When a new agent is introduced into therapeutics it is important to obtain reliable comparison with existing drugs. Examination of the published reports on guanethidine, methyldopa, and bethanidine provides only an approximate estimate of their comparative merits. Most reports indicate that about 70% of patients achieve reasonable control of their blood pressure with each drug. However, the conditions of the trials varied in many respects, such as levels of blood pressure accepted as good and fair control, the severity of the hypertension in the patients treated, and the clinic routine. In addition, it is difficult to obtain a clear idea of the acceptability of these drugs by patients and of the incidence of side-effects. It was with these factors in mind that, following our initial studies with bethanidine (Johnston, Prichard, andRosenheim, 1962, 1964), we designed a formal trial to compare bethanidine with the established drugs guanethidine and methyldopa.Patients.-Details of the 30 patient-volunteers completing the trial are summarized in Table I; four of the original 34 patients were withdrawn (see below). The patients were selected solely by the criteria that it was thought necessary to treat them with potent hypotensive drugs and that they were able to attend regularly. All except one patient were on potent drugs before the trial-14 on bethanidine, 11 on guanethidine, and 4 on methyldopa. Method Summary of TrialA within-patient comparison was designed in which each patient received bethanidine, guanethidine, and methyldopa. These drugs were prepared in identical capsules and were given in random order, the randomization being stratified according to the treatment the patient was receiving before the trial.Patients were seen at two-weekly intervals during the trial (except for the intrusion of their holidays) under After careful consideration it was not thought desirable for physician A to be " blind." Safe and reasonably rapid adjustment of the dose was essential in order to avoid exposing the patients to unnecessary risk, and as the duration of action of the drugs varies different dose schedules have to be followed. The final decision on instructions to adjust the dose had to be tempered with the knowledge of any side-effects being experienced, most notably symptoms of postural hypotension. In addition, the drugs have several characteristic side-effects which would have permitted physician A in many instances to know which drug was being used.Previous to the " period of assessment " (see below) on each of the three drugs there was a " run-in period." The run-in period was to enable the dose of each drug to be adjusted to obtain the optimal therapeutic effect. The run-in before the first drugs also served to familiarize the patients with clinic procedure, to ensure that they understood the " weekly symptom record sheet" (see below) which they kept, and, lastly, it went some way to ensure that the greater part of the hypotensive effect of increased interest by the physician became stabilized before the tr...

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The problem of assessing the numerous new drugs offered to clinicians is continuously increasing. It is not always possible, even if desirable, to mount a substantial and definitive therapeutic trial for each new drug in a single department. In these circumstances close observation of a few patients in several centres may provide data adequate to justify more general distribution of a new drug, with minimal diversion of workers from their other tasks. The animal pharmacology of a new adrenergic beta-receptor blocking agent. pronethalol, has been reported by Black and Stephenson (1962), and some aspects of the human pharmacology by Dornhorst and Robinson (1962 Recording of Data.-Patients were asked to take glyceryl trinitrate as usual for the attacks of pain, but not prophylactically, and to keep a record of the attacks of pain and number of tablets taken. They were given a record sheet for each week, each day being divided into four periods starting at the time pronethalol (or placebo) was taken. They were asked to fill in their sheet at the end of each period and ,to record the time of onset of any attacks of angina, their duration; to assess severity as mild, moderate, or severe; to note the number of glyceryl trinitrate tablets consumed; and to record any comments they desired. Patients were supplied with a known number of glyceryl trinitrate tablets, and this number was recorded on their sheet and checked with the number remaining in the bottle when they attended at the next visit. Clinicians saw the same patients weekly and recorded their progress without reference to previous assessment sheets. Patients were asked standard questions, and their subjective impressions and any complaints of side-effects were noted.Assessment.-See results. Selection of Patients.-The case-notes of over 100 patients with a diagnosis of angina were examined and only 21 of these subjects were considered to be suitable for this study of a new drug-that is, those having at least two attacks of angina regularly each week, and without other disease or complications that might make the trial of a new drug inadvisable. The pain had to be of characteristic nature, site, and radiation, brought on by exertion, relieved by rest and/or glyceryl trinitrate, and lasting one to three minutes. Of these patients, nine had to be withdrawn during the early stage before the double-blind study began, for the following reasons: (1) hypersensitivity in two .patients (measles-like rash in 2nd week in one, and angioneurotic oedema, "collapse " 2nd day in the other); (2) diarrhoea in one patient (refused to continue)-(3) depression in one patient on a high dose-he then went abroad; (4) angina subsided, apparently spontaneously in one patient ; (5) fatal myocardial infarct in one patient; (6) one patient objected to having his tablets " mucked about "; and (7) two defaulted.

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