Comparative studies with 15(R)-15-methylprostaglandin E2 (arbaprostil) in rat femoral arterial preparations in vivo and in vitro.

1. The vasodilator responses to 15(R)-15-methylprostaglandin E2 (arbaprostil), prostaglandin (PG) E2 and acetylcholine (ACh) administered into the femoral artery intra-arterial (i.a.) of anesthetized rats were attenuated by i.a. infusion of methylene blue, while that to nicardipine remained unaffected in the same dose-range of methylene blue. 2. The vasocontractor responses to arbaprostil and PGE2 in isolated femoral arterial strips were significantly potentiated by removal of the endothelium and the presence of NG-monomethyl L-arginine, while that to U-46619 remained unaffected under the same condition. 3. The present result indicates that the endothelium-dependent mechanism may play an important role in the vascular response to arbaprostil, like PGE2 and ACh.

Protective effects of arbaprostil against indomethacin-induced gastric lesions in rats: significance of maintained gastric blood flow.

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.

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

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.

A report of three multiclinic trials evaluating arbaprostil in arthritic patients with ASA/NSAID gastric mucosal damage. The Upjohn Company Arbaprostil ASA/NSAID Gastric Mucosal Damage Treatment Study Groups.

Three randomized, placebo-controlled multiclinic trials involving arbaprostil dosages of (a) 10 micrograms; (b) 25 micrograms; and (c) 10, 25, or 50 micrograms orally for 4 wk in patients older than 18 yr with rheumatoid arthritis or osteoarthritis who had endoscopically documented nonsteroidal antiinflammatory drug-associated gastric mucosal damage were conducted in the United States. All patients continued taking the nonsteroidal antiinflammatory drugs and were reendoscoped after 4 wk of therapy. Success at that time was defined as complete resolution of all gastric mucosal damage. Six hundred fifty-eight patients were enrolled in the three trials. Significantly more patients experienced healing in the arbaprostil treatment groups in all trials compared with those who received placebo. The healing rates in the various trials were 68% and 32% (10 micrograms vs. placebo; p = 0.007); 77% and 23% (25 micrograms vs. placebo; p less than 0.001); and 52%, 46%, 35%, and 16% (50, 25, and 10 micrograms vs. placebo; p less than 0.001, less than 0.001, and 0.002, respectively). Diarrhea, mostly of a mild nature, was the only arbaprostil-associated side effect and was found with the 25- and 50-microgram dosages (33% and 59%, respectively). No exacerbation of arthritis signs or symptoms was found. Arbaprostil at doses with varying effects on gastric acid secretion (25 and 50 micrograms) was documented in these trials to be an effective and safe agent for healing gastric mucosal damage associated with aspirin or other nonsteroidal antiinflammatory drugs in patients with either rheumatoid arthritis or osteoarthritis without adversely affecting joint symptomatology.

An evaluation of arbaprostil at multiple doses for the treatment of acute duodenal ulcer: a randomized double-blind placebo-controlled international trial.

Six hundred and thirty patients were enrolled in a randomized double-blind placebo-controlled trial evaluating two arbaprostil dosages (25 micrograms and 50 micrograms) qid for 4 wk for the treatment of acute duodenal ulcers. The healing rates in the placebo, 25-micrograms, and 50-micrograms treatment groups were 39%, 51%, and 60%, respectively. Smoking was found to adversely affect the healing rates in all the treatment groups. Pain severity was less with either arbaprostil treatment. The only side effect found was diarrhea: 10%, 14%, and 32% in the placebo, 25-micrograms, and 50-micrograms treatment groups, respectively. Severe diarrhea occurred in 1% of those patients who received the 50-micrograms dosage regimen, but in none of the other two groups. Arbaprostil at these two dosage levels, when given for 4 wk, appears to be a safe and efficacious agent for the treatment of acute duodenal ulcers.

Arbaprostil's [15(R)-15-methyl PGE2] effects on intrauterine pressure in the nonpregnant and pregnant human female--a report of four clinical trials.

Four clinical trials evaluating arbaprostil's effects on the human uterus are reported. The initial two trials measured intrauterine pressures in nonpregnant and pregnant human females following arbaprostil doses of 10, 25, and/or 50 mcg. No statistical differences were found at any dosage level in either study for average uterine resting pressures, average peak pressures, the number of contractions or Montevideo units. Subsequently, two trials determined the abortifacient potential of arbaprostil in pregnant women during the first trimester. The first utilized total daily doses of 400 and 800 mcgs. while the second used total daily doses of 1200 and 1600 mcgs. Vaginal spotting was noted in one woman receiving 400 mcgs, three receiving 1200 mcgs. and in two receiving 1600 mcgs. One episode of moderate bleeding was seen in the latter study. Based on these studies, arbaprostil exhibits little potential for inducing abortifacient activity at these dosages in these patient populations.

Arbaprostil [15(R)-15-methyl prostaglandin E2] in a single nighttime dose of either 50 or 100 micrograms in acute duodenal ulcer.

To determine the efficacy of single nighttime doses of arbaprostil [15(R)-15-methyl prostaglandin E2], 50 or 100 micrograms for 4 wk, a double-blind randomized placebo-controlled multiclinic trial was undertaken. Success was defined as complete healing of the ulcer documented by endoscopy. Fifty-one of 64 patients enrolled were considered evaluable. Ulcer healing was