John L. Emmerson

Stimulation of hepatic drug-metabolizing enzymes by chlorophenothane (DDT); the relationship to liver enlargement and hepatotoxicity in the rat.

Abstract To study the relationship between induction of drug-metabolizing enzymes, liver enlargement and hepatotoxicity, we have administered DDT [1,1,1-trichloro-2,2-bis( p -chlorophenyl)ethane] to weanling male rats for 14 days. While administration of DDT at dietary concentrations of 0.5 or 2 ppm had no effect on the rate of p -nitroanisole ( p -NA) O -demethylation, concentrations of 4–750 ppm produced an increase in the rate of metabolism proportional to the log dose. Extrapolation of this portion of the dose-response curve to the abscissa provided a calculated no-effect level of 3.27 ± 1.02 ppm. At dietary concentrations greater than 750 ppm there was no further increase in p -NA metabolism. Liver weight increased in proportion to the dose when rats were maintained on diets containing 128–512 ppm DDT. Levels less than 128 ppm had no effect, and concentrations greater than 512 ppm produced a submaximal increase in liver weight. Although the total homogenate protein concentration (mg/g liver) was not affected by DDT administration, the microsomal protein concentration was increased by dietary concentrations above 16 ppm. Only in animals fed dietary levels above 750 ppm, in which there was no further increase in p -NA metabolism, were signs of neurotoxicity apparent. These results suggest that stimulation of drug-metabolizing enzymes, and the accompanying increase in liver weight and microsomal protein, are manifestations of a physiological adaptation.

Genotoxicity studies on the preemergence herbicide trifluralin

This paper reports the results of studies conducted within the Lily Research Laboratories and discusses additional studies with trifluralin that have been reported in the literature

Preclinical toxicology studies with tobramycin

Abstract Tobramycin, an aminoglycoside antibiotic, has been administered to mice, rats, cats and dogs for toxicologic evaluation. The sc LD50 values in mice and rats were 441 and 969 mg/kg, respectively. Deaths were preceded by CNS depression and occurred within 1 hr of treatment. A 100 mg/kg iv dose in chloralose-anesthetized cats produced a moderate, transient decrease in blood pressure and a significant decrease in inspiratory volume and soleus twitch force. Rats were given daily sc doses of 15–120 mg/kg for 3 months. Renal tissue change, the only drug effect evident histologically, ranged in degree from a slight reparative nephrosis at the lowest dose to cortical tubular necrosis in some rats that received the highest dose. In a 1-month study, a daily im dose of 7.5 mg/kg had no apparent effect on dogs, but a 30 mg/kg dose produced severe renal damage. Vestibular injury occurred within less than 30 days in all cats that received daily sc doses of 50 mg/kg, but no vestibular changes were observed in cats that were given 65 doses of 25 mg/kg. The toxicologic effects observed in tobramycin-treated animals were qualitatively and quantitatively similar to those observed with gentamicin.

Acute toxicity of propoxyphene salts

Abstract The acute toxicity of oral and parenteral doses of propoxyphene HCl was studied in laboratory animals. Large iv, im, or ip doses of propoxyphene HCl produced clonic and tonic convulsions in mice, rats, and dogs. Death from oral doses of propoxyphene HCl was preceded by convulsions in dogs but not in rodents or rabbits. Other effects included hypoactivity and body rigidity in rodents, and salivation, ataxia, and weakness in dogs. Animals given lethal doses of propoxyphene showed profound respiratory depression, which was judged to be the primary cause of death. Respective LD50 values for propoxyphene HCl in the mouse, rat, and dog were 28, 15, and 29 mg/kg iv and 282, 230, and 100 mg/kg po. Comparative acute oral toxicity tests were conducted on the 2-naphthalene sulfonate (napsylate) salt of propoxyphene. In equimolar doses, propoxyphene napsylate, a relatively insoluble salt, was about one-half as toxic as propoxyphene HCl in rodents and clearly less toxic in dogs. Plasma concentrations of propoxyphene indicated that the differences in the acute oral toxicity of propoxyphene HCl and propoxyphene napsylate were due to the more gradual absorption of the latter salt.

Studies on the tissue distribution of d-propoxyphene

The early phases of the tissue distribution of d-propoxyphene were studied in rats after single doses of the N-methyl-14C-labeled drug given intravenously (10 mg/kg), subcutaneously (20 mg/kg), or orally (20 mg/kg). Upon intravenous injection the drug rapidly localized in the lung, liver, kidney, and other internal organs at concentrations that were 10–20 times greater than those found in the blood. Administration of the drug by other routes resulted in lower, but more prolonged tissue concentrations. Irrespective of the route of administration blood concentrations of 1–2 μg/ml persisted throughout the first hour after the drug was given. A intravenous dose of 6 mg/kg resulted in similar blood concentrations in dogs. The blood concentrations of d-propoxyphene in the rat were found to be relatively stable in the presence of changing drug concentrations in other tissues.

