In 1969, ARCAMONE1) discovered adriamycin (ADM). UMEZAWA et al.2) discovered aclacinomycin with less toxicity than ADM. As a consequence of further study, they developed THP-adriamycin (4'-O-tetrahydropyranyladriamycin), as shown in Fig. 1 which has similar or more potent antitumor effect than ADM. MATHE et al.3) proved that cardiotoxicity of THP-adriamycin was less severe or similar to aclacinomycin. As we tried to use THP-adriamycin for head and neck tumors, we report here the primary effects and side effects of THP-adriamycin.

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In selection of drugs to be used in the treatment of biliary tract infections, sensitivity of causative organisms to drugs and tissue concentrations of the drugs constitute important factors. In the present study we treated patients with cholelithiasis with cefoperazone (CPZ) and piperacillin (PIPC), both of which have been reported to show high concentrations in the bile, and concentrations of the drugs in serum, cholecystic bile and various sites of the wall of gallbladder were determined. In addition the drug concentrations in the serum and bile at the 1st and 7th postoperative days were also determined. The following results were obtained.
1. Comparison of concentrations of CPZ and PIPC at various sites of the wall of gallbladder revealed that both drugs showed high levels in the bottom, body and neck areas of the gallbladder with no difference by sites. The concentration ratios against serum for these drugs were 71.8 and 83.6%, showing good transference into tissue.
2. The mean concentrations of CPZ and PIPC in the cholecystic bile were as high as 448.8 and 381.6μg/ml, the ratio against serum being about 4:1.
3. The serum concentrations of PIPC at the 1st and 7th postoperative days were 116 and 137μg/ml at 60 minutes after starting drip infusion, with no difference between these 2 days.
4. In the bile concentrations of PIPC on both postoperative days showed the peak levels of 2,587 and 1, 157μg/ml at 120 minutes after starting drip infusion. The concentrations at the 1st postoperative day were higher.
5. The recovery rate of PIPC from the bile was also higher at the 1st postoperative day.
From the results that both drugs showed high levels in the wall of gallbladder and also showed high levels in the bile immediately after the operation, PIPC and CPZ are considered to be effective drugs for biliary tract infections.

