hr-810 and Body-Weight

Cefpirome serum concentrations were measured by microbiological assay in 30 patients after five to nine days of treatment with 1 or 2 g bd for moderate to severe infection of presumed bacterial origin. Patients with serum creatinine (SCr) greater than 220 mumol/L were excluded. The age of patients ranged from 34-86 years. Creatinine clearance (Clcr) was calculated from age, sex, weight and SCr. The range of SCr was 63-220 mumol/L and the range of Clcr was 18-169 mL/min. The correlation coefficient with cefpirome clearance was 0.464 for SCr and 0.747 for Clcr. More than half of the patients with Clcr less than 50 mL/min had SCr within the normal range of 70-150 mumol/L. Mean cefpirome clearance in patients with Clcr 18-50 mL/min was 42.7 mL/min, which is very similar to the figure of 43.5 mL/min reported in a single dose volunteer study in patients with renal failure. Mean cefpirome clearance in patients with Clcr greater than 80 mL/min was 107.6 mL/min. In conclusion, these data on cefpirome clearance obtained after multiple dose treatment of patients with presumed bacterial infection are consistent with data previously obtained from single dose volunteer studies and support the currently recommended dose regimens. Clinicians should take account of age, weight and sex when estimating renal function from SCr.

Topics: Adult; Age Factors; Aged; Bacterial Infections; Body Weight; Cefpirome; Cephalosporins; Creatinine; Female; Humans; Injections, Intravenous; Male; Metabolic Clearance Rate; Middle Aged

Chronic intravenous toxicity studies in monkeys were carried out with 3-[(2,3-cyclopenteno-1-pyridinium)-methyl]-7-[2-syn-methoximino - 2-(2-aminothiazol-4-yl)-acetamido]-ceph-3-em-4-carboxylate (cefpirome, HR 810; CAS 84957-29-9) a new cephalosporin derivative. In a 90-day study in rhesus monkeys (4 males/4 females per group) dosages of 0, 50, 160 and 500 mg/kg/day were administered. In a 6-month study 5 groups of 6 male and 6 female cynomolgus monkeys received NaCl-solution (0.9%), the vehicle, and 50, 200 or 800/400 mg/kg/d (the highest dosage had to be lowered after the first week due to acute drug intolerance). For clarification of the dose relationship to the findings in the 800/400 mg/kg group, a supplementary 6-month study with 500 mg/kg cefpirome including a vehicle control was also performed. 50 mg cefpirome/kg/d was well tolerated; so too were 160 and 200 mg/kg apart from a slight beta 2-microglobulinuria and/or enzymuria. Almost exclusively at the high dosages retching and vomiting, and exclusively at the high dosages diarrhea, inappetence and physical weakness were sporadically seen in the first phase of the studies. 500 and 400 mg/kg led to increasing signs of discrete renal tubular changes (enzymuria, beta 2-microglobulinuria, cylindruria and minimal histological changes in 2 animals of the 400 mg/kg group). In one rhesus monkey (500 mg/kg) and two cynomolgus monkeys (800 mg/kg) severe kidney damage had developed within the first week. In all dosage groups of the 90-day study special histological methods revealed a dose-dependent increase and enlargement of lysosomes in the epithelia of the proximal renal tubules. Increased cytolysis was, however, not observed. In all the studies there was a dose-dependent increase in the kidney weights of the intermediate and highest dosage groups. The females of the 400 mg/kg group showed slight anemia accompanied by a slight increase in the reticulocyte count. One animal of this group died prematurely probably due to pulmonary embolism. The signs of slight renal impairment including lysosome enlargement, and the slight anemia proved to be reversible.

