The pharmacokinetics of astromicin (ASTM), a new aminoglycoside antibiotics, was studied in dogs after intramuscular (i. m.), intravenous (i. v.) or drip intravenous (d. i. v.: for 0.5, 1hr. or 2hrs.) administration at a dose of 20mg/kg. The pharmacokinetic parameters were calculated using one-compartment open model (i. m.) or two-compartment open model (i. v. and d. i. v.).
1. The peak plasma levels of ASTM were 34.1mcg/ml (i. m.), 50.5mcg/ml (d. i. v., 0.5hr.), 39.8mcg/ml (d. i. v., 1hr.) and 28.2 mcg/ml (d. i. v., 2hrs.), respectively.
2. The pharmacokinetic parameters (T1/2, AUC_∞, Kel, Vd and Cl) of ASTM except C_max and T_max were similar for different routes of administration.
3. Urinary recovery rates of ASTM were 90.5% (i. m.), 95.2% (i. v.), 91.6% (d. i. v., 0.5hr.), 92.6% (d. i. v., 1hr.) and 93.5% (d. i. v., 2hrs.) by 24 hours.
4. After intramuscular, intravenous or 1 hour drip intravenous administration of ASTM, no active metabolite was found in urine of dogs.

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A phase I study on intravenous drip infusion of astromicin (ASTM, KW-1070), an aminoglycoside antibiotic, was performed on 9 healthy adult male volunteers to investigate the safety and pharmacokinetics of this drug.
1. ASTM 200mg was dissolved in 250ml of saline and given to each of 6 volunteers by drip infusion in 1hour. For comparison, 200mg of ASTM in 1 ml of saline was injected intramuscularly. No subjective and objective reactions were found, and laboratory test value did not show any change possibly caused by ASTM.
2. In a single administration study, C_max was 10.8μg/ml by intramuscular injection and 12.0μg/ml by intravenous drip infusion. The areas under the time-serum concentration curve were 35.6μg.hr/ml and 34.9 μg.hr/ml, respectively; that is, the serum levels of ASTM after one-hour intravenous drip infusion changed almost identically to those after intramuscular injection.
3. In a multiple administration study, the change in serum levels of ASTM after the ninth administration was approximately the same as that after the first one. This means that no accumulation of ASTM in serum occurred.
4. Recovery rates of ASTM in urine up to 8 hours after a single intramuscular injection and a single intravenous drip infusion were 85.4% and 87.5%, respectively. These results also support the conclusion that there is no accumulation of ASTM in the body by repeated administrations.

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Astromicin (ASTM) was administered intravenously to 4 healthy adult volunteers with an average body weight of 62kg using a continuous infusion apparatus at a constant rate of 200mg in 1 hour (Group I), 400mg in 1 hour (Group II) and 200mg in 2 hours (Group III). Concentrations of the drug in serum and urine were detemined by high power liquid chlomatography (HPLC). The mean serum concentration of the 4subjects reached the peak of 13.32μg/ml in Group I, 22.12μg/ml in Group II and 9.89μg/ml in Group III. The peak concentration was achieved at the end of infusion and was dose-related. After 8 hours, the concentration dropped to less than 1μg/ml in all groups. The urinary recovery rate was 90% in 8 hours and 95% in 24 hours. T1/2 (β) analyzed by the two-compartment open model was 1.64-1.72 hours, AUC_∞was also dose-related, such as 33. 1μg·hr/ml and 31.6μg·hr/ml in Group I and Group III, and 57.6μg·hr/ml in Group II.
It is recommended for amikacin (AMK) that the peak serum concentration should not exceed 35μg/ml and the maximum concentration before the next infusion should be less than 5μg/ml. In these experiment, ASTM which is lower in toxicity than AMK did not approach 35μg/ml even at the peak level with the dosage of 400mg in 1hour. Furthermore, the excretion of the drug was fast and the serum levol of the drug became much lower than 5μg/ml very quickly. These facts indicate that ASTM should be much safer than AMK.
Judging from reported MIC values of ASTM against S. aureus and Gram-negative bacilli, effective dose levels of ASTM by intravenous drip infusion route are estimated to be 200-400mg twice a day.

