a no correlation between the concentrations of elastase and lysozyme was observed. These findings suggest a reduction of the defense mechanism occurred because the concentrations of both lysozyme and lactoferrin in cervical mucus during preterm labor (positive CAM) decreased.

As one of the biodefense mechanisms, lactoferrin (LFN) in the secreta of female genital organ may be an interesting biological material in view of its antimicrobial activity. In the present study, we investigated antimicrobial activities of LFN and its combination with cefpodoxime proxetil (CPDX-PR), we also as evaluated clinical effect of CPDX-PR. The following results were obtained. 1. Antimicrobial activities of LFN were tested against 15 strains of 10 species of bacteria, and potent activities against Staphylococcus aureus 209P, Escherichia coli, Klebsiella pneumoniae and Proteus spp. were found. 2. In a concomitant use of LFN with CPDX-PR (a checkerboard method), synergistic actions were observed against S. aureus 209P, E. coli STf, K. pneumoniae 602 and Pseudomonas aeruginosa 1046, and additive actions against E. coli NIHJ and Providencia rettgeri 1603. In 3 strains, the MICs of CPDX-PR in the presence of LFN were reduced to1/64. 3. In the evaluation of clinical effect of CPDX-PR, efficacy rates were 53/57 (92.9%) in a patient group with infections. The incidence of adverse reaction was 0/57.

Flomoxef (FMOX) was administered as an initial treatment for chorioamnionitis complicating possible spontaneous abortion or premature delivery and preterm PROM (premature rupture of the membranes), and the clinical effectiveness of the drug, and the usefulness of fetal fibronectin (FFN) as a diagnostic marker of premature delivery were evaluated. 1. Clinical effects of drip infusion of FMOX (2-4 g/day) with and without tocolysis for the treatment of chorioamnionitis were evaluated in 43 patients with possible spontaneous abortion or premature delivery and those with preterm PROM (n = 43). Changes in the FFN level in the vaginal secretion were also studied in 11 patients. 2. It was possible to prevent premature delivery in 7 (26.9%) of 26 patients, and the latent period of preterm PROM was longer than 8 days in 6 (46.2%) of 13 patients. 3. The FFN level decreased slightly in patients for whom FMOX was effective, and the outcome was satisfactory in those whose FFN levels were less than 200 ng/ml. However, the outcome was poor in those whose FFN levels were higher than 1,000 ng/ml. These findings suggest that changes in the FFN level in the vaginal secretion reflect the clinical course of chorioamnionitis as do changes in CRP.

In the development of infectious diseases at non-pregnancy and at pregnancy, correlations between bacterial flora in the vagina and portio vaginalis and the ascending infections of those bacteria have recently been discussed. To clarify the cause of those infectious diseases, we studied the localization of microorganisms in genital regions. Patients undergone abdominal total hysterectomy (n = 172) were employed as subjects, and microorganisms isolated from 4 genital regions were studied. In addition, the preventive effect of cefmetazole (CMZ) against postoperative infections was analyzed in 479 cases including the hysterectomy cases mentioned above. The results obtained are summarized as follows: 1. The isolation rate of microorganisms at non-pregnancy, from subjects of 30 to 69 years old, was 65.6% (82/125) in the vagina and portio vaginalis, 52.1% (25/48) in the cervical mucus, 7.3% (9/124) in the uterine cavity and 0% (0/47) in the ovarian surface. 2. Numbers of microorganisms isolated in each region were 99 strains in the vagina and portio vaginalis, 28 in the cervical mucus, 10 in the uterine cavity and none in the ovarian surface. Isolation of aerobic Gram-positive bacteria (60-89.3%) and anaerobic Gram-positive bacteria (7.1-30%) were varied in each region. Lactobacillus spp. (38 strains), Staphylococcus epidermidis (20 strains) and Propionibacterium acnes (10 strains) were isolated from vagina and portio vaginalis, and Lactobacillus spp. (17 strains) were the most often isolated bacteria from the cervical mucus.(ABSTRACT TRUNCATED AT 250 WORDS)

