Orexins/hypocretins regulate drinking behaviour.

Orexin/hypocretins are recently identified neuropeptides which regulate feeding behaviour. We found orexins increased water intake when administrated intracerebroventricularly to rats. The effect of orexin-A was more potent as compared with orexin-B, suggesting the possible involvement of OX(1) receptor. The efficacy of orexin-A was almost comparable with that of angiotensin II, and the effect lasted more than 3 h. Prepro-orexin mRNA level was up-regulated when rats were deprived of water. Orexin-immunoreactive varicose axons were observed in the subfornical organ and area postrema, regions implicated in drinking behaviour. These observations suggest a physiological role for orexin as mediators that regulate drinking behaviour.

Orexin-induced food intake involves neuropeptide Y pathway.

Orexins (orexin-A and -B) are recently identified neuropeptides, which are thought to be implicated in the regulation of feeding behavior. We used a NPY-Y1 receptor specific antagonist, BIBO3304, to examine whether NPY is involved in orexin-induced feeding behavior. Intracerebroventricular administration of orexin-A (10 nmol) induced food intake in rats (food intake for 3 h; vehicle 0.3+/-0.2 g vs. orexin-A 10 nmol, 4.0+/-0.5 g, n=4). Orexin-induced feeding behavior was partially inhibited by prior administration of BIBO3304 (3 h food intake: orexin-A 10 nmol, 4.0+/-0.5 g vs. BIBO3304 (60 microgram) + orexin-A 10 nmol, 2.2+/-0.2 g, n=4). A low dose of BIBO3304 (30 microgram) did not show a significant inhibitory effect. BIBO3457, an inactive enantiomer, used as a negative control, did not show any inhibitory effect on orexin-A-induced feeding behavior. Fos expression was observed in NPY-containing neurons in the arcuate nucleus 1 h after orexin-A (10 nmol) was administered intracerebroventricularly (control 0.3+/-0.08%, orexin-A 10.2+/-0.8%, n=5 rats/group). These observations suggest that NPY is involved in orexin-induced feeding behavior. However, BIBO3304 did not completely abolish the effect of orexin-A. These results suggest that orexin-A elicits feeding behavior partially via the NPY pathway. The NPY system could be the one of downstream pathways by which orexin-A induces feeding behavior. Another pathway may also be involved in orexin-A-induced feeding behavior, because BIBO3304 did not completely abolish orexin-A-induced feeding behavior.

Orexin-mediated feeding behavior involves both leptin-sensitive and -insensitive pathways.

Orexin-A and -B are neuropeptides that are implicated in the regulation of vigilance states and energy homeostasis. Orexins are specifically produced by neurons located within the lateral hypothalamic area (LHA), a region implicated in the regulation of feeding behavior. Here, we examined the functional interactions between orexins and anorectic factors [leptin, alpha-melanocyte-stimulating hormone (alpha-MSH) and glucagon-like peptide-1 (GLP-1)] in rats. Intracerebroventricular injection of orexin-A (10 nmol) potently augmented food intake in rats. Neuropeptide Y (NPY) (0.3 nmol) and galanin (3 nmol) also induced a transient increase in food intake. Both NPY- and galanin-induced feeding behaviors were completely inhibited by preadministration of leptin (3 microg), while the same or a higher dose (10 microg) of leptin only partially inhibited orexin-A or -B-induced increase of food intake. Preadministration of anorectic peptides (alpha-MSH and GLP-1), which are shown to be regulated by leptin, abolished NPY-induced feeding; however, orexin-induced feeding was only partially inhibited by these anorectic peptides. These observations suggest that NPY- and galanin-induced increases of feeding involve a leptin-sensitive pathway, while orexin-induced feeding involves both leptin-sensitive and -insensitive pathways.

[A study of clinical application of cefmetazole in perinatal period (author's transl)].

