During the period from September 1981 to March 1982,363 bacterial isolates were obtained as possible pathogens from 311 patients with lower respiratory tract infections at 12 medical institutions in Japan. Of these clinical isolates, mostly from the sputum, a total of 231 isolates including 19 strains of Staphylococcus aureus, 33 strains of Streptococcus pneumoniae, 90 strains of Haemophilus influenzae, 65 strains of Pseudomonas aeruginosa, 17 strains of Klebsiella pneumoniae and 7 strains of Escherichia coli were tested in vitro for minimal inhibitory concentrations (MIC) of 17 antimicrobial agents, and their antimicrobial susceptibility distribution and cumulative percentages of inhibited isolates by increasing concentrations of drugs were determined. The data were further analyzed to investigate the interrelation between such parameters as the age-distribution of patients by diseases of the respiratory system, sex and types of infection and the species and frequency of isolation of the organisms, and also the relationship between the antimicrobial chemotherapy prior to collection of clinical specimens and the species and incidence of the bacterial isolates. In respiratory infections, it is frequently that chemotherapy should be instituted with an appropriate drug even before the causative organism can be identified and assessed for its antimicrobial susceptibility. The present data may provide valuable informations in selecting appropriate drugs in practical, clinical use.

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Single use of ticarcillin (TIPC, Monapen®) was administered in 57 cases and combination therapy of TIPC and S-sulfonated human immunoglobulin (Venilon®) was carried out in 23 patients who were either with severe infection, very old or in poor general conditions. The results obtained were as follows.
1. Effective rate of single use of TIPC was 100% (3/3) in cases with infection, 50% (3/6) in cases with infection in which prior antibiotics therapy was poorly effective and 100% (48/48) in post operative cases.
2. Effective rate of combination therapy of TIPC with S-sulfonated human immunoglobulin was 85.7% (6/7) in cases with infection, 71.4% (5/7) in cases with infection in which prior antibiotics therapy was poorly effective and 100% (9/9) in post operative cases.
3. In laboratory findings, mild elevations of transaminase were recognized in 6 cases but restored to normal values without specific therapy.
4. Side effect such as diarrhea, exanthema, fever, nausea and vomiting was not found in our cases.

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Bacampicillin (BAPC) is a esterified derivative of ampicillin (ABPC) developed recently by the Swedish company.
In present investigation we measured the concentration of ABPC in plasma, lung and tracheobronchial tissues from normal, pleuritis and pneumonitis male albino rabbits after an oral administration of BAPC.
1. In these 3 groups plasma level of ABPC reached the maximum at 30-50 minutes after oral administration, then showed a gradual decrease. The decaying curves of pleuritis and pneumonitis groups were steeper than that of control group.
2. Plasma level of ABPC in pneumonitis group at the maximum value was about 1/2 comparing with that in control and pleuritis groups.
3. ABPC levels of tracheobronchial tissues in pleuritis and pneumonitis groups were higher than that in control group at 60 minutes after oral administration of BAPC. On the other hand, tissue level of ABPC in control group was higher than that in pleuritis and pneumonitis groups at 120 minutes after oral administration of BAPC.
4. ABPC level of lung tissues (L1 and L5) in control group was higher than that in pleuritis and pneumonitis groups at 60 minutes after oral administration of BAPC, on the other hand ABPC level of L3 in control group was lower than that in pleuritis and pneumonitis groups.
5. ABPC levels of lung tissues (L1-L5) at 120 minutes after oral administration of BAPC were higher in control group comparing with that in pleuritis and pneumonitis groups.

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Bestatin (NK421) is a peptide with low toxicity, which was separated from the fermentation filtrate of Streptomyces olivoreticuli as an inhibitor of aminopeptidase B and has the chemical structure shown below (Fig. 1). It has been found to inhibit markedly aminopeptidase B and leucine aminopeptidase via antagonistic actions with their substrates and to potentiate immune response such as delayed hypersensitivity. It has been shown to activate the defense mechanism and inhibit the growth of cancer.
We examined the acute toxicity of NK421 in mice, rats and dogs and here describe the results of the toxicological studies.

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Bestatin (NK421) is a peptide which was isolated from the fermentation filtrate of Streptomyces olivoreticuli by UMEZAWA and coworkers and inhibits aminopeptidases such as aminopeptidase B or leucine aminopeptidase via antagonistic actions with their substrates.It has been shown to potentiate various immune responses and to exert an antineoplastic action. When used alone or combined with other drugs, NK421 has been shown to possess a promising anticancer effect.
We have already studied the acute toxicity of NK421 in mice, rats and dogs 2 and reported that it shows very low toxicity especially following oral administration.
In the present experiment, we have conducted a subacute toxicity test in male and female Beagle dogs following successive 90times oral dosing and the recovery test following a withdrawal period for5 weeks in an attempt to examine possible toxicological manifestations and confirm the safety of NK421.

