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General pharmacological properties of cefoperazone (CPZ) were studied in various experimental animals.
CPZ showed the following effects with intravenous injection to experimental animals.On the central nervous system, CPZ caused vomiting in dogs at 500mg/kg, pyrexia and slow waves in electroencephalogramin rabbits at1,000mg/kg.On the motor and sensory nervous systems, CPZ enhanced slightlythe twitch tension of musculus gastrocnemius induced by electrical stimulation in rats at500mg/kg.On the respiratory, cardiovascular and autonomic nervous systems, CPZ increased transiently the respiratoryrate and potentiated the depressor response to Ach at125mg/kg, increased femoral blood flow, potentiated the pressor response to Adr in dogs and decreased the contraction of nictitating membraneinduced by electrical stimulation in cats at500mg/kg, and then raised the systolic blood pressure in rabbits at1,000mg/kg.On the blood, CPZ decreased ChE activity in rabbit plasma at250mg/kg, prolonged bleeding time in mice at500mg/kg and prothrombin time in rabbits at1,000 mg/kg.On the smooth muscle organs, CPZ enhanced slightly gastric motility in rabbits and ileal motility inguinea pigs at62.5and125mg/kg respectively, and promoted gastrointestinal propulsion of BaSO₄ mealin mice at1,000mg/kg.On the urinary organ, CPZ increased urine volume and electrolytes excretionin dogs at 500 mg/kg.
Subcutaneous injection of CPZ scarcely showed any significant effect in experimental animalsunder the dose of2,000mg/kg.
In the in vitro experiments, CPZ enhanced slightly the motility of isolated rabbit gastrointestinaltract at10^-3g/ml.
Assuming the single clinical dose of CPZ should be10-40mg/kg, it is concluded that the occurrence of pharmacological effects observed in experimental animals seems to be very rare clinically.

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Muscular injury caused by cefoperazone (CPZ) was compared with that of cefazolin (CEZ), cephaloridine (CER) or cephalothin (CET) in adult and juvenile male rabbits.
These drugs were dissolved by the way of clinical use and were injected singly into the musculus vastus lateralis.Then, the degree of muscular injury at the time of 48 hours and 7 days after the injection was judged from muscle weight ratio, gross local observation and histological observation.
The degree of muscular injury caused by these drugs was compared also with that of saline, 0.75% or 6% acetic acid.
The following results were obtained:
There was no difference among CPZ, CEZ and CER on the degree of muscular injury and these changes were almost equal to those of 0.75% acetic acid, however severer than that of saline.While, muscular injury caused by CET was severer than that of CPZ, CEZ, CER or 0.75% acetic acid, butmilder than 6% acetic acid.
The inflammatory reaction against these drugs was almost similar in adult and juvenile rabbits.

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The subacute toxicity test of cefoperazone (CPZ) in Beagle dogs with the intravenous administrationfor 35 days has been reported from our laboratory.In the present experiment, the subacute toxicity test of CPZ in Beagle dogs was carried out for longer administration period than before.
CPZ was given intravenously to each group (2 or 4 dogs) at dose level of 100 mg/kg/day, 200 mg/kg/day and 400 mg/kg/day respectively for 3 months.Cefazolin (CEZ) was used intravenously for positive control using 4 dogs at dose levelof 200 mg/kg/day and physiological saline was given intravenously to 2 dogs for 3 months.
1) In Beagle dogs received high dose of CPZ, transient vomiting, salivation and diarrhea wereobserved immediately after the administration.
2) Signs of anemia, such as decrease of erythrocyte and value of hemoglobin and hematocrit, and increase of reticulocytes of the peripheralblood and in fragility of red cell associated with decrease of food intake, were observed in 2 female dogs given CPZ of 400 mg/kg/day.In only one of thesedogs, a positive reaction of COOMBS test was shown.The anemia recognized in these 2 dogs seems to be of hemolytic nature.
3) The weight of thymus was decreased in all of 4 dogs given CPZ at 400 mg/kg/day and in 2 out of 4 dogs given CPZ at 200 mg/kg/day, respectively.
4) Based on the fact that no abnormalities were found in dogs given CPZ at 200 mg/kg/day excepta slight decrease of weight of thymus in some of them, the maximum safety dose of CPZ was thoughtto be 200 mg/kg/day.