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Studies were carried out on the in vivo kinetics and clinical efficacy of latamoxef (LMOX) in neonates and premature infants. The results are summarized below.
1. Serum concentration and T1/2 following intravenous injection of LMOX to neonates
LMOX was intravenously administered to neonates as one shot doses of 10mg/kg and 20mg/kg. The serum concentration of LMOX showed a dose-response to the 10 and 20mg/kg doses in each of the 0-3 day-old group, 4-7 day-old group and 8-28 day-old group. The T1/2 values were as follows; for the 10mg/kg dose, 5.17 hours in the 0-3 day-old group, 3.28 hours in the 4-7 day-old group and 2.79 hours in the 8-28 day-old group; for the 20mg/kg dose, 5.58 hours in the 0-3 day-old group, 3.46 hours in the 4-7 day-old group and 3.14 hours in the 8-28 day-old group. Thus, it is seen that the half-life of both dosages decreased as the infants became older.
2. Serum concentration and T1/2 following intravenous injection of LMOX to premature infants
Similar to the case of neonates described above, the concentration of LMOX in the serum of the premature infants showed a dose-response to the 10mg/kg and 20mg/kg dosages. The T1/2 values for the 0-3, 4-7 day-old and 8-28 day-old groups were 7.54, 3.93 hours and 6.25 hours, respectively, for the 10mg/kg dose, and 10.8, 4.05 hours and 3.23 hours, respectively, for the 20mg/kg dose. Again, it is seen that the half-life of both dosages decreased as the age of the prematurely-born infants increased.
3. Serum concentration and T1/2 following 1-hour intravenous drip infusion of LMOX to neonates
LMOX was administered to neonates in doses of 10mg/kg and 20mg/kg, by i. v. drip infusion over a 1-hour period. With both dosages, the peak serum concentration of LMOX occurred at the time of completion of the infusion. The T1/2 values for the 0-3, 4-7 day-old and 8-28 day-old groups were 5.41, 3.68 hours and 1.92 hours, respectively, for the 10mg/kg dose, and 5.31, 2.67 hours and 4.86 hours, respectively, for the 20mg/kg dose.
4. Urinary excretion of LMOX in neonates and premature infants
The percentage of the administered LMOX dose contained in the urine excreted during the 6-hour period following intravenous administration of LMOX to neonates and premature infants was determined. In the neonates, this percentage was 39.6% of the 10mg/kg dose and 49.0% of the 20mg/kg dose, while in the premature infants the excretion levels were 47.9% of the 10mg/kg dose and 42.4% of the 20mg/kg dose.
5. LMOX concentration in cerebrospinal fluid
Six patients with purulent meningitis were intravenously administered LMOX in a dose of 50mg/kg, repeated 4-6 times per day (1 patient was administered 22.0mg/kg by i. v. drip infusion). The LMOX concentration in the cerebrospinal fluid (CSF) was determined to range from 6.29 to 49.9μg/ml, with a mean of 22.4 μg/ml, for the period of the first 8 days after dosing, and a range of 2.88 to 10.4μg/ml, with a mean of 7.8μg/ml, was found for the period from the 9th day onward after dosing. The transfer to the CSF was thus good. In addition, the ratio of LMOX concentration in CSF and serum was found to show a maximum of 89%, with a mean of 28.2%.
6. Clinical results
The clinical efficacy of LMOX therapy was evaluated in a total of 111 patients, consisting of 84 neonates and 27 young infants of 29-to 60-day-old. With regard to the administered dosage, 151-300mg/kg/day was given to patients with purulent meningitis, while 41-150mg/kg/day was administered to patients with other infections. These dosages were divided into 2-4 doses per day, administered as one shot intravenous injections.
(1) Clinical efficacy during neonatal period
Of the 7 patients with purulent meningitis, the clinical efficacy was rated as “good” or “excellent” in 5 patients, for an efficacy rate of 71.4%.

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Fundamental and clinical studies on latamoxef (LMOX) in the perinatal period were carried out, and following results were obtained.
1. Concentration of LMOX was showed high peak levels in maternal serum, umbilical serum and amniotic fluid. LMOX seemed to be a very transferable compound to human tissues.
2. LMOX was administered to 28 cases of various perinatal infections. Clinical responses were excellent in 13 cases, good in 15 cases and poor in none. And 140 cases of prophylactic use in the field of perinatal period were evaluated in good.
3. No side effect was seen and an abnormal laboratory finding, the increase of GPT, was observed in only 1 case.
4. LMOX was a highly useful antibiotic in perinatal infections, the safe dose range of LMOX into the perinatal mothers was estimated to be 2g/day, with the maximum safe dose being 4g/day.