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Bestatin (NK421) which was isolated from the fermentation filtrate of Streptomyces olivoreticuli by UMEZAWA and coworkers is a peptide with an inhibitory action against aminopeptidase B. As it is known to potentiate various immune responses, activate biophylactic mechanism and inhibit cancer, it is expected to be effective as a clinically promising agent for immunotherapy of cancer.
We already described in acute toxicity tests in mice, rats and dogs that NK421 showed very low toxicity, though their toxicities varied among the administration routes.Especially, the toxicity of NK421 was very low when administered orally.
In the present study, in an attempt to study the possible toxicity and confirm the safety of the drug, we performed the chronic toxicity test of NK421 following successive 540 times oral dosing (for a period of a year and a half) in male and female Beagle dogs and the recovery test following the withdrawal period of 5 weeks, already having studied the subacute toxicity of NK4213 following 90times dosing through an oral route in male and female Beagle dogs in the previous experiment.In this report, the results are described.

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Bestatin (NK421) is a substance which was found in the fermentation filtrate of Streptomyces olivoraticuli in the series of aminopeptidase B inhibitors and which inhibits strongly aminopeptidase B and leucine aminopeptidase. When used alone or combined with other anti-cancer agents, it shows a potent antitumor activity with a very low toxicity.
In the present study, we carried out various experiments including antigenicity test in rabbits and guinea pigs, a ocular mucosal irritation test as a local irritation test in rabbits and mutation assay using Salmonella typhimurium in a series of safety evaluation of NK421 and the results are presented.

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Micronomicin (MCR) is a new aminoglycoside antibiotic produced by Micromonospora sagamiensis var. nonreducans which was isolated from soil collected at Sagamihara City by NARA et al. This antibiotic shows a close similarity to gentamicin C components in physical and chemical properties. The antibacterial activity of MCR is broad-spectrum and almost equal to that of gentamicin C complex. MCR exhibits particularly high activity against Pseudomonas, Proteus, Klebsiella pneumoniae, Serratia, etc.as well as against some Pseudomonas aeruginosa strains resistant to gentamicin C1a.
Toxicological studies of MCR were carried out for safety evaluation as follows:
Studies were carried out to assess acute toxicity, when administered in 1 hour by drip intravenous infusion to Wistar rats, Japanese White rabbits and Beagle dogs.
The results of the studies are summerised as follows:
1. There was no difference on acute toxicity between drip intravenous infusion (d.i.v.) and intramuscular injection (i.m.) in rats. However, acute toxicity of d.i.v. was less than that of bolus intravenous administration (i.v.) in rats.
2. Acute toxicity of d.i.v. was stronger than that of i.m. in dogs when administered in rats.
3. Acute toxicity varied with species, and it was ranked in rabbits-adogs>rats.
4. There was no difference on symptoms between d.i.v. and i.m.

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Micronomicin (MCR) is a new aminoglycoside antibiotic produced by Micromonospora sagamiensis var.nonreducans which was isolated from soil collected at Sagamihara City by NARA et al.This antibiotic shows a close similarity to gentamicin C components in physical and chemical properties.The antibacterial activity of MCR is broad-spectrum and almost equal to that of gentamicin C complex. MCR exhibits particularly high activity against Pseudomonas, Proteus, Klebsiella pneumoniae, Serratia, etc. as well as against some Pseudomonas aeruginosa strains resistant to gentamicin C1a.
Toxicological studies of MCR in rats were carried out by intravenous injection for safety evaluation.
Study on subacute toxicity: Wistar rats were injected intravenously with MCR at the dose levels of 4, 10, 25, 63mg/kg and 100mg/kg for 30days.
The results of the studies are as follows:
1. In the subacute toxicity study, animals died at the dose level of 100mg 1kg (10 out of 30 animals). Main changes observed were renal disorders and ataxia which showed a close similarity to those seen in intramuscular toxicity studies in rats. The renal histological disorders occurred mainly at the dose levels of 25mg/kg and over, but they were slight at the dose levels of 25mg/kg. Ataxia was observed at the dose levels of 63mg/kg and over, but its grade was slight at the dose level of 63mg/kg.
2. The maximum safety dose was equal to in the intramuscular subacute toxicity in rats, 10mg/kg.

