On the importance of agonist concentration-gradients within isolated tissues. Increased maximal responses of rat vasa deferentia to (–)-noradrenaline after blockade of neuronal uptake

It is assumed often that blockade of agonist uptake processes in isolated tissues results only in shifts to the left of the concentration-response curves to the agonist with no concomitant increase in the maximal response. This may not be true in tissues where diffusion is not fast enough to permit penetration of the agonist to a sufficient number of muscle cells for production of tissue maximal response. Under these circumstances an agonist-concentration gradient is created within the tissue which, when altered, could lead to an increase in the maximal response to the agonist. The increased maximal responses of rat vasa deferentia to (–)-noradrenaline after blockade of neuronal uptake by either cocaine or desmethylimi-pramine have been analysed in terms of a concentration-gradient hypothesis. The data are compared with a theoretical calculation based on a model of restricted diffusion of enzymesubstrates into structured tissues. Both the experimental data and theoretical calculations suggest that an altered concentration-gradient of (–)-noradrenaline within the muscle layers of rat vasa deferentia is responsible for the increased maximal response. The effects of such gradients are discussed in terms of quantitation of drug-receptor phenomena and as a caveat to ascribing increases in maximal responses to post-synaptic effects of uptake inhibitors.     

Ulcerative Colitis and Persistent Liver Dysfunction

Six hundred and eighty-one patients with ulcerative colitiswho attend the outpatient clinic in Oxford have been screenedfor the presence of persistently abnormal liver function tests.Of the 21 patients (3.0 per cent) found with abnormalliver function17 (2.4 per cent) were shown by cholangiography to have primarysclerosing cholangitis. The liver biopsiesfrom those patientsdemonstrated a wide range of histological features and werediagnostic of primary sclerosing cholangit is in only 50 percent of the patients. When persistently abnormal liver function tests are demonstratedin patients with ulcerative colitis it is likely thatprimarysclerosing cholangitis will be present (81 percent of patientsin this study), and in order to make a reliable diagnosis itis necessary to perform cholangiography in addition to liverbiopsy. A close association with primary sclerosing cholangitisand histo-compatability antigens HLA B8 and DR3 is also reported.     

An assessment of methods of treating viral warts by comparative treatment trials based on a standard design

A series of eleven comparative wart treatment trials undertaken between 1969 and 1975 and involving 1802 patients is described. A method of coding provided groups of patients matched for age, type, number and duration of warts, within which treatments could be randomized. The variation in response to treatment was shown to be influenced significantly by these factors and the level of cure to depend on the proportions of the various response groups within the population under consideration. These proportions were found to vary geographically and at different periods. In all the trials the results were assessed at 12 weeks. In the treatment of hand warts, the percentage cure of patients treated with liquid nitrogen fell significantly from 75 to 40% when the interval between freezings was increased from 3 to 4 weeks. The average number of freezings required for a cure was 3 I amongst all patients cured by 6 or less freezings at intervals of 2 or 3 weeks. In a two–centre trial there was no significant difference between the percentage cure of patients with hand warts treated with liquid nitrogen (69%) and of those applying a paint containing salicylic and lactic acids (SAL) (67%). Patients receiving both treatments concurrently did better (78%) but the difference was not found to be statistically significant. In the treatment of simple plantar warts the percentage cure for the SAL paint (84%) was found to compare favourably with that for a podophyllin treatment (81%). Only one of the patients cured by the paint in that trial was found to have had a recurrence after 6 months. The paint was found to be satisfactory for use under general practice conditions. Additions to the formula did not alter its effectiveness. In the treatment of mosaic plantar warts the overall percentage cure for the SAL paint in a series of comparative trials (1969–75) was 45%. In these trials it was compared directly with one or more other preparations. No differences were found between its efficacy and that of 10% buffered gluteraldehyde (47%), 40% benzalkonium chloride dibromide (Callusolve 40) (30%) and 5% 5-fluorouracil in dimethyl sulphoxide (53%). Only 25% of thirty-six patients treated with 5% idoxuridine in dimethyl sulphoxide were cured. Throughout the trials approximately 30% of patients with hand warts, 2o% of those with simple plantar warts and 50% of those with mosaic plantar warts were found to be resistant to treatment. The adoption of treatment with SAL paint for hand warts and simple plantar warts by the general practitioners in the Edinburgh area has proved satisfactory. Only resistant cases are now referred to hospital and these can be treated within a few weeks instead of 4-5 months as was the case in 1969.     

A DOUBLE BLIND CROSS OVER TRIAL OF GONADOTROPHIN RELEASING HORMONE (LHRH) IN SEXUALLY IMPOTENT MEN

A double blind cross over trial of 500 μg of gonadotrophin releasing hormone or placebo subcutaneously every 8 h for 4 weeks in ten men with secondary sexual impotence is reported. No obvious clinical improvement occurred but statistical analysis of a libido score showed some overall improvement, especially the spontaneous occurrence of erections during the treatment period (P < 0.05).