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Fundamental and clinical studies on cefaclor (CCL) have been performed and the following results were obtained.
1. CCL was orally administered to NZW rabbits at the dose of 20mg/kg, and its concentrations in blood and various tissues of oral organs were determined. Pattern of change in its blood concentration after the administration was similar to that of change in its concentration in the tissues of oral organs. Its concentration in blood was the highest followed by gingiva, parotid gland, submandibular gland, cervical lymphnode and tongue in descending order.
2. Comparative studies of CCL against cephalexin (CEX) were conducted in 5 healthy volunteers with cross over method. The 5 volunteers were orally given 500mg of CCL or CEX at 1 dose after meal. Peak blood levels of CCL and CEX were 14.8μg/ml at 2 hours and 11.5μg/ml at 3 hours, respectively.
3. The dose of 750 or 1,500mg/day of CCL in 3 divided doses was orally administered to 71 patients with acute purulent infections in oral tissues for 3 to 13 days. Evaluation of effect was determined by the criteria for evaluation of antimicrobial agents in oral surgery. Out of the 70 patients, excellent clinical response was observed in 18 patients, good in 40, and poor in 12. Effective rate was 83%.
4. In vitro antibacterial activities (MIC) of CCL and CEX were studied in 74 out of 81 strains (41 from aerobes and 40 from anaerobes) isolated from 47 patients. CCL showed stronger antibacterial activities than CEX. MICs of CCL against 30 strains of Gram-positive anaerobes were distributed from 0.10 to 3.13μg/ml with a peak of 0.78μμg/ml.
5. As adverse reaction due to CCL, eruption was observed in only 1 patient.
6. Laboratory tests in 61 patients who received CCL showed elevation of GOT in 1 patient and elevation of GOT and GPT in 1 patient.
From the above fundamental and clinical results, CCL was considered to be a useful antibiotic for the treatment of acute purulent infections caused by aerobes and anaerobes in oral surgery field.
1. CCL was orally administered to NZW rabbits at the dose of 20mg/kg, and its concentrations in blood and various tissues of oral organs were determined. Pattern of change in its blood concentration after the administration was similar to that of change in its concentration in the tissues of oral organs. Its concentration in blood was the highest followed by gingiva, parotid gland, submandibular gland, cervical lymphnode and tongue in descending order.
2. Comparative studies of CCL against cephalexin (CEX) were conducted in 5 healthy volunteers with cross over method. The 5 volunteers were orally given 500mg of CCL or CEX at 1 dose after meal. Peak blood levels of CCL and CEX were 14.8μg/ml at 2 hours and 11.5μg/ml at 3 hours, respectively.
3. The dose of 750 or 1,500mg/day of CCL in 3 divided doses was orally administered to 71 patients with acute purulent infections in oral tissues for 3 to 13 days. Evaluation of effect was determined by the criteria for evaluation of antimicrobial agents in oral surgery. Out of the 70 patients, excellent clinical response was observed in 18 patients, good in 40, and poor in 12. Effective rate was 83%.
4. In vitro antibacterial activities (MIC) of CCL and CEX were studied in 74 out of 81 strains (41 from aerobes and 40 from anaerobes) isolated from 47 patients. CCL showed stronger antibacterial activities than CEX. MICs of CCL against 30 strains of Gram-positive anaerobes were distributed from 0.10 to 3.13μg/ml with a peak of 0.78μμg/ml.
5. As adverse reaction due to CCL, eruption was observed in only 1 patient.
6. Laboratory tests in 61 patients who received CCL showed elevation of GOT in 1 patient and elevation of GOT and GPT in 1 patient.
From the above fundamental and clinical results, CCL was considered to be a useful antibiotic for the treatment of acute purulent infections caused by aerobes and anaerobes in oral surgery field.

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Conditions for the susceptibility test of Campylobacter jejuni to fosfomycin (FOM) were studied and it was concluded that the following procedure is most appropriate for routine tests.
The test organisms were subcultured in 0.5ml of heart infusion broth (Difco) in test tubes for a microplanter (Sakuma Seisakusho) and incubated in a GasPak jar with a CampyPak and catalyst (BBL) at 37°C for 44-48 hours. The cultures were then diluted 100-fold in the same broth and inoculated with a microplanter on test plates. The test plates were nutrient agar (Difco) supplemented with 0.2% MgCl2 and 5% defibrinated horse blood. The plates were then incubated under the condition as described above and the growth of the cells was examined.
It should be noted that drying of plates for more than 1 hour caused significant loss of viability of the cells.

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Ceftriaxone (CTRX) was examined in the blood level and urinary excretion between a healthy group of 2 persons receiving 1g CTRX for 1 day and the other of 3 patients with renal failure receiving 1g for 3 days, both by intravenous injection or intravenous drip infusion.
1. In the healthy group, the blood half-life time of CTRX was 6.0 hours in 1 person and 8.2 hours in the other, being 7.1 hours on average.
2. The mean blood level in the healthy group was 199μg/ml at peak and was 13μg/ml at 24 hours after administration. In patients with renal failure, the peak blood level ranged from 136.8 to 161.1μg/ml on the 1st day, from 163.1 to 217.0μg/ml on the 2nd day and from 156.4 to 189.7μg/ml on the 3rd day, showing no tendency of getting higher, while the bottom level did from 15.2 to 47.4μg/ml on the 1st day, from 23.3 to 67.9μg/ml on the 2nd day and from 10.9 to 72.6μg/ml on the 3rd day.
3. The urinary excretion rate was 54.6±3.7% on average in the healthy group while it ranged from 13.7±1.8 to 27.9±7.9% in the patient group.
4. CTRX was effective especially against E. coli among the strains clinically isolated from the patients with renal failure.
5. No side effects were observed in any case.

