Jay E. Birnbaum

Cutaneous erythema and blood pressure lowering effects of topically applied 16-vinylprostaglandins.

Topically applied 16-vinylprostaglandins demonstrate the property of rapid transit through the skin and a profound effect on the cutaneous vasculature. At low concentrations in the guinea pig and rabbit. 15-deoxy-16-hydroxy-16-vinyl-PGE2 (DHV-PGE2) and its methyl ester (DHV-PGE2Me) elicit a distinct and persistent erythema which is restricted to the area of application and is not associated with a wheal. Skin temperatures are elevated for several hours following application. Accordingly, these compounds may have therapeutic utility in conditions where local blood flow is compromised or where an enhanced blood flow is desired . In the spontaneously hypertensive rat, topically applied DHV-PGE2 and DHV-PGE2Me produce a dramatic and persistent lowering of blood pressure. The maximal effects are comparable to those obtained wit equal oral or intravenous doses and are maintained for a longer period of time. Moreover, with the topical route, there is no prolongation in the time required for onset of action (3-5 minutes). It appears that while the skin presents only a minimal diffusion barrier to these compounds, a sufficient depot is maintained to give sustained release and prolonged duration. Transdermal delivery of 16-vinyl prostaglandins may offer a convenient means of achieving a clinical antihypertensive effect without the characteristic side effects generally associated with oral or intravascular prostaglandins.

Bronchodilator activity of a PGE2 analog in animals and in man

A C-11 substituted PGE2 analog, DHET-PGE2 [alpha-11-deoxy-11 alpha-(2-hydroxyethylthio)-PGE2 methyl ester], was demonstrated to exert potent bronchodilator activity in three in vivo models of augmented airway resistance: (1) acute bronchospasms, induced by 5-hydroxytryptamine, histamine and acetylcholine in the anesthetized guinea pig, (2) acute bronchospasm, induced by pilocarpine, in the anesthetized dog, and (3) chronic bronchospasm, induced by SO2 exposure, in the unanesthetized dog. In acute and 30-day toxicological studies in the dog, no cardiovascular, respiratory or gastrointestinal side effects were observed at aerosol doses at least 1,000 times those required for efficacy. In vitro, DHET-PGE2 effectively relaxed isolated preparations of dog bronchus that had been contracted with carbachol. In clinical studies, human asthmatics and bronchitics responded consistently to beta-agonist bronchodilators but variably to DHET-PGE2. Overall, increases in pulmonary resistance or decreases in FEV1 were observed with DHET-PGE2. Subsequent evaluation in isolated carbachol-contracted human bronchus revealed that, in contrast to the bronchodilator activity of PGE1 and beta-agonists, DHET-PGE2 and PGE2 induced contraction. Considered along with results from previous clinical studies on other PGs, these data underscore the difficulties in making extrapolations on this class of compounds from animal models to humans and suggest that human bronchial tissue may provide the only appropriate preclinical test system for predicting the clinical efficacy of PG bronchodilators.

Nasal vasoconstrictor activity of a novel PGE2 analog

A novel PGE2 analog (CL 116,069) was shown to be effective in dogs as a nasal decongestant. Threshold doses were approximately 0.1 microgram/kg with intravenous administration and between 0.08 and 4 microgram with topical administration. CL 116,069 was compared to 17-phenyltrinor PGE2 (CL 116,147), a compound recently studied in humans, and xylometazoline, a well-known nasal decongestant. When given i.v., efficacious doses of xylometazoline tended to raise blood pressure and be shorter acting than the PGs, which did not affect blood pressure. When given topically, all three were long-acting. CL 116,069 usually had the lowest threshold and CL 116,147 usually induced the smallest response. All three agents were more effective than PGE1 or PGE2. A 30-day (b.i.d., topical) toxicity test with CL 116,069 produced no inflammation or nasal pathology and no loss in tissue sensitivity. In vitro examination of xylometazoline and CL 116,069 for vasoconstrictor activity on dog isolated mucosa revealed a response profile similar to that observed with these agents in vivo; i.e., the magnitude of response was comparable for both agents but the t 1/2 was only 74 minutes for xylometazoline and greater than 6.5 hours for CL 116,069. The data suggest that CL 116,069 may provide a therapeutic alternative in which constriction of the nasal blood vessels need not be associated with a generalized vasoconstrictor liability.

Prostaglandins and congeners XIII (1). The synthesis of dℓ-erythro-16-methoxyprostaglandins

dl-Erythro-16-methoxy-PGE2, PGA2, PGF2alpha, 11-deoxy PGE1, and 11-deoxy PGF1alpha have been prepared via the cuprate conjugate addition procedure. These congeners are less potent than the parent prostaglandins as stimulators of isolated gerbil colon contractions and as bronchodilators in the guinea pig Konzett assay.

Studies on a leukocyte elastase inhibitor present in the culture medium of inflamed synovial tissue

Abstract The spent medium of cultured inflamed synovial tissue contains a potent inhibitor of leukocyte elastase. This leukocyte elastase inhibitor has no effect on leukocyte cathepsin G and pancreatic elastase is only marginally affected. The inhibitor is a glycoprotein, stable to heat, acid and reductive alkylation. Pretreatment of the inhibitor with either trypsin or chymotrypsin results in its inactivation.

A Comparison of a Synthetic Prostaglandin and Xylometazolin Hydrochloride as Nasal Decongestants

A synthetic prostaglandin E2 analog was compared in the dog to xylometazoline hydrochloride and natural PGE1 and PGE2 for nasal decongestant activity. Using both in vivo nasal patency tests and in vitro nasal blood vessel contraction tests, the synthetic analog was more effective, was very long-acting, and did not change blood pressure at effective systemic or topical doses.

Prostaglandin E antagonist activity of 11-deoxy-16, 16-trimethyleneprostaglandin E1

11-Deoxy-16,16-trimethyleneprostaglandin E1 is a potent inhibitor of prostaglandin E-induced contractions of the gerbil colon. The antagonism is directed specifically against the prostaglandin E receptor and is not manifested when contractions are induced by either prostaglandin F2 alpha or acetylcholine.