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Micronomicin (MCR) is a new aminoglycoside antibiotic produced by Micromonospora sagamiensis var. nonreducans which was isolated from soil collected at Sagamihara City by NARA et al. This antibiotic shows a close similarity to gentamicin C components in physical and chemical properties. The antibacterial activity of MCR is broad-spectrum and almost equal to that of gentamicin C complex. MCR exhibits particularly high activity against Pseudomonas, Proteus, Klebsiella pneumoniae, Serratia, etc. as well as against some Pseudomonas aeruginosa strains resistant to gentamicin C1a.
Subacute toxicity studies of MCR in rabbits were carried out by drip intravenous infusion (d.i.v.) comparing with intramuscular injection (i.m.) for 30 days (doses; d.i.v.=4, 25, 63 mg/kg. i.m.=63mg/kg).
The results of the studies are as follows:
1. Animals did not die at any dose. Renal disorders occurred mainly at the dose level of 63mg/kg; they were almost similar to those observed when administered by i.m., and the grade of disorders in d.i.v. was the same as in i.m.
2. The maximum safety dose was 4mg/kg.

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Micronomicin (MCR) is a new aminoglycoside antibiotic produced by Micromonospora sagamiensis var. nonreducans which was isolated from soil collected at Sagamihara City by NARA et al. This antibiotic shows a close similarity to gentamicin C components in physical and chemical properties. The antibacterial activity of MCR is broad-spectrum and almost equal to that of gentamicin C complex. MCR exhibits particularly high activity against Pseudomonas, Proteus, Klebsiella pneumoniae, Serratia, etc. as well as against some Pseudomonas aeruginosa strains resistant to gentamicin C1a.
Fertility studies of MCR in rats were carried out by intravenous injection for safety evaluation (Dose; 25, 50mg, kg and 75mg kg). The results of studies are as follows.
1. There was no adverse effect on fertility ability at any dose.
2. Suppression of adult body weight gain was observed slightly at all dose level in male and at the dose level of 75mg/kg in female.

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Micronomicin (MCR) is a new aminoglycoside antibiotic produced by Micromonospora sagamiensis var. nonreducans which was isolated from soil collected at Sagamihara City by NARA et al. This antibiotic shows a close similarity to gentamicin C components in physical and chemical properties. The antibacterial activity of MCR is broad-spectrum and almost equal to that of gentamicin C complex. MCR exhibits particularly high activity against Pseudomonas, Proteus, Klebsiella pneumoniae, Serratia, etc. as well as against some Pseudomonas aeruginosa strains resistant to gentamicin C1a.
Teratogenicity studies of MCR in rabbits were carried out by intravenous injection for safety evaluation (Dose; 25, 50mg/kg and 70mg/kg). The results of studies are as follows.
1. Fetal malformation attributable to MCR was not observed at any dose.
2. There was no adverse effect on new borns at any dose.

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Micronomicin (MCR) is a new aminoglycoside antibiotic produced by Micromonospora sagamiensis var. nonreducans which was isolated from soil collected at Sagamihara City by NARA et al. This antibiotic shows a close similarity to gentamicin C components in physical and chemical properties. The antibacterial activity of MCR is broad-spectrum and almost equal to that of gentamicin C complex. MCR exhibits particularly high activity against Pseudomonas, Proteus, Klebsiella pneumoniae, Serratia, etc. as well as against some Pseudomonas aeruginosa strains resistant to gentamicin C1a.
Perinatal and postnatal studies of MCR in rats were carried out by intravenous injection for safety evaluation (Dose; 25, 50mg/kg and 75mg/kg). The results of studies are as follows.
1. There was no adverse effect on delivery and nursing ability in dams at any dose.
2. There was no adverse effect at any dose on postnatal development of offspring, such as weight gain, postnatal differentiation, spontaneous motor activity, learning, sexual maturation and reproductive performance.
3. Renal toxicity was observed at dose of 75mg/kg in autopsy of dams after treatment.

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Absorption, tissue distribution and excretion of micronomicin (MCR) were studied in rats after intramuscular or 30 minutes drip intravenous administration (10mg/kg). Serum levels of MCR were measured by bioassay, enzyme immunoassay and high pressure liquid chromatography. The pharmacokinetic studies of MCR after intramuscular or drip intravenous administration were carried out using one-compartment open model or two-compartment open model, respectively.
1. Among 3 assay methods, similar pharmacokinetic parameters of MCR were obtained.
2. In the simulation of serum levels of MCR, the differences between the measured and calculated serum levels after intramuscular or drip intravenous administration were less than 19% of the former levels.
3. After intramuscular or drip intravenous administration of MCR, similar changes of the organ (kidneys, lungs, spleen and liver) levels were observed.
4. Urinary recovery rates of MCR amounted to 82.3% or 91.6% by 24 hours after intramuscular or drip intravenous administration, respectively.
5. After intramuscular or drip intravenous administration of MCR, no metabolites were found in urine of rats.

