A review of the history of research and development of, semisynthetic penicillins shows that studies aimed at development of oral preparations broadening of the spectrum of antimicrobial activity and development of compounds active against resistant Staphylococci, by chemical modifications of 6-aminopenicillanic acid with different radicals attached to the free amino gtoup at the 6-position of the acid have yielded a variety of new compounds. In-recent years, however, efforts have largely been directed to development of compounds with pronounced usefulness in the treatment of infections by Gram-negative bacilli because of the transfigurations of principal pathogens.
Pivmecillinam is a semisynthetic penicillin with profound activity specifically against Gramnegative bacilli, developed by LUND et al.1) in 1972 for oral administration.
Laboratory and clinical evaluations of this new antibiotic were reported at the Symposium on Pivmecillinam on the occasion of the 24th Congress of the Japan Society of Chemotherapy2) in 1976, where the drug was characterized as follows:
1) It is effective by oral administration in infections with Gram-negative bacilli such as E. coli, Klebsiella, Enterobacter, Citrobacter, or Proteus (including indole-positive species).
2) It is remarkably active against E. coli and is effective even against those E. coli strains resistant to ampicillin (ABPC) andjor amoxicillin (AMPC).
3) In general clinical trials, treatment with the drug even in doses of as low as 150-200mg (potency) per day unfailingly produced satisfactory clinical responses in patients with simple urinary tract infections. The drug is well tolerated and virtually devoid of adverse effects.
4) The usual single doses being relatively low, it can be supplied in the form of small tablets which are easy to swallow.
Our previous clinical experience with pivmecillinam in urinary tract infections yielded similar conclusions.3)
In order to evaluate the efficacy, usefulness and safety of pivmecillinam (PMPC) in the treatment of patients with acute simple cystitis we performed a double-blind clinical study on the drug using as control nalidixic acid (NA), an established drug frequently used with proven usefulness for this condition.

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[in Japanese]

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Studies on acute toxicities of pepleomycin sulfate were carried out in both sexes of mice and rats, comparing with bleomycin, and male dogs.
Pepleomycin was administered subcutaneously, intravenously and intraperitoneally in both sexes of mice and rats, and intravenously in male dogs respectively.
Mice and rats were observed respectively for 10 and 14 days after the administration. LD₅₀values were calculated by the method of LITCHIFIELD & WILCOXON.
LD₅₀ values of pepleomycin were 4-6 times smaller than those of bleomycin in all routes of mice, but difference between them was not significant in all routes of rats.
Additionally sex-difference of LD₅₀ values was scarcely recognized in all routes of both species.
Toxicological findings observed in common to all routes of both species were ataxia, depression, tremor and epiphora, and only in all routes of mice, head-twitch, running-round and rolling were especially recognized as toxic behavior, which were not observed in bleomycin.
Hepatic and renal lesions were recognized biochemically and histopathologically in the survived rats.
The dogs treated with pepleomycin 50 and 30 mg/kg had the decrease in food intake and the loss of body weight. They became moribund in 9-36 days after administration. In these dogs the lesions of liver and kidney were severely recognized in biochemical and histopathological findings.
One of them which received 50 mg/kg recovered biochemically and histopathologically in 209 days after administration by the supplemental nutrition in early stage.

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Studies on subacute toxicity and its recovery of pepleomycin sulfate (NK 631) were carried out in both sexes of rats. NK 631 was administered intraperitoneally in dose levels of 0.3, 0.9, 2.7, 8.1 and 24.3mg/kg/day for 30days. After finishing administration of NK 631 for 30days, 5 animals
of each group were proceeded to recovery test for 35days.
During the course of the experiment, the body weight gains were suppressed in all dose levels except in 0.3mg/kg group of male rats. The deaths were found in the animals treated with doses over 24.3mg/kg during treatment period and in those over 2.7mg/kg during recovery period.
In biochemical and urinary analysis, the increases of serum GPT, BUN, Mg, Ca and urine glucose were moderately recognized in 8.1mg/kg group. Additionally, in macroscopical and histopathological findings, bone damage was found in the animals treated with doses over 2.7mg/kg during recovery period, and renal lesions were found in those over 2.7 mg/kg during treatment and recovery periods.
From these results, the maximum safety dose of NK 631 in subacute toxicity using rats were estimated to be about 0.3mg/kg.

