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Biomedical subjects

V M Traina

Publications and source records attributed to V M Traina.

9 recordsLinked to original sources
PubMed1997

Activation of CGS 12094 (prinomide metabolite) to 1,4-benzoquinone by myeloperoxidase: implications for human idiosyncratic agranulocytosis.

Many marketed pharmaceuticals are known to cause idiosyncratic agranulocytosis in humans. Similarly prinomide, an antiinflammatory drug, was associated with a low incidence of agranulocytosis (<0.3%) in clinical trials, even though chronic toxicity studies in rodents and primates showed no evidence of agranulocytosis with either prinomide or its parahydroxy metabolite, CGS 12094. To investigate mechanisms for this human specific toxicity, experiments were conducted to study the metabolism of prinomide and CGS 12094 by myeloperoxidase (MPO), a major enzyme of neutrophils and leukocyte progenitor cells. Although prinomide was not metabolized by human MPO, CGS 12094 was rapidly metabolized (>90%; 2 min); this reaction was dependent on H2O2 and MPO and was inhibited by azide. During the MPO-catalyzed metabolism of CGS 12094, reactive intermediates that irreversibly bound to protein and cysteine were generated. One of the reactive metabolites generated was identified by mass spectroscopy and trapping with cysteine as 1,4-benzoquinone, a compound implicated in the myelotoxicity associated with benzene. Thus during conditions which lead to elevated levels of H2O2 (e.g., active inflammation), CGS 12094 is rapidly metabolized by MPO to reactive intermediates that may be related to prinomide-induced agranulocytosis.

Agranulocytosis↗
PubMed1994

Functional and morphological characterization of neuropathy induced with 5-lipoxygenase inhibitor CGS 21595.

Peripheral toxic neuropathy induced in rats with a 5-lipoxygenase inhibitor CGS 21,595 was characterized using special functional tests and pathological procedures. Functional tests included measurement of grip strength, landing foot splay, assessment of sensorimotor and autonomic functions and monitoring of motor activity. Pathological procedures consisted of perfusion fixation, embedding in plastic, teasing of isolated nerve fibers, and light and electron microscopy. Male and female albino rats received the test article orally by gavage on 5 days per week. To characterize the development of the lesion animals treated with 1000 mg/kg were examined and sacrificed at 2-week intervals until termination at 10 weeks. In a separate study, the dose-effect relationship was examined in groups of animals treated with 50,200 or 1000 mg/kg for 10 weeks. Neurotoxicity occurred only in animals treated with 1000 mg/kg and was first detected following 4 weeks of treatment. Although there were no overt clinical signs of neurotoxicity, functional examination detected a reduction of grip strength, increased landing foot splay and reduced motor activity. Neuropathological examination revealed peripheral segmental demyelination affecting predominantly the Schwann cells in the ventral spinal nerve roots. Owing to its unusual localization in the nervous system and to subtlety of functional signs, peripheral segmental demyelination represents a special diagnostic challenge in toxicological safety studies.

1-Naphthylamine↗
PubMed1992

Toxic peripheral neuropathy with demyelination in Sprague-Dawley rats given CGS 21595--a 5-lipoxygenase inhibitor.

Male and female Sprague-Dawley rats were given CGS 21595, a pro-drug that is almost immediately metabolized to CGS 19213, a naphthoquinone that acts as a 5-lipoxygenase inhibitor. The compound was administered by gavage to five groups of Sprague-Dawley rats (group Nos. 1, 5, n = 30; group Nos. 2-4, n = 20) at daily doses of 0, 50, 150, 500, or 1,000 mg/kg for 13 weeks. Rats in the higher dose groups had a reduced weight gain, but significant neurologic signs were not observed. A peripheral neuropathy consisting predominantly of myelin destruction in the spinal nerve roots and sciatic nerves in male rats treated with greater than or equal to 150 mg/kg CGS 21595 and in female rats treated with greater than or equal to 50 mg/kg CGS 21595 for 13 weeks. This lesion was not fully reversible after a recovery period of 4 weeks. Lesions consisted of ballooning of myelin sheaths, infiltration by macrophages, demyelination, and occasional areas of remyelination. Axons were generally preserved, and the brain and spinal cord were not affected. Male and female rats in all treatment groups had cytoplasmic hyaline droplets in the proximal renal tubules. This change was reversible after 4 weeks and was not associated with any other adverse effects on the kidney.

1-Naphthylamine↗
PubMed1988

Tapetal changes in beagle dogs following oral administration of CGS 14796C, a potential aromatase inhibitor.

