Various derivativei of L-cpteine obtained by conversion to an-S-S-bond in the mucoprotein by means of-SH in the chemical structure are widely used as expectorants because they show mucous dissolving action. Recently, there have been reports that L-cysteine derivatives lower the potencies Of viiious antibiotics.1-5);
Various typet of antibiotiat eyiteine-type expectorants are often used concomitantly for the treatment of bacterial infecticiiis in rispiratory tract diseases, and any decrease in the antibiotic potency presehtt Major t4erapeutic problem.
We invesiigited effects of tour cysteine derivatives on 12 antibiotics, ampicillin (ABPC), amoxicillin (AMPC),(SBPt), cefazolin (CEZ), cephalexin (CEX), cephalothin (CET), oxytetracycline (OTC), doxycycline (DOTC), minocycline (MINO), erythromycin (EM), ribostamycin (YSM) and lincomycin (LCM), widely used clinically in vitro, with the minimum inhibitory concentration (MC) obtained by the liquid dilution method as an index. L-Cysteine, acetylcysteine, ethylcysteine and mecysteine lowered the potencies of almost all of the antibiotics at high concentrations (500mcg/ml), but at low concentrations (12.5mcg/ml), mecysteine lowered the potencies of only three antibiotics and L-cysteine thote of only four antibiotics, while acetylcysteine decreased the potencies of six and ethylcysteine those of seven antibiotics.

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In the first in this series of reporte 1), we reported the effects of cysteine compounds on the minimum inhibitory concentrations (MIC) of antibiotics in vitro to indicate the interaction between cysteine compounds and antibiotics.
In this report, we investigated L-methylcysteine hydrochloride (mecysteine, Pectite®). Among the antibiotics, i. e. sodium cephalothin (CET), cephalexin (CEX) and lincomycin hydrochloride (LCM), which had their potencies lowered by a concentration of 25mcg/ml of mecysteine, which is considered to approximate the concentration in the blood at clinical doses, in the first report, CEX and LCM administered per os were selected. Ampicillin (ABPC) which was reported to have its potency lowered by cysteine by RYUGE et al. 2, 3) and SATAKE et al.4, 5) was also selected and the interaction was investigated using the serum concentration of the antibiotics in humans as an index.
The subjects were 15 volunteers divided into three groups: the ABPC, CEX and LCM groups (5 persons each). The administration the same method, for all groups, started with administration of the antibiotic alone, followed by concomitant administration of the antibiotic and 100mg of mecysteine one week later.
The results showed that the serum concentrations due to a single oral administration simultaneously of 100mg of mecysteine and 250mg of ABPC, 250mg of CEX or 500mg of LCM were the same as the respective serum concentrations of ABPC, CEX and LCM administered alone, and there were no significant differences.

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Antitumor activity of new anthracycline antibiotics aclacinomycin A, MA 144 N 1 and MA 144 S 1 was studied on 11 cell lines of ascitic hepatoma in Donryu rats. These compounds showed similar antitumor spectrum against AH hepatoma; moderate effect on AH 13, 44, 66, 66 F, 7974 and 60 C in the ip inoculation-ip treatment system. Aclacinomypin A showed a marked antitumor effect on AH 41 C in the iv-iv system, and AH 44 in the iv-ip and iv-po systems. The antitumor spectrum of aclacinomycin A seems to be different from that of adriamycin.

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New antitumor anthracycline antibiotic, aclacinomycin A was given to dd-mice and Wistar rats for acute toxicity study. The LD₅₀ values were 29-39mg/kg (i. v., i. p. and s. c.) and 62-69mg/kg (p. o.) in mice, and 18-28mg/kg (i. v., i.p. and s. c.) and 58-59mg/kg (p. o.) in rats, respectively, which were calculated by mortality rate during a 14 day observation period. Depression of spontaneous activity, anorexia, diarrhea and slight alopecia were observed. Autopsy findings in animals killed by drug included atrophy of the thymus and spleen, and hyperemia and hemorrhage in the stomach and intestines. But no remarkable change was found in animals which survived through the observation period. Mongrel dogs were given the drug intravenously at 3, 5, 7.5, 10 and 15mg/kg, respectively. All dogs (3/3) in the three higher dose groups and 1/3 dog in 5mg/kg dose group died within day 0-5. Others survived more than 27 days. Depression of spontaneous activity and anorexia were found from 30 minutes to 2 hours after administration, followed by vomiting and diarrhea. Increase of GOT, GPT and LDH and decrease of WBC count were detected in dogs which died. Hyperemia and hemorrhage of the lungs, stomach and intestine were found among the groups given higher doses, whereas no significant changes were recognized among the two lower dose groups.