Topics: Acetylglucosamine; Aminolevulinic Acid; Animals; beta 2-Microglobulin; Blood Cell Count; Blood Chemical Analysis; Body Weight; Cefpirome; Cephalosporins; Female; gamma-Glutamyltransferase; Injections, Intravenous; Macaca fascicularis; Macaca mulatta; Male; Organ Size

Acute toxicity of cefpirome sulfate (CPR) was examined in 6-week-old mice and rats and immature (5-day-old) rats. The LD50 values of CPR (mg/kg) were as follows: (1) mice: intravenous, 2420 (95% confidence limits, 2122-2758) for males and 2400 (2181-2640) for females; intraperitoneal, 3850 (3407-4351) for males and 4200 (3889-4536) for females; and oral, 16200 (14781-17755) for males and 18500 (17290-19795) for females. (2) 6-week-old rats: intravenous, 1900 (1784-2023) for males and 2080 (1953-2215) for females; intraperitoneal, 6550 (6179-6943) for males and 5800 (5311-6334) for females; subcutaneous, more than 10000 for both sexes; and oral, more than 8000 for both sexes. (3) 5-day-old rats: subcutaneous, between 1750 and 2500 for males and 2080 (1651-2621) for females. Major changes in general health conditions observed in 6-week-old mice and rats were decreased spontaneous activity, lying prone, tremor, respiratory changes (slow or deep respiration, gasping), clonic or clonic-tonic convulsions. In the 6-week-old rats dosed subcutaneously, vocalization, writhing and cutaneous changes at the injection site (dark reddening or blackening, swelling, exfoliation, depilation, induration) were also observed. In the 5-day-old rats dosed subcutaneously, the changes noted were slow respiration, writhing, cyanosis, and dark reddening and swelling of the skin at the injection site. After administration, transient depression of body weight gain or loss of body weight was observed in the mice and rats except the rats dosed orally. These changes disappeared at 7 days after administration at latest, and all surviving animals showed favorable body weight gain thereafter. Necropsies revealed hemorrhage under meninges in the brain in many of the mice and rats which died. Other findings included subcutaneous changes at the injection site in the 6-week-old and 5-day-old rats dosed subcutaneously (dark reddening, retention of dark red fluid, retention of red, white or dark red gelatinous material) and changes in the peritoneal cavity in the 6-week-old rats dosed intraperitoneally (red or dark red spots on the serous membrane, reddening of adipose tissues).

Topics: Animals; Body Weight; Cefpirome; Cephalosporins; Female; Lethal Dose 50; Male; Mice; Mice, Inbred ICR; Rats; Rats, Inbred Strains

Cefpirome sulfate (CPR) was administered subcutaneously at 200, 500, and 1000 mg/kg/day to male rats for 5 weeks from 6 through 40 days of age and examinations were made to determine whether the antibiotic caused any detrimental effects on male sexual development when administered to juvenile rats. Cefotetan (CTT) was given at 1000 mg/kg/day as a positive control. Incrustation occurred at the injection site during administration in all treated groups. The CPR groups had no compound related changes in fertility, spermatozoa, and reproductive organs, while the CTT group showed decreased testicular weight, abnormal fertility and spermatozoa, and atrophied germinal epithelium of seminiferous tubules, atrophied epididymis, and decreased number of spermatozoa. From the results of this investigation, it may be concluded that CPR had no effects on male sexual development when administered to juvenile rats.

Topics: Animals; Body Weight; Cefpirome; Cephalosporins; Fertility; Genitalia, Male; Male; Organ Size; Rats; Rats, Inbred Strains; Reproduction; Sexual Maturation; Spermatozoa