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The pharmacokinetics of micronomicin (MCR) were studied in dogs after intramuscular (i.m.) and drip intravenous (d.i.v., 0.5, 1 and 2 hours) administration (10mg/kg).
After i.m. administration, the plasma levels of MCR followed a one-compartment open model, and after d.i.v. administration it followed a two-compartment open model.
1. The peak plasma levels of MCR after i.m., 0.5, 1 and 2 hours d.i.v. administration were 28.7 6.5, 36.7±3.6, 30.2±5.1 and 20.3±2.3mcg/ml, respectively.
2. The pharmacokinetic parameters (T1/2, AUC, Kel, Vd and Cl) of MCR except Cmax and Tma, were not differentiated by the route of administration.
3. Urinary recovery of MCR after d.i.v. administration was equal to that of MCR after i.m. administration.

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Pharmacological effects, mainly on its muscle-relaxant of micronomicin (MCR) were studied.
1. Intravenous infusion of MCR at a dose of 20mg/kg/hour did not influence on both respiration rate and cardiovascular functions in anesthetized rabbits.
2. When MCR was injected to anesthetized rabbit at an intravenous dose of 100mg/kg, a respiratory arrest followed by a cardiac arrest was observed. This effect was antagonized by either treatment with CaCl2 or artificial respiration.
3. In slant test, MCR at a dose of 100mg/kg (i.v.) in mice induced muscle relaxation. This effect was weakened by slowing the injection speed of the drug.
4. Intravenous injection of MCR potentiated the lethality induced by either d-tubocurarine or succinylcholine.
5. Intravenous injection of MCR influenced on neither pentobarbital sodium-, ethyl ether-, nor halothane-induced anesthesia in mice.
From these results, intravenous infusion of MCR at a dose of 20mg/kg/hour that is considered as 5-10 times of clinical dose (120-240mg/day) did not influence on both respiration and cardiovascular functions.

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Protective effects of intravenous administration of micronomicin (MCR) on mouse experimental infections were investigated.
Mice were better protected by intravenous administration in S. marcescens T-55 experimental infection than subcutaneous administration. No remarkable differences were found between the two administrations in cases of P. aeruginosa BMH No.1 and E. coli GN 2411-5 infections.
Intravenous administrations of MCR, gentamicin (GM), dibekacin (DKB), amikacin (AMK) and sisomicin (SISO) protected the infection of P. aeruginosa BMH No.1 in a similar extent. MCR was more effective intravenously than AMK; DKB and AMK; DKB, AMK and SISO in experimental infections of E. coli GN 2411-5; S. marcescens T-55; P. aeruginosa KY-8510 harboring aminoglycoside inactivating enzyme AAC (6')-4, respectively.

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The basic pharmacokinetics of micronomicin (MCR) were studied in 4 healthy adult volunteers. MCR 60 and 120 mg were intravenously administered in 30 and 60 minutes at constant rates by means of continuous infusion apparatus. The same dosages were also tested by intramuscular route. The concentrations of MCR in serum and urine were determined by HPLC and analyzed following the twocompartment open model after intravenous treatment and following the one-compartment open model after intramuscular treatment.
When MCR was given by intramuscular route, the mean serum concentration of 4 subjects reached a peak of 3.98μg/ml at 30 minutes after a dose of 60 mg and 6.7μg/ml at 30 minutes after that of 120 mg. The peak concentration was achieved at the end of intravenous infusion and was dose-related, since it was 6.1 and 10.5μg/ml after a 30-minute infusion of 60 and 120 mg, respectively, and 4.85 and 9.43μg/ml after a 60-minute infusion of 60 and 120 mg, respectively. At 8 hours, concentrations dropped to less than 0.1μg/ml and to 0.2μg/ml or less after 60 and 120mg, respectively, regardless of the route and rate of administration. The mean urinary recovery up to 8 hours ranged 84 to 92% of the dose.
There were no appreciable differences in pharmacokinetic parameters among 4 modes of intravenous infusion, with a T1/2 (β) of 1.43-2.02 hours. In the case of intramuscular treatment, parameters analyzed following the one-compartment open model were on similar levels to corresponding values found after intravenous treatment and the T1/2 was 1.39 hours after 60mg and 1.43 hours after 120 mg. The AUC was 1.8-2.0 times larger after 120mg than after 60mg, showing a relationship to the dose.
Steady-state serum concentrations after repeated doses of 120mg MCR every 12-hour were calculated from the above kinetic data. The Cmax was 10.59μg/ml when the 120mg doses were infused in 30 minutes and 9.03μg/ml when they were given in 60 minutes. Serum concentrations exceeding 6.25μg/ml were maintained for 39 minutes after 30-minute infusion and for 49 minutes after 60-minute infusion. Thus, infusing 120mg in 60minutes was superior in safety and efficacy to infusing the same dosage in 30 minutes. A single 60mg dose given in 30 and 60 minutes by intravenous route and given by intramuscular route showed a Cmax of 6.03, 4.93 and 3.71μg/ml, respectively, and maintained serum concentrations over 3.13μg/ml for 51, 55 and 43 minutes, respectively. It seemed more effective to use 60mg by intravenous route, either infused in 30 or 60 minutes, than by intramuscular route against organisms the MICs to which approximated 3μg/ml.

