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Following results were obtained from intravenous administration of T-1982 (cefbuperazone) 1 g by measuring its concentrations in uterine arterial serum, cubital venous serum, oviduct, ovary and several sites in uterine tissue. Endometrium showed the highest concentration among various uterine tissues by any administration (bolus injection, dripping infusion for 1 or 2 hours). Transfer concentrations about 1 hour after the end of 1 hour drip infusion proved to be almost the same as 2 hours drip infusion. In the field of obstetrics and gynecology, it was considered that T-1982 has good efficacy in infections especially caused by E. coli, Klebsiella and Proteus.

The change in 3',5'-cyclic adenosine monophosphate (c-AMP) concentration was observed in various organs of rats in gonadal cycle in adult group and with aging (30, 70, 100, 120 weeks), and in human ovaries with aging. 1) The average c-AMP concentration of ovaries of rats showed a significant change with estrus cycle and was higher in the following sequence: proestrus, diestrus II, diestrus I and estrus phase. This tendency was also seen in hypothalamus and pituitary, but was not statistically significant, 2) The average c-AMP concentration in tissues began to decline significantly from 70 weeks in cerebral cortex and hypothalamus, and from 80 weeks in ovaries. However, on the other hand the concentrations in pituitary, liver and adrenal declined markedly from 100 weeks. 3) The c-AMP in ovaries of 80 weeks rats by pregnant mare serum (PMS) road increased by 0.5-fold in concentration, and by 0.6-fold in whole tissue relative to that of 30 weeks rats. 4) A significant difference in serum LH and FSH level between ovarian artery and vein was not found in cycling mature group, non-cycling climacteric group and post-menopausal group of women. 5) Both average concentrations and total values of c-AMP in ovaries of non-cycling climacteric and post-menopausal women were lower than those of mature cycling women. This fact may imply a different response by ovarian tissues such as corpus luteum, follicle and other tissues to gonadotropin. From these results of c-AMP in tissues, it is concluded that the decline of ovarian function with aging of rats was relatively earlier than pituitary, although being delayed compared with hypothalamus, and were the ovarian function in humans declined in the premenopausal period.

This experiment was undertaken to compare the steroidogenesis in human ovary at different stage of the cycle. Fifteen subjects, 8 in follicular, 7 in luteal phase were selected for this study. On hysterectomy, both ovarian and peripheral venous blood were collected simultaneously and follicle or corpus luteum were obtained. Steroid levels including pregnenolone(P5) 17 alpha-OH-P5, DHA, androstenediol (AD), progesterone(P4), 17 alpha-OH-P5, androstenedione(delta 4A) and testosterone(T) were measured by radioimmunoassay. Tissue were homogenized and incubated with labeled P5, 17 alpha-OH-P5, DHA and AD in the presence of NAD t 37 degrees C. As gas phase, CO was used. Metabolites were extracted and separated by TLC. 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) activity was expressed as the amounts of delta 4-steroid formed from corresponding delta 5 substrate. The levels of P5, P4, 17 alpha-OH-P4, DHA, delta 4A, T in the ovarian vein and the concentration of P5, 17 alpha-OH-P5, DHA, P4, 17 alpha-OH-P4, T in the ovarian tissue obtained in luteal phase were significantly higher than that in follicular phase. The results suggested that the delta 5 pathway seem to be active in corpus luteum. In follicular phase, highest concentration of 17 alpha-OH-P5 among delta 5 in ovarian vein and 17 alpha-OH-P4 among delta 4 steroid in ovarian vein and tissue was noticed. 3-beta-HSD activity was lower in follicle than that in corpus luteum. Substrate specificity was noticed in 3 beta-HSD in follicle and it was found that 17 alpha-OH-P5 seemed to be the most potent substrate for the enzyme. The difference of steroidogenesis between follicular and luteal phase was demonstrated in human ovary.