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Serum and myocardial concentrations of cefotaxime (CTX) were measured in 20 adult patients undergoing cardiac surgery. To all of these patients 1.0g of CTX was given intravenously (in the range of 13.7-29.0mg/kg) at the beginning of operation. The serum concentrations of CTX were determined at 5, 10, 30, 60 minutes and 120 minutes after administration. Myocardial concentrations of CTX were also determined at about 30 minutes (group I), 60 minutes (group II) and 120 minutes (group III).
The following results were obtained.
1. Average serum CTX concentrations were 132.8±34.1μg/ml at 5 minutes, 92.0±23.1μg/ml at 10 minutes, 44.6±12.3μg/ml at 30 minutes, 24.5±7.7μg/ml at 60 minutes and 12.3±4.9μg/mI at 120 minutes after administration.
2. Average myocardial CTX concentrations were 10.0±3.7μg/g in group I, 3.6±2.1μg/g in group II and 2.3±1.8μg/g in group III.
3. The myocardial/serum concentration ratio was 0.22±0.14 in group I, 0.15±0.08 in group II and 0.18± 0.12 in group III, respectively.
These results suggested that the serum and myocardial concentrations of CTX were high enough to be prophylactic and therapeutic against not only aerobic but also anaerobic and opportunistic infections during and after cardiac surgery.

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In vitro susceptibilities of 3,286 strains of various pathogens isolated from clinical materials in 1983 to various cephem antibiotics were studied using the Showa disk diffusion test. The following antibiotics were evaluated: cephalexin (CEX), cephalothin (CET), cefazolin (CEZ), cefotiam (CTM), cefoxitin (CFX), cefmetazole (CMZ), cefotaxime (CTX), cefoperazone (CPZ), ceftizoxime (CZX), cefmenoxime (CMX) and latamoxef (LMOX).
S. aureus: Susceptible strains to CET, CEZ, CTM, CFX and CMZ with MIC less than 15μg/ml accounted for 93, 75, 93, 70 and 96% of the strains tested, while those to CTX, CPZ, CZX, CMX and LMOX for 89, 65, 61, 86 and 62%, respectively. Susceptible strains to CEX at MICs ≤20μg/ml were 60%. Prevalence of bacterial resistance to CEX and CEZ, which have been used extensively, was greater than that to CET, CTM or CMZ, showing a bimodal distribution of MICs. The third generation cephems studied, in general, also showed bimodal distributions of MICs.
S. pyogenes: All strains studied were susceptible to CET, CTX, CPZ, CZX, CMX and LMOX at MICs 15μg/ml. However, susceptible strains to CEZ, CTM, CFX and CMZ accounted for 95, 95, 80 and 90%, respectively, while those to CEX at MICs ≤20μg/ml for 79%.
S. pneumoniae: At MICs less than 3μg/ml, all strains were susceptible to all cephem antibiotics tested.
S. faecalis: Only a very few strains were susceptible to these antibiotics.
E. coli, K. pneumoniae and Proteus spp.: Susceptible strains of E. coli and K. pneumoniae to CEX at MICs ≤20μg/ml accounted for 80 and 81% of the strains tested, while those of indole negative and positive Proteus for 69 and 4%, respectively. Strains of E. coli susceptible to CET, CEZ, CTM, CFX and CMZ at MICs ≤15μg/ml were 78 to 96%, while those to CTX, CPZ, CZX, CMX and LMOX were 94 to 100%. Those of K. pneumoniae to these 2 groups of antibiotics were 81 to 95% and 94 to 100%, respectively. Susceptible strains of indole negative Proteus to the former group were 81 to 93% and those to the latter were 100%. Those of indole positive Proteus to CET and CEZ were 2 to 6%, whereas those to CFX, CTM and CMZ were 61 to 96%, but strains susceptible to CTX, CPZ, CZX, CMX and LMOX were 93 to 100%.
H. influenzae: Susceptible strains to CET, CEZ, CTM, CFX and CMZ at MICs ≤15μg/ml were 83, 32, 87, 74 and 79%, respectively. On the other hand, all strains were susceptible to CTX, CPZ, CZX, CMX, and LMOX at the same MICs.
P. aeruginosa: No susceptible strains to CET, CEZ, CTM, CFX and CMZ were observed at MICs ≤15μg/ml and to CEX at MICs ≤20μg/ml, but susceptible strains to CTX, CPZ, CZX, CMX and LMOX at MICs ≤15μg/ml were 60, 65, 48, 49 and 39%, respectively.
S. marcescens: 82 to 90% of strains were susceptible to CTX, CZX, CMX and LMOX at MICs ≤15μg/ml, but no significant susceptibility to other antibiotics studied was observed.
Enterobacter, Citrobacter and Acinetobacter spp.: The third generation cephems showed significant activity against these pathogens except CPZ to Acinetobacter spp., whereas the first and second generation cephems were ineffective (susceptible strains 59 to 98% vs. 2 to 69%).

