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Prior administration of phenobarbitone to male and female rats dosed orally or intravenously with griseofulvin caused a fall in blood levels of the antibiotic. The effect of a single oral dose of phenobarbitone was significant after 12 hr and maximal between 12 and 48 hr, and it lasted for at least 96 hr; it was more pronounced when the barbiturate was administered repeatedly. Liver slices from animals dosed with phenobarbitone metabolized griseofulvin more rapidly than did those from undosed animals. The possible relevance of these findings to the clinical use of griseofulvin is discussed.

The pharmacological properties of conessine, 3-/3-dimethylamino-con-5-ene, a steroidal alkaloid obtained from the bark and seeds of Holarrhena antidysenterica have been described (Burn, 1914;Stephenson, 1948). Quaternary salts of the alkaloid have been prepared (Polstorff & Schirmer, 1886;Bertho, 1944) but do not seem to have been examined pharmacologically. We report here the results of an investigation of structureactivity relationships in a series of quaternary ammonium compounds derived from conessine or related steroids which possess neuromuscular blocking properties of the non-depolarizing type. The results for one compound, NN'-dimethylconessine, which is typical of this group and has been submitted for clinical trial, are recorded in detail. METHODS CatsAdult cats of either sex were anaesthetized by intraperitoneal injection of chloralose (80 mg/kg) with pentobarbitone sodium (10 mg/kg). The right hind limb was set up in the horizontal position on a Brown-Schuster myography stand. The sciatic nerve was ligated, cut centrally and stimulated peripherally using shielded silver electrodes. Twitches and tetani were elicited in the tibialis anterior and soleus muscles by square wave pulses of 0.2 msec duration and of twice the strength required to produce maximal twitches of the muscles. The muscles were attached to flat steel springs and the contractions recorded semi-isometrically on a smoked paper. The muscles were warmed with a lamp and kept moist with liquid paraffin saturated with physiological saline. In some experiments, stimuli of supramaximal strength and 0.5 msec duration were applied directly to the tibialis anterior muscle between the tendon and the drill in the femur, using shielded silver wire. Close-arterial injections were made to the tibialis anterior muscle as described by Brown (1938). Gross muscle action-potentials were recorded on a Tektronix 502 dual-beam oscilloscope from platinum electrodes inserted through the belly and tendon of the tibialis muscle, and the antidromic nerve action potentials were recorded from shielded platinum electrodes placed on the sciatic nerve. Drugs were injected into the right external jugular vein through a tap cannula, and the left carotid arterial pressure was recorded using a mercury manometer. Artificial respiration was applied through-a. tracheal cannula connected to a Palmer respiration pump.

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