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Biomedical subjects

D B Meyers

Publications and source records attributed to D B Meyers.

13 recordsLinked to original sources
PubMed1988

Preclinical pharmacology of a new serotonergic receptor antagonist, LY281067.

The preclinical pharmacologic activity of LY281067 shows it to be a potent and highly selective serotonergic (5-HT2) receptor antagonist. Based upon binding studies with 5-HT2 receptors in brain cortical membranes and block of 5-HT-induced contractions in the rat jugular vein, LY281067 showed high affinity at 5-HT2 receptors with a dissociation constant of approximately 1 nM. Furthermore, LY281067 was a highly selective 5-HT2 receptor antagonist without appreciably binding to 5-HT1, D1 or D2 receptors or interacting with histamine (H1), cholinergic, beta adrenergic or alpha-1 adrenergic receptors in smooth muscle. LY281067 had modest affinity at alpha-2 receptors with a dissociation constant of approximately 100 nM. Oral bioavailability of LY281067 in spontaneously hypertensive rats was excellent with an oral to i.v. dose ratio approximating 4, based upon blockade of pressor responses to 5-HT as an in vivo estimate of 5-HT2 receptor antagonist activity. Furthermore, LY281067 blocked quipazine-induced increase in serum corticosterone concentration, an increase thought to be mediated by activation of central 5-HT receptors. After oral administration to rats, LY281067 antagonized vascular 5-HT2 receptors with a relatively long duration of action (greater than 6 hr), an observation likely to be related to plasma concentrations of both the parent and an active metabolite. Lastly, LY281067 was relatively nontoxic, possessing a therapeutic index of approximately 1000 after oral administration to rats. In summary, LY281067 is a potent and highly selective, orally active 5-HT2 receptor antagonist with a relatively long duration and wide margin of therapeutic safety.

Animals↗
PubMed1985

Toxicology of indecainide hydrochloride in mice, rats, and dogs.

Indecainide is a new (investigational) drug for treating cardiac arrhythmias. When given orally to either young adult rats or mice, the LD50 was ca. 100 mg/kg. Leg weakness, tremors, and occasional convulsions were seen in rodents given doses in the lethal range. Dogs and monkeys survived a single oral dose of 25 mg/kg; however, there was a pronounced increase in duration of the PR and QRS intervals. In a 3-month subchronic toxicity study, rats fed dietary levels equivalent to 20 mg/kg/day indecainide were unaffected. Body weight gain was slightly depressed in both sexes of the 40-mg/kg dose group and moderately reduced in both sexes of the 85-mg/kg dose group. Alkaline phosphatase values were minimally increased in females of the 85-mg/kg dose group. In a 3-month subchronic toxicity study, dogs were given daily doses of 0, 6.25, 12.5, or 25 mg/kg indecainide. One male in the 12.5-mg/kg dose group and two females in the 25-mg/kg dose group died during the study. EKG recordings showed a prolongation of the PR and QRS intervals in all treated dogs. In addition, there was a notch in or just prior to the R wave. There were no histopathology findings related to treatment in rats and dogs in the 3-month subchronic rat and dog studies.

Administration, Oral↗
PubMed1985

Toxicology of indecainide hydrochloride after intravenous administration to rats and dogs.

Subchronic 1-month intravenous toxicity studies on indecainide, an antidysrhythmic agent, were conducted in rats and dogs. Rats (10 males, 10 females/group) were given daily intravenous (i.v.) doses of 0, 3, 6, or 9 mg/kg of indecainide for 1 month. 6 Of 10 males and 1 of 10 females given 9 mg/kg died during the test period. All but 2 animals from the other test groups survived. The high end of these daily doses was close to the acute single lethal dose, and the deaths were not unexpected. There were no treatment-related hematologic or serum chemistry changes in the surviving animals. No treatment-related histopathologic changes occurred in any of the animals. Groups of dogs (2 males, 2 females per group) were given daily i.v. injections of 0, 1.5, 3, or 4.5 mg/kg of indecainide for 1 month. 2 Of 4 dogs died after receiving multiple daily doses of 4.5 mg/kg. No treatment-related histopathologic changes were present in these animals. Dogs given doses of 1.5 or 3 mg/kg tolerated daily injections of the compound with no overt signs of toxicity and without hematologic, serum chemistry or histologic changes. Electrocardiograms revealed prolonged PR, QRS, and QT intervals in dogs from all three dose groups. Rats and dogs tolerated daily intravenous doses of indecainide as high as 6 and 3 mg/kg, respectively, with no evidence of any effect of treatment except the expected pharmacological action on the myocardium.

Animals↗
PubMed1979

Rat lymphocytic thyroiditis associated with ingestion of an immunosuppressive compound.

Lymphocytic thyroiditis was induced in young Wistar rats by feeding them the immunosuppressive compound frentizole [1-(6-methoxy-2-benzothiazolyl)-3-phenyl urea] for 1 year. About half of the rats given 0.060 and 0.150% frentizole in the diet had lymphocytic thyroiditis. The incidence of thyroiditis was low in the group given the high dose because of severe anemia and hepatic disease which resulted in increased mortality. Reversibility of the thyroid lesion was indicated by reduced incidence rates at 15 and 18 months after treatment was stopped at 1 year. The thyroiditis was characterized by interstitial infiltrates of many lymphocytes and plasma cells and fewer macrophages with mild degenerative changes in the follicular epithelium. This inflammatory cell infiltrate was generally diffuse but occasionally was multifocal, particularly in thyroid glands of rats late in the reversibility phase of the study. The inflammatory cell infiltrate caused the thyroid glands to be several times normal size. Sera from rats with lymphocytic thyroiditis contained hemagglutinating antibody against rat perfect correlation between the presence of anti-thyroglobulin antibody and enlarged thyroid glands. Fine granular deposits of IgG and complement were identified in some areas of the follicular basement membrane. We concluded that the lymphocytic thyroiditis was immunologically mediated, at least in part, by anti-thyroglobulin antibody.

Animals↗