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Cessation of daily caffeine consumption produced changes in cerebral blood flow velocity and quantitative EEG. These changes may be related to classic caffeine withdrawal symptoms of headache, drowsiness and decreased alertness.

1 SK&F 93944 (temelastine), a novel histamine HI-receptor antagonist, has been studied in a variety of in vitro and in vivo test systems. 2 SK&F 93944 was a competitive antagonist of histamine-induced contractions of guinea-pig ileum with a pA2 of 9.55 and a weak, non-competitive, inhibitor of the effects of histamine on guinea-pig atrium. 3 In anaesthetized guinea-pigs SK&F 93944 displaced histamine bronchoconstriction dose-response curves at doses which had negligible effects on histamine tachycardia. 4 In anaesthetized cats SK&F 93944 antagonized depressor responses to the histamine HI-receptor agonists, 2-(2-aminoethyl)pyridine and betahistine, at doses which had no effects on responses to the histamine H2-receptor agonist, dimaprit. described HI-receptor antagonists in that it lacks a tertiary amino group and is largely unprotonated at physiological pH. This paper describes the pharmacology of SK&F 93944 in a range of in vitro and in vivo models designed to evaluate both its potency and selectivity. In addition, studies are described which show that the compound has negligible ability to cross the bloodbrain barrier in rats, and is consequently highly unlikely to elicit CNS side-effects. A Animals were artificially ventilated through a tracheal cannula using the volume of air just required to fill the lungs at an airway pressure of 12 cmH2O. A pressure transducer was inserted into the outflow limb of the system to measure airway inflation pressure as an index of resistance. Blood pressure, heart rate and airway pressure were registered continuously on an electronic recorder (Lectromed, Ml 9). Dose-response curves for histamine-induced bronchoconstriction and tachycardia were constructed in each animal prior to and following intravenous injection of a histamine HI-receptor antagonist at a series of doses. In a further series ofexperiments with SK&F 93944, carbachol was used as the agonist to elicit bronchoconstriction.Studies in anaesthetized cats Studies were carried out in cats of either sex, body weight 1.65-3.15 kg. Following induction of anaesthesia the trachea was cannulated. Systemic blood pressure was measured from a catheter in one carotid or femoral artery and monitored on a Lectromed M19 recorder. Heart rate was measured with an instantaneous rate meter triggered by the blood pressure pulse. Injections of drugs and supplementary doses ofanaesthetic were made via cannulae inserted into the femoral and/or brachial veins.Studies with selective histamine receptor agonists Cats were anaesthetized with sodium pentobarbitone, 60 mg kg-' i.p. Responses to 2-(2-aminoethyl) pyridine (2-PEA), betahistine and dimaprit were obtained in separate groups of cats, using procedures described by Owen (1975 Vascular permeability changes were measured 15 min after injection of histamine since preliminary experiments indicated this time to be optimal in the rat. At this time the rats were again anaesthetized, the abdomen opened and a I ml sample of blood taken from the vena cava. The animals were then killed and th...

The systemic cardiovascular effects of a novel 5-hydroxtryptamine (5-HT)(1B/1D)-receptor agonist were investigated in the anaesthetised dog. SB 209509 (VML 251) was more potent than sumatriptan in producing increases in carotid vascular resistance after intravenous administration and was similar in potency to sumatriptan after sequential intraduodenal administration at 30-min intervals. In open-chest dogs, sequential intravenous administration of SB 209509 or sumatriptan produced marked increases in carotid vascular resistance without changing coronary vascular resistance. In contrast to sumatriptan, after administration of high doses of SB 209509 (>790 nmol/kg), a reduction in coronary vascular resistance was observed. After a single bolus intraduodenal dose of SB 209509 (260, 520, or 790 nmol/kg), increases in carotid vascular resistance could be detected over a 5-h period. Sumatriptan (i.d.), 2.4 micromol/kg but not 700 nmol/kg, produced a sustained effect similar to the effects of SB 209509 (790 nmol/kg). In all experiments, SB 209509 and sumatriptan had minimal effects on arterial blood pressure or heart rate but produced marked changes in carotid vascular resistance over the same concentration range. SB 209509 was rapidly absorbed after intraduodenal administration in conscious dogs and had good bioavailability. These data indicate that SB 209509 is a potent 5-HT(1B/1D)-receptor agonist that is rapidly absorbed from the duodenum. The effects of SB 209509 are long lasting and selective for the carotid vascular bed.