The characteristics of specific receptors for prolactin (PRL) in the ovary were examined. The binding of 125I-ovine PRL to the receptor was dependent upon time, temperature, and tissue concentration. Equilibrium was reached by 16 h at 23 degrees C in the 12.5 mg tissue/tube. Scatchard analysis revealed a high affinity, low capacity and single class of binding site. Ovine PRL bound to rat liver membranes with a Kd (dissociation constant) of 3.51 X 10(-10) M and to rat ovarian membranes with a Kd of 2.21 X 10(-10) M, respectively. The number of binding sites in rat liver and ovary were 205.2 fmoles/mg of protein and 226.1 fmoles/mg of protein, respectively. Bound 125I-ovine PRL was displaceable by unlabelled human, ovine and rat PRL but not by rat LH, FSH, TSH or GH. However, on the immunological aspects, 125I-ovine PRL bound only to anti-ovine PRL serum but did not bind to anti-human PRL serum or anti-rat PRL serum. Unlabelled human and rat PRL could not inhibit the binding of labelled ovine PRL to the anti-ovine PRL serum. These data indicate the existence of specific PRL receptors in the rat ovary, the characteristics of which are similar to those of receptors in the liver. The binding specificity for various mammalian species suggests a difference between biological and immunological binding sites of the PRL molecule.

Fundamental and clinical studies on T-1982 (cefbuperazone), a new cephamycin antibiotic, were carried out, and the following results were obtained. When T-1982 was administered at a dose of 1 g by intravenous drip infusion for 30 minutes or 1 hour, the concentration in serum showed as high as 23.0 micrograms/ml or 25.0 micrograms/ml even 2 hours after administration. The concentrations in the genital tissues about 5 hours after administration ranged 1.2-45.6 micrograms/g for 30 minutes drip infusion and 0.9-26.8 micrograms/g for 1 hour drip infusion. From these results, T-1982 was supposed to maintain the in vivo concentration to inhibit 80-100% the growth of bacteria such as S. aureus, E. coli, Klebsiella, Proteus, S. marcescens and Gram-negative anaerobic bacteria, B. fragilis which were often isolated clinically in the field of obstetrics and gynecology. When T-1982 was administered at a dose of 1-2 g twice a day to 14 patients with female genital infection; 2 intrauterine infection, 2 pyometra, 7 pelveoperitonitis, 1 adnexitis, 1 adnexal abscess and 1 vaginal cuff abscess, the clinical results were excellent in 9, effective in 4 and poor in 1. The efficacy rate was 92.9%. No side effects nor abnormalities in laboratory findings were observed in any of the 14 cases. These results suggest that T-1982 has efficacy for the treatment of obstetrical and gynecological infections.

A pharmacokinetics and platinum concentration in the gynecologic organs were measured following the intravenous drip infusion of 375 mg/m2 of CBDCA. Total platinum (TP) in plasma decreased biphasically and free platinum (FP) was almost monophasically eliminated. The t 1/2 of FP was about 51 min. and the percentage of FP out of TP at four hours after administration was more than 92%, which was much higher proportion compared with that of cisplatin (CDDP). A cumulative excretion of platinum in the urine within 24 hours was 69%. The platinum concentration in the benign part of portio and endocervix were higher than that of malignant portion, although there were no significant differences in other pelvic organs such as ovary and tubes. However, pelvic lymph-nodes showed less platinum concentration both in metastatic and non-metastatic tissues. Platinum concentration in the tissue did not change significantly with lapse of time. Bone marrow suppression was observed especially in the patients who had received chemotherapy or radiotherapy. No renal toxicity was observed even without any hydration and gastro-intestinal toxicity was much milder than that of CDDP.