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Subacute toxicity and its recovery of pepleomycin sulfate was studied in both sexes of beagle dogs.
At dose levels of 2.4, 1.2 and 0.6 mg/kg, pepleomycin was administered intramuscularly to dogs for 30 successive days. Two dogs of the 1.2 mg/kg dose group were used for recovery test for 35 days.
As general symptoms, the dicrease of food intake, the loss of body weight, ulceration of foot pad, nail root necrosis and onychoptosic, ulcer of tongue and labia, and alopecia, dermatitis and necrosis at friction sites were observed the more severely in high dose groups, as those in bleomycin were.
The death occurred in the 2.4mg/kg dose group of both sexes.
The lesions of liver and kidney were recognized in the 2.4 and 1.2mg/kg dose groups of both sexes on biochemical, histopathological or urinary findings.
Additionally slight fibrous change of lung was observed in all dose groups.
Generally subacute toxicity of pepleomycin was revealed approximately in the same as or in a little stronger degree than that of bleomycin, and its recovery was hardly recognized during its period.
The maximum safty dose in this studies is estimated to be between 0.3 and 0.6mg/kg in dogs.

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Studies on chronic toxicity and its recovery of pepleomycin sulfate (NK 631) were carried out in both sexes of rats. NK 631 was administered intraperitoneally in dose levels of 0.15, 0.3, 0.6, 1.2 and 2.4mg/kg/day for 180 days. After finishing administration of NK 631 for 180 days, animals of each group were proceeded for 35 days recovery test.
During the course of the experiment, the body weight gains were suppressed in all dose levels except for 0.15mg/kg group of female. The deaths were found in all dose levels except for 0.15 mg/kg level of male during treatment and recovery periods.
In biochemical and urinary findings, the increase of serum BUN, Mg, inorganic P. and urine glucose were slightly recognized in the animals treated with doses over 0.6mg/kg.
Additionally, in macroscopical and histopathological findings, bone damage and renal lesions were found in the animals treated with doses over 0.6 mg/kg during treatment and recovery periods.
From these results, the maximum safety dose of NK 631 in chronic toxicity study using rats were estimated to be at less than 0.15 mg/kg

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The comparative studies in the short term intermittent toxicity of pepleomycin (NK631) and bleomycin (BLM) were performed on 10 beagle dogs of 13-15 months old. Two dogs per group were injected intravenously with NK631 and BLM in doses 5.0 and 2.5 mg/kg body weight every fourth day for 11 treatment. Two dogs served as control and were injected with saline solution. In the group of 5.0mg/kg of NK631, one dog was sacrificed on day 37 of the treatment and another one dog died onday 33 of the treatment. All the dogs of other group survived until the end of the treatment. The toxicity to the hepatic and renal damage caused by NK631 was stronger than the BLM. On the contrary, the toxicity to lung and various mucocutaneous regions was weaker than the BLM. The grade of pulmonary fibrosis of NK631 was about 1/2 and 2/3 of the BLM in dose of 5 mg/kg and 2.5 mg/kg, respectively. Other toxicological changes such as anorexia and weight loss were almost similar to the BLM.

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1. Whether NK 631 is antigenic to guinea pigs and rabbits was studied by the methods of active and passive anaphylactic shock tests, SCHULTZ-DALE reaction, passive cutaneous anaphylaxis, OUCHTERLONY, tanned red cell haemagglutination test and test according to the U.S. Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics. However, none of the tests proved NK 631 to be antigenic.
2. The immunosuppressive effect of NK 631 was studied by delayed hypersensitivity to picryl chloride in normal and L-1210 tumor bearing mice. Therapeutic dosis of NK 631 was no immunosuppressed but toxic dosis of NK 631 was slightly decreased in ear thickness of delayed hypersensitivity.
3. The acute irritative effect of NK 631 and of bleomycin was studied by single instillation to the rabbit eye mucous membrane with 0.1 ml of either of 10, 33 and 100 mg/ml solution of the drugs in physiological saline.
The irritative effect of NK 631 on the eye mucous membrane at each concentration was slightly severe than that of bleomycin at the same concentration. However, the manifestations were only mild to moderate dilatation of the conjunctival and nictating membrane blood vessels and eye mucous, and recoverd or were mitigated 48 hours after the instillation. No severe changes such as corneal opacity, corneal desquamation, swelling and deaquamation of the conjunctival and nictating membrane were observed.
The histopathological examination revealed no striking changes.
4. Mutagenicity of NK 631 and of bleomycin on Salmonella typhimurium strain TA 100 and TA 98 was studied. It was definitely shown that neither NK 631 nor bleomycin exerted any mutagenic action on either test strains.