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Pharmacokinetics of MCR administered by 1 hour intravenous drip infusion were studied in healthy volunteers by two-compartment model. In 120mg-dosage group (n=3) studies were made by single administration, and in 60 mg-dosage group (n=4) were administered twice daily and continued until a total of 9 doses.
Results: When MCR was administered in a 60 mg dosage, its Cnia. was 4.3±0.3μg/ml (mean±S.D.) after the 1st dose and 3.7±0.4μg/ml after the 9th dose, while it was 8.8±1.0μg/ml when the dosage was 120mg. It should be noted that in the case of repeated dosing with 60mg, serum levels just before administration were always below the analytical limit. The mean of T 1/2was 1.69±0.14 hours, remaining stable at all determination. The kinetic parameters that showed different values between determinations performed after the 1st and 9th 60 mg doses were V1 (0.107 vs 0.164 L/kg) and Kel (1.02 vs 0.68 hr-1). This was also the case with comparison of 2 different dosage groups (60 mg 1st vs 120 mg; V1: 0.107 vs 0.135L/kg, Kel: 1.02 vs 0.72hr-1). There was no evidence indicative of side effect of MCR.
Discussion: The above results demonstrated that Cmax and other kinetic parameters were little influenced by whether MCR was administered by intravenous drip infusion or by intramuscular injection. There was a little larger difference in AUC between those 2 routes of administration but the difference seemed negligible when the same dosage was used. Pharmacokinetic studies are to be continued in subjects whose renal function is impaired in different ways to establish the optimum dosage regimen for MCR.

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In recent years, aminoglycoside agents as well as β-lactam antibiotics have been increasingly used with increased incidence of opportunistic infection caused mainly by Gram-negative bacteria. Therefore, we administered micronomicin sulfate (MCR), reportedly lower in nephrotoxicity, at doses of 60 and 120mg by intravenous drip infusion for 1 and 2 hours to healthy male volunteers and determined the blood level and the urinary recovery rate.
1. The peak of blood level after 1 hour infusion of MCR was 7.3μg/ml in the 60mg group and 9.5μg/ml in the 120mg group. T1/2 (β) was 3.34 and 2.48 hours respectively.
2. The peak of blood level after 2 hours infusion of MCR was 5.7μg/ml in the 60mg group and 8.7 μg/ml in the 120 mg group. T1/2 (β) was 3.36 and 3.71 hours respectively.
3. In the 120mg group, the urinary recovery rate for the first 24 hours was 53.5% after 1 hour infusion and 60.9% after 2 hours infusion. In the 60mg group, the rate was higher, 90.1 and 98.6% respectively.
4. It was suggested that intravenous drip infusion of 120mg of MCR for 1 hour is comparable to intramuscular injection of the same dose.
Further, safety and effectiveness of this drug were studied in 7 clinical cases of urological infection.
1. Good results were obtained in 7 clinical cases given 60 or 120mg of MCR by intravenous drip infusion.
2. Neither side effects nor abnormal laboratory findings were observed in clinical cases.

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The drip infusion of micronomicin (MCR) in the field of surgery and gynecology was investigated. MCR was administrated by drip infusion to 73 cases of surgical diseases and 31 cases of gynecological diseases.
The clinical effective rate of MCR alone was 68% in all cases and that of MCR combined with other antibiotics was 89%. No remarkable side effect of drip infusion of MCR was found in all cases. Drip infusion of MCR was found to be as effective and safe as intramuscular injection of the antibiotic.

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