The fundamental study of cefmetazole treatment in a clinical situation during the perinatal period were made, and the following results were obtained. Absorption of CMZ in pregnant women is rapid; and the intravenous injection intravenous drip infusion and intramuscular injection of CMZ all reached their peak serum levels in a short time with a half-life of approximately 1 hour or so. The transference of CMZ to the fetus through placenta is good. It is so good that a single dose of 0.5 approximately equal to 1.0 g by intravenous injection, intravenous drip infusion or intramuscular injection can obtain desired concentration levels covering MIC of main causative pathogenic organisms in the cord blood, amniotic fluid and blood in the fetus. Therefore, the administration of CMZ with this dose and method of administration once or twice daily can prevent or treat intrauterine infection. The transition of CMZ to mother's milk is a small quantity and the transition of CMZ through mother's milk to a neonate is considered to be a very small amount. The absorption of CMZ in neonate is rapid. It reaches a peak serum concentration 15 minutes after the intravenous injection. The half-life varies depending on the number days after birth. With the administration of 20 mg/Kg, the half-life at 0 day after birth is 6.32 approximately 6.78 hours, 3.79 hours at 1st day after birth and 2.27 approximately 2.72 hours at 5th-6th day after birth. Excretion into the urine is slow on 0 day after birth and becomes rapid on the 6th day after birth, coinciding with the maintained level of CMZ in the blood. Positive results were obtained from the overview of CMZ administration in the prophpylaxis or treatment of intrauterine infection during the perinatal period. No abnormalities were noted from the examinations performed on a neonate delivered from a mother who had received CMZ during perinatal period. Judging from the various results mentioned above, 20 mg/kg of CMZ administered to a neonate twice a day at 12 hour intervals would be sufficient to attain therapeutic efficacy.

[Fundamental and clinical studies on imipenem/cilastatin sodium in the field of obstetrics and gynecology].

A combination of imipenem (MK-0787), a new carbapenem antibiotic, plus cilastatin sodium (MK-0791), a dehydropeptidase inhibitor (MK-0787/MK-0791 = 1:1) was studied in the field of obstetrics and gynecology and the following results were obtained. Absorption and penetration into genital organ tissues were good. Following a 0.5 g/0.5 g intravenous drip infusion, the maximum plasma concentration in uterine arterial blood was 20.8 micrograms/ml, and the maximum concentrations of the drug in tissues were 9.9 approximately 16.8 micrograms/g, and these levels of MK-0787 exceeded the MIC values against main causative organisms. Rates of elimination of the drug from the tissue and from the plasma were similar. Against gynecological and obstetrical infections, a dose of 0.5 g/0.5 g twice daily for an average duration of 6.3 days produced a clinical efficacy ratio of 94.4% (17/18) and a bacteriological effects rating of 76.9% (10/13). As side effects, one patient showed an eruption and another had an elevated GOT and GPT. Based on the above results, MK-0787/MK-0791 appears to be effective against gynecological and obstetrical infections.

[Pharmacokinetic and clinical studies of ceftazidime in perinatal period].

Pharmacokinetic studies and clinical evaluations of ceftazidime (CAZ) were carried out in perinatal mothers and infants, and following results were obtained. The CAZ was promptly absorbed after intravenous injection or intravenous drip infusion in pregnant women, producing dose-related peak serum levels. Placental transference to the fetus was good. After intravenous injection or intravenous drip infusion of 1.0-2.0 g of CAZ, drug concentration in umbilical serum and amniotic fluid exceeded MICs of CAZ against main pathogenic organisms. Levels of CAZ in umbilical serum ranged 0.2-15.6 micrograms/ml after 1.0 g intravenous injection or intravenous drip infusion, and 0.7-27.2 micrograms/ml after 2.0 g intravenous injection, and those in amniotic fluid were 1.4-21.3 micrograms/ml after 1.0 g administration and 2.0-27.0 micrograms/ml after 2.0 g administration. According to the above results, it is possible to successfully prevent or treat perinatal infections by twice a day administration of CAZ at 1.0-2.0 g/dose. Clinically, CAZ was effective in the treatment of perinatal infections and the prophylaxis of intrauterine amniotic infection without any side effect. Moreover, newborn infants delivered from mothers receiving CAZ treatment did not have any abnormalities in laboratory test. The penetration of CAZ into mother's milk was low, thus the transfer of CAZ from milk to newborn infants should be low. The above results demonstrated that CAZ is a clinically useful antibiotic for the prophylaxis and the treatment of perinatal infections.

