The response of normal and asthmatic subjects to prostaglandins E2 and F2alpha by different routes, and their significance in asthma.

Although PGE2 and PGF2alpha have potent effects on the human bronchus by aerosol, they are less potent when given by the intravenous route. Prostaglandin E2 may cause bronchoconstriction. Indomethacin had no effect on day-to-day asthmatic symptoms, or challenge-induced asthma, suggesting that prostaglandins are not fundamental to the pathogenesis of asthma.

Is there an increase in monoamine-oxidase activity in depressive illness?

In a group of depressed patients who had either been treated with or considered suitable for monoamine oxidase (M.A.O.) inhibitor therapy, a highly significant decrease in conjugated tyramine output was observed after an oral tyramine load compared with normal controls. However, there was no difference in conjugated isoprenaline output between the two groups after isoprenaline ingestion, even though this amine is almost solely metabolised by what is likely to be the same conjugation mechanism. Whilst some explanation in terms of altered gut motility is conceivable, it seems more likely that the apparent deficit in tyramine conjugation in depression represents an increase in functional M.A.O. activity. Consequently, this enzyme would metabolise a greater proportion of available amine, causing a proportionately large decrease in the smaller conjugate pool.

Effects of inhaled prostaglandins E1, E2, and F2alpha on the airway resistance of healthy and asthmatic man.

1. Changes in specific airway conductance after the inhalation of aerosols of prostaglandins (PG) E1, E2, and F2alpha were investigated in healthy and asthmatic subjects. 2. Inhalation of 155 nmol (55 mug) of PGE1 or 156 nmol (55 mug) of PGF2 resulted in consistent minor bronchodilatation in healthy subjects, but in asthmatic patients airway conductance increased significantly, along with subjective improvement. Isoprenaline (988 nmol; 550 mug) inhalation resulted in a similar increase in conductance to that obtained after these two prostaglandins, whereas a control aerosol had no effect. In contrast to the isoprenaline aerosol, both PGE1 and PGF2 were highly irritant to inhale. It was concluded that this made them unsuitable for therapeutic use. 3. Prostaglandin F2alpha inhalation resulted in a dose-related bronchoconstriction in healthy and asthmatic subjects. Asthmatics were approximately 150 than were the healthy subjects but there was very wide and significant variantion in the sensitivity of the asthmatic subjects. In contrast the asthmatic subjects were only 8-5 times more sensitive to histamine than the healthy subjects with less variation in response of individual subjects. The reasons for the hyper-reactivity of asthmatic subjects to PGF2alpha is unknown and no correlation could be drawn between increased sensitivity and age, type of asthma, or treatment. 4. The effects of disodium cromoglycate, flufenamic acid, atropine methonitrate, PGF2 and isoprenaline on PGF2alpha-induced bronchoconstriction were investigated in healthy subjects. Prostaglandin E2 reversed PGF2alpha-induced bronchoconstriction, as did isoprenaline, but prior treatment with the other drugs had no effect in preventing bronchoconstriction.

Peripheral neuropathy and indomethacin.

A patient with seronegative inflammatory polyarthritis developed a predominantly motorperipheral neuropathy associated with the use of indomethacin. Three other cases of peripheral neuropathy associated with indomethacin treatment have been reported to the Committee on Safety of Medicines. In all cases the neuropathy regressed when indomethacinwas stopped. Peripheral neuropathy should be recognized as a rare complication of indomethacin therapy and considered in the differential diagnosis of a neuropathy accompanyingrheumatoid arthritis.

Plasma levels and beta-adrenoceptor blockade with acebutolol, practolol and propranolol in man.

1 The degree of beta-adrenoceptor blockade of isoprenaline-induced tachycardia has been determined in three healthy volunteers after the administration of single oral doses of acebutolol, practolol or propranolol. 2 Plasma levels of these drugs were determined either colorimetrically (acebutolol and practolol) or fluorimetrically (propranolol). The colorimetric assay of acebutolol in plasma is fully described but the other drugs were assayed by published methods. 3 The degree of beta-adrenoceptor blockade and the plasma level for acebutolol and practolol were well correlated, whereas in the case of propranolol correlation was poor, due in part to the presence in plasma of active metabolites not detected by the fluorimetric assay. The plasma levels of practolol and propranolol are in agreement with those previously reported. 4 The maximum cardiac beta-adrenoceptor blockade achieved in this study with the respective single oral doses of acebutolol (300 mg), practolol (400 mg) or propranolol (40 mg) were similar in each of the three subjects. Therefore the beta-adrenoceptor blocking potencies of these drugs against isoprenaline-induced tachycardia are inversely related to these doses; indicating that propranolol is 7-8 times more potent than acebutolol and the latter slightly more potent than practolol.

Antagonistic Action of Aerosols of Prostaglandins F(2)alpha and E(2) on Bronchial Muscle Tone in Man.

Experiments were carried out in healthy male volunteers to investigate the effect of the inhalation of prostaglandin F(2)alpha (PGF(2)alpha) on airways resistance and the influence of the subsequent inhalation of prostaglandin E(2) (PGE(2)). Airways resistance, which reflects the tone of smooth muscle in the larger airways in man, was measured by total body plethysmography.The inhalation of PGF(2)alpha (40-60 mug) caused an increase in airways resistance in all subjects. Both PGE(2) (55 mug) and isoprenaline (550 mug) given by metered aerosol promptly reversed the bronchoconstriction induced by PGF(2)alpha, but isoprenaline was more effective in this respect.A role for these prostaglandins in the control of bronchial muscle tone is discussed.

Effect of M & B 17803A, a new -adrenoceptor blocking agent, on the cardiovascular responses to tilting and to isoprenaline in man.

1. DL-1-(2-acetyl-4-n-butyramidophenoxy)-2-hydroxy-3-isopropylaminopropane hydrochloride (M & B 17803A) was given to four healthy volunteers in single oral doses of up to 300 mg. There were no subjective effects and no significant alterations in the heart rate, systolic and diastolic blood pressure in the seated position or in the forced expiratory volume or in the electrocardiogram within 6 h of the dose. There were no abnormalities in haematological tests and estimations of the serum glutamyloxaloacetic transaminase.2. Oral doses of both M & B 17803A and propranolol inhibited the increase in heart rate which occurs on tilting from the supine to the 80 degrees head up position. The results suggest that the degree of beta-adrenoceptor blockade produced by M & B 17803A (100 and 300 mg) is comparable to that of propranolol (10 and 40 mg) respectively. Propranolol is 7.5-10.0 times as potent as M & B 17803A when compared by this method. There were no significant changes in the systolic or diastolic blood pressure after any of the treatments, in either of the positions studied.3. M & B 17803A was also effective in inhibiting the increase in heart rate produced by the intravenous infusion of isoprenaline and in two subjects the degree of beta-adrenoceptor blockade produced by M & B 17803A (300 mg) was comparable to that of propranolol (40 mg). M & B 17803A is a competitive beta-adrenoceptor blocking agent and the duration of the pharmacological activity of both M & B 17803A and propranolol appeared to be very similar as assessed by this method.4. In separate experiments with small oral doses of M & B 17803A no evidence of a selective action on myocardial beta-adrenoceptors was obtained from the study of changes in heart rate and diastolic blood pressure (sphygmomanometric recording).