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We investigated the effects on peripheral sympathetic nervous function of monofluoromethyldopa (MFMD, RMI 71963), a selective, enzyme-activated, irreversible inhibitor of L-aromatic amino acid decarboxylase. Three daily injections of 2.5, 25, or 100 mg/kg MFMD to rats reduced the dopamine and norepinephrine concentrations in the heart and increased those of L-dopa. Sedation was seen with the two highest doses of MFMD. Cardiovascular responses in the pithed rat to stimulation of the whole spinal sympathetic outflow and to injections of tyramine were reduced by treatment with MFMD. Both the reduced sympathetic function and the depleted transmitter store were restored by infusions of dopamine. Norepinephrine depletion and functional inhibition were obtained with smaller doses of MFMD (3, 6, and 10 mg/kg daily) given for longer periods (10 days). Blood pressure in spontaneously hypertensive rats was reduced by treatment with MFMD, 25 mg/kg, daily for 3 days. In vitroresponses to nerve stimulation of portal veins declined during incubation with MFMD or α-methyl-p-tyrosine; responses of atria were unaffected. Changes in norepinephrine concentrations of portal veins and atria closely paralleled the changes in function. MFMD is the first compound which depletes peripheral norepinephrine concentrations by inhibiting transmitter biosynthesis at the decarboxylase step. Such depletion results in inhibition of sympathetic function in vivoand introduces a novel approach to pharmacological manipulation of the activity of the peripheral sympathetic nervous system.

During a consensus conference in Lugano, Switzerland, 175 statements on controlled clinical trials were drafted by 47 representatives from academia, governmental registration agencies and industry in nine countries. Their opinion on these statements was similar to that of 47 ‘matched pairs’ who did not attend the conference. Thus, the opinion of participants and non-participants appears to reflect the general opinion of those currently involved in designing, conducting and analysing controlled clinical trials. The Lugano statements give answers to the following questions: Is the controlled clinical trial in a crisis? What is the motivation to perform controlled clinical trials? Is it possible for a physician participating in a controlled clinical trial to act in the patient's best interest? Is it possible to obtain truly informed consent in a controlled clinical trial? When is it ethical to withhold active treatment in a controlled clinical trial? What are the controversial issues in the design of a good controlled clinical trial? Is there a double standard with respect to efficacy and adverse drug reactions in controlled clinical trials? What are the alternatives to controlled clinical trials and when should they be performed? How can sponsor bias be minimized? How should an ethics committee decide whether a controlled clinical trial is Should? ethical registration agencies become directly involved in the planning and conduct of controlled clinical trials? Do the declarations of Tokyo and Helsinki facilitate the conduct of ethically valid controlled clinical trials? Is it possible to create an international standard for the conduct and regulation of controlled clinical trials? Why do messages from controlled clinical trials filter into medicine so slowly? Is it possible to bridge the gap between controlled clinical trials and clinical reality? What are the costs of doing and not doing controlled clinical trials? When should drug companies decide to start a trial programme with a specific compound? Is there public hostility against controlled clinical trials? If so, how can it be reduced? The respondents almost unanimously felt that controlled clinical trials are a must; the public must be told that progress in medicine depends on controlled clinical trials, that patients often benefit from participating in them and that the alternative, practising in the face of constant uncertainty, is worse than the possible disadvantages related to the conduct of the trial.

2-Difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ornithine decarboxylase, causes marked changes in the polyamine metabolism of ventral prostate when given to adult rats in drinking water (20 g/l) for 3 consecutive days. A 90% inhibition of ornithine decarboxylase activity is accompanied by approx. 80% decreases of the concentrations of putrescine and spermidine and by a 36% decrease in spermine. Concomitantly, S-adenosylmethionine decarboxylase activity increases 7-fold and the concentration of decarboxylated S-adenosylmethionine 450-fold. When DFMO is given to immature rats for 12 consecutive days the above described changes are accompanied by a marked reduction in the age-dependent increases of the wet weight and RNA and DNA contents of the ventral prostate. In adult rats DFMO decreases the weight and RNA content of the ventral prostate within 4 days by 32% and 24% respectively and maintains them constant for the next 19 days. After 23 days of treatment, the prostatic weight is 46% of that of control animals of the same age, whereas the weights of other organs are only slightly decreased. Cytological studies carried out at this time show that DFMO reduces the size of both prostatic acini and the epithelial cells lining the acini.