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Wistar rats, both male and female, were treated with aclacinomycin A at 4 dosage levels (0.375, 0.75, 1.5 and 3.0mg/kg/day) by daily intraperitoneal injection for 30 days. Several rats died in the two higher dose groups (1.5mg/kg/day: male 2/8 and 3.0 mg/kg: male 8/8, female 8/8). Piloerection, anorexia, depression of spontaneous activity, diarrhea and slight incontinence were observed in rats in 3.0mg/kg/day dose group. Body weight gain decreased after day 3 in rats receiving 1.5 and 3.0mg/kg/day. A significant decrease in the total WBC count and a slight decrease in RBC count were observed in animals of 1.5mg/kg/day dose group which were survived for 30 days. Autopsy findings demonstrated atrophy of the thymus and spleen, and hyperemia and hemorrhage in the intestine. The atrophy of the thymus and decreased hematopoiesis in the bone marrow were histologically noted in the two highest dose groups. No cardiotoxicity was observed.

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[in Japanese]

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A new anthracycline antitumor antibiotic, aclacinomycin A, was labeled with ³H uniformly or with ¹⁴C simultaneously at the anthracycline nucleus and L-rhodosamine. These labeled drugs were administered intravenously to normal dd mice, solid type Sarcoma 180 tumor-bearing ICR mice, normal or pregnant Wistar rats and normal rabbits, respectively. ¹⁴C-Aclacinomycin A given to rabbits (5mg/kg) was rapidly cleared from the blood and transferred to tissues. But low level of radioactivity (equivalent to about 0.5mcg/ml) was remained in the blood even 8-10 hours after administration. About 45% of the radioactivity were recovered from the urine and 20% from the feces by 72 hours after administration.
Tissue levels of ³H-¹⁴C-aclacinomycin A given to normal and tumor-bearing mice were highest in the lungs and spleen. Higher distribution was obserbed also in the liver and kidneys 2 hours after administration. Bioassay revealed that the drug was present in the lungs and spleen in biologically active form and in the liver and kidneys in inactive form, respectively. In the tumor tissue the radioactivity was low but it persisted for 48 hours.
Autoradiography with ¹⁴C-aclacinomycin A in rats demonstrated that radioactivity due to the drug distributed in the lungs, spleen, kidneys, thymus, intestine, lymph nodes, bone marrow, salivary gland, hypophysis and pineal body but it was rapidly cleared. About 0.2% of radioactivity given to a pregnant rat were transferred to a fetus when ¹⁴C-aclacinomycin A was administered intravenously on the 18-19th day of pregnancy.

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An anthracycline antitumor antibiotic, aclacinomycin A, was given to mice, rabbits or dogs intravenously to study the pharmacokinetics by photometric assay based on the absorption of anthracycline ring.
The drug was rapidly eliminated from the blood in these animals. Drug levels were much higher in the blood cells than in the plasma. Tissue levels in dogs were 50-100 times higher than the blood levels, which showed the drug was rapidly transferred from the blood to tissues after administration. Higher levels were observed in the lungs, spleen and lymph nodes, where the drug was present as aclacinomycin A itself and the glycoside-type metabolites that were biologically active. The active form was also detected in the pancreas, heart, thymus, bone marrow and gastrointestinal tract.
In the liver and kidneys, biologically inactive aglycone-type metabolites were observed. About 2-4% of the drug given to rabbits or dogs was recovered in the urine by 72 hours after administration, in which only 10% of the excreted drug was active form in rabbits but about 65% in dogs. The rest was inactive aglycone-type metabolites that were excreted almost in the conjugated form. Biliary excretion also contributed to the total clearance of the drug.
Aclacinomycin A was absorbed even by oral administration in rabbits and dogs. Tissue distribution of the drug orally given to dogs was similar to that in intravenous administration, except that higher levels of active form were detected in the gastrointestinal tract and of inactive form in the liver.