Metabolism of trifluralin in the rat and dog

Abstract The metabolism of trifluralin (2,6-dinitro- N,N -di- n -propyl-α,α,α-trifluoromethyl- p -toluidine), a preemergence herbicide, was studied in rats. About 80% of an oral dose of trifluralin was found to be excreted in the feces, while the remaining portion appeared in the urine. Unchanged trifluralin was isolated from the feces. Oral doses of trifluralin were not readily absorbed from the gastrointestinal tract. One other product, present in fecal material, was identified as an amino derivative of trifluralin resulting from the reduction of one nitro group. The absorbed fraction was found to be extensively metabolized. Three urinary metabolites, formed by nitro reduction and/or the removal of one or both propyl groups, were isolated and identified. N -Dealkylation and nitro reduction were shown to be two of the principal pathways for the metabolism of trifluralin. The metabolic fate of trifluralin was similar in the rat and the dog.

Short-term toxicity of propoxyphene salts in rats and dogs

Abstract Two salts of d -propoxyphene, the hydrochloride and the 2-naphthalene sulfonate (napsylate), were compared in short-term toxicity studies. In rats and dogs the effects produced by daily administration of equimolar doses of these salts were indistinguishable. Large daily doses of propoxyphene, representing between 40 and 110 times the maximum human clinical dose, resulted in liver enlargement, slight fatty change in the liver, and reduced growth rate in rats. Signs of developing toxicity in dogs were observed during 90 days of treatment with oral doses of 30–40 mg/kg of propoxyphene HCl or equivalent doses of propoxyphene napsylate. The following effects were dose-related in incidence or degree: loss of body weight, increased serum alkaline phosphatase values, increased liver weight, and slight fatty change in the liver. Lower doses were tolerated by dogs without significant toxicity.

Oncogenicity study of trifluralin in B6C3F1 mice

B6C3F1 mice were maintained for 24 months on diets containing 0, 563, 2250 or 4500 ppm trifluralin. These dietary concentrations corresponded to daily doses of approximately 70, 285 or 570 mg/kg body weight, respectively. The control group contained 120 mice/sex and treated groups consisted of 80 mice/sex. There were no treatment-related effects on the survival, appearance or behaviour of the mice. Survival at test termination was at least 67% in each group. Compared with controls, mean body weight was significantly reduced in a dose-related manner in mice of both sexes given the 2250 and 4500 ppm diets. At 21 months, the reduction in body weight was greater than or equal to 15 and greater than or equal to 30%, respectively. At study termination, dose-related decreases in erythrocytic and leucocytic values were also observed at dietary levels of 2250 and 4500 ppm. In clinical chemistry evaluations, blood urea nitrogen levels and alkaline phosphatase activity in mice of both sexes were significantly increased at trifluralin levels of 2250 and 4500 ppm. Blood urea nitrogen also showed a marginal increase in females given the low dose of trifluralin. Alanine aminotransferase activity was significantly increased in males at all treatment levels. Although there were a number of absolute and relative organ weight changes in all three treatment groups that were significantly different from the control values, the reduced relative kidney weights in males and the increased relative liver weights in both sexes at dietary levels of 2250 and 4500 ppm were the only changes that could be correlated with altered clinical chemistry values.(ABSTRACT TRUNCATED AT 250 WORDS)

A METHOD FOR THE THIN-LAYER CHROMATOGRAPHY OF ANALGESIC DRUGS AND RELATED COMPOUNDS IN NON-AQUEOUS SYSTEMS.

Abstract A thin-layer chronmatographic procedure is described which is applicable to natural and synthetic alkoidal drugs. Neutral organic solvents are used to develop silica gel plates in an atmosphere of ammonia vapor. Identical results are given upon development of the plate when either the free base or a salt form is spotted for chromatography. The procedure is shown to offer more convenience and versality than an existing method in which alkaline silica gel layers are used.

Reproduction and teratology studies on propoxyphene napsylate.

Abstract Propoxyphene napsylate was studied in reproduction and teratology experiments in rats and in a teratology experiment in rabbits. Rats were given daily oral doses of 0, 100, 200, or 400 mg/kg, while rabbits were treated with oral doses of 0, 32, or 80 mg/kg/day. In neither species were there any signs of druginduced teratogenicity. Large doses of the drug (200, 400 mg/kg/day) impaired the reproductive capacity of mating or pregnant female rats (i.e., reduced fertility, stunting and decreased viability of the progeny), but these doses also induced distinct maternal toxicity; daily doses of 200 or 400 mg/kg resulted in the death of approximately 20% of the female rats.