[Pharmacokinetic and clinical studies of cefotiam in the perinatal period].

Pharmacokinetic studies and clinical evaluations of cefotiam (CTM) were carried out in perinatal mothers and infants and following results were obtained. The drug was promptly absorbed after intravenous injection or intravenous drip infusion in pregnant women, producing dose-related peak serum levels. Placental transfer to the fetus was effective. After intravenous injection or intravenous drip infusion of 1-2 g of CTM, drug concentration of the umbilical cord blood, amniotic fluid and fetal blood exceeded MICs of the drug against main pathogenic organisms. By administration of the dose of 1-2 g twice a day, therefore, perinatal infections should be successfully prevented or treated. Clinically, CTM was effective in the treatment of perinatal infections. Moreover, newborn infants delivered from mothers receiving CTM treatment had drug concentrations higher than MICs of CTM against main pathogenic organisms. Blood CTM concentrations in infants, however, did not remain high very long after birth, and these infants did not exhibit any abnormalities in laboratory tests. Penetration of CTM into mother's milk was ineffective, thus the transfer of CTM from milk to newborn infants was negligible. These results demonstrated that CTM is a clinically useful antibiotic for the prophylaxis and the treatment of perinatal infections.

[Experimental and clinical studies on BRL 25000 (clavulanic acid-amoxicillin) in the field of obstetrics and gynecology].

BRL 25000, consisting of 250 mg amoxicillin (AMPC) and 125 mg clavulanic acid (CVA), was studied in the field of obstetrics and gynecology. Tissue concentrations The concentrations in venous serum and arterial serum of uterus, different sites uterus, oviduct and ovarium were determined. Tissue concentrations of AMPC and CVA corresponded to 45--75% and 20--50%, respectively of serum concentrations. The good responses were obtained in cases with intrapelvic infection and the overall clinical effective responses were obtained in 100% of patients. Effectiveness was found microbiologically and clinically in infections due to AMPC resistant organisms. No side effects were found.

[Pharmacokinetics and clinical studies on cefpimizole in the field of obstetrics and gynecology].

Cefpimizole (AC-1370), a new cephem antibiotic, was studied in the field of obstetrics and gynecology, and the following results were obtained. The absorption and tissue penetration of AC-1370 into intrapelvic genital organs were good. The peak serum level in the uterine artery after an intravenous drip infusion for 30 minutes was 49.0 micrograms/ml. High concentrations were obtained also in genital organ tissues; the maximum concentrations were 24.4 approximately 39.0 micrograms/g after an intravenous drip infusion. The changing patterns of the tissue concentrations were similar to those in the serum. The penetration of AC-1370 into intrapelvic dead space exudate was good. The level reached a peak of 35 micrograms/ml at 2 approximately 4 hours after an intravenous drip infusion with 1 g and 3.7 micrograms/ml after 12 hours. AC-1370 was effective in 20 out of 21 cases (95.2%) with gynecoobstetrical infections such as intrauterine, intrapelvic infection and mammitis, administered with 1 approximately 2 g twice a day. Few side effects were observed.

[A study of clinical application of cefotaxime in the perinatal period].

Pharmacokinetic studies of cefotaxime (CTX) were carried out in perinatal mothers and infants. CTX was promptly absorbed after intravenous injection, intravenous drip infusion and intramuscular injection in pregnant women, producing dose-related peak blood levels. Placental passage to the fetus was favorable. After intravenous injection, intravenous drip infusion and intramuscular injection of 500--1,000 mg of CTX, drug concentrations of the cord blood, amniotic fluid and fetal blood exceeded MICs of the main pathogenic organisms. By administration of this dose 1 to 2 times daily it is possible to successfully prevent or treat uterine infections. Passage of CTX into the milk of lactating mothers was minimal, suggesting that only minute quantities can possibly be transferred from the milk to newborn infants. Absorption of CTX in neonatal infants was prompt. The peak blood levels of 47.9 micrograms/ml were attained 15--30 minutes after intravenous injection of 20 mg/kg. The half-life ranged from 2.4--5.56 hours, depending on the number of days postpartus. CTX was effective in the prophylaxis and therapy of perinatal uterine infections.