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The general pharmacology of aclacinomycin A, a new antitumor antibiotic, was studied in mice, rats, guinea-pigs, frogs, rabbits and dogs. The LD₅₀ values of aclacinomycin A were 32.5mg/kg (i. v.), 30.1mg/kg (i. p.), 33.9mg/kg (s. c.) and 69.7mg/kg (p. o.), respectively in male mice, and 28.8mg/kg (i. v.), 21.1mg/kg (i. p.), 26.4mg/kg (s. c.) and 58.6mg/kg (p. o.), respectively in male rats. Aclacinomycin A had no effect on the central nervous system except potenciation of the pentobarbital sodium-induced anesthesia in mice. The contraction of isolated heart was stimulated in frogs while slightly inhibited in rabbits at higher concentration. Transient increases in the heart rate and the blood flow of peripheral vasculature were observed but the blood pressure was slightly lowered with respiratory excitation in anesthetized rabbits and dogs. The ECG (II-lead) demonstrated slight depression of R wave amplitude and slight sinus arrhythmia in dogs.
Aclacinomycin A inhibited the contraction of isolated smooth muscle and antagonized some spasmogens. It inhibited the spontaneous movement of isolated rabbit ileum and rat uterus at higher concentration, and antagonized acetylcholine, histamine, serotonin and barium chloride in the contraction of isolated guinea-pig ileum. The antagonism was conpetitive to oxytocin and non-conpetitive to acetylcholine in rat uterus, and nonconpetitive to noradrenaline in rat deferent duct. The drug showed no apparent effect on the gastrointestinal propulsion in mice and on mucous membrane of the stomach in rats. However, it depressed gastric acid secretion in rats while slightly increased bile secretion in guinea-pigs. Urine volume and urinary excretion of electrolytes (Na⁺, K⁺) decreased in rats. Vascular permeability was slightly inhibited by the drug in rabbits and mice. No hemolytic effect was shown. Aclacinomycin A showed no antigenicity in anaphylactic reaction and Sctwurz-DALE reaction in guinea-pigs.

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Recently, it has been known that the treatment with paromomycin sulfate is effective against many kinds of tapeworm. Paromomycin sulfate was used for treating 56 patients with Diphyllobothrium latum aged 2-65 years old.
Parotnomycin was administered orally in the dose of 25-50mg/kg. All cases with Diphyllobothriasis latum were successfully treated with paromomycin. The drug was well tolerated and no side effects were observed in any patients.

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W-1062, a newaminoglycoside antibiotic, was tested for the evaluation of audiotoxicity in administration at higher dosage and compared with the audiotoxicity of gentamicin.
KW-1062 was given at dosage of 50, 100 and 150mg/kg intramuscularly for 4 weeks to each group consisting of 10 healthy guinea pigs, respectively.Gentamicin was administered at dosage of 25, 35, 50 and 100mg/kg in the same way as in KW-1062 to the guinea pigs.
In the present study the differential frequency pinna reflex test in the frequency range from 20kHz to 0.5kHz was performed before and during administration of the drugs, to evaluate the audiotoxicity.
Comparison of number of animal with pinna reflex loss and extent of frequency range of pinna reflex loss revealed that KW-1062 at dose of 150mg/kg is less audiotoxic than gentamicin at 50mg/kg and100mg/kg, and approximately equivalent in audiotoxicity to gentamicin at dose of 35mg/kg.

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A new antibiotic designated tendomycin was isolated from the culture of Strepto-myces No.9034. The antibiotic is active against Gram-positive bacteria, fungi and cultured cancer cells, and shows an inhibitory effect of EHRLICH carcinoma in mice.

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