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Astromicin (ASTM), a new aminoglycoside antibiotic, was administered to 7 patients with renal disorders. Concentrations of ASTM in blood were determined for pharmacokinetic analysis. ASTM was administered by intravenous drip infusion over 1 hour at a dose of 200mg to each of 6 patients and at a dose of 100mg to 1 patient. Renal function was observed by the clearance of intrinsic creatinine (Ccr) as the indicator.
Concentrations of ASTM in blood became higher and retention times longer as degrees of the loss of renal function were larger. Although ASTM is proved to be one of drugs with the highest degree of safety compared with other existing aminoglycoside antibiotics, it should be administered with care to patients with renal disorders.

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Astromicin (ASTM, Fortimicin ®) is a pseudodisaccharide aminoglycoside antibiotic. The ASTM exhibited excellent activity against Gram-positive and Gram-negative bacteria but was only weakly active against Pseudomonas aeruginosa.
In vitro synergistical activities of ASTM combined withβ-lactam antibiotics have been reported against P. aeruginosa previously. In this paper, we investigated the in vivo combination efficacies of ASTM and β-lactam antibiotics latamoxef (LMOX), cefoperazone (CPZ), piperacillin (PIPC) and cefsulodin (CFS) against experimental infection with P. aeruginosa in both normal and immunosuppressed mice. In normal mice, the combination of ASTM with these β-lactam antibiotics produced significantly greater protective effects than the single use of individual antibiotics against both strains of P. aeruginosa BMH No.1 and E-2. In mice immunosuppressed with cyclophosphamide, the combination of ASTM with LMOX or CFS also exhibited synergistic protective effects against P. aeruginosa BMH No.1, but PIPC and CPZ did not.
From the above results, the combination therapy of ASTM with β-lactam antibiotics appeared to be effective against experimental infections with P. aeruginosa in mice.

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We investigated the effect of astromicin (ASTM) on a defence mechanism. The existence of ASTM (100μg/ml) did not influence the ability of phagocytizing and killing by the mouse peritoneal exudated polymorphonuclear leukocyte (PMN). We observed no change of either phagocytizing and killing or phagocytizing ability of PMN by a pretreatment with ASTM (100μg/ml). When the luminol-dependent chemiluminescence of PMN was examined, a slight decrease of relative light intensity in the presence of ASTM was observed at a concentration of 100μg/ml or 50μg/ml. There was, however, no change of relative light intensity in the presence of 20μg/ml of ASTM.
The chemotaxis of PMN was not influenced in the presence of even 100μg/ml of ASTM. We also examined whether a combination effect existed between ASTM and either fresh human serum or fresh mouse serum in vitro. Considerable combination effects were observed against E. coli, P. aeruginosa, S. marcescens, K. pneumoniae and S. aureus.
From these results, we concluded that ASTM did not exert a detrimental effect on examined functions of PMN which is important in the nonspecific host defence mechanism in the early phase of bacterial infections. We also concluded that ASTM, which had a synergic effect with a human serum factor, was a safe and effective chemotherapeutic agent.

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A pharmacokinetic study on ceftizoxime suppository (CZX-S), a new rectal suppository of ceftizoxime (CZX), was carried out in the field of obstetrics and gynecology.
Concentrations of CZX after single rectal administrations of a 500mg dose in peripheral venous serum, uterine arterial serum and internal genital organs of 15 patients who received simple panhysterectomy were examined.
Peak levels of CZX in peripheral venous serum were 7.26 to 8.88μg/ml at 30 minutes after the administration.
Concentrations of CZX in internal genital organs reached 2.12 to 8.96μg/g at 30 minutes after the administration and then decreased slowly, but still remained at 0.37-3.12μg/g after 4 hours.

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The MK-0787/MK-0791 is a combination of imipenem (a carbapenem antibiotic) and cilastatin sodium (a dehydro peptidase-I inhibitor) in a 1 to 1 ratio, which produces a higher urinary recovery of imipenem than imipenem alone.
The MK-0787/MK-0791 was used in 8 female patients with intrapelvic infections.
Clinical efficacies were very good in all the patients.
There were neither subjective nor objective side effects nor abnormal laboratory findings.