[Pharmacokinetic studies on cefsulodin in perinatal period].

Pharmacokinetic studies on cefsulodin (CFS) were carried out in perinatal mothers and infants. The results obtained are summarized as follows. 1. CFS was promptly absorbed upon intravenous drip infusion in pregnant women, producing dose-related peak serum levels. Placental transference to the fetus occurred quickly and at high levels. Upon intravenous drip infusion of 1-2 g of CFS, drug concentration of the cord blood and amniotic fluid exceeded MICs of clinically isolated strains of Pseudomonas aeruginosa. These levels in cord blood ranged 3.3-16.9 micrograms/ml upon 1 g intravenous drip infusion and 0.8-21.6 micrograms/ml upon 2 g intravenous drip infusion, and in amniotic fluid they were 1.3-15.6 micrograms/ml upon 1 g administration and 5.5-17.9 micrograms/ml upon 2 g administration. The drug was transferred into newborn infant through placenta, showing no tendency to accumulate. According to the above results, it appears possible to successfully prevent or treat perinatal infections through administration of the dose of 1-2 g twice daily. 2. Moreover, newborn infants delivered from mothers receiving CFS administration showed no laboratory test abnormalities. 3. The penetration of CFS into mother's milk occurred at low levels, and the transference from milk to newborn infants appeared to occur at even low levels. The above results have demonstrated that CFS is a clinically useful antibiotic for prophylaxis and treatment of perinatal Pseudomonas infections.

[Pharmacokinetic and clinical studies on cefodizime in obstetrics and gynecology].

Cefodizime (CDZM), a new cephem antibiotic, was studied in terms of its pharmacokinetics and clinical efficacy in the field of obstetrics and gynecology, and the results are summarized as follows: Concentrations of CDZM in serum and genital tissues following 1 g drip infusion (30 min.) were determined and good penetration of CDZM into tissues was recognized. The maximum level in uterine arterial serum was 56.25 micrograms/ml and maximum tissue levels ranged 23.56-40.64 micrograms/g which were above its MIC80's for main pathogenic organisms. Peak concentrations of CDZM in pelvic dead space exudates following 1 g intravenous bolus injection or drip infusion ranged 6.25-6.52 micrograms/ml. The clinical efficacy of CDZM in 17 cases of obstetrical and gynecological infections was investigated using a dose of 1-3 g daily. The clinical efficacy rate was 88.2% (15/17 cases). Bacteriologically, the eradication rate was 83.3%. No side effects or abnormal laboratory test values were observed.

[Fundamental and clinical studies on cefmenoxime in perinatal period].

Pharmacokinetic studies and clinical evaluations of cefmenoxime (CMX) were carried out in perinatal mothers and infants. The following results obtained are summarized as follows. 1. CMX was promptly absorbed upon intravenous injection in pregnant women, reached dose-related peak serum level shortly after administration. Placental penetration into the fetus occurred quickly and at high levels. After intravenous injection of 1 g of CMX, drug concentrations in the cord blood and amniotic fluid exceeded MICs of main pathogenic organisms. The drug transferred into newborn infants were followed by measuring serum level of the newborn. These levels were related to levels of umbilical cord blood and the drug was eliminated gradually from the newborn without accumulation. According to the above results, it appears possible to successfully prevent or treat perinatal infections, through administration of the dose of 1 g twice daily. 2. Clinically, CMX was effective in the treatment of perinatal infections and prophylaxis of intra-uterine amniotic infections without any severe side effect. 3. Moreover, newborn infants delivered from mothers receiving CMX treatment were without abnormalities in laboratory test results. 4. The penetration of CMX into mother's milk was hardly observed and the transference from milk to newborn infants appeared to be occur only at very low levels. The above results have demonstrated that CMX is a clinically useful antibiotic for prophylaxis and treatment of perinatal infections.

[Clinical evaluation of aztreonam in the field of obstetrics and gynecology].