A six-month intraperitoneal chronic toxicity study of cefpirome sulfate (CPR) in rats as well as a two-month recovery study were carried out at dose levels of 51.2, 128, 320 and 800 mg/kg/day. The results are as follows. 1. CPR caused no remarkable clinical signs in the general condition of the animals. 2. Body weight gain was depressed in males and females given 800 mg/kg/day. Food consumption, however, was not afected at any dose level. Water consumption increased in males and females at dose of greater than or equal to 320 mg/kg/day. 3. Except an increase in urine volume in males at 800 mg/kg/day, no abnormalities in urinary parameters were found. 4. Frequent decreases in erythrocyte count, hematocrit and hemoglobin concentration were seen in males and females of the 800 mg/kg/day group. At this dose, certain males and females also showed an increase in the reticulocyte count. 5. The serum-biochemical examinations showed a very slight or slight decrease in total cholesterol in males and females given 320 mg/kg/day or more, and increases in uric acid and inorganic phosphorus concentration in some males and females given 800 mg/kg/day. 6. Very slight or slight increases in spleen weight in males and females at a dose of greater than or equal to 320 mg/kg/day, in thyroid weight in females at a dose of greater than or equal to 320 mg/kg/day and in kidney weight in males given 320 mg/kg/day or more as well as in females at 800 mg/kg/day were measured. Further, a decrease in thymus weight was seen in females of the 800 mg/kg/day group. 7. At autopsy, very slight or slight reddish browning of the thyroid was seen in males given 320 mg/kg/day or more and in females given 800 mg/kg/day.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Animals; Blood; Body Weight; Cefpirome; Cephalosporins; Female; Injections, Intraperitoneal; Kidney; Male; Rats; Rats, Inbred Strains; Thyroid Gland

A fertility study was performed in rats by intraperitoneal administration of cefpirome sulfate (CPR) at dose levels of 0 (control), 200, 400 and 800 mg/kg/day. Male rats were treated for 60 days before mating and during the mating period. Female rats were administrated the substance from 14 days before mating to day 7 of pregnancy. The females were sacrificed on day 21 of pregnancy for examination of their fetuses. No animal died during the administration period. Loose feces were observed in both male and female animals in the 400 and 800 mg/kg/day groups. Body weight gain was suppressed in both male and female animals in the 800 mg/kg/day group and in male animals in the 400 mg/kg/day group. There were no significant differences in food and water intakes between treated and control groups. Autopsy revealed the enlargement of the caecum in males in the 200, 400 and 800 mg/kg/day groups. The kidney and adrenal weights were significantly increased in males in the 200, 400 and 800 mg/kg/day groups. Fertility and reproductive ability in both sexes, and estrus cycles in female rats were not affected by administration of CPR. There were no lethal effect and growth-inhibiting or teratogenic effects on the embryos and the fetuses. The results suggest that the non-effective dose level of CPR was lower than 200 and 200 mg/kg/day for general toxicity in male and female parent animals respectively, 800 mg/kg/day for reproductive ability in parent animals and in embryos and fetuses.

Topics: Abnormalities, Drug-Induced; Animals; Body Weight; Bone and Bones; Cefpirome; Cephalosporins; Dose-Response Relationship, Drug; Female; Fertility; Fetus; Male; Organ Size; Pregnancy; Rats; Rats, Inbred Strains

A teratogenicity study was performed in rats by intraperitoneal or intravenous administration of cefpirome sulfate (CPR) at dose level of 0 (control), 200, 400 and 800 mg/kg/day to dams from day 7 to day 17 of pregnancy. Twenty one to twenty eight female rats in each intraperitoneal and intravenous administrated group were sacrificed on day 21 of pregnancy for examination of their fetuses, and ten to thirteen female rats in each intraperitoneal administrated group were allowed to deliver for the postnatal examination of their offsprings. In the 800 mg/kg/day intravenous administrated group, two dams out of twenty four died during administration period, however no animal died in any intraperitoneal administrated group. The doses of 400 and 800 mg/kg/day caused piloerection, diarrhea or loose feces in the both administration routes, and accelerated breathing, a decrease in spontaneous activity, systemic spasms, cataleptic symptoms and wild running in the intravenous route. The suppression of body weight gain was detected in the 800 mg/kg/day intraperitoneal administrated group and 200, 400 and 800 mg/kg/day intravenous administrated groups, however there were no significant differences in food and water intakes between treated and control groups. At autopsy, enlargement of caecum and an increase in adrenal weight were detected in the 800 mg/kg/day groups of both administration routes. Body weight of the fetuses was decreased in both sexes in the 800 mg/kg/day group and in male fetuses in the 400 mg/kg/day group, and placental weight was decreased in the 800 mg/kg/day group, in the both administration routes respectively. However, embryonal or fetal mortality and incidences of external or visceral anomalies were not increased. In offspring, the dose of 800 mg/kg/day caused very slight suppression of body weight gain, however CPR had no adverse effects on the postnatal development such as viability, differentiation, emotionality, learning ability or reproductive performance. The results suggest that the non-effective dose level of CPR is 200 mg/kg/day in maternal animals and fetuses, 400 mg/kg/day in offsprings in intraperitoneal route, lower than 200 mg/kg/day in maternal animals and 200 mg/kg/day in fetuses in intravenous route respectively.

