The interaction of the prostaglandin E derivative rioprostil with oral anticoagulant agents.

The prostaglandin E1 analogue rioprostil was tested for potential interaction with oral anticoagulant therapy in healthy male volunteers. The effect of rioprostil (0.3 mg, twice a day) was investigated on acenocoumarol (10 mg per subject, n = 7) and phenoprocoumon (0.2 mg/kg, n = 6) single-dose pharmacokinetics and pharmacodynamics. Plasma levels of thrombotest, prothrombin (factor II), and factor VII activities were assayed. Rioprostil, 7 days pretreatment, did not affect control parameters of blood coagulation activity. During the rioprostil period the effect of phenprocoumon on thrombotest and factor VII activities was significantly weaker (p less than 0.02, ANOVA) compared with the control experiment. The effect of acenocoumarol on thrombotest activity was significantly weaker at 24 and 31 hours. None of the pharmacokinetic parameters tested were affected by rioprostil medication. The findings suggest that prostaglandins, at least those of the E series, attenuate the anticoagulant action of the oral anticoagulant agents by a mechanism not related to any pharmacokinetic interaction.

In vitro characterization of prostanoid EP-receptors in the non-pregnant human myometrium.

1. Prostaglandin receptors of the PGE type have been characterized in the non-pregnant human myometrium in vitro according to the scheme of Coleman et al. (1984) by use of the agonists PGE2, sulprostone, rioprostil, AY23626, butaprost, misoprostol, 16,16-dimethylprostaglandin E2, enprostil and iloprost, and, the antagonist AH6809. 2. All prostanoids tested were active in non-pregnant human myometrium either as stimulators and/or inhibitors of spontaneous activity or both. Biphasic responses to PGE2 indicate that at least two receptor types of the EP-receptor exist, one mediating relaxation and the other mediating contraction. 3. Further evidence for the EP-receptor mediating excitation and relaxation was provided by the action of the EP2-/EP3-receptor selective prostanoids rioprostil, AY23626 and misoprostol, and the EP1-/EP2-receptor selective agonist 16,16-dimethylprostaglandin E2. 4. Butaprost, an EP2-receptor selective agonist, produced potent inhibition of spontaneous activity in the tissue which was generally longer-lasting than that evoked by the natural prostanoid PGE2. 5. The EP1-/EP3-receptor selective agonist sulprostone and the EP3-receptor agonist enprostil produced potent contractile responses supporting the presence of contractile EP3-receptors in the non-pregnant human myometrium in vitro. 6. The EP1-/IP-receptor selective agonist, iloprost, produced mixed responses in non-pregnant human myometrium. The contractile response was inhibited by the EP1-receptor antagonist AH6809. However, responses to the EP1-/EP3-receptor selective agonist sulprostone were unaffected by AH6809 which may indicate that only a small population of EP1-receptors is present. 7. Therefore it would seem that a heterogeneous population of EP-receptors is present in the non-pregnant human myometrium.

Effect of rioprostil on aspirin-induced gastrointestinal mucosal changes in normal volunteers.

Rioprostil, a 15-deoxy-16-methyl prostaglandin E1, was evaluated for its effect on aspirin-induced gastrointestinal mucosal changes in normal volunteers. Fifty-six normal male volunteers were evaluated by endoscopy in a double-blind, placebo-controlled study. Aspirin was given at a dose of 975 mg four times per day. Rioprostil was given at doses of 60, 120, and 300 micrograms four times per day. Rioprostil, at both antisecretory and subantisecretory doses, prevented or reduced aspirin-induced injury. Increased stool frequency was the most common side effect and appeared to be a dose-related effect of rioprostil occurring at only antisecretory doses.

Gastric effects of a prostaglandin E1-derivate (rioprostil) on acid, alkaline, and mucus secretion.

In a double-blind crossover study, the gastric effects of a single oral dose of rioprostil (150 and 300 micrograms) or placebo were compared in basal conditions and during a 120-minute pentagastrin infusion. A slight decrease in basal acid output and a nonsignificant rise in basal bicarbonate secretion were observed with the 300-micrograms dose. Pentagastrin-stimulated acid secretion was reduced by the prostaglandin derivate, especially with the 300-micrograms dose. Compared with placebo, 300 micrograms of rioprostil significantly stimulated basal mucoprotein secretion and bicarbonate and mucus output during pentagastrin infusion. The results suggest that 300 micrograms of rioprostil exerts both a moderate antisecretory activity and a strengthening effect on the gastric mucus-bicarbonate barrier.

