Protective effects of arbaprostil against indomethacin-induced gastric lesions in rats: significance of maintained gastric blood flow. (1/6)

The purpose of the present study was to investigate the relationship between the effects of 15(R)-15-methylprostaglandin E2 (arbaprostil) on gastric blood flow (GBF) and its protective effects on gastric lesions in rats. The GBF of anesthetized rats was measured by two different methods: Total blood flow into the stomach (total GBF) was determined by means of an ultrasonic pulsed Doppler flow meter; and gastric mucosal blood flow (mucosal GBF) was measured by nonradioactive microspheres. Systemic blood pressure (SBP), heart rate (HR) and gastric vascular resistance (GVR) were recorded simultaneously. Arbaprostil (10-100 micrograms/kg) given i.v. did not affect resting total or mucosal GBF even though it decreased SBP and GVR. Significant improvement of the total and mucosal GBF decreased by indomethacin pretreatment (10 mg/kg, i.v.) was observed by administration of arbaprostil (10-100 micrograms/kg, i.v.) in a dose-dependent manner. Furthermore, i.v.-administration of this agent, in the same dose-range, prevented the formation of gastric lesions induced by indomethacin. The present result suggests that mitigation for the ischemic state of the gastric mucosa may be one of the important mechanisms for the prophylactic and curative effect of arbaprostil on gastric lesions induced by indomethacin.  (+info)

Acid-promoted epimerization of arbaprostil, 15(R)-15-methylprostaglandin E2, elicits gastric antisecretory activities in rats. (2/6)

Gastric acid antisecretory activities of 15(R)-15-methylprostaglandin E2 (arbaprostil) preincubated or not preincubated with 0.9% physiological saline, the pH of which was precisely adjusted to less than 4.30, were examined in pylorus-ligated rats, and compared with those of 15(S)-15-methylprostaglandin E2 (15(S), epimer of arbaprostil). 15(S), unlike arbaprostil without preincubation, when s.c.-administered to rats significantly inhibited gastric acid secretion in a dose-dependent manner (30-300 micrograms/kg). However, arbaprostil preincubated at 37 degrees C for 30 min with 0.9% saline, at pHs of 4.30, 2.75 and 1.20, respectively, showed the following order of pH-dependent antisecretory activities: 1.20 greater than 2.75 greater than 4.30. An increase in 15(S) formation from arbaprostil in a pH-dependent manner was also observed by radioisotopic experiments under the same incubation conditions using [3H]-labeled arbaprostil. The present result suggests that the gastric antisecretory effect of arbaprostil can be mainly explained in terms of the formation of 15(S) after oral administration.  (+info)

Gastric antisecretory activity of 15(R)-15-methylprostaglandin E2, arbaprostil, in dogs. (3/6)

The gastric antisecretory activity of 15(R)-15-methylprostaglandin E2 (arbaprostil) was compared with that of natural prostaglandin (PG) E2 in Pavlov pouch dogs. Arbaprostil significantly inhibited pentagastrin- and food-stimulated gastric secretion when it was administered directly into the pouch at a dose of 10-30 micrograms/pouch and 30-300 micrograms/pouch, respectively. Natural PGE2, however, was inactive up to 1000 micrograms/pouch. The data indicate that arbaprostil is a potent, long-acting orally active antisecretory drug that may be useful for the treatment of peptic ulcer disease.  (+info)

Effects of 15(R)-15-methyl prostaglandin E2 (arbaprostil) on gastric secretion and various gastric lesions induced in rats. (4/6)

We studied the effects of 15(R)-15-methyl prostaglandin E2 (arbaprostil) on gastric secretion and various acute and chronic gastric lesions produced in rats. Arbaprostil significantly inhibited gastric secretion in 4 hr-pylorus-ligated preparations when given intraduodenally in a dose of 30 or 100 micrograms/kg. The agent, however, significantly stimulated gastric secretion of rats with either a ligated or intact pylorus when given orally in doses of 3-100 micrograms/kg. Orally administered arbaprostil dose-dependently prevented the development of HCI-ethanol-, histamine-, water-immersion stress-, or indomethacin-induced gastric erosions. Intraduodenally administered arbaprostil also dose-dependently prevented the development of aspirin-induced gastric erosions in pylorus-ligated rats. Arbaprostil, given orally in doses of 1-100 micrograms/kg twice daily for 2 weeks, had little or no effect on the healing of acetic acid-induced gastric ulcers. However, oral administration of the agent in a dose of 3 or 10 micrograms/kg twice daily for 4 weeks significantly accelerated the healing of acetic acid-induced gastric ulcers. The increase in doses up to 100 micrograms/kg twice daily for 4 weeks had no effect on ulcer healing. These results indicate that arbaprostil, at either antisecretory or even acid stimulating doses, is effective in preventing the development of acute gastric erosions and in accelerating the healing of chronic gastric ulcers.  (+info)

Femtomole analysis of prostaglandin pharmaceuticals. (5/6)

An analytical method is described whereby the major classes of prostaglandins are fully resolved by microcolumn liquid chromatography and detected at the subfemtomole level by laser-induced fluorescence. The prostaglandins are labeled with the fluorescent reagent 4-bromo-methyl-7-methoxycoumarin and are subsequently separated on a high-efficiency fused-silica microcolumn (0.2 mm i.d., 1.06 m length, 150,000 theoretical plates). The optimal chromatographic conditions consist of a 3-micron octadecylsilica packing material and an isocratic mobile phase of 47.6% methanol, 23.8% acetonitrile, and 28.6% water. The prostaglandin derivatives are detected directly on the microcolumn by laser fluorimetry, using a helium/cadmium laser (325 nm, 15 mW) as the excitation source together with a simple filter/photo-multiplier optical detection system. In real sample matrices, the prostaglandin PGF2 alpha is readily quantifiable from the detection limit (0.3 fmol) to the formulation strength of the therapeutic agent Lutalyse (Upjohn), spanning more than six orders of magnitude in concentration. The simplicity and general applicability of the present analytical methodology and instrumentation suggest that this technique can be used to attack a wide variety of biomedically important problems with exceptional sensitivity and selectivity.  (+info)

Dose response inhibition in man of meal-stimulated gastric acid secretion by 15(R)-15-methyl prostaglandin E2, given orally. (6/6)

15(R)-15-methyl prostaglandin E2 was given orally to healthy male volunteers. Thirty minutes later a 10% peptone meal was introduced into the stomach, and the acid response was measured by continuous intragastric titration with 0.5 N NaOH for the next two hours. The prostaglandin inhibited acid output in a dose dependent manner; the ED50 (dose inhibiting acid output by 50%) was as little as 10 micrograms per subject (or approximately 140 ng/kg). This compound is the most potent orally active inhibitor of gastric acid secretion in man that is known. It is likely that the antisecretory and cytoprotective properties shared by 15(R)-15-methyl prostaglandin E2 would be beneficial in the treatment of peptic ulcer and in preventing recurrences.  (+info)