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Following results were obtained from drip intravenous administration of imipenem/cilastatin sodium (MK-0787/MK-0791)(500mg/500mg) by measuring concentration of MK-0787 in uterine arterial plasma, cubital venous plasma, oviduct, ovary and several sites in uterine tissue in cases of simple hysterectomy, and pelvic cavity fluid in cases of radical operation.
1. Cervix uteri, portio vaginalis, myometrium showed higher concentration among various uterine tissues in any time after the end of administration.
2. In cases of radical operation, the pelvic cavity fluid showed 6.6-7.8μg/ml at 5 hours after the end of administration.
3. In the field of obstetrics and gynecology, it was considered that MK-0787/MK-0791 has good efficacy in infections especially caused by Gram-positive aerobic bacteria.

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The penetration of imipenem/cilastatin sodium (MK-0787/MK-0791) into tissues of 6 patients and clinical efficacy in 21 patients with infectious diseases were studied in the field of obstetrics and gynecology. The results are summarized below.
1. The transfer of MK-0787/MK-0791 into genital organ tissues was very good.
2. The clinical efficacy was evaluated for 11 patients with intrauterine infections, 5 patients with intrapelvic infections and 5 patients with other infections. Clinical responses were excellent in 7 (33.3%), good in 13 (61.9%) and poor in 1 patient (4.8%), and the efficacy rate was 95.2 percent.
3. Infective bacteria were eradicated in 4, diminished in 2, unchanged in 1 and replaced by other bacteria in 2 patients.
4. No side effect was observed.

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Seven patients with gynecologic infections were treated with the new carbapenem class of antibiotic, imipenem/cilastatin sodium (MK-0787/MK-0791) at a dose level of 500mg/500mg or 250mg/250mg administered intravenously every 12 hours for 5 days.
The results obtained were as follows.
Clinical effects of MK-0787/MK-0791 were analyzed in 7 patients, including 1 case with pelvic peritonitis, 2 cases with endometritis, adnexitis and pelvic peritonitis, abdominal abscess, vaginal cuff infection and parametritis, and pyometra.
Excellent clinical response was seen in 3 cases and good response in 4 cases.
No side effect nor abnormal finding in clinical laboratory values was seen in all patients.

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

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Fundamental and clinical studies on imipenem/cilastatin sodium (MK-0787/MK-0791) were carried out and the following results were obtained.
Concentrations of MK-0787 in plasma and uterine tissues were determined at 30 minutes to 390 minutes after the completion of an intravenous drip infusion of 500mg/500mg of MK-0787/MK-0791 sodium.
Levels of MK-0787 in oviduct, ovary, endometrium, myometrium, uterine cervix and portio vaginalis were 5.1, 5.3, 4.2, 6.6, 5.2μg/g and 6.0μg/g, respectively, at 30 minutes after the completion of the infusion. These levels far exceeded the MICs of MK-0787 against major pathogens (Gram-negative rods and anaerobic bacilli) most often isolated in the field of obstetrics and gynecology.
MK-0787/MK-0791 was administered by intravenous drip infusion to 11 patients, including 4 with pelvic peritonitis, 4 with adnexitis and one each with peritonitis, tubo-ovarian abscess, and endometritis, at a dose of 1g/1g-1.5g/1.5g per day for a period of 4 to 9 days. Clinical response was excellent in 2 and good in 9. No adverse reactions or abnormal laboratory findings were observed in any of the patients.

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To evaluate the penetration of imipenem/cilastatin sodium (MK-0787/MK-0791) into the female genital organ, concentrations of MK-0787/MK-0791 in antecubital vein blood, portio vaginalis, myometrium, endometrium, ovary and oviduct of patients who underwent simple hysterectomy and in the pelvic dead space exudate of patients who underwent radical operations for cancer of the uterine cervix were determined and analyzed using a two-compartment model.
Concentrations at the end of a 30 minutes drip infusion of 500mg/500mg of MK-0787/MK-0791 were 48.38/52.69μg/ml in plasma from the antecubital vein, 9.46/14.92μg/g in the portio vaginalis, 14.10/9.79μg/g in the myometrium, 6.47/11.42μg/g in the endometrium, 14.72/13.30μg/g in the ovary and 10.59/13.62μg/g in the oviduct.
Maximum concentrations of MK-0787 and MK-0791 in the pelvic dead space exudate were 10.66μg/ml at 1.33 hours and 12.74μg/ml at 1.15 hours after the start of the drip infusion, respectively.
The concentration in plasma from the antecubital vein after an infusion of 1,000mg/1,000mg of MK-0787/MK-0791 reached 68.37/61.57μg/ml at the end of a 60 minutes drip infusion, and the maximum concentration of MK-0787 in the pelvic dead space exudate was 20.02μg/ml at 1.50 hours after the start of the drip infusion and that of MK-0791 was 14.90μg/ml at 2.01 hours after the start of the drip infusion.
MK-0787/MK-0791 was administered to 9 patients with obstetric and gynecological infections, and clinical efficacies were found to be excellent in 1, good in 6, and poor in 2 patients.