Prostaglandin E analogue inhibition of pancreatic enzyme secretion.

The effect of native prostaglandins and their methylated analogues on pancreatic enzyme secretion remains unclear, with previous studies reporting inconsistent results. To determine whether the E series prostaglandins directly influence pancreatic secretion, we studied the effect of rioprostil, a prostaglandin E1 analogue, and 16,16-dimethyl prostaglandin E2 (DMPGE2), a prostaglandin E2 analogue, on enzyme release from dispersed guinea pig pancreatic acini. Basal amylase release (4.3 +/- 0.6% of total acinar content) was not altered by either analogue (10(-10)-10(-5) M). A 50% inhibition of maximal cholecystokinin stimulation (10(-9) M; 28.8 +/- 1.2%) was seen with rioprostil (10(-7) M; 14.6 +/- 1.3%) and DMPGE2 (10(-6) M; 15.9 +/- 0.7%) (both p less than 0.005). Prostaglandin inhibition of carbachol-stimulated amylase was less pronounced. The most effective inhibitory dosage with maximal carbachol (10(-5) M; 30.2 +/- 1.9%) was 10(-6) M for both rioprostil (19.2 +/- 1.6%) and DMPGE2 (22.4 +/- 1.7%) (both p less than 0.005). Incubation of acini with A23187, phorbol ester, and 1-oleoyl-2-acetyl-glycerol resulted in a dose-dependent increase in amylase release that was not altered by maximal concentrations of either prostaglandin analogue. Our results indicate that rioprostil and DMPGE2 can directly inhibit pancreatic acinar secretion. This effect appears to occur before activation of the inositol phospholipid system.

BAY P 1455, a thiazolylaminobenzimidazole derivative with gastroprotective properties in the rat.

The antiulcer activity of BAY P 14551 a thiazolylaminobenzimidazole derivative, was evaluated in different experimental ulcer models and its antiulcer activity was compared to that of different reference drugs. The overall activity of the compound was equal to or more potent than that of reference antiulcer drugs, such as pirenzepine, cimetidine and carbenoxolone, but it was not as potent as rioprostil. The ED50 values (expressed as mumol/kg p.o.) were 68 (confidence limits: 51-91) for indomethacin-induced ulcers, 21 (confidence limits: 13-31) for stress-induced ulcers and 1260 mumol/kg p.o. (confidence limits: 412-3800) for ulcers induced by absolute ethanol. The compound had no activity against cysteamine-induced duodenal ulcers and lost its cytoprotective activity in adrenalectomised rats. Since inhibition of gastric acid secretion was seen, if at all, only with the higher doses, the gastro-protective action of BAY P 1455 seemed not to be due to an antisecretory effect, but more likely to a gastroprotective action as hypothesised for prostaglandins.

Antiulcer effect of rioprostil, a prostaglandin E1 analog, in combination with antacid.

Rioprostil, a primary alcohol prostaglandin E1 analog, is currently undergoing clinical evaluation for use in the treatment of peptic ulcer disease. Since antacids are often used in conjunction with other antiulcer agents, studies were conducted to determine if concomitantly administered antacid modifies the antiulcer activity of rioprostil. This investigation showed that concomitant administration of antacid (0.25-1.0 ml Maalox) does not inhibit the ability of rioprostil (0.125-4.0 micrograms/kg, p.o.) to prevent ethanol-induced gastric lesions in rats. The antiulcer effect of the drug combination was additive, suggesting that each compound acts independently to prevent gastric bleeding. These results in animals suggest that clinically the use of antacid will not compromise the efficacy of rioprostil and that the combination may be a useful mode of therapy for the treatment of peptic ulcer disease.

Antigastrolesive, gastric antisecretory, diarrheagenic and mucus-stimulating effects in rats following topically applied rioprostil, a synthetic prostaglandin E1 analog.

