An evaluation of the toxicity of moxalactam in laboratory animals.

The toxicity of moxalactam in laboratory animals was evaluated with six species. The acute toxicity of moxalactam was lower than that of cefazolin. The subchronic and chronic toxicity of moxalactam was studied for periods of one to six months at dosages of 100-3,500 mg/kg per day in rats, 100-1,600 mg/kg per day in dogs, and 100-500 mg/kg per day in monkeys. Treatment-related effects were limited to soft stool, cecal dilatation, and slight anemia resulting from local injury at the injection site in the higher dosage groups. All the effects were reversible and less severe than those caused by cefazolin. Studies of reproduction in rats, mice, and rabbits indicated that moxalactam had no teratogenicity and no adverse effects on fertility of parental animals and on gestation or growth and reproductive capacity of offspring. Comparative studies of nephrotoxiticity in rabbits demonstrated that moxalactam was considerably less nephrotoxic than cefazolin, cefotiam, and cefotaxime.

Ethanol-moxalactam interactions in vivo.

Adverse reactions similar to disulfiram reactions observed in volunteers given moxalactam prompted an investigation to determine whether moxalactam, like disulfiram, leads to an accumulation of acetaldehyde during ethanol metabolism. Concentrations of ethanol and acetaldehyde in blood of male Wistar rats given test compounds and ethanol were determined by gas chromatography. Moxalactam, like disulfiram, had no effect on concentrations of ethanol but increased the concentrations of acetaldehyde. However, the effect after treatment with moxalactam was less than after treatment with disulfiram. The interval between pretreatment with moxalactam and administration of ethanol that gave the maximal effect ranged from 3 to 24 hr. When ethanol was given before or at the same time as moxalactam, no effect was observed. Cefamandole and cefoperazone, which, like moxalactam, have a methyltetrazolethiol side chain, increased concentrations of acetaldehyde, but penicillin G, carbenicillin, cephalothin, cephradine, cefoxitin, cefazolin, and cefotaxime had no effect. For prevention of a disulfiram-like reaction, physicians should caution patients to avoid alcoholic beverages for several days after treatment with moxalactam, cefamandole, or cefoperazone.

Toxicology of vancomycin in laboratory animals.

The 50% lethal dose (LD50) of vancomycin for rodents was higher than that of tobramycin but much lower than that of cefamandole nafate. The rodents died in clonic convulsions immediately after receiving vancomycin. The LD50 for dogs similar to that for rodents; however, deaths occurred several days after administration of vancomycin and resulted from renal failure. Rapid intravenous administration of vancomycin to dogs produced a significant decrease in blood pressure that was prevented by pretreatment with the antihistamine methapyrilene. Subchronic administration of vancomycin to laboratory animals in doses of 12.5-400 mg/kg caused no systemic toxicity. Concomitant administration of vancomycin and tobramycin to rats resulted in significantly increased nephrotoxicity compared to that caused by either agent alone. The nephrotoxic response of rats receiving vancomycin was only partially reversed by large volumes of water given orally before and after the drug.

Inhibition of the efflux of organic ions from renal cortical slices.

Cyanine 863 inhibited the efflux of tetraethylammonium ion from slices of rat or rabbit renal cortex while the efflux of p-aminohippuric acid was unaffected. Dinitrophenol increased the efflux rate of both the cation and anion. Cyanine also decreased the dinitrophenol-enhanced efflux of tetraethylammonium (TEA).

Hydrolysis of cefamandole nafate to cefamandole in vivo.

The hydrolysis of cefamandole nafate, and the O-formyl ester of cefamandole, to cefamandole was studied in vivo in dogs and normal human subjects. After administration of cefamandole nafate to dogs or humans, the parent compound disappeared rapidly from plasma. Disappearance was slightly faster in dogs (half-life [t1/2], 4--6 min) than in humans (t1/2, 6--9 min). The calculated rate constant for hydrolysis of cefamandole nafate was also higher in dogs than in humans, yielding t1/2 values of 6--7 min and 10--17 min, respectively. The rapid hydrolysis of cefamandole nafate to cefamandole in vivo, combined with the partial hydrolysis of cefamandole nafate in vitro before administration (caused by Na2CO3 in the formulation), resulted in circulating levels of cefamandole nafate lower than those of cefamandole. In humans the disappearance of cefamandole nafate was not significantly altered after administration of large (4.0 g) or multiple (4.0g every 6 hr) doses of cefamandole nafate.

