Seymour Ehrenpreis

Block of electrically induced contractions of guinea pig longitudinal muscle by prostaglandin synthetase and receptor inhibitors.

Inhibitors of prostaglandin synthetase as well as prostaglandin receptor inhibitors block electrically induced contractions of the longitudinal muscle of the guinea pig ileum. This blockade is selectivety reversed by some prostaglandins, particularly those of the E series. There is a very close parallel between the potency with which the synthetase inhabitors block transmission and inhibit the enzyme. That blockade is actually accompanied by inhibition of synthesis of PG was shown by inhibition of arachidonic acid contractions of the tissue by indomethacin. The inhibition of transmission by indomethacin involves block of acetylcholine release as shown by direct assay and by the fact that physostigmine can reverse the block. Physostigmine also reverses block of transmission by prostaglandin receptor inhibitors and by morphine but not that produced by chlorpromazine or papaverine. Other evidence for a presynaptic site of action for the synthetase and PG receptor inhibitors is indicated by lack of effect of blocking concentrations on response of the tissue to exogenous acetylcholine. That prostaglandin reverses block of transmission by a presynaptic effect was shown by lack of reversal of atropine and papaverine inhibition of electrically induced contractions; both of these drugs produce this effect directly on the smooth muscle. These results are compatible with the previous postulate that a prostaglandin system, comprised of prostaglandin, its synthesizing enzyme and its receptor, is directly involved with the release of acetylcholine in the ileum.

The Clinical Implications of First‐Pass Metabolism: Treatment Strategies for the 1990s

The first‐pass effect is real. It may pose obstacles to the treatment of disease, and strategies need to be developed to address the problem that first pass can cause. First we have to look at identifying the problem, and this symposium has helped to further emphasize that the problem exists and awareness is increasing. The first‐pass effect has been a basic tenant of pharmacology but an area not receiving active research interest and one that is often overlooked in the clinical arena. Avoiding drug interactions is a consideration, and that is a major challenge to the field of clinical pharmacology. Clinicians need to be aware of the problem, aware of the danger areas with drugs, and first pass. Another alternative is to turn to chemical modification of a drug that avoids needing to take first pass into consideration.

Mechanism of development of tolerance to injected morphine by guinea pig ileum

Abstract Injection of a large dose of morphine into a guinea pig results in a block of electrically-induced contractions of the ileum in vitro . A similar dose is almost ineffective in guinea pigs given morphine chronically. The time course for development of this tolerance has been determined in guinea pigs injected twice daily with morphine 100 mg/kg and challenged on various days with 750 mg/kg of the drug. Animals similarly injected but not challenged served as controls. The inhibitory effect of the challenging dose on electrical stimulation of longitudinal muscle decreased with successive days of morphine administration; by the 10th day there was almost complete tolerance to the challenging dose. Sensitivity of the tissues of chronically morphinized unchallenged controls towards acetylcholine, serotonin, histamine and norepinephrine was essentially the same as that of naive animals. The potency of morphine in vitro in blocking electrical stimulation was also unchanged by chronic morphine administration in the above manner. Thus tolerance to injected morphine cannot be explained by reduced affinity of the drug for the opiate receptor. Tissues of chronically morphinized animals gave a contracture with naloxone, the extent of the contracture increasing with time of drug administration. This naloxone effect is attributed to displacement of morphine from a new opiate receptor site induced during morphine administration. It is suggested that this new receptor is involved in tolerance to injected morphine as well as some aspects of the withdrawal syndrome.

Histamine release as the basis for morphine action on bile duct and sphincter of Oddi.

We have investigated the mechanism by which morphine contracts hog bile duct and sphincter of Oddi. Morphine contraction is antagonized by naloxone, competitively on the sphincter, noncompetitively on the bile duct. Diphenhydramine at low concentration (3.4 X 10(-6)M) also antagonizes both actions of morphine. Histamine has a very potent contracting action on the sphincter and bile duct and this is antagonized by diphenhydramine. Burimamide only weakly antagonizes the actions of morphine or histamine. Compound 48/80 causes a pronounced contraction of sphincter and bile duct following which morphine effects are greatly attenuated. These results suggest that morphine-induced contraction of the sphincter of Oddi and bile duct is mediated by a two step reaction involving interaction with a specific opiate receptor leading to the release of histamine which combines with an H1 receptor to produce the effect.

Therapeutic approach to unstable angina: Nitroglycerin, heparin, and combined therapy

The term “unstable angina” is generally used to describe different clinical conditions such as accelerated angina pectoris (increase of severity and frequency of known chronic angina), angina at rest, prolonged angina associated with ST segment and T wave changes, and new onset angina. The prognosis of patients with these clinical syndromes differs considerably, with the worst prognosis for those with prolonged angina or angina at rest. Therefore management of unstable angina, including the aggressiveness and timing of interventional techniques, initially depends on the clinical presentationi Unstable angina often progresses to myocardial infarction simultaneously with the progression of an underlying thrombotic process,, Both aspirin and heparin favorably influence the clinical course of patients with unstable angina. In three large trials,2W4 aspirin has been shown to reduce mortality and protect against myocardial infarction. Utility of heparin in unstable angina. Heparin (5000 U intravenous bolus, followed by 1000 U/hr) was more effective than aspirin in relieving acute ischemic symptoms in patients with unstable angina,57 6 and was significantly more effective than placebo in preventing acute myocardial infarction in such patients.5 In one study,2 which included only patients with unstable angina, heparin was administered as a continuous infusion, with the dose adjusted to maintain the coagulation time at 1.5 to 2 times control values. Excluding the aspirin-treated patients, myocardial infarction occurred in 1 of 118 heparin

Prostaglandin-norepinephrine interaction in guinea pig longitudinal muscle

Abstract Norepinephrine block of electrically induced contractions of the guinea pig longitudinal muscle-myenteric plexus preparation reverses spontaneously. PGE 1 or E 2 fails to alter rate of reversal in the presence of ascorbic acid but increases the rate in its absence. Using spectrophotometry, it could be demonstrated that PGE 1 or E 2 significantly increases the rate of autoxidation of norepinephrine, thereby accounting for the pharmacological interaction observed.