The efficacy and safety of early therapy with imipenem/cilastatin sodium (IPM/CS) were studied in patients who had chorioamnionitis with preterm PROM or threatened abortion and premature delivery. The following results were obtained. 1. The clinical efficacy of IPM/CS administered by intravenous drip infusion at daily dosages of 1 to 2 g as concurrent treatment with antiuteronics (ritodrine hydrochloride or terbutaline sulfate) was studied in patients with threatened abortion and premature delivery in the 11th to 34th week of pregnancy (n = 9), or premature PROM in the 23rd to 36th week (n = 9). 2. Response to IPM/CS were good in all of the patients with threatened abortion and premature delivery. Latent periods were prolonged for more than 7 days in 44.4% (4/9) of the patients with preterm PROM. 3. Changes in elastase appeared to be significant as those in CRP for inflammatory markers. 4. These findings combined with our previous results indicate that treatment of preterm PROM before the 32nd of pregnancy prolongs the latent period.

The efficacy and safety of imipenem/cilastatin sodium (IPM/CS) were studied in patients with obstetric and gynecologic infections and in those given the drug as prophylaxis against postoperative infections. The following results were obtained: 1. Efficacy rates were 96.0% (48/50) in patients with obstetric and gynecologic infections and 100% (28/28) in those with urinary tract or other infections. The overall efficacy rate was 97.4% (76/78). Bacteriologically, 30 organisms were isolated from 28 patients. The eradication rate was 95.2% (20/21) and the efficacy rate was 96.4% (27/28). 2. Changes in blood elastase before and after treatment were compared with those in CRP, WBC, and ESR in the patients with obstetric and gynecologic infections. The changes in elastase were similar to those in CRP. 3. The efficacy rate was 98.0% (48/49) in the patients given prophylaxis against postoperative obstetric and gynecologic infections. 4. An adverse reaction was observed in only one patient (diarrhea), and abnormal laboratory findings were noted in 2 patients (elevation of GOT and GPT). These results indicate that IPM/CS is very useful for the treatment of obstetric and gynecologic infections.

An in vitro study was done to evaluate combination use of aspoxicillin (ASPC) with each of 3 beta-lactam preparations, ceftazidime (CAZ), cefmetazole (CMZ) and aztreonam (AZT). The results obtained are summarized as follows: 1. ASPC has strong activity against Gram-positive bacteria and anaerobic bacteria, while CMZ and CAZ have strong activity against Gram-negative bacteria. 2. Rates of beta-lactamase producing strains among the isolated bacteria (a total of 383 isolates) were 4.4% among Gram-positive bacteria, 71.6% among Gram-negative bacteria and 89.3% among anaerobic bacteria. The overall rate of beta-lactamase secreting strains among all isolates was 46.5%. 3. Efficacies of combination uses were studied using the FIC index. Combination of ASPC and CAZ was effective against 95.0% of the isolates, ASPC and AZT against 85.7%, and ASPC and CMZ against 83.5%. Combination of ASPC and CMZ showed antagonism in 12.8% of the isolates. In conclusion, combination use of ASPC with any one of CMZ, AZT or CAZ proved to be highly effective. In particular, combination of ASPC and CAZ appeared to be the best in view of complementing antibacterial spectra.

We investigated the clinical efficacy and the safety of levofloxacin (LVFX, DR-3355) in obstetrical and gynecological infections and the following results were obtained. 1. Clinical efficacies were evaluated as excellent in 2 and good in 9 cases, hence the efficacy rate was 100%. 2. Bacteriologically, the eradication rate was 16/17 (94.1%). 3. No Side effects nor abnormal changes in laboratory test results were observed. These results indicated that LVFX was highly useful in the treatment of obstetrical and gynecological infections.

We evaluated the clinical efficacy and safety of intramuscular (as a new route of administration) imipenem/cilastatin sodium (IPM/CS) in patients with intrauterine infections which are typical in the field of obstetrics and gynecology. The obtained results are summarized as follows. 1. Twenty-seven patients were treated with IPM/CS, 250 mg/250 mg b.i.d. (3 patients), 500 mg/500 mg b.i.d. (22) and other dosages (a change in dosing regimen, 2). The duration of treatment ranged from 3 to 11 days and the total dosage during an entire course of treatment varied from 1.5 to 9.0 g. The drug was suspended in a lidocaine solution and administered in the gluteal muscle of the patients. 2. Clinical efficacies were excellent in 7 patients (26%), good in 19 (70%) and poor in 1 (4%) and the overall efficacy rate was 96.3%. All of the 8 patients who had not previously showed improvements with treatment by other antibiotics responded well to this drug. 3. Bacteriologically, the clinical efficacy rate was 95.8% (23/24) and the eradication rate was 76.2% (16/21). 4. No adverse effects due to the drug were observed. As abnormal laboratory test results, transient elevations of GOT and GPT were noted in one patient.

