Six month inhalation studies of pirbuterol acetate aerosol in the beagle dog and squirrel monkey.

Groups of Beagle dogs and Squirrel monkeys were exposed to aerosols of pirbuterol acetate, a new bronchodilator at doses of 0, 200, 400 and 800 micrograms of pirbuterol/kg body weight daily for 6 months. Each group consisted of 4 dogs or 6 monkeys per sex. Dogs were exposed by face mask and monkeys were exposed by head only in a manifold. Plasma drug concentrations indicated that expected levels of drug exposure were achieved in both species. No significant alterations were revealed in physical appearance and body weights, hematological and blood biochemical analyses, urinalyses, ophthalmoscopy, assessment of cardiovascular status, pulmonary function or gross and histopathology. Examination of the respiratory tract showed no morphological changes that could be attributed to pirbuterol acetate inhalation.

Nantradol hydrochloride: pharmacokinetics and behavioral effects after acute and chronic treatment.

Studies with [3H]nantradol hydrochloride indicate that nantradol is extensively metabolized after oral administration. By using a liquid chromatography assay with electrochemical detection, specific for both nantradol and desacetylnantradol, only desacetylnantradol is detected in plasma of rats and dogs dosed with nantradol. In animal analgetic tests, desacetylnantradol exhibits activity at least equal to nantradol. Together, these findings and additional in vitro enzymatic studies suggest that desacetylnantradol is the analgetically active species in vivo. In rats and dogs, desacetylnantradol has an apparent half-life of about 2 hr. No evidence for drug accumulation or alteration of drug metabolizing enzymes is noted from desacetylnantradol plasma level determinations during 90 days of oral and 14 days of i.m. dosing in dogs or rats at doses of 0.125 to 0.5 mg/kg i.m. and 2.5 to 10 mg/kg p.o. The static ataxia test in dogs was used to assess behavioral tolerance after chronic dosing (90 days); unlike delta 9-tetrahydrocannabinol only modest tolerance development is observed.

Comparative pharmacology and clinical efficacy of newer agents in treatment of heart failure.

The animal and human pharmacology of several new drugs (prazosin, trimazosin, pirbuterol, and carbazeran) useful in the treatment of congestive heart failure (CHF) is delineated in relation to the pharmacology of other agents employed for CHF management. Prazosin and trimazosin are selective alpha 1-blockers that cause a balanced increase in cardiac output (CO) and reduction in left ventricular filling pressure (LVFP); the reduction in diastolic blood pressure with these drugs is significantly related to increase in treadmill exercise, fall in LVFP, and increase in CO. Pirbuterol is a relatively selective beta 2-agonist with somewhat greater effects on CO than on LVFP. Early promise in CHF therapy is being shown by a novel series of cyclic adenosine monophosphate (cAMP) phosphodiesterase inhibitors with combined direct inotropic and vasodilator effects. Double-blind long-term studies demonstrate persistent efficacy of prazosin and trimazosin in CHF as measured by improvement in New York Heart Association functional class, treadmill exercise performance, and noninvasive measures of cardiac function; these data are supported by studies in which repeat cardiac catheterization has been performed after several months of therapy. Double-blind studies of other CHF drugs are in progress.

Pharmacokinetics and cardiopulmonary effects in dogs of sublingual pirbuterol, a new bronchodilator.

The time course of plasma concentrations of sublingually administered pirbuterol was investigated in anesthetized dogs; there was a dose-related increase in plasma drug concentrations which reached maximum values 1 hr or more after administration. In a second study plasma drug levels were correlated with antagonism of histamine-induced changes in pulmonary compliance and resistance which also reached maximum values 1 hr or more after drug administration, although marked antagonism was apparent at 15 to 30 min; blood pressure was unaltered at any dose level and heart rate was influenced only at the highest dose level. A convenient method for study of the bioavailability of sublingual formulations is described, and the potential usefulness of a sublingual dosage form of pirbuterol is discussed.

Selected ion monitoring assay for the bronchodilator pirbuterol.

A selected ion monitoring assay has been developed to measure plasma levels of the bronchodilator pirbuterol in animals and man. Pirbuterol is extracted from plasma with acetone + potassium carbonate and after further purification is converted to its trimethylacetyl derivative. With the use of the stable isotope labeled internal standard, pirbuterol-d9, precisions of 10% and 6% were achieved at plasma concentrations of 1 and 20 ng ml-1, respectively. The synthesis of the deuterium labeled internal standard is described.

Flumizole, a new nonsteroidal anti-inflammatory agent.

Flumizole is a potent anti-inflammatory agent in animal models with an inhibitory activity severalfold that of indomethacin in rat foot edema and prostaglandin synthetase tests. The drug was well absorbed from the GI tract when administered in the solution used in pharmacological assays. However, markedly poorer absorption of the solid form of this poorly water-soluble agent led to the development of a flumizole dispersion with polyethylene glycol 6000. The solid dispersion exhibited an increased dissolution rate in simulated gastric fluid and improved absorption properties in dogs relative to unformulated flumizole. Studies with a capsule formulation of the solid dispersion in human volunteers were indicative of good drug absorption. Plasma levels of flumizole were rapidly achieved and declined with a short half-life (2-7 hr) in rats, dogs, and humans.