Prostaglandins may have many biological actions including hypotensive and antipeptic ulcer activity. The purpose of this investigation was to determine if the primary alcohol prostaglandin E1 analog rioprostil1 prevents ethanol-induced gastric lesions (antigastrolesive activity), inhibits gastric acid secretion (antisecretory activity), or causes diarrhea in rats when administered topically, and to compare these responses to the effect of rioprostil following enteral (oral or intraduodenal) administration. Rioprostil exhibited antigastrolesive activity in rats when administered either orally or when applied topically. The topical antigastrolesive potency of rioprostil against ethanol-induced lesions [ED50 = 3.7 (0.5-12) micrograms/kg] was similar to its oral potency [ED50 = 1.9 (1.7-2.2) micrograms/kg]. In 4 hr pylorus-ligated rats, topically administered rioprostil inhibited total gastric acid output with a potency [ED50 = 5.1 (2.6-24) mg/kg] similar to intraduodenal administration [ED50 = 3.7 (2.8-5.3) mg/kg]. In addition, in these rats rioprostil increased mucin levels and did not cause dermal irritation. Finally, the incidence of diarrhea was lower when rioprostil was applied topically than when given orally with a 16-fold difference in potency between these two routes of administration. These data show that when rioprostil is applied via the skin it has antigastrolesive, gastric antisecretory and mucus stimulatory effects in rats equal to enteral administration, and a diarrheagenic potency lower than following oral administration. This profile suggests that topical administration of rioprostil may be a useful means of delivery for clinical treatment of peptic ulcer disease.

The synthetic prostaglandin E1 analogue rioprostil reduces the nephrotoxic potential of cyclosporine A.

Acute CyA nephrotoxicity involves alteration in the proximal tubule and leads to glomerular lesions. Administration of a vasodilatator agent such as the prostaglandin E1 analogue Rioprostil (Bayer AG, BAY 06893) might prevent preglomerular vasoconstriction and hence reduce cyclosporin nephrotoxicity. As an increased excretion of urinary enzymes as a consequence of CyA-nephrotoxicity is well known we investigated in 40 male Wistar rats the excretion of three urinary enzymes: the brush border enzyme gamma-glutamyltransferase (GGT), the leucine aminopeptidase (LAP), and the lysosomal enzyme N-acetyl-beta-glucosaminidase (NAG). Additionally we determined s-creatinine and CyA plasma level. The kidneys were studied histologically at the end of the study. Wistar rats receiving 20 or 50 mg CyA/kg/d showed a marked deterioration in renal function and an increase of all urinary enzymes determined. In the rats receiving 20 mg CyA/kg/d and Rioprostil (150 micrograms/d) renal function and the enzymes determined remained in the normal range. There was no change in the enzyme excretion and only a minor improvement of renal function in rats receiving 50 mg CyA/kg/d and Rioprostil. Histological findings showed prevention of CyA nephrotoxicity in the 20 mg/kg/d group and diminished renal damage in the 50 mg/kg/d group.

The effects of rioprostil on gastric emptying and intragastric acidity.

Rioprostil is a 16-methyl-16-hydroxy alcohol analogue of prostaglandin E1 with anti-secretory activity. We have compared the effects of the orally administered drug with those of placebo and of intravenous ranitidine on the rate of gastric emptying of liquids and on the disposal of acid in the stomach, by measuring the response to an intragastrically instilled acid load in 10 healthy male volunteers. The results show that rioprostil significantly increases the rate of gastric emptying compared with placebo and also significantly reduces the recovery of acid from the stomach. Reduction in the amount of intragastric acid was also observed after intravenous administration of ranitidine but the latter drug did not influence the rate of gastric emptying. We conclude that rioprostil, like ranitidine, reduces the amount of acid in the gastric lumen mainly by inhibiting the gastric secretory response to the instilled acid load, while the action of rioprostil on gastric emptying is independent of its gastric antisecretory properties. The combination of pharmacological actions--increasing the rate of gastric emptying of liquids and inhibiting gastric secretion of acid--indicates that rioprostil may be of value in the management of gastro-oesophageal reflux.

Rioprostil: a clinical experience in gastric ulcer treatment.

The efficacy and tolerability of the prostaglandin E1 derivative rioprostil (Bay o 6893) was studied in a randomized, double-blind, placebo-controlled trial in 40 patients affected by acute gastric ulcer. At the end of the eight weeks period ulcer healing was achieved in 85% of the rioprostil-treated patients and in 60% of the placebo-treated ones (p less than 0.05). Rioprostil produced a significant reduction of pain and also improved the clinical status. This positive outcome was noted both in smokers and in non-smoking patients, while only this last group improved during the placebo treatment.

Discovery and synthesis of rioprostil.

Between 1972 and 1979 a research team at Miles Laboratories produced 1200 prostaglandin analogues as potential pharmaceuticals. Most of these analogues were produced using the Sih synthesis. They were screened in several animal models and a few were found to inhibit gastric acid secretion in the rat. The best compound (TR-4698, rioprostil) is being pursued as an anti-ulcer and cytoprotective agent. An improved synthesis of this compound involves the use of n-butyllithium and copper (I) cyanide in a one-pot conjugate addition of a vinyl tin intermediate with a chiral alkylated cyclopentenone. Multihundred gram lots of rioprostil are produced with only one chromatography, that of the final substance, needed.

