Protection against aspirin-induced human gastric mucosal injury by bosentan, a new endothelin-1 receptor antagonist.

BACKGROUND: Gastric ulceration induced by aspirin and by non-steroidal anti-inflammatory drugs (NSAIDs) is a major clinical problem. The mechanism of injury is unclear. There is evidence that NSAID-induced injury may cause endothelin activation. Endothelin-induced vasoconstriction has been shown to be capable of causing gastric ulceration. AIM: To investigate whether acute gastroduodenal injury induced in humans by aspirin can be prevented by the endothelin-1 antagonist, bosentan. METHODS: Eighteen healthy volunteers each received 5 x 900 mg aspirin every 12 h on three separate occasions (with either placebo, bosentan 700 mg or misoprostol 400 mg). Treatment order was randomized by Latin square design. Subjects were endoscoped and erosions counted before and 90 min after the first and last dose of aspirin. Plasma concentrations of bosentan were measured up to 5 h post-dose. RESULTS: There was a significant reduction in the mean number of erosions in the aspirin plus bosentan and aspirin plus misoprostol groups after the first dose of aspirin, compared with controls (aspirin plus placebo) (P<0.05). This was not sustained after the fifth dose of aspirin in the aspirin plus placebo and aspirin plus bosentan groups, but was still present in the aspirin plus misoprostol group. The mean plasma concentration of bosentan measured 3.5 h post-dose fell from 4510 (95% CI: 2791-6230) ng/mL after the 1st dose to 2508 (95% CI: 1733-3283) ng/mL after the 5th dose (P = 0.02). CONCLUSION: Endothelin receptor antagonism by bosentan can protect the gastric mucosa against aspirin damage. After five doses, bosentan levels fell, possibly because of enzyme induction, and protection was no longer evident. Further investigation is needed to assess whether higher doses would be effective.

Oxytocin-induced oestrus in the goat.

Subcutaneous administration of oxytocin between days 3-6, inclusive, significantly reduced the length of the oestrous cycle in goats. Concomitant oral administration of the prostaglandin synthetase inhibitor, meclofenamic acid, completely prevented this effect. Oxytocin treatment did not affect the duration of the posttreatment cycles.

Spontaneous and oxytocin induced uterine motility during the oestrous cycle in goats.

Spontaneous uterine motility and reactivity to intravenously administered oxytocin were recorded through the oestrous cycle in a group of goats. Contractions during oestrus were of significantly greater amplitude than in dioestrus and both the sensitivity and degree of response to oxytocin were greater in the oestrous phase. Evidence from a previous study suggests that the depressed spontaneous and oxytocin-induced motility in dioestrus is due to the predominating influence of progesterone during this stage of the cycle.

Effects of female sex hormones on uterine motility and reactivity to oxytocin in goats.

Uterine motility was recorded for several weeks in 10 ovariectomised goats, using small intra-uterine balloons, to study the effects of female sex hormones on uterine activity and reactivity to oxytocin. Oestradiol stimulated uterine contractions and increased both the sensitivity and intra-uterine pressure response to oxytocin. When progesterone was administered in addition to oestradiol, spontaneous uterine motility became irregular with low amplitude contrations; the sensitivity and reactivity to oxytocin was significantly depressed.

Removal of corpora lutea in pregnant goats: effect of intrauterine indomethacin.

Removal of corpora lutea from seven goats during late pregnancy (122 to 129 days) resulted in an abrupt decline in uterine venous plasma progesterone concentrations within 10 min and abortion after a mean interval of 29.88 +/- 1.64 (SD) h. Abortion was preceded by a significant increase in uterine venous plasma PGF concentration either before or coincident with palpable cervical softening. Intrauterine, extra-fetal administration of indomethacin, as a single dose, in a further five lutectomised goats significantly prolonged the interval to abortion and delayed both cervical ripening and the increase in plasma PGF.

Effect of oral meclofenamic acid on uterine motility and reactivity to oxytocin in goats.

Spontaneous uterine motility and reactivity to intravenous oxytocin were recorded in eight ovariectomised, oestrogen-primed goats before and after oral meclofenamic acid treatment. Spontaneous motility was completely abolished within 50 to 100 min of meclofenamate administration. However, although uterine reactivity to oxytocin was significantly reduced, the sensitivity was not altered. It is suggested that, in the goat, oxytocin has two effects on the uterus: it increases myometrial activity and also stimulates prostaglandin synthesis.

Forthcoming changes in the misuse of drugs legislation.

The effects of the new regulations on veterinary practice are minimal. Veterinarians are mainly concerned with drugs in schedules 2 and 3 to the regulations and the requirements relating to these drugs are virtually unchanged. Pentazocine (Fortral) has been added to schedule 3 and from April 1, 1986, veterinarians must comply with the following additional requirements with respect to this drug or any other in schedule 3: use of written requisition for purchase of supplies and the prescription requirements for controlled drugs. Further details of the legislation applying to the labelling and dispensing of medicinal products and the requirements relating to schedule 2 controlled drugs, can be found in 'Legislation Affecting The Veterinary Profession in the United Kingdom', 4th edn (1984) Royal College of Veterinary Surgeons. For details of the legislation relating to schedule 3 drugs, see VR, December 22/29, 1984, p649.

Veterinary surgeons and the medicines (Labelling) Amendment Regulations 1977.

Further changes to the medicine labelling regulations have important implications for practising veterinary surgeons. They amend the regulations made recently by specifying warning labels and other special labelling requirements for certain types of veterinary medical products.