Aztreonam (AZT), a new monobactam antibiotic was evaluated on clinical efficacy and bacteriological response in gynecological and obstetrical infections, and the following results were obtained. AZT was given to 22 cases with obstetrical and gynecological infections at a dose of 1 g X 2 times daily and 86.4% of clinical efficacy, 45.5% of eradicated rate on diagnosis, 52.5% of bacteriological response on isolated organisms and 83.3% of bacteriological effect on cases isolated Gram-negative bacteria were assessed. Side effect incidence was very low.

[Studies on flomoxef in the perinatal period].

Pharmacokinetic, bacteriological and clinical studies on flomoxef (FMOX) in the perinatal period were carried out with the following summary of the results. Antibacterial effects of FMOX on the growth of methicillin-resistant Staphylococcus aureus (MRSA, MIC 400 micrograms/ml), methicillin-sensitive S. aureus (MSSA, MIC 0.78 microgram/ml), Escherichia coli (MIC 3.13 micrograms/ml and MIC 0.20 microgram/ml) in amniotic fluid were determined and it was found that the activity of FMOX was enhanced in the amniotic fluid. FMOX rapidly penetrated into tissues and sera of pregnant women upon intravenous injection and its maternal serum concentrations reached their peak levels shortly after administration. Placental penetration of FMOX to the fetus was good and, after single intravenous injection of 1 g, the concentrations of FMOX in the umbilical cord serum and amniotic fluid exceeded MICs against major causative organisms of perinatal infections. These results indicate that single intravenous injection of FMOX 1 g twice a day is effective for the treatment and prophylaxis of perinatal infections. Injection of FMOX for the treatment of 14 cases of puerperal infections showed excellent clinical effectiveness with 100% clinical effect and 81.8% bacteriological response. No side-effect was observed in any case. All of these results suggested clinical usefulness of FMOX in the perinatal period.

[Clinical evaluation of tinidazole on anaerobic infections in the field of obstetrics and gynecology].

The bacteriological and clinical effect of tinidazole (TDZ) was evaluated in 16 cases of intrauterine, intrapelvic and vulvar infection caused by anaerobic organisms and the following results were obtained. Anaerobes were detected in 16 cases, including 1 case with anaerobes alone and 15 cases with mixed anaerobes and aerobes. Eight different species and 24 strains were detected. A single species was isolated from 9 cases, 2 species from 6 cases and 3 species from 1 case. The main species detected were Bacteroides fragilis and Peptostreptococcus spp. of which 9 strains (37.5%) each were isolated. Escherichia coli and B. fragilis was the most frequently occurring combination. The peak MIC values of TDZ were 0.78 micrograms/ml for B. fragilis and 1.56 micrograms/ml for Peptostreptococcus spp. Most other organisms were also sensitive to TDZ. The bacteriological response of the anaerobic infections to TDZ was 87.5% and overall clinical efficacy was 87.5%. Few side effects were observed.

[Fundamental and clinical studies of T-1982 (cefbuperazone) in the field of obstetrics and gynecology].

T-1982 (cefbuperazone), a new cephamycin antibiotic, was studied for its MICs against clinical isolates, transfer into uterine tissues and clinical efficacy in the field of obstetrics and gynecology. The following results were obtained. The MICs of T-1982 were measured against 397 strains of 13 species. In antibacterial activity, T-1982 was equal to CTT but inferior to CMZ against Gram-positive bacteria. Against Gram-negative bacteria, T-1982 was superior to CEZ and other cephamycin antibiotics, i.e. CMZ and CTT. The activity of T-1982 was almost equal to that of CMZ and superior to that of CTT against B. fragilis. T-1982 concentrations in various uterine tissues attained the peaks of 16.8-35.9 micrograms/g at 34 minutes after intravenous administration of 1 g, the tissue/serum ratios being 34-72%. The tissue concentrations were about 3-4 micrograms/g even at 5-5.5 hours after administration. T-1982 was intravenously administered at a dose of 1 g twice daily to 5 cases with obstetrical and gynecological infections. All the cases responded to the therapy. Elevated GOT and GPT were observed in 1 case, but they returned to normal on 8 days after the therapy.

[The effect of tinidazole on the anaerobic bacterial flora in patients undergoing gynecological surgery].