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In vitro and in vivo antibacterial activities of MT-141, a new cephamycin, against anaerobic bacteria were compared with those of cefmetazole (CMZ), cefoxitin, cefotaxime, ceftizoxime, latamoxef and cefazolin to obtain the following results.
1. MT-141 showed high activity against a wide variety of anaerobic bacteria including B. fragilis and C. difficile except for Eubacterium lentum, E. aerofaciens and B. furcosus.
2. Antibacterial activity of MT-141 against anaerobic bacteria was almost independent of inoculum size, medium, pH and serum addition.
3. In vitro development of resistance of MT-141 against P. variabilis and B. fragilis was comparable to that of CMZ.
4. Successive parenteral administration of MT-141 into mice did not cause abnormal proliferation of C. difficile.
5. MT-141 showed excellent therapeutic effect against experimental subcutaneous abscess in mice caused by B. fragilis.

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The acute toxicity of MT-141 was studied in adult Beagle dogs with intravenous (i.v.) or intramuscular (i.m.) administration to obtain following results.
1. MT-141 at the doses ranging from 2,500 to 7,500 mg/kg i.v. caused no effect on life, bodyweight, food intake, eyeground and ECG in male and female Beagle dogs.
2. MT-141 produced an increase in water intake, urine volume, WBC and LAP and a decrease in Lymph., U-Na, U-K and OP, but any histopathological change was not caused in the organs and tissues. It is suggested that these changes in blood, serum and urine are due to mechanical and transient effects induced by infusing a large volume of hypertonic solution of MT-141 into cephalic vein.
3. When 1,000 or 2,000 mg/kg of MT-141 was injected into the muscles of hind legs, the hind legs had difficulty in walking. It is very probable that this change was due to mechanical effects induced by injecting a hypertonic solution of MT-141 at a rate of 70-130 ml/dog.
4. An injection of 1,000 or 2,000 mg/kg i.m. of MT-141 changed activity of GPT, GOT and CPK in the serum within the limit of physiological variations but did not caused any effect on the other toxicological parameters such as bodyweight, food intake, water intake, urine volume, eyeground examination, ECG and histopathological examination.
5. It is concluded from the above-mentioned results that MT-141 at the dose of 2,500-7,500 mg/kg i.v. or 1,000-2,000 mg/kg i.m. has no significant toxicity in Beagle dogs.