Toxicologic evaluation of cefamandole nafate in laboratory animals.

The safety of cefamandole nafate in laboratory animals was evaluated in six species. The acute toxicity of cefamandole after intravenous or subcutaneous administration was similar to that of cephalothin sodium. The subacute and chronic toxicity of cefamandole was studied in rats and dogs for periods of two weeks to six months at doses of 250--1,000 mg/kg per day in rats and 125--1,500 mg/kg per day in dogs. No evidence of significant systemic toxicity was observed in these studies. There were, however, various degrees of local injury at the injection sites that resulted in slight decreases in hemoglobin, hematocrit, and red blood cell counts in the animals in which injury at the injection site was most severe. Studies of reproduction in rats and mice indicated that cefamandole nafate had no teratogenic effects and no adverse effects on fertility, gestation, or growth of offspring. Comparative studies of nephrotoxicity in rabbits demonstrated that the nephrotoxicity of cefamandole nafate was considerably less than that of cefazolin.

Age-dependent renal accumulation of cephaloridine in the rabbit.

The accumulation of cephaloridine in the renal cortex of the rabbit was studied in vitro and in vivo in rabbits of various ages. The cortical concentration of cephaloridine, the cortex/serum ratio, and the slice/medium ratio determined by incubation of cortical slices in cephaloridine-containing media rose from birth to adult levels at approximately 1 month of age. Pretreatment with procaine penicillin G stimulated the ability to accumulate cephaloridine in vitro and in vivo. The data indicate that the lack of susceptibility of immature rabbits to cephaloridine nephrotoxicity is due to the lack of development of the anionic transport system which is apparently necessary to achieve the high cortical concentrations of cephaloridine that result in renal injury.

Effect of cefamandole nafate on the toxicity of tobramycin.

Because of the potential for an interaction between cephalosporins and aminoglycosides leading to renal injury, an evaluation of the effect of a new cephalosporin, cefamandole nafate, on the toxicity of the aminoglycoside tobramycin was performed in laboratory animals. High doses of cefamandole nafate did not increase the acute toxicity (lethality) of tobramycin in rats or mice. In a subacute experiment in rats, dose-related tobramycin nephrotoxicity, as evidenced by blood urea nitrogen changes, increased kidney weights, and histologically determined tubular nephrosis and necrosis, was observed. Concomitant treatment with cefamandole nafate, 500 mg/kg, did not increase tobramycin nephrotoxicity, but protected against the aminoglycoside-induced renal injury. Determination of tissue radioactivity after administration of [(14)C]tobramycin indicated that cefamandole nafate treatment resulted in uniformly lower tobramycin tissue concentrations compared with the control, suggesting that the protective effect was produced by enhanced excretion of tobramycin after cefamandole nafate treatment.

The simultaneous quantitative determination of cephalothin and cefazolin in serum by high pressure liquid chromatography.

Conventional microbiological assay procedures for cephalosporins in serum do not allow the determination of serum concentrations if more than one cephalosporin is present in a single sample. An HPLC procedure has been developed which permits the simultaneous quantitative determination of cefazolin sodium and cephalothin sodium in serum. Reverse phase chromatography using methanol in 0.2 M ammonium acetate as the mobile phase was employed to separate and quantitate the two cephalosporins in a trichloroacetic acid supernatant solution prepared from serum.

Delineation of the relative antibacterial activity of cefamandole and cefamandole nafate.