Treatment of duodenal ulcer with rioprostil: a randomized multicentre double-blind study.

The effectiveness of rioprostil, 300 micrograms b.d. is evaluated in evolutive duodenal ulcer in a double-blind study in five French and North African centres. A total of 115 patients are included in the study (57 in the rioprostil group and 58 in the placebo group). After a 4-week treatment period, a significantly higher endoscopic healing rate is observed in the rioprostil group (57%) compared with the placebo group (33%) (p less than 0.01). The mean time with abdominal pain is significantly lower in the rioprostil group (5.6 +/- 4.4 days) compared to the placebo group (12.7 +/- 5 days) (p less than 0.001). Clinical and biological tolerance is excellent. The only side effect is diarrhoea (3.5% in the rioprostil group). In only one case does diarrhoea necessitate cessation of treatment. Rioprostil, 300 micrograms b.d., is thus effective in the treatment of developing duodenal ulcer.

Rioprostil in the acute and long-term treatment of peptic ulcers: a review.

The new prostaglandin E1 analogue, rioprostil, significantly accelerates healing and the elimination of pain in cases of peptic ulcer. The anti-ulcerous potency of this prostaglandin is equivalent to that of cimetidine. In comparison with ranitidine, there is a positive trend in favour of the H2-receptor antagonist, ranitidine, which has a more pronounced antisecretory effect than rioprostil. The differences in the healing rates during treatment with rioprostil and ranitidine are statistically significant in some cases, whereas those relating to pain alleviation are not. In contrast, the therapeutic efficacy of the two substances is almost identical in cases of Ulcus ventriculi. Rioprostil can be used with much the same success as ranitidine for preventing the recurrence of duodenal ulcers. The frequency of diarrhoea during rioprostil treatment, 300 micrograms b.d. and 600 micrograms nocte, is approximately 10%. In only about 1% of the patients does the rioprostil treatment have to be discontinued because of this adverse reaction.

Rioprostil in the healing of duodenal ulceration: a short report.

A preliminary analysis on a group of 182 patients participating in a large, multicentre trial comparing nocturnal rioprostil, 600 micrograms and ranitidine, 300 mg, is presented. The results are confined to the ulcer healing properties. Healing rates are 61% and 77%, respectively, at 4 weeks, and 86% and 96% at 8 weeks. The advantage of ranitidine reaches statistical significance at 8 weeks (p less than 0.05). About 20% of patients taking rioprostil report loose bowels or diarrhoea, but only two patients withdraw for this problem.

Pharmacokinetics of rioprostil in rats.

The pharmacokinetics of rioprostil in rats has been investigated following a single intravenous or oral dose of rioprostil between 0.004 and 10 mg/kg. Rioprostil is eliminated from plasma following an intravenous dose rapidly (t1/2 = 0.22 h) and nearly exclusively by biotransformation. The high total clearance (CL = 5.4 l.h-1.kg-1) indicates an additional extrahepatic metabolism. A systemic bioavailability of 2%, in spite of a rapid and nearly complete absorption (fa = 90%), indicates an extended first-pass effect. Twenty-four hours after the administration of [3H]rioprostil the residual radioactivity in the animal amounted to less than 1% of the dose administered.

Gastric antisecretory and antigastrolesive pharmacology of rioprostil.