Although it has been reported that the incidence of methicillin-resistant Staphylococcus aureus (MRSA) infections is extremely low in the obstetrics/gynecology setting, we recently had 5 patients with MRSA infections in the obstetrics/gynecology departments of 4 clinics in Yamagata Prefecture from September 1990 to February 1991. 1) Classified by disease, 4 of the patients had intrauterine infections (3 puerperal intrauterine infections and 1 intrauterine infection) and 1 had a postoperative wound infection. 2) Classified by treatment after the MRSA isolates had been determined, 2 of the patients were given imipenem/cilastatin alone (which turned out to be effective), 2 were given concomitant IPM/CS + quinolone agents (ofloxacin, tosufloxacin; effective) and 1 was given minocycline and OFLX. The principal lessons we learned from these cases are that attention should be paid to the occurrence of MRSA infection even in the obstetrics/gynecology field and that the method of selecting and administering antibiotics to prevent and treat such infections should be reconsidered.

We conducted clinical efficacy and safety tests of flomoxef (FMOX, 6315-S) in the perinatal infections and obtained the following results. 1. A total of 25 patients was treated: 16 patients with intrauterine infections, 2 patients with pelvioperitonitis, 4 patients with urinary tract infections and 3 patients with other infections. FMOX was injected at a daily dose of 2-4 g for 3-15 days (6-60 g for total dose) by intravenous drip infusion, intravenous injection or their combination. 2. The clinical efficacy rate was 96.0% of 25 patients: excellent in 4 cases (16.0%), good in 20 cases (80.0%) and poor in 1 case (4.0%). Bacteriological effects obtained were: eradicated in 14/16 cases (87.5%) replaced in 3 cases. 3. There were no subjective or objective side effects, nor were any abnormal laboratory test values attributable to the drug. From these findings, we consider that FMOX treatment appears to obtain good clinical and bacteriological responses and in safe in perinatal period infections.

In order to understand the clinical efficacy of cefteram pivoxil (CFTM) in the treatment of asymptomatic bacteriospermia, the following studies were performed. 1. Concentrations of CFTM in the semen after oral administration of 200 mg to normal healthy adults (n = 5) reached a maximum level of 0.66 +/- 0.04 microgram/ml in 5 hours after the administration, then decreased rapidly, and averaged 0.15 +/- 0.03 micrograms at 7 hours after administration. 2. Activities of CFTM, cefaclor (CCL) and lomefloxacin (LFLX) against bacteria which were detected in semen (n = 65) (11 aerobic bacterial strains and 48 anaerobic bacterial strains) were retrospectively studied. The study of activities of these 3 agents against anaerobic bacteria showed that CFTM tended to be more active than CCL, LFLX, and similar tendency was noted in LFLX more than CCL against Peptostreptococcus sp. When penetration of antibiotic agents into semen is considered, however, some anaerobic bacteria as well as some aerobic bacteria may not be eradicated or inhibited, hence farther studies are needed to facilitate the selection of proper methods of administration as well as that of effective antibiotics.

Clinical effects of combined use of aztreonam (AZT), amikacin (AMK) and clindamycin (CLDM) in 46 cases with infectious diseases in obstetrics and gynecology were retrospectively studied in 2 groups, and the following results were obtained. 1. No significant difference in efficacy rates was noted between AZT plus CLDM treated group (n = 25) and AMK plus CLDM treated group (n = 21) (96.0% vs. 95.2%), while rate of excellent efficacy was slightly higher in AZT plus CLDM group than AMK plus CLDM group (24.0% vs. 14.3%). 2. No significant difference in bacteriological clinical effects was also noted between the 2 groups, while bacteriological eradication rate was higher in the AZT plus CLDM group than in the other group (76.2% vs. 50.0%), and the difference was particularly clear in the eradication rates of aerobic, Gram-negative bacteria (88.9% vs. 30.0%). 3. Subjective and objective side effects, and abnormalities of clinical test results were not found in either group.