CGS 14796C, cis-1-[(4-[(1-imidazolyl)methyl]-cyclohexyl)methyl)imidazole succinate, has been evaluated as a potential aromatase inhibitor. As part of the safety evaluation program, a 3-month oral toxicity study was performed in which beagle dogs were administered CGS 14796C by gavage at 5, 15, or 50 mg/kg/day. Ophthalmoscopically, changes in the tapetum lucidum affecting dogs from the 15 and 50 mg/kg dose levels were diffuse areas of pigmentation varying in appearance from a brownish peppered or mottled to a more uniform brown similar to that of the nontapetal area of the fundus. Tapetal reflectivity was absent or markedly reduced. Within the pigmented area, multiple islets (yellow, green, or orange) of tapetal cells were visible, suggestive of destruction of the tapetum. In no instance was retinal destruction, edema, vascular changes, or detachment observed. Ophthalmoscopic examinations performed during recovery revealed changes of slight increase in tapetal islets, suggestive of a slight progression and organization within the tapetum followed by an arrest of the toxic insult within the tapetal tissue. At light and electron microscopic examination of the ocular tissues, the lesions were tapetal cell degeneration/atrophy. These results demonstrated that the taptetum lucidum was a target tissue of toxicity for CGS 14796C, and indicated that the findings are without toxicological significance in atapetal species, including man, whose globes do not have this structure.

Administration, Oral↗
PubMed1984

Effect of equilibration zones on stability, uniformity, and homogeneity profiles of vapors and aerosols in the ADG nose-only inhalation exposure system.

A commercially available, inexpensive, nose-only exposure chamber was modified to include removable equilibration zones, and the effect of these zones on chamber performance was determined. Since limited performance data were available concerning this unit, a more extensive characterization was performed. EPA limit concentrations (greater than or equal to 5 mg/liter) of toluene vapor or corn oil aerosol, and relatively low concentrations of uranine aerosol (less than or equal to 50 micrograms/liter) were produced by standard techniques. The presence or absence of equilibration zones did not affect the stability or uniformity of toluene vapor atmospheres, with the coefficient of variation (CV) not exceeding 3.33% in all experiments. In contrast, the presence of two equilibration zones was found to progressively enhance the uniformity of the inhalable test aerosols in the animal exposure zone (CV less than or equal to 3.16%). Matrix sampling revealed that in both uranine and corn oil experiments, the center matrix point concentration was consistently lower than samples taken in the actual animal breathing zone. Equilibration zones markedly reduced the difference between breathing zone and center point concentrations. These performance data indicated that the modified ADG nose-only exposure system performed exceptionally well with the materials that were studied. Results were comparable to those describing whole-body chamber performance. The ready availability of this inexpensive prototype lends itself to standardization of techniques between laboratories.

Aerosols↗
PubMed1973

Toxicological, pathological, and teratological studies in animals with cephradine.

Cephradine, a semisynthetic cephalosporin antibiotic, has a low order of oral and parenteral toxicity in animals. The oral LD(50) in mice and rats ranged from 5 to >8 g/kg, and the intraperitoneal LD(50) values in mice and rats were 0.7 to 1.5 g/kg and 4.0 g/kg, respectively. The intravenous LD(50) in mice ranged from 3.0 to 3.8 g/kg. In anesthetized dogs, intravenous doses of cephradine (40 and 120 mg/kg, given 45 min apart) had no effect on either the renal or cardiovascular systems. Single intramuscular injections (0.25 ml or 0.5 ml of a solution containing 125 to 235 mg of cephradine/ml) elicited no signs of either pain or local irritation in dogs, and only transient signs of slight-to-moderate irritation were observed in rabbits. In subacute toxicity studies, cephradine was administered for 4 weeks to rats (daily intraperitoneal doses of 160, 480, or 1,600 mg/kg) and dogs (daily intravenous doses of 80, 240, or 800 mg/kg); in addition, over a 2-week period, monkeys were given daily intravenous doses of 60, 180, or 600 mg/kg. No clinical, biochemical, gross, or micropathological changes due to cephradine were observed in these animals; especially notable was the absence of any signs of nephrotoxicity. In chronic toxicity studies, daily doses of cephradine were administered orally to rats (100 to 1,000 mg/kg), dogs (50 to 500 mg/kg), and monkeys (50 to 500 mg/kg) for 26, 26, and 13 weeks, respectively. Significant responses were observed only in rats, in which grossly enlarged, but histologically normal, ceca developed, a common finding in rodents dosed with antibiotics; in addition, there were increases in the relative and absolute weights of the adrenal glands. None of these effects was observed in rats that were necropsied 3 weeks after termination of dosage. In reproduction studies in mice and rats given either daily oral doses (100 or 300 mg/kg) or daily intraperitoneal doses (rats only; 80 or 320 mg/kg) of cephradine, no drug-related teratogenic changes in the offspring were observed.

Abnormalities, Drug-Induced↗