By conventional laboratory evaluation procedures, the in vitro antibacterial activities of cefamandole and its O-formyl ester, cefamandole nafate, appear virtually identical. When the activities of these two compounds were examined for their ability to lyse log-phase cultures of susceptible bacteria, however, cefamandole was found to be about 10 times more active than cefamandole nafate. Cefamandole nafate was shown to be rapidly converted to cefamandole in bacteriological media, with a half-life of less than 1 h at a pH of 7.0 or above. At pH 6.0, in log-phase inhibition experiments, however, cefamandole nafate is more stable, allowing delineation of the activity between cefamandole and cefamandole nafate. The efficacy of cefamandole was identical to that of cefamandole nafate in treating experimental animal infections, indicating that rapid conversion of cefamandole nafate to cefamandole occurs in vivo.

Nephrotoxicity of cephaloridine in newborn rabbits: role of the renal anionic transport system.

The nephrotoxicity of cephaloridine, cefazolin and mercuric chloride was studied in rabbits of various ages. Cephaloridine produced dose-related elevations in serum urea nitrogen, creatinine and renal tubular necrosis in adult and 30-day-old rabbits, only slight changes at 15 days of age and no effect in 5-day-old rabbits. Cefazolin also produced dose-related nephrotoxicity in adult rabbits but no effect in 15-day-old rabbits. Mercuric chloride administration resulted in similar nephrotoxicity in 5-, 15- and 30-day-old rabbits and adults. The development of susceptibility to cephaloridine nephrotoxicity paralleled the maturation of the renal anionic transport system as determined by the accumulation of p-aminohippurate by renal cortical slices in vitro. Substrate stimulation of the anionic transport system by p-aminohippurate or penicillin increased the nephrotoxicity of cephaloridine in between rabbits. The authors concluded that the lack of cephaloridine nephrotoxicity in newborn rabbits is due to the incomplete development of the renal anionic transport system.

Rapid analysis of cefazolin in serum by high-pressure liquid chromatography.

A high-pressure liquid chromatography (HPLC) method has been developed for the analysis of cefazolin in serum. Serum was deproteinized by the addition of 6% trichloroacetic acid and injected onto a reverse-phase column with a mobile phase of 10 to 15% methanol in 1% aqueous acetic acid. Cefazolin chromatographed without interference from ultraviolet-absorbing components of serum, with a retention time of 3.1 min. Standard curves comparing peak area with concentration prepared from dog or human sera were linear over a range of 1.6 to 200 mug/ml. Results from the HPLC assay were compared with microbiological assays (cylinder plate method) on both standard serum samples and sera from dogs and human subjects receiving intramuscular cefazolin. The HPLC method was somewhat more accurate in comparison with the microbiological assay performed on serum samples of known concentration. The comparison of results from an analysis of serum levels of dogs or human subjects receiving cefazolin indicated that the two methods would lead to identical conclusions concerning pharmacokinetics or the achievement of therapeutic serum levels. The HPLC assay method presents an alternative to conventional microbiological assays, with marked improvement in speed (30 min) and considerable potential for future development.

Disposition of cyproheptadine in rats, mice, and humans and identification of a stable epoxide metabolite.

Radioactivity was excreted in the urine and feces of rats, mice, and humans after a dose of 14C-cyproheptadine. The major metabolite in rat urine was unconjugated, but the majority of radioactive materials in mouse and human urine were conjugated with glucuronic acid. Identification of the rat urinary metabolite of cyproheptadine as an epoxide was accomplished with mass spectrometry and other methods. The rat metabolite was 10.11 -epoxydesmethylcyproheptadine and accounted for about 25% of a 45-mg dose of cyproheptadine per kg. Only a small amount of this epoxide was found in mouse urine, and none was apparent in the urine of two humans who received 5 mg of the drug. Dihydrodiols, which could arise by epoxide hydrase hydrolysis of possible 10.11-epoxy metabolites, were not found in the urine of any of the species studied. The spoxide found in rat urine appears to be unusually stable to in vivo hydrolysis. Possible implications of these results in the species-selective pancreotoxicity of cyproheptadine in the rat are presented.