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The 30-day subacute toxicity of MT-141 was studied in adult Beagle dogs with intravenous (i.v.) administrations of 100 to 1,200 mg/kg/day. The obtained results were as follows.
1. MT-141 at the doses lower than 800 mg/kg/day i.v. had no toxicity in male and female Beagle dogs.
2. An increase in water intake was closely related to that in urine excretion after i.v. treatments with 1,200 mg/kg/day of MT-141 in the males and females.
3. MT-141 at the doses higher than 1,000 mg/kg/day i.v. of MT-141 caused slight local irritation at the site of injection in the males and females.
4. In the females, the dose-dependent changes induced by treatments with the doses above 1,000 mg/kg/day i.v. of MT-141 were a significant decrease in the level of serum K and a significant increase in the activity of serum LAP.
5. In the males, this compound produced significant dose-dependent changes in toxicological parameters such as a decrease in the activity of GOT at the doses higher than 1,000 mg/kg/day i.v., a descent in the levels of U-K, U-Cl and OP at the dose of 1,200 mg/kg/day i.v., an elevation in the level of serum α₁-and α₂-G, and an increase in the volume of excreted urine at the dose of 1,200 mg/kg/day i.v.
6. It is concluded from the above-mentioned results that the maximal “no effective” dose of MT-141 is 800 mg/kg/day i.v. and the toxic dose of MT-141 is above 1,000 mg/kg/day i.v. in male and female Beagle dogs.

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MT-141 was dosed to male and female Beagle dogs through intravenous (i. v.) route at 100, 200, 400 and 800 mg/kg/day for 182 days. The toxic effects of MT-141 were as follows.
1. The male and female Beagle dogs exhibited no particular behavior and symptom except vomiting and soft stool after treatments with 800mg/kg/day i. v. of MT-141.
2. MT-141 even at the high doses of 400 to 800mg/kg/day i. v. did not significantly change toxicological parameters such as consumption of food and water, volume of excreted urine, electrocardiogram, eyeground and analysis of blood, serum and urine.
3. Only one of 4 male Beagle dogs died of severe intestinal invagination, which is not related to the drug effect, at 120th day after the start of treatments with the highest dose of 800mg/kg/day i. v. of MT-141. The fatality of Beagle dogs for 800mg/kg/day of MT-141 was 25% (1/4) in males and 0% (0/4) in females.
4. MT-141 caused the hemorrhage accompanied with fibrosis and round cells at the site of injections but the change induced by MT-141 was not so much different from that by saline.
5. MT-141 at the highest dose induced histopathological changes in only 2 females, such as atrophy and degeneration of cardiac muscle, necrosis and fibrosis of hepatic cells and hyperplasia of spleen and bone marrow cells.
6. Electron-microscopic examinations revealed no ultrastructural change related to the toxicity of MT-141 in the livers and kidneys.
7. It is considered from the above-mentioned results that the maximal “no effective” dose is 400mg/kg/day i. v. in male and female Beagle dogs.

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The local irritation of MT-141 was compared with that of cefmetazole (CMZ) in rabbits to obtain following results.
1. Microscopic observations revealed that the irritative activity of 10% solution of MT-141 in blood vessels was not so much different from that of saline and 10% solution of CMZ when they were injected twice a day into vein retroauricularis of rabbits for 7 days.
The histopathological changes induced by 10% solution of MT-141 were similar to those by 10% solution of CMZ but somewhat different from those by saline, because both compounds caused slight necrosis in the tissue around vessels. Histopathological observations suggested that the occurrence of necrosis was due to the leakage of them during injections.
2. The local irritation of MT-141 by an injection of 1ml of its solution into muscle vastus lateralis was compared with that of CMZ in rabbits. The potencies of irritative activity of the test solutions were summarized in the following order; saline<5% MT-141 <10% MT-141 10% 10% CMZ<0.75% acetic acid<6.0% acetic acid.
3. The above-mentioned results suggest that MT-141 has low irritating activity when injected through intravenous or intramuscular route for clinical practice as 5% or 10% solution.