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The antimicrobial and antitumor activities, and the pulmonary toxicity of pepleomycin (NK631) were studied in comparison with bleomycin (BLM).
NK631 showed a broad antimicrobial spectrum against gram positive and gram negative bacteria equally to BLM, and its activity was about twice higher than BLM.
NK631 showed higher activity on cultured HeLa S₃ cells and higher antitumor effect on the transplanted tumors of EHRLICH solid carcinoma in mice, AH66 and AH66F ascites hepatoma in rats, and lower antitumor effect on EHRLICH ascites carcinoma in mice than BLM. Similarly to BLM, NK631 did not show satisfactory activity on L1210 leukemia in mice. NK631 showed marked effect on chemically induced squamous cell carcinoma, spontaneous lymph sarcoma of a dog, human and dog gastric cancer heterotransplanted in nude mice equally to BLM. Furthermore NK631 exhibited remarkably higher antitumor activity on lymph node metastasis of AH66 ascites hepatoma of rats and chemically induced gastric carcinoma of rats than BLM.
Pulmonary toxicity of NK631 was low as 1/3 in incidence and 1/4 in grade of the BLM in old mice system. This trend was confirmed by chemical analysis of hydroxyproline in lung.

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1. Organ distribution of pepleomycin (NK631) in mice and rats was studied. NK631 was found at higher levels than bleomycin (BLM) in skin, lung, stomach, solid tumor, etc. in mice and rats.
Furthermore NK631 was detected in the mesenteric and lumbar lymph node, esophagus and prostate in rats and also distributed at about twice as high levels as BLM in the AH109A hepatoma cellmetastasized lymph nodes.
2. For the elucidation of reason on low pulmonary toxicity of NK631 which is in spite of 1.5 times highly disttibution in lung compared with BLM, inaetivation of various BLMs by high molecular fraction of lung of mice and rats was determined. The order of inactivation rate of various BLMs in lung was as follows: BLM-M5196>NK631>BLM>BLM-HPE. There is an encouraging coincidence between index of pulmonary fibrosis in mice and inactivating rate in lung.
3. A comparative study on the serum level and urinary excretion of NK631 and BLM was performed in dogs. The blood level and urinary excretion rate of both drugs were ahnost similar.
4. The blood levels of NK631 were comparable to those of BLM in cancer patients.

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Absorption, excretion, distribution and metabolism of pepleomycin sulfate (NK631) were investigated in rats after intravenous administration of ₃H-NK631 by whole-body autoradiography, CM-Sephadex column chromatography and high performance liquid chromatography. The highest radioactivity was found in kidney, followed by cartilage, blood, lung, esophagus, adrenal gland and skin at 0.5 hour after the administration and little radioactivity was observed in central nerve system. The NK631 and deamide NK631 were identified as major (90%) and minor metabolites in the 24-hour urine.

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[in Japanese]

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Pharmacological actions of pepleomycin sulfate (NK 631) which is a new antitumor agent derived from bleomycin were studied and the following results were obtained.
NK 631 had no significant influences on the central, motor and sensory nervous systems at relatively higher doses (5s 10 i.v., i.p., s.c.). NK 631 (5-40 mg/kg, i.v.) caused a slight decrease in blood pressure in anesthetized rats and slight increases in blood pressure, heart rate and peripheral blood flow in anesthetized dogs.
NK 631 (1-4 mg) given close-arterially caused a slight increase in the developing tension in the isolated blood-perfused papillary muscle. NK 631 slightly contracted the isolated guinea pig ileum and rat uterus but did not affect the contraction of isolated guinea pig trachea. NK 631 caused significant increases in urine output and Cl excretion in saline loaded rats at 20 mg/kg, i.p. By the local injection of NK 631, a slight edema of rat paw and an increase in rabbit cutaneous permeability were observed.
The intraperitoneal injection of NK 631 caused a significant increase in leakage of dye injected intravenously into the peritoneal cavity of mice. NK 631 did not affect hemolysis and prothrombin time at 10^-4g/ml.
In pharmacological actions, significant differences between NK 631 and pepleomycin were not observed.

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