Fundamental and clinical studies on T-1982 (cefbuperazone), a new cephamycin antibiotic, in the field of obstetrics and gynecology were carried out, and the following results were obtained. The levels of T-1982 transferred to uterine artery, elbow vein and uterus were determined after intravenous drip infusion of 1.0 g for 1 or 2 hours. No difference of concentration between uterine artery and elbow vein was observed from 45 minutes to 5 hours after the end of administration. The concentration of T-1982 in uterine artery ranged from 9.8 to 48 micrograms/ml after drug administration, and decreased slowly, but remained at about 10 micrograms/ml even 5 hours after the end of administration. Endometrium exhibited comparatively higher concentration of T-1982, but the difference of concentration was not observed among the other uterine tissues. T-1982 concentration ratios of various uterine tissues to elbow vein blood ranged from 172 to 10.2%, and mean ratio was 34.7%. Also, T-1982 concentration of more than 3 micrograms/g in each tissue was maintained for 2 hours after the end of administration. Clinical results on abscess of Bartholin's gland (1) and adnexitis (1) were good, although bacteria were not detected. No side effects caused by the drug were observed. These results indicate the usefulness of T-1982 in the treatment of infections in obstetrics and gynecology.

Effects of intra-uterine or tail vein administration of prostaglandin (PG) F2 alpha on hormone levels in ovaries were studied. Adult Wistar rats weighing 150-180 g were used. PGF2 alpha was injected into the uterine lumen (100 ng/rat) and tail vein (200 ng/0.1 ml) of estrus rats, respectively, and intra-uterine administration of PGF2 alpha was given to hypophysectomized rats. Variation in the levels of ovarian steroids (estradiol, progesterone, 20 alpha-hydroxypregn-4-en-3-one (20 alpha-OH-P) were studied. The amount of PGF2 alpha injected into rats was minute compared with that of the usual PGF2 alpha injection (microgram/0.1 ml). Before start of the experiments, the levels of ovarian steroids of adult rats in all stages of estrous were measured. Each of the three steroids showed a maximum level at the time of proestrus. When PGF2 alpha was administered into the uterine lumen and tail vein of rats, the level of estradiol increased gradually, while that of progesterone and 20 alpha-OH-P decreased sharply at 10 min (p <0.05) after administration. On the other hand, when PGF2 alpha was given into the uterine lumen of hypophysectomized rats, the reverse pattern was seen, that is, estradiol decreased, whereas progesterone and 20 alpha-OH-P gradually increased. Thus, the intrauterine administration of PGF2 alpha does have an effect on levels of ovarian steroids.

Although there have been several reports indicating the existence of GnRH or GnRH-like substance in the rat ovary, its synthesis as well as its physiological role in the ovary still remains unknown. In the present study, GnRH mRNA in the rat ovary was examined by using a cRNA probe complementary to the gene of the rat GnRH. The hybridizing band of 700bp was found in the extract from the rat ovary by northern blotting with 32P-labeled GnRH cRNA. In situ hybridization with 35S-labeled cRNA revealed that the site of synthesis of GnRH was granulosa cells and its synthesis was stimulated by the administration of PMSG. These results suggest that GnRH is synthesized in the rat ovary and may play a role in the local regulation of ovarian function.

Fundamental and clinical studies were made on T-1982 (cefbuperazone) and the results were obtained as follows. Serum and uterine tissue concentrations of T-1982 were determined at 26 minutes before and at 20 to 80 minutes after the completion of intravenous drip infusion of 1 g. The levels of T-1982 in the fallopian tube, ovarium, endometrium, myometrium and uterine cervix were 23.7, 19.5, 50.5, 10.9 micrograms/g and 17.5 micrograms/g at 20 minutes after the completion of infusion. The levels were sufficiently effective against major pathogens (Gram negative bacteria and anaerobic bacilli) isolated in the field of obstetrics and gynecology. T-1982 was administered to 11 patients, including 7 of acute adnexitis, each one of pelveoperitonitis, pyometra, puerperal fever, and 1 of puerperal fever with sepsis, at a dose of 1-2 g twice a day for a period of 5 to 9 days by intravenous injection or intravenous drip infusion. Clinical responses were excellent in 5, good in 3 and poor in 3. No adverse reactions nor marked changes in laboratory findings were observed in any of the cases treated with T-1982.