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Fundamental and clinical studies on imipenem/cilastatin sodium (MK-0787/MK-0791), a new carbapenem antibiotic, were performed and the following results were obtained.
1. Concentrations of MK-0787 and MK-0791 in serum, internal genital organs and retroperitoneal fluid were determined after a 30 minutes drip infusion of 500mg/500mg dose.
Venous serum levels of MK-0787 and MK-0791 were 47.3 to 67.5μg/ml and 44.2 to 61.4μg/ml, respectively, at the end of the administration.
Sufficient transfer of MK-0787 and MK-0791 to internal genital organs and retroperitoneal fluid was demonstrated.
2. In clinical trials, MK-0787/MK-0791 was given to 18 cases with obstetrical and gynecological infections, such as endometritis, puerperal fever, pelvic peritonitis, parametritis and lymphocystitis. The clinical efficacy was evaluated as excellent in 1 case, good in 14 and poor in 3. The efficacy rate was 83.3%.
In a bacteriological study, 43 strains were isolated from 16 cases and the eradication rate was 61.1%.
No side effects were observed in any of the cases.
In laboratory findings, a transient elevation of GOT, GPT was noted in 1 case.
From the above results, it was concluded that MK-0787/MK-0791 was useful drug for infections in the field of obstetrics and gynecology.

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Many different infections including urinary tract infections occur in the field of obstetrics and gynecology. Furthermore, in most cases, it is practically impossible to clearly identify causative organisms as in cases of pelvic peritonitis and parametritis. In many incidents, causative organisms consist mainly of Escherichia coli, and recently, Enterococcus faecalis, Bacteroides fragilts, Klebsiella pneumoniae, Pseudomonas aeruginosa, etc. have also been identified. Because the new antibiotic, imipenem/cilastatin sodium (MK-0787/MK-0791), is very effective against these bacteria, and because of its wide spectrum, we believe it is especially effective against infections of obstetrics and gynecology.
The distribution of this antibiotic into various organs and tissues was similar to other drugs, and it reaches a high level in internal genital organs, hence it should be effective for the treatment of obstetric/gynecological infections. Its toxicity is low also, and no side effects nor abnormal laboratory findings were observed in our trials. Results of our trials are summarized below:
1. Of 9 cases of obstetric/gynecological infections, the antibiotic showed excellent effectiveness against 2, good against 6, for the efficacy ratio of 89%.
2. No side effects nor abnormal laboratory findings were observed.

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Fundamental and clinical studies of imipenem/cilastatin sodium (MK-0787/MK-0791), a new carbapenem antibiotic, were carried out.
The results obtained were summarized below.
1. At a dose of 500mg/500mg, the penetration of MK-0787/MK-0791 into internal genital organs was good. The penetration of MK-0787/MK-0791 into pelvic dead space exudate was also good.
2. Clinical results obtained were good in 4 patients and poor in 1, with an efficacy rate of 80%.
No side effects were observed, but 1 patient showed slight elevations of GOT, GPT, Al-P and LDH.
3. From these results, MK-0787/MK-0791 appeared to be a useful drug for the treatment of various infections in the field of obstetrics and gynecology.

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A new carbapenem antibiotic and renal dipeptidase inhibitor, imipenem/cilastatin sodium (MK-0787/MK-0791) were studied for the distribution into various tissues and for clinical aspects in obstetrical and gynecological fields. The following results were obtained.
1. Concentrations of the drug in arterial blood, venous blood, and internal genital organs following an intravenous drip infusion were measured. The results demonstrated good transfer of the drug into various internal genital organs.
2. Four patients with bacterial infections were treated with MK-0787/MK-0791. Therapeutic results were good in 2 cases for, an effective rate of 50%. No side effects were noted in any cases.
The above results suggested that MK-0787/MK-0791 may be a useful antibiotic for infectious diseases in the field of obstetrics and gynecology.