We performed abdominal hysterectomy and administered aztreonam (AZT) for prophylaxis of postoperative infections, and investigated influences of the antibiotics on vaginal bacterial flora. The obtained results are summarized as follows. 1. Patients administered with AZT were studied (n = 48) for bacteria isolated from their vaginae preoperatively and at the 7th and the 14th days postoperatively. Groups of patients administered with cephalothin (CET), cefamandole (CMD) and latamoxef (LMOX) were also studied for comparison. 2. In the AZT group, the rate of isolation of aerobic Gram-positive bacteria was high (68.8-81.4%) whereas those of aerobic Gram-negative and anaerobic bacteria were low. 3. When changes in isolation frequencies of bacteria from the subjects preoperatively to postoperatively were compared, the following tendencies were observed: increase in the rate of aerobic Gram-positive bacteria was larger in the LMOX group than in the AZT group whereas decrease in the rate of aerobic Gram-negative bacteria was largest in the LMOX group followed by the AZT group then by the CMD group. Rates of decrease of anaerobic bacteria showed similar tendencies to the latter. Isolation rates of Candida sp. showed the largest increase in the LMOX group, followed by CET, CMD then AZT groups.

Clinical effects of aztreonam (AZT), a monobactam antibiotic, on perinatal infections were studied with the following results: 1. Efficacy rate of AZT in the clinical application to 12 cases of perinatal infections via 2-4 g/day drip infusion (total dosage 8-24 g) was 91.7% (11/12). Breakdown of the effects according to diseases were "excellent" for mastitis (n = 3), pyelonephritis (n = 1) and urinary tract infection (n = 1), and "good" for a total of 6 cases, i.e., amnionitis (n = 2), amniotic fluid infections (n = 3) and external genital infection (n = 1). 2. Results of bacteriological studies were "eradicated" (n = 1), "replaced" (n = 4), "appeared" (n = 2) and "unknown" (n = 5). MIC values of AZT (10(6) cells/ml) were in a range of 25- greater than 100 micrograms/ml in 1 case of cervicitis (complicated with amnionitis) in the 13th week of pregnancy where AZT was found non-effective. 3. Neither subjective nor objective side effects nor abnormal clinical values were observed during the treatment with AZT.

The relationship between indigenous bacterial floras in the lower genitals and the uterocervical region is of importance due to a barrier-like role against ascending infections through the mechanism of the localized protection at a boundary of the uterocervical region. Therefore, bacterial flora in the uterocervical and uterine regions was studied in cases for which gynecological operations were performed (n = 77). 1. Ratios of incidences of the detection of bacteria on the uterocervical and in the uterine regions were 50/77 (64.9%) and 6/77 (7.8%), respectively. When different age groups are compared, the detection ratio from the uterocervical region was high among patients in the 40 s, and all the cases in which bacteria were detected from the uterine region were in the 40 s. 2. Gram-positive bacteria were detected at a high ratio, and anaerobic bacteria were noted in the uterocervical region, and ratios of detection of Staphylococcus epidermidis, Lactobacillus sp. and Propionibacterium acnes were high. Six strains of Gram-positive bacteria and 1 strain of Candida sp. were noted in the uterine region. 3. When cefmetazole (CMZ) was administered for the prevention of the infections after these panhysterectomy cases examined here, no postoperative infectious diseases nor adverse reactions were noted.

Analysis was made to determine concentrations of cefmetazole (CMZ) in maternal serum, and intrauterine tissues of myometrium, placenta, fetal membrane, amniotic fluid and fetal lung after one shot intravenous infusion of 100 mg of CMZ to rabbits with 25th day-pregnancy, and the following results were obtained. 1. Concentrations of CMZ in maternal serum, myometrium and placenta reached their maximum levels in 30 minutes after administration, then decreased rapidly. 2. The concentration of CMZ in the fetal membrane reached its maximum level in 30 to 60 minutes after the administration, then it decreased to a nearly constant level. 3. The concentration of CMZ in the amniotic fluid showed its maximum level in 30 minutes after administration, then decreased, but somewhat increased again thereafter. 4. The concentration of CMZ in the fetal lung was elevated gradually after administration, then decreased after reaching its maximum level at 90 minutes, after administration to a nearly constant level. It was deemed, however, that higher concentrations would be necessary to achieve therapeutic effects because attained concentrations were lower than those in other tissues.