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The subacute toxicity test of cefoperazone (CPZ), a new cephalosporin antibiotic, was carried out in both sexes of Beagle dogs. CPZ was injected to Beagle dogs intramuscularly at dose levels of 500,250 and 125 mg/kg/day for 3 months. The same amount of physiological saline was injected to control dogs intramuscularly for 3 months.
The following results were obtained:
1) Sign of severe pain was shown immediately after injection in groups of CPZ at 500 and 250 mg/kg/day. In the same groups, the focal necrosis, hemorrhage, cell infiltration and fibrosis of muscles of injected site were noted microscopically.
2) In only one out of 6 dogs given CPZ at 500 mg/kg/day for 3 months, decrease of red bloodcells and in values of hemoglobin and hematocrit and increase of reticulocytes in the peripheral blood were observed. In the same dog, splenomegaly and extramedullary hematopoiesis in the liver was found histopathologically, and in addition, the body weight and the food intake decreased during the administration period, associated with the development of anemia.
3) In dogs receiving up to 250 mg/kg/day, atrophy of the thymus was recognized at autopsy and slight decrease of cortical limphocytes was seen histopathologically.
4) Based on these results, the maximum safety dose of CPZ was thought to be 125 mg/kg/day from the present experiment.

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The absorption, distribution and excretion of sodium 7-[D (-)-α-(4-ethyl-2, 3-dioxo-1-piperazinecarboxamido)-α-(4-hydroxyphenyl) acetamido]-3-[(1-methyl-1H-tetrazol-5-y1) thiomethyl]-3-cephem-4-carboxylate (cefoperazone, CPZ) were studied in rats andmice with¹⁴C-labelled CPZ (¹⁴C-CPZ)
(1) Serum protein binding rate of 14C-CPZ was13.5% in mice and about45% in rats.
(2) After both intravenous and intramuscular administration of ¹⁴C-CPZ in rats, blood levels maintained highly in proportion to the dose.But after oral administration blood levels were hardly observed.
(3) With regard to distribution pattern of radioactivity after parenteral administration of14C-CPZ in mice and rats, a significant specific difference was not found.The radioactivity was rapidly distributed into various organs and tissue levels were highest in liver and kidney, followed by bladder, intestine, stomach, lung, heart, ovarium, uterus, adrenal and pancreas.
(4) The tissue levels of new born rats were observed continuously higher in blood and almost every organs except liver and kidney as compared with adult rats.
(5) After both intravenous and intramuscular administration of 50 mg/kg in rats, about 14.4-25.5% and about 75.6-84.4% of radioactivity were respectively excreted in urine and feces within120 hours. As to after subcutaneous administration in mice, about 30.9% and about67.3% of radioactivity were excreted in urine and feces.
(6) A considerable radioactivity was excreted rapidly in bile after parenteral administration in rats, but which was hardly reabsorbed from gastrointestinal tracts.
(7) In the case of intravenous administration in rats, as the dose was higher, the urinary excretion rate was higher, but the biliary excretion rate was lower.
(8) On the administration to pregnant rats and maternal rats that were supplying infantile rats with milk, the transport of radioactivity to fetus and infantile rats was hardly observed.
(9) After intravenous administration in bile duct ligated rats, blood levels maintained highly as compared with normal rats.While in ureter ligated rats, blood levels were observed the same level as normal rats.
(10) After intravenous administration in bile duct ligated rats, the most part of radioactivity was excreted in urine within 48 hours.
(11) The metabolite was hardly detected in urineand bile of rats.And¹⁴C-CPZ was almost stable in homogenates of liver, kidney and small intestine of rats.