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Fundamental and clinical studies on imipenem/cilastatin sodium (MK-0787/MK-0791) were carried out and the results obtained were summarized below.
1. The transfer of MK-0787/MK-0791 into female genital organ tissues was found to be satisfactory.
2. The transfer of MK-0787/MK-0791 into umbilical arterial blood, umbilical venous blood and amniotic fluid was relatively good.
3. A dose of 1,000mg/1,000mg perday of MK-0787/MK-0791 was given to each of 6 gynecology patients for 5-22 days and satisfactory clinical effect was obtained in 5 patients out of 6 patients.
No notable side effects or abnormal laboratory findings were observed except for a moderate in elevation in S-GOT/S-GPT in 1 case.

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The following results were obtained during pharmacokinetic, bacteriological and clinical evaluation of the usefulness of the combination (1: 1) of imipenem (MK-0787) and cilastatin sodium (MK-0791), an inhibitor of dehydropeptidase-I, in the treatment of patients with obstetric and gynecologic infections.
1. Plasma concentrations of MK-0787 in antecubital vein and uterine artery were 18.2μg/ml and 16.4μg/ml, respectively, and of MK-0791 were 9.5μg/ml and 10.3μg/ml, respectively, at 1.28 hours after the end of a drip infusion of 0.5g/0.5g of MK-0787/MK-0791.
Plasma concentrations of both MK-0787 and MK-0791 decreased slowly, and concentrations of the former in antecubital vein and uterine artery were 0.7μg/ml and 1.0μg/ml, respectively, and of the latter were 1.5μg/ml and 1.9μg/ml, respectively at 2.83 hours after the end of a drip infusion.
Concentrations of the 2 agents in female genital tissues decreased with increasing time in a manner similar to concentrations in the plasma.
2. Clinical responses in 10 patients were excellent in 2 and good in 8, and the efficacy rate was 100 percent.
Organisms were isolated from all 10 patients before the treatment, but were eradicated in 9 patients by the treatment.
3. No side effects were observed, but increase of eosinocytes was observed in 1 patient.

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Fundamental and clinical studies were performed by our study group to evaluate the usefulness of the combination (1: 1) of imipenem (MK-0787), a carbapenem antibiotic, and cilastatin sodium (MK-0791), an inhibitor of dehydropeptidase-I, in the treatment of patients with obstetric and gynecologic infections. The following results were obtained.
1. Antimicrobial activities of MK-0787 were tested with inocula of 10⁶ cells/ml of organisms isolated from patients with obstetric and gynecologic infections.
Peak MIC's of MK-0787 were ≤0.20μg/ml for S. aureus, ≤0.20μg/ml for S. epidermidis, 1.56μg/ml for E. faecalis, 0.39μg/ml for E. coli, ≤0.20μg/ml for K. pneumoniae and ≤0.20μg/ml for B. fragilis.
2. When 0.5g/0.5g of MK-0787/MK-0791 was administered by a 30-minute intravenous drip infusion, maximum concentrations of MK-0787 in all female genital tissues were obtained at the end of the infusion, and C_max. ranged from 9.4μg/g to 17.0μg/g.
In addition, the maximum concentration of MK-0787 in pelvic dead space exudate was 13.2μg/ml at 88 minutes after the start of the infusion. The penetration of MK-0787/MK-0791 into female genital tissues and dead space exudate was found to be good and sufficient to cover MIC's against organisms isolated from patients with obstetric and gynecologic infections.
3. Clinical efficacy was evaluated in 201 evaluable patients out of a total of 253 patients with obstetric and gynecologic infections.
Clinical responses were excellent in 2, good in 181 and poor in 18 patients, and the efficacy rating was 91.0 percent.
Efficacy ratings classified by types of infections were 93.2% (82/88) for intrauterine infections, 83.0% (39/47) for intrapelvic infections, 100% (26/26) for adnexitis, 90.0% (18/20) for infections of the external genital organs and 90.0% (18/20) for other infections.
Side effects were observed in 6 of the 253 patients; rash in 4, nausea and vomiting in 1 and diarrhea in 1 patient.
Abnormal laboratory findings were observed in 10 of the 253 patients; elevation of GOT, GPT, LDH and Al-P in 1, elevation of GOT, GPT and Al-P in 1, elevation of GOT and GPT in 4, elevation of GPT in 1, elevation of BUN in 1, increase of eosinophiles in 1, decrease of segmented neutrophils in 1 patient

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