Asymptomatic bacteriospermia was studied as an entity and its treatment was investigated in 65 subjects who clinically needed their semen tested. The obtained results are summarized as follows. 1. The rate of detection of bacteria in semen was 89.2%, and the rates of detection of aerobic and anaerobic bacteria were 55.4% and 70.8%, respectively. Forty Gram-positive strains were identified among the aerobic bacteria; rates of detection for Staphylococcus epidermidis and Enterococcus faecalis were high, and 6 strains (9.2%) of Streptococcus agalactiae were also present. The rate of detection of Gram-negative bacteria was low; only 3 strains were identified. Among the anaerobic bacteria 90 Gram-positive strains were identified; the rate of detection of Peptostreptococcus (58 strains) was high, and only 11 strains of Gram-negative bacteria were present. 2. Among cefaclor (CCL), cephalexin, lomefloxacin, latamoxef and flomoxef (FMOX), FMOX was, in general, superior to the other drugs in terms of antibacterial activities against those strains isolated from semen. 3. Bacterial changes were observed in the semen specimens from 11 subjects who were subjected to oral administration of CCL (1,500 mg/days). After the treatment, 25 strains of bacteria disappeared but 7 strains remained among 32 strains that were present before treatment, and 23 strains appeared due to superinfection.

Ceftriaxone (Ro 13-9904, CTRX), a newly developed parenteral cephalosporin antibiotic was clinically evaluated in gynecoobstetric infections and the following results were obtained. CTRX was administered by intravenous drip infusion twice a day in a daily dose of 2 to 4 g to 10 cases with gynecoobstetric infections, consisting of 8 with intrauterine infections, 1 with adnexitis and 1 with infection of external genitalia. The global clinical efficacy was excellent in 2 and good in 6 out of 8 cases with intrauterine infections, and in 2 others, the efficacy rate being 100%. Bacteriologically, the eradication of bacteria was observed in 5, unchange in 2 and alternation of bacteria in 2 among 9 cases where the causative strains were detected. Neither adverse reaction nor laboratory test abnormality was observed. The above-mentioned results suggest that CTRX is a highly safe antibiotic expected to be excellent in the clinical efficacy and bacteriological effects.

Cefmenoxime (CMX) was administered to protect against postoperative infections in 52 cases of cesarean section and 50 cases of total abdominal hysterectomy. These two represent common operations in the gynecological field. Group I was given the agent at a total dose of 14 g (postoperatively 4, 4, 2, 2 and 2 g), group II at a total dose of 10 g (postoperatively 2, 2, 2, 2 and 2 g) and group III at a total dose of 10 g (2 g during operation and postoperatively 2, 2, 2 and 2 g). 1. When comparing the fever index between the groups, group III showed the lowest level regardless of the type of operation. 2. When comparing clinical test values between the groups, low values of white blood cell count (P less than 0.05, P less than 0.01) and erythrocyte sedimentation rate (P less than 0.05) were observed in group III with cesarean section, and significant decreases in white blood cell count (P less than 0.05) and CRP (P less than 0.01, P less than 0.001) were observed in group III with total abdominal hysterectomy. The above results indicate that the administration of CMX during operation was the most effective method of administration for protection against postoperative infections in terms of changes in fever index and clinical test values.

The antibacterial activity of human cervical mucus in non pregnant or pregnant women were investigated employing the standard blood agar plates. Antibacterial activity of lysozyme and combined effect of lysozyme with cefmetazole (CMZ) were also investigated. The results obtained are summarized as follows: 1. Cervical mucus had an antibacterial activity against Bacillus subtilis, but had no antibacterial activity to any other organisms tested. When cervical mucus was heated at 100 degrees C for 5 minutes, its antibacterial activity was lost. 2. Antibacterial activity of cervical mucus combined with CMZ were obtained against Streptococcus pyogenes only, and no effect was observed against other organisms. 3. Lysozyme had an antibacterial activity against Escherichia coli, B. subtilis, Staphylococcus aureus, Bacteroides fragilis, but when combined with CMZ no antibacterial activity was observed.