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The distribution of cefoperazone (CPZ), a new semisynthetic cephalosporin antibiotic, was studied by macroautoradiography following a single intravenous or subcutaneous administration of 100mg/kg¹⁴C-CPZ to rats, mice, pregnant mice and experimental pyelonephritic mice.
(1) In whole body autoradiograms of rats administered subcutaneously and mice administered subcutaneously and intravenously, their distribution patterns of the radioactivity werefound to be similar to each case.The radioactivity was distributed at high concentration in the liver, kidney, lung, tongue, salivary gland, skin, gastrointestinal tracts and retina.The radioactivity was rapidly excreted in urine and bile.And it was observed that the radioactivity excreted through bile was not reabsorbed from gastrointestinal tracts.
(2) In pregnant mice administered intravenously, the radioactivity was observed the same level as whole blood level in placenta, while was hardly observed in fetuses.
(3) In the experimental pyelonephritic mice administered intravenously, a considerable radioactivity was concentrated on the acute inflammatoryarea.

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The therapeutic efficacy of cefoxitin (CFX) in chronic respiratory tract infection was evaluated in patients who poorly responsed to other antibiotics.
To 20 patients, CFX was administered 2g b.i.d. intravenously by drip infusion.Clinical efficacy was judged based on the criteria by score.
1.Bacterial elimination rate with CFX was 73.7%.
2.A clinical cure rate of 80.0% was obtained by doctors in charge.
3.According to the score assessment, the overall clinical effectiveness rate was 60.0%, clinical symptom cure rate was 85.0% and improvement rate of X-ray findings was 55.0%.
4. Usefulness rate which was assessed by clinical effect and side effect was 70.0%.
5.No side effects and abnormal laboratory findings were observed in this study.
We used the new antibiotic CFX in patients with chronic respiratory tract infections who responsed poorly to other antibiotics and obtained satisfactory results.Especially CFX indicated more effective possibility in cases from whom Gram-negative bacilli were isolated.

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Radioimmunoassays for unique aminoglycoside antibiotics, three fortimicin components, have been developed using antisera obtained from rabbits injected with fortimicin A-, isofortimicin A-or fortimicin B-BSA conjugate, respectively.Fortimicins were tritiated with N-succinimidyl-[2, 3-³H] propionate.
For fortimicin A, the standard curve was linear on a logit-log plot yielding an sensitivity of 0.2 ng/tube.A correlation coefficient of 0.99 was obtained between the radioimmunoassay and a microbioassayfor fortimicin A in human sera.In the assay cross-reaction occurred with fortimicin derivatives and there was no cross-reaction with neomycin, kanamycin, sagamicin, amikacin, dibekacin, penicillinsand cephalosporins.
From the comparison of the specificity observed in three kinds of antisera, the following conclusionshave been obtained: (1) Anti-fortimicin A and anti-isofortimicin A antisera were specific for the correspondinghaptens.(2) In fortimicin B-BSA conjugate and ³H labeled antigen of fortimicin B, the fortamine ring might be inverted from the 4C1 conformation to the lc, conformation.Thus the specificity of anti-fortimicin B antisera for fortimicins resembled to that of anti-fortimicin A antisera.

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KW-1062 was administered intramuscularly at a daily dose of 360 mg for 5 days to 50 patients suffering from chronic complicated urinary tract infections. The following results were obtained.
1.Clinical response was excellent in 3 cases (6%), moderate in 23 (46%) and poor in 24 (48%);the overall effectiveness rate was 52%.
2.In bacteriological results, 58 (75.3%) out of 77 strains were eradicated and 19 strains (24.7%) persisted. P. aeruginosa was eradicated in 9 (52.9%) of 17 strains and Serratia in 10 (83.3%) of 1
2 strains.
3.The MIC levels of KW-1062 were slightly lower than those of gentamicin (GM) and almost the same as those of dibekacin (DKB).But against clinically isolated Serratia, KW-1062 was found to be more active than DKB.
4.As to side effects, this series showed no evidence of hepatic and renal dysfunction and hearing disturbance except a case which showed elevated GOT and GPT.

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[in Japanese]

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