SUMMARY Cyclotropium bromide, a new antimuscarinic agent, inhibits gastrointestinal motility in animals at lower doses than those required to inhibit gastric acid secretion and salivation. In man, cyclotropium bromide suppresses fasting and meal stimulated colonic motility. This study investigated the effects of single oral doses of 60 mg cyclotropium bromide, 60 mg hyoscine N-butylbromide and placebo on gastric emptying and on antral motor activity. Twenty four healthy men (mean age 25 years) participated in three experiments one week apart. The drugs were administered, in random double blind fashion, 30 minutes before the ingestion of a semisolid test meal labelled with 74 MBq (2 mCi) 99mTc sulphur colloid. A gamma camera coupled to a computer monitored gastric emptying together with amplitude, frequency, and propagation velocity of antral contractions. Cyclotropium bromide and, to a lesser degree, hyoscine N-butylbromide delayed gastric emptying and reduced contraction amplitude, but did not affect frequency and propagation velocity of antral contractions. Cyclotropium bromide was significantly more active than hyoscine N-butylbromide; the effects of hyoscine N-butylbromide differed significantly from placebo. Antral contractile activity was present all the time. After cyclotropium bromide, there was a significant correlation between antral contraction amplitude and gastric emptying. No adverse side effects occurred with any one treatment. In conclusion, cyclotropium bromide markedly inhibits gastric emptying and reduces antral contraction amplitude.Cyclotropium bromide (CTB; Helopharm, Berlin) is a quarternary ammonium compound exhibiting differential activities at muscarinic receptor sites. In that rat, cyclotropium bromide administered subcutaneously or intraduodenally is 10 times less active in reducing gastric acid secretion than atropine, whereas its antagonistic effect on acetylcholine induced spasms of the guinea pig rectum is 7.3 times and the effect against pilocarpine induced spasms 2-8 times stronger than that of atropine.Tachycardia, mydriasis, and inhibition of salivary secretion occur only at high dosages (Helopharm, Berlin, unpublished data). In man it has been shown that a single oral dose of 60 mg cyclotropium bromide inhibits fasting and meal stimulated colonic

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The effect of an orally administered combination of naproxen sodium 550 mg and codeine phosphate 60 mg on threshold and tolerance to electrically induced pain, and on the threshold to thermally induced pain, was compared with the effects of naproxen sodium 550 mg alone, codeine phosphate 60 mg alone, and placebo. 16 female and 16 male, healthy young subjects, took part in four experiments on consecutive days of one week. On each day one treatment was administered, in random order, under double blind conditions. The combination increased threshold and tolerance to electrically induced pain and the threshold thermally induced pain markedly more than did naproxen sodium alone. Naproxen sodium plus codeine was also more effective in increasing threshold and tolerance to electrically induced pain than was codeine alone; the latter increased the threshold and tolerance to electrically induced pain and the threshold to thermally induced pain markedly more than placebo. Naproxen sodium alone had a relatively weak effect on the three pain measures. Reaction time to acoustic stimuli and the side effect profile were not significantly influenced by any of the treatments, and no severe adverse effects occurred. It is concluded that the combination of naproxen sodium 550 mg and codeine phosphate 60 mg, as indicated by its effects on experimentally induced pain, can produce more intense analgesia than the same doses of naproxen sodium and codeine administered alone, and that naproxen sodium and codeine phosphate given in combination enhanced each other's effect in an additive manner.

Natural enkephalins exert weak and transitory analgesic effects. The synthetic enkephalin, FK 33-824 (FK), is less susceptible to metabolic breakdown and produces long-lasting analgesia in animals. The present studies examined the effects of FK on threshold and tolerance of electrically evoked pain in man under double blind conditions. 1.0 mg FK given intramuscularly (saline control) increased tolerance significantly without affecting the pain threshold, but also produced vasodilatation and feelings of oppression and heaviness (study I). In study II, where 50 mg betazole was employed as "placebo" because of its vasodilatatory effects, 1.0 mg FK increased pain tolerance significantly more than 0.25 mg FK while the threshold remained unchanged. Self-ratings of activation and well-being decreased; those of oppression increased, as did reaction time, equally after 0.25 and 1.0 mg FK but were not altered by betazole. In conclusion, 1.0 mg FK i.m. increases tolerance but not perception of pain, thus mimicking the analgesic effects of morphine.

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Ceruletide (INN proposed by the WHO) or, as it was named formerly, caerulein is a decapeptide of the amino acid sequence Pyr-Gln-Asp-Tyr(SO3H)-Thr-Gly-Trp-Met-Asp-Phe-NH2 and is structurally related to the cholecystokinin (CCK) -gastrin family. It was isolated from the skin of the Australian hylid frog Hyla caerulea by the group of Erspamer' and synthesised subsequently.2 The peptide has been reported to stimulate myoelectrical spiking as well as the contractile activity of the distal duodenum and the jejunum in man3 4 and, in the rat,5 to increase the tone of all segments of the small intestine except of the duodenum, and to reduce the transit time strikingly not only in healthy subjects but also in patients suffering from postoperative intestinal paralysis.6'l These actions of ceruletide parallel those of its mammalian counterpart cholecystokinin which has been shown to increase dose relatedly the motor activity of the jejunum 11-13 and to increase jejunal but not duodenal and ileal spike activity. 14 It has been discovered recently that these peptides not only have potent effects on the gastrointestinal tract but also are endowed with analgesic properties: in mice ceruletide and cholecystokinin 5, 10, and 20 utg intramuscularly would exert both stimulating effects on the motor activity of the upper jejunum and analgesic effects on experimentally induced pain in healthy human subjects. Methods SUBJECTSSixteen healthy men ranging in age from 20 to 32 years (mean 25-4 years) were studied. Only subjects not taking drugs at the time of the experiment, having regular bowel movements, and without any history of gastrointestinal disease or previous abdominal surgery were included. They were given a short explanation of the purpose of the research and a description of the procedures to be followed. They were further given a description of any reasonably foreseeable risks or discomforts. Written