The various effects have been examined against the anaerobes by administering tinidazole when the operations of gynecology and obstetrics and the following results were obtained. 1. The serum concentrations after the single administration of 1,000 mg of TDZ showed 56.6 micrograms/ml of the peak value (3 hours) and 27.7 micrograms/ml of 24 hours value, and the antibacterial potency was maintained for a long duration. The concentration in the vaginal secretions was 21.8 micrograms/tampon within 24 hours. 2. The detections of anaerobes were made in 74 cases, before the administration, with the results of 1 case alone and 73 cases mixed with aerobes, 10 species and 133 strains being detected, which comprise 33 cases with 1 species, 27 cases with 2 species mixed, 10 cases with 3 species mixed and 4 cases with 4 species mixed. The main species detected were Bacteroides fragilis in 46 strains (34.6%), Peptostreptococcus spp. in 31 strains (23.3%) and Peptococcus spp. in 26 strains (19.5%). 3. The MIC values of the detected bacteria to the TDZ centered upon 0.78 micrograms/ml for Bacteroides fragilis, 3.13 micrograms/ml for Peptococcus spp. and 0.78 micrograms/ml for Peptostreptococcus spp. and those of the others were low, a lot of those being of sensitive strains. 4. The bacteriological effects on the anaerobes were, after the medication, observed to be 71.4% and found significantly more effective than 33.3% of natural eradication and decrease observed in the not administered group. 5. Clinically, no anaerobic infections were observed often operation and the therapeutical effects were observed. A little side effect was observed. 6. According to the above-mentioned results, it was observed possible to prevent from the anaerobic infections after operation in gynecology and obstetrics by administration of TDZ.

[Bacteriological, pharmacokinetic and clinical studies on the use of ceftriaxone in the perinatal period].

Laboratory studies and clinical evaluation of ceftriaxone (CTRX) were carried out with mothers and infants in perinatal period. The presence of synergistic effect between CTRX and amniotic fluid were studied using a broth dilution method. Stronger effects were recognized when both agents were present together compared to each agent alone by the fact that values of MIC and MBC became closer together for Escherichia coli as well as for Streptococcus agalactiae. Against the growth of E. coli, a synergism was observed, but for S. agalactiae, only an additive effect was found. The placental transmission of CTRX upon the administration was rapid, and the blood CTRX level reached its peak shortly after the intravenous administration of the drug. The transport of the drug into the fetus through placenta was excellent and one dose of 1 g of CTRX gave drug concentrations in the umbilical cord serum and amniotic fluid higher than MIC's against main pathogenic organisms. According to these results, it should be possible to treat or prevent perinatal infections by a dose of one gram per day of CTRX, once or twice daily. Cases of perinatal infections were treated with CTRX. An effective treatment without side effects was obtained. No physical abnormalities nor unusual laboratory test results were recognized in neonates delivered from mothers who received CTRX administration. The penetration of CTRX into mothers' milk was low, thus the drug transfer into neonates through the breast-feeding should not be a problem. It appears, from the above study, that CTRX is a clinically useful antibiotic for the prophylaxis and the treatment of perinatal infections.

[Studies on aztreonam in the perinatal period].

Pharmacokinetic, bacteriological and clinical studies on aztreonam (AZT) in the perinatal period were carried out with the following summary of the results. Antibacterial effects of AZT on bacterial growth of Escherichia coli (MIC 12.5 micrograms/ml) and Pseudomonas aeruginosa (MIC 50 micrograms/ml) in amniotic fluid were determined and it was found that the activity of AZT is enhanced in amniotic fluid. AZT rapidly penetrated into tissues and sera of pregnant women upon intravenous (i.v.) injection and its maternal serum concentrations reached their peak levels shortly after the injection. Placental penetration of AZT to the fetus was good and, after single i.v. injection of 1 g, the concentrations of AZT in the umbilical cord serum and amniotic fluid exceeded MICs against major Gram-negative bacilli. These results indicate that single i.v. injection of AZT 1 g twice a day is effective for the treatment and prophylaxis of perinatal infections. Injection of AZT for the treatment of puerperal infections showed excellent clinical effectiveness with 100% eradication of aerobic Gram-negative rods. No side-effect was observed in any case. All of the results suggested clinical usefulness of AZT in the perinatal period.