Andrejs Purmalis

Ultrastructural studies of the hepatic changes brought about by Clindamycin and Erythromycin in animals.

Abstract In the hepatocytes of purebred beagles, treated po with 600 mg/kg of clindamycin, whorled figures formed in lysosomes within 24 hr. The greatest abundance (100 or more) and maximum development (2–4 μ) of these pericanalicular dense bodies occurred after 7–10 days of treatment. Such inclusions were shown to be transient and formed rarely or not at all when daily treatments of 300 mg/kg or less were given for as long as 1 yr. After a single po dose of 1000 mg/kg was given to immature male rats of the Upjohn Sprague-Dawley line, whorled figures formed within 30 min in the peribiliary areas of the hepatocytes. With continued treatment, the whorled figures were more frequently multicentric but were not as numerous as in the dog. An apparent increase in autophagic vacuoles and minor changes in the endoplasmic reticulum and mitochondria (at 1500 mg/kg) suggested that the turnover of worn-out organelles may have been accelerated. A single po dose of 1000 mg/kg of erythromycin in the rat produced nonprogressive degenerative changes in a minor portion of hepatic mitochondria in 24 hr. Membrane-bound whorled figures of the type derived from autophagic vacuoles were formed in small numbers. Simultaneous administration of phenobarbital and erythromycin for 10 days resulted in two apparently unrelated ultrastructural responses. Whorled figures were formed in autophagic vacuoles, mitochondria, and secondary lysosomes when erythromycin was given po to beagles at a level of 600 mg/kg for 10–30 days.

The Propionic Acids. Gastrointestinal Toxicity in Various Species

The propionic acids represent the largest chemical class of nonsteroidal anti-inflammatory agents (NSAID). Several of them are widely used, both in the United States and internationally. This paper discusses observations made on fenoprofen, flurbiprofen, ibuprofen and naproxen. Of these compounds, three are racemates; the fourth, naproxen, is an enantiomer. As a group, the propionic acids, along with most members of the other classes of NSAID, produce gastrointestinal damage in most species. These lesions vary from erythema, hemorrhage and erosion to ulceration and peritonitis. As might be expected, the degree of gastrointestinal intolerance depends on many factors: the individual compound, the dose-level, the duration of the period of drug administration, and the pharmacokinetics and metabolism in a given species. For example, in our experience the rat is less tolerant of NSAID than is the monkey, and the dog is less tolerant than the rat. Gastrointestinal lesions have been seen following both parenteral and oral administration; these findings suggest that factors other than local irritation play a role in the development of lesions. Most NSAID inhibit prostaglandin cyclo-oxygenase activity, which results in a prostaglandin deficiency at the tissue level. The administration of relevant exogenous prostaglandins, such as 16,16-dimethyl PGE2, has been shown to inhibit the gastrointestinal toxicity accompanying the administration of several NSAID, including some of the propionic acids.

Comparison of Effect of Progesterone and 11-Ketoprogesterone upon Glycosuria of Partially Depancreatized Rat

Summary Partially depancreatized force-fed rats were injected with 1 to 100 mg per day of progesterone and 1 to 32 mg per day of 11-ketoprogesterone. Very large doses of progesterone caused exacerbation of the diabetes and 11-ketoprogesterone was found to be significantly more potent in this respect. The diabetogenicity of 11-ketoprogesterone is manifest in either the presence or absence of the adrenal glands.

Further toxicologic studies of lincomycin

Abstract Additional toxicity studies of lincomycin hydrochloride, a new antibiotic effective against grampositive organisms, are reported. Oral dosages of 800 and 1000 mg/kg, respectively, were well tolerated in the dog and rat for a period of 3 months. No significant indication of irritation was observed when 150 mg of lincomycin was injected into a joint cavity of the rabbit. Tolerance upon intrathecal injection of 50 mg in the dog was regarded as rather good considering the difficulties inherent in a multiple cisternal tapping. No evidence of a teratogenic effect was observed in term-fetuses from rat dams injected with 300 mg/kg of lincomycin. The oral and subcutaneous LD 50 s in the rat were determined to be 15,645 and 9778 mg/kg, respectively.

Effect of continuous injection of glucagon upon glycosuria of partially depancreatized rats.

Summary When a highly purified preparation of glucagon was administered to partially depancreatized, force-fed rats by continuous intravenous injection there was temporary exacerbation of the diabetes. The continuous subcutaneous injections of glucagon to normal and to partially depancreatized rats were ineffective in the doses (0.05 to 1 mg/rat/day) tested.

Effect of Ethylenediamine upon Glycosuria of the Partially Depancreatized Rat

Summary The subcutaneous injection of ethylenediamine in 10 partially depancreatized rats caused exacerbation of diabetes in each animal but the glycosuria returned to the pre-injection level when the administration of the compound was stopped.

Effect of Continuous Injection of Epinephrine upon the Glycosuria of Partially Depancreatized Rats

Summary Epinephrine was administered to normal and to partially depancreatized force-fed rats by continuous subcutaneous injection for periods of 3 and 4 weeks. Simultaneously the control animals were injected with saline. Increased amounts of glucose were excreted by both normal and partially depancreatized rats during the injection of epinephrine. The peak response occurred on the second day after starting the injection of epinephrine or increasing the dose. All of the animals showed adaptation to epinephrine so that the peak response was not sustained.