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Effects of placebo and BHT 933 on autonomic reactivity.

BHT 933 (2-amino-6-ethyl-4,5,7,8-tetrahydro-6 Hoxazolo-[5,5-d]-azepin-dihydrochloride) was originally synthesised as an alternative to the morphine-like antitussive agents. Preliminary pharmacological studies indicated that whilst the compound had significant anti-tussive activity in animals and man it was also a hypotensive agent of the 'clondine-type' (Kobinger & Pichler, 1977; van Zwieten & Timmermans, 1980). Although much less potent than clonidine BHT 933 was considerably more selective as an q2 -adrenoceptor agonist (Timmermans & van Zwieten, 1980). Preliminary dose finding studies in man suggested that 5 mg orally might be a suitable dose for more detailed investigation in human volunteers. In the following study the effects of BHT 933 (4.5 mg tablet) on autonomic reactivity has been compared with placebo in twelve fit young male adults. The mean age of the volunteers was 28 years (range 22 to 37 years) and the weight range was 57 to 85 kg (mean 69.3 kg). All but one volunteer admitted to consuming alcohol, but only three subjects smoked and none heavily. Each subject gave informed consent in writing. The subjects took no other drugs for at least 7 days prior to the investigation and fasted (food and fluids) from 20.00 h the previous evening. The drug was taken with 20 ml of water and no food was permitted until 2 h after the dose, when a light breakfast was eaten. From 4 h after the dose light meals and fluids were permitted ad libitum, except that no coffee, tea, alcohol or tobacco was allowed. Blood pressure was measured using an electronic sphygmomanometer (BE 237R) and a continuous record of heart rate was obtained using a Tektronic ECG monitor (412) connected to a pen recorder. The same arm was used for all blood pressure recordings, and preliminary experiments, using both the electronic sphygmomanometer and a stethoscope indicated that the apparatus recorded diastolic blood pressure at stage 5. A complex series of measurement was made before the dose and at 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h after it. These included a measure of sedation using a 100mm visual analogue scale marked at one end, 'Wide awake' and at the other 'Nearly asleep', and a measure of salivary flow, using four weighed dental cotton wool rolls which were placed in the buccal pouches and one either side of the tongue for 2 min and then rapidly expelled into a weighed pot. Supine blood pressure was obtained after the subject had been lying quietly for 10 min. The subject was then asked to stand up and blood pressure and pulse rate were measured every 30 s for 3 min. A cold pressor test was carried out by immersing one hand in a mixture of crushed ice and water for 1 min and recordings of heart rate and blood pressure were taken at 30 s intervals. The response to mental arithmetic was obtained by requesting that the subject recited out loud an unfamiliar times table (e.g. 47 times table). Blood pressure and pulse were measured at 30 s intervals. The systolic overshoot of Valsalva's manoeuvre was recorded after a 20 s blow on a mercury column to 40 mmHg. Each subject took part in the experiment on two occasions, receiving either placebo or 4.5 mg BHT 933 on a double-blind basis. At least 1 week was allowed between drugs. BHT 933 caused a fall in supine systolic blood pressure which was significantly greater than that produced by placebo 2 to 6 h after ingestion (Table 1). However, no significant effects were seen on diastolic blood pressure, although the BHT subjects tended to exhibit lower diastolic pressures 1 and 2 h after ingestion. It was interesting to note that both placebo and BHT 933 treated subjects exhibited a marked fall in diastolic pressure 4 to 8 h after ingestion (Table 1).