The clinical efficacy and the safety of imipenem/cilastatin sodium (IPM/CS) in perinatal infections were studied. The results are summarized below. 1. Clinical efficacy was evaluated in 12 patients with intrauterine infections (endometritis), 3 patients with amniotic fluid infections, 2 patients with puerperal fever and 3 patients with other infections. The drug was administered by intravenous drip infusion at a 0.5g to 1.0g dose as IPM and the total doses during an entire course of treatment were 1.5g to 15g. 2. Clinical efficacies were excellent in 4 (20%) and good in 16 patients (80%) and the efficacy rate was 100%. Ten patients had not improved upon treatments with other previous antibiotics. 3. Infective bacteria were eradicated in 4, decreased in 1, and replaced in 6 patients. 4. No side effects or abnormal clinical laboratory test values were observed in any patient.

The effects of various substances involved in the inhibition of uterine contraction on the uterine muscle of pregnant rats were studied in vitro in terms of uterine contraction and alterations in cyclic nucleotides. 1) The inhibitory effect of 4-aminoantipyrine (4AA) on uterine contraction showed a pattern of decline, being less potent that tranylcypromine. The effect of nifedipine was the most potent, followed by ritodrine, tranylcypromine, RU 486 and 4AA, in that order. The inhibitory effects were diminished by administration of ONO-802.PGF2 alpha. 2) Cyclic nucleotide levels changed according to the potency of each agent in the process of inhibition. Although the level of c-AMP tended to increase and that of c-GMP tended to decrease, there were no changes in their levels when nifedipine was administered. 3) Blood and uterine muscle levels of c-AMP were increased in pregnant rats that had been given ritodrine prior to hysterectomy, and there was no inhibitory effect of ritodrine in comparison with pregnant rats that had not been given the agent. The pregnant rats that had been given ritodrine prior to hysterectomy also showed no significant change in the level of c-AMP in the bath-medium.

Cefazolin (CEZ) and ceftizoxime (CZX) were administered prophylactically to prevent postoperative infections after cesarean section and abdominal simple panhysterectomy, common obstetrical/gynecological procedures. The results were summarized as follows. Total fever indices in cesarean sections for the 2 drug groups were examined and CEZ (n = 8) and CZX (n = 10) indices were found to be 6.0 +/- 3.67 degree hours and 3.6 +/- 1.16 degree hours, respectively. In abdominal simple panhysterectomies, CEZ (n = 11) and CZX (n = 11) indices were 8.15 +/- 5.17 degree hours and 4.26 +/- 2.24 degree hours, respectively. Further, there was a lower daily fever index with CZX than with CEZ in both operation groups. Counts of WBC in both procedure groups were lowest on the 5th postoperative day in the CZX group, so was for the CRP. As for the ESR, the CEZ group was much higher than the CZX group especially in abdominal simple panhysterectomies. Neither subjective/objective side effects nor abnormal laboratory findings were observed in either CEZ or CZX group of patients.

Ceftriaxone (CTRX) was studied for its efficacy and safety in 8 cases of infection during the perinatal period; 6 before, and 2 after delivery. The results obtained are recognized as follows: 1. CTRX was administered by intravenous drip infusion at a daily dose between 2 and 4 g for 2 to 10 days (a total dose: 4 to 20 g) each of 8 cases of infections during the perinatal period; 3 of amniotic fluid infection and 1 each of intrauterine infection, puerperal fever, puerperal wound infection, appendicitis and pyelonephritis. CTRX was evaluated to be very effective in 3, effective in 3 and ineffective in 2, with an efficacy rate of 75% (6/8). 2. Two strains of Enterococcus faecalis and 1 each of Pseudomonas cepacia and Streptococcus intermedius were isolated. All of them were eradicated by the CTRX treatment bacteriologically. 3. No adverse reactions were observed subjectively or objectively. A slight transient elevation of GOT, GPT and Al-P was observed in 1 case. No abnormal sign was observed in neonates.