Topics: Abnormalities, Drug-Induced; Animals; Body Weight; Bone and Bones; Cefpirome; Cephalosporins; Dose-Response Relationship, Drug; Female; Fetal Death; Fetus; Male; Motor Activity; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Inbred Strains; Reproduction

Subchronic and chronic toxicity studies in rats were performed with 3-[(2,3-Cyclopenteno-1-pyridinium)-methyl]- 7-[2-syn-methoximino-2-(2-aminothiazol-4-yl)-acetamido] -ceph-3-em-4- carboxylate (cefpirome, HR 810), a new cephalosporin derivative. In subchronic (14 day) studies cefpirome was intravenously administered in dose levels up to 1500 mg/kg/d with good kidney tolerance. Signs of renal functional impairment were observed (800 and 1500 mg/kg) but histologically no morphological changes could be detected. The chronic intraperitoneal administration (90 day) of cefpirome at dose levels of 400 or 1600 mg/kg/d resulted in some reversible changes in hematology (slight anemia), serum-chemistry parameters (liver), urinalysis (proteinuria), and histopathology (increased numbers and enlargement of lysosomes in proximal tubular epithelia of the kidneys and pigment deposits in follicle epithelia of the thyroids), predominantly in high-dose animals. The "no effect level" is considered to be 100 mg/kg/d in this study.

Topics: Animals; Blood Cell Count; Blood Chemical Analysis; Body Weight; Cefpirome; Cephalosporins; Eating; Female; Liver Function Tests; Male; Organ Size; Proteinuria; Rats; Rats, Inbred Strains; Time Factors

A perinatal and postnatal study was performed in rats by intraperitoneal administration of cefpirome sulfate (CPR) at dose levels of 0 (control), 200, 400 and 800 mg/kg/day to dams from day 17 of pregnancy to day 21 after delivery. Twenty one or twenty two dams in each group were allowed to deliver for the postnatal examination of their offsprings. No animal died. Loose feces were observed in the 800 mg/kg/day group. Body weight gain of the dams was retarded in the 800 mg/kg/day group in the early stage of treatment. Food intake was reduced simultaneously in the 200, 400 and 800 mg/kg/day groups. Autopsy revealed the enlargement of caecum in the 800 mg/kg/day. The adrenal weight was increased in the 400 and 800 mg/kg/day groups, and the kidney weight was increased in the 800 mg/kg/day group. The body weight of pups at birth in the 800 mg/kg/day group was slightly lower than that in the control group. The body weight of male pups in the 800 mg/kg/day group decreased transiently during rearing period. However, CPR had no adverse effects on the postnatal development such as viability, differentiation, emotionality, learning ability or reproductive performance. The results suggest that the non-effective dose level of CPR is lower than 200 mg/kg/day for general toxicity, 800 mg/kg/day for reproductive ability in maternal animals and 400 mg/kg/day in offsprings respectively.

Topics: Abnormalities, Drug-Induced; Animals; Animals, Newborn; Body Weight; Cefpirome; Cephalosporins; Dose-Response Relationship, Drug; Female; Fetal Death; Fetus; Male; Motor Activity; Organ Size; Pregnancy; Rats; Rats, Inbred Strains; Reproduction