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A fertility study of MT-141 was performed in SD rats with the intramuscular (i. m.) injections at the dose levels of 400, 800 and 1,600mg/kg/day. The male rats were injected with MT-141 for 63 days before mating and during the mating period, while the female rats were injected with MT-141 from the 14th day before mating up to the day 7 of gestation. All pregnant rats were sacrificed on day 20 of gestation followed by external, visceral and skeletal observations of their fetuses. The results are summarized as follows.
1. The suppression of body weight gain was observed in males given above 800mg/kg/day i. m. and in females of all treated groups during early period of gestation. However, no significant differences were found between treated groups and the control with regard to copulation rate and conception rate.
2. Though no defects were observed for visceral and skeletal specimens in the fetuses of treated groups, MT-141 produced a delayed ossification of forelimbs in the fetuses at the doses above 800mg/kg/day and of sternebrae at the dose of 1,600mg/kg/day.
3. It is concluded from the above-mentioned results that the maximal “no effective” dose of MT-141 on the fertility is above 1,600mg/kg/day i. m. in parental rats and less than 800mg/kg/day i. m. for the fetuses.

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A teratogenicity study of MT-141 was performed in SD rats and Japanese white rabbits. The pregnant rats were administered intramuscularly (i. m.) with MT-141 at the dose levels of 200, 400, 800 and 1,600 mg/kg/day from the day 7 up to the day 17 of gestation. The pregnant rabbits were administered intravenously (i. v.) with the drug at the dose levels of 10, 20 and 40 mg/kg/day from the day 6 up to the day 18 of gestation. The results are summarized as follows. 1. Rats
Though the administrations with MT-141 at all dose levels did not change body weight gain and water intake of treated dams, a slight suppression in the food comsumption was produced by MT-141 at the dose of 1,600 mg/kg/day.
The examinations on cesarean section revealed no effect of MT-141 on teratological parameters such as external malformation and frequency of visceral and skeletal anomalies in the fetuses.
MT-141 at all dose levels exerted no toxic effect on developmental, functional and behavioral parameters in F₁rats and on mating, fertility and pregnancy of F₁rats. Furthermore, there was no effect of MT-141 on the findings in cesarean section of F₁rats. The fetuses from F₁rats had no malformation of external appearance, viscera and skeleton.
2. Rabbits
MT-141 had no significant effect on body weight gain and food consumption of dams at the all dose levels, but caused a slight suppression in the water intake at the doses more than 20 mg/kg/day. One rabbit aborted in each group given 20 or 40 mg/kg/day. One rabbit died in the group given 20 mg/kg/day.
Examinations on cesarean section showed that MT-141 at the dose of 40 mg/kg/day produced a decrease in body weights of females and an increase in dead or resorbed fetuses followed by a decrease in live fetuses. MT-141 is no effect malformation of external appearance, viscera and skeleton in the fetuses of all treated groups.
3. The above-mentioned results suggest that MT-141 has no teratogenic effect on pregnant rats and rabbits. It is concluded from these results that the maximal “no effective” dose of MT-141 on fetal toxicity is above 1,600 mg/kg/day i. m. for pregnant rats and 10 mg/kg/day i. v. for pregnant rabbits.

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A perinatal and postnatal study of MT-141 was performed in SD rats. The dams were administered in-tramuscularly (i. m.) with MT-141 at the dose levels of 400, 800 and 1,600 mg/kg/day from the day 17 of gesta-tion until the day 21 post delivery. The results are summarized as follows.
1. No significant adverse effects of MT-141 were observed on the body weight gain, food consumption and water intake in dams of all groups treated with the drug during the perinatal and postnatal period.
2. MT-141 did not change parameters of reproductive study in birth, development, physiological function and behavior of F₁ rat.
3. This compound had no effect on the fertility in F₁ rats and also did not caused significant defects in the external appearance, viscera and skeleton of fetuses from dams (F₁).
4. It is concluded from these results that the maximal “no effective” dose of MT-141 is above 1,600 mg/kg/day i. m. for dams and the offsprings.

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