Rioprostil, a primary alcohol prostaglandin E1 analogue, inhibits gastric acid secretion, both in vivo and in vitro, and prevents the formation of experimentally-induced gastric lesions in rats and dogs. In vitro experimental evidence suggests that the mechanism of the gastric antisecretory activity of rioprostil involves inhibition of the membrane bound histamine-stimulated adenylate cyclase. In vivo, rioprostil inhibits gastric acid secretion in 4-h pylorus-ligated rats, in gastric fistula dogs stimulated by betazole, tetragastrin, bethanechol, or 2-deoxy-D-glucose, and in Heidenhain pouch dogs stimulated by food. Rioprostil can completely prevent macroscopically visible gastric lesions induced by a variety of noxious agents in rats, including 50% ethanol, aspirin, indomethacin, strong acid, strong base and hypertonic saline. In dogs, rioprostil, but not the H2-blockers cimetidine or ranitidine, totally prevents endoscopically visible gastric lesions induced by aspirin tablets or 60% ethanol, and accelerates the healing of established aspirin-induced gastric lesions from 20 days (vehicle control) to 6 days (33 micrograms/kg p.o., t.i.d.) or 11 days (3 micrograms/kg p.o., t.i.d.). The precise mechanism for the antigastrolesive activity of rioprostil is not known, but may involve increased mucus and bicarbonate secretion, maintaining or increasing gastric mucosal blood flow, increasing the rate of cellular restitution, or possibly antigastrin activity that has been demonstrated in dogs. In rats, rioprostil also prevents duodenal lesions induced by cysteamine, small intestinal lesions induced by indomethacin, and colonic lesions induced by ethanol. The antisecretory and antigastrolesive potency of rioprostil given transdermally to rats is similar to its potency when given systemically, although its diarrhoeagenic potential is lower when given topically compared to oral administration. When used in combination with several non-steroidal anti-inflammatory drugs (NSAIDs) in a model of arthritis in rats, rioprostil inhibits gastric lesion formation without interfering with the anti-inflammatory or analgesic potency of the NSAIDs. In addition, concomitant use of either antacid or cimetidine with rioprostil does not inhibit either the antisecretory or antigastrolesive potency of rioprostil, with the effect of the combination being additive. The doses required to inhibit formation of experimentally-induced gastric lesions in both rat and dog are lower than those required to inhibit gastric acid secretion. This separation of antigastrolesive from antisecretory activity distinguishes rioprostil from other non-prostanoid antisecretory agents, such as histamine H2- receptor antagonists, and establishes rioprostil as a 'selective antigastrolesive agent' (SAGA).(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of rioprostil on the postprandial glucose, GIP, insulin and gastrin levels in volunteers.

The study is of double-blind crossover design. In the first part of the study, rioprostil (300 micrograms and 600 micrograms) is given orally with a solid breakfast to 9 healthy male volunteers. Both doses of rioprostil delay and reduce the 3-h postprandial GIP release. They also reduce the maximal postprandial insulin concentration, but only rioprostil (600 micrograms) reduces the 3-h integrated release of insulin significantly (by approximately 20%). Neither dose modifies the postprandial glucose gastrin levels significantly. In another study two groups of 6 volunteers are studied in parallel; they are given either rioprostil (600 micrograms) or a placebo each evening for 14 days. On the mornings before and on days 13 and 14 of the study the volunteers take a solid breakfast and blood glucose is measured 1 h and 2 h postprandially. The results show that no differences in the basal and postprandial glucose levels are observed. In conclusion, rioprostil given with a meal can reduce the insulin release but it does not change the postprandial blood glucose levels when given as a single dose or repeatedly in an evening dose. This study shows that rioprostil can be given to patients with diabetes.

Effect of rioprostil, an oral prostaglandin E1 analogue, on lower oesophageal sphincter pressure and on the motility of the distal oesophagus in healthy volunteers.

The influence of rioprostil on the resting pressure of the lower oesophageal sphincter (LESP) and on the bolus-stimulated contraction wave amplitude of primary peristalsis is investigated in 9 healthy male volunteers receiving placebo or 300 micrograms and 600 micrograms of rioprostil orally in a randomized, double-blind, threefold crossover study. Manometry is performed using the low-compliance pneumohydraulic infusion system. The results show that: rioprostil, 600 micrograms, slightly increases LESP (ns) and contraction wave amplitudes, measured 10 cm above the lower oesophageal sphincter (LES) (p = 0.0039); rioprostil in both doses does not change the contraction wave amplitudes of the distal oesophagus, 5 cm above the LES; the duration of the peristaltic contractions is not altered. We conclude that rioprostil, in doses which effectively inhibit gastric acid and pepsin secretion and heal peptic ulcers, has no inhibitory effects on oesophageal motility. Studies are warranted, therefore, to establish the efficacy of rioprostil in the treatment of reflux oesophagitis.

The effects of prostaglandins on gastric emptying.

This review summarizes the effects of prostaglandins on gastric emptying in animals and man. It appears that prostaglandin E2 (PGE2) and prostaglandin F2 alpha increase the rate of gastric emptying in animals. PGE2 increases the emptying of liquids from the human stomach; more recently developed prostaglandin analogues, however, such as misoprostil and trimoprostil, have no effect on the rate of emptying of the human stomach. The PGE1 analogue, rioprostil, increases the rate of emptying of an acid load from the stomach; it does not, however, affect gastric emptying of a meal consisting of meat broth and glucose. It is concluded that prostaglandins do not affect the rate of gastric emptying of solids, but that some of these compounds do increase gastric emptying of liquids in both animals and man.