The biological effects of prolactin (PRL) on the uterus and ovary, and the cooperative action of PRL and estrogen to these tissues were investigated in the female white rabbit. 1) Estrogen receptor (ER), progesterone receptor (PR, not in ovary) and PRL receptor were demonstrated in the rabbit uterus and ovary. The dissociation constant determined by Scatchard analysis was approximately at the level from 10(-10)M to 10(-9)M in each ligand binding to receptor. 2) In the pseudopregnant rabbit, b-PRL (30 iu/kg) increased the uterine and ovarian weight (p less than 0.001, p less than 0.01 respectively) but neither altered the steroid levels, nor the uterine and ovarian cytoplasmic ER levels. In the uterus, b-PRL increased the PRL receptor levels and tended to increase the nuclear ER levels. 3) In the ovariectomized immature rabbit, b-PRL (30 iu/kg) increased in uterine weight (p less than 0.05), decreased the uterine cytoplasmic ER levels (p less than 0.05), but increased the nuclear ER levels (p less than 0.05). With estrogen, b-PRL increased the uterine weight (p less than 0.05); tended to increase the cytoplasmic and nuclear ER levels, and increased the cytoplasmic PR levels (p less than 0.05). 4) In the ovariectomized immature rabbit, b-PRL did not change the histological finding of the uterus, whether estrogen was primed or not. In the pseudopregnant rabbit, b-PRL accelerated the progestational proliferation of the uterus. These results indicated that PRL demonstrated the biological effect on the rabbit uterus and ovary directly via PRL receptor, and that PRL enhances the estrogenic action, giving the effect on the mechanisms related with ER in the rabbit uterus.

To elucidate the significance of fibrinolytic enzymes in ovulation, the changes in the levels of plasminogen activator, plasminogen and plasmin activity were examined using prepubertal rats and sows treated with PMS and hCG. The following results were obtained. 1) The superovulation in rats was blocked with antifibrinolytic agents. 2) Plasminogen and plasminogen activator in the supernatant of rat ovarian homogenates increased toward ovulation. But plasmin activity did not show the significant change. 3) When the superovulation of the rats was blocked with indomethacin, plasminogen remained constant, but plasminogen activator was almost affected. 4) In the supernatant of follicle wall homogenates and the follicular fluid of sows, plasminogen decreased, but plasmin activity increased toward ovulation. 5) Plasminogen activator was produced by rat ovarian granulosa cells, but hCG, gonadotropins, prostaglandins and indomethacin did not activate the production of plasminogen activator in the granulosa cells.

A growth factor which stimulates DNA synthesis in resting mouse Balb/c 3T3 cells (3T3 cells) has been extracted from human follicular ovaries and partially purified. The dialyzed cytosol stimulated 3H-DNA synthesis in 3T3 cells dose-relatedly. When the extract was subjected to salting-out procedures with ammonium sulfate, there was found a 60% saturation cut containing growth promoting activity. Ion exchange on a cation exchanger of the active 60% cut produced an active fraction in the 1M NaCl elute. Gel filtration of ovarian cytosol yielded an active fraction that eluted between chymotrypsin (25,000 MW) and cytochrome C (12,400 MW). The data presented here indicate the presence of an endogenous growth factor in human ovary. The factor appears to be a basic protein, heat-labile and soluble in 40% or less ammonium sulfate, with a molecular weight of between 12,400-25,000. With respect to the biochemical characteristics, this growth factor is quite similar to the porcine ovarian growth factor previously reported.

1) Serum concentrations of cefoxitin (CFX) was lower than that of cefazolin (CEZ), but the tissue concentrations of CFX were higher in ovary, oviduct and uterus compared with CEZ. 2) CFX was administered to 15 patients with moderate intrapelvic or urinary tract infections at a dose of 4 g per day for 5 to 7 days. The overall results obtained were as follows; excellent in 6 cases, good in 6 cases. The CFX treatment was effective in all patients, 8 cases, with intrapelvic infections. 3) The majority of organisms detected were E. coli (12 strains), and the antimicrobial activity of CFX against them was superior to those of CEZ and CET. 4) No side effects and abnormal laboratory findings were observed. 5) It is considered that CFX will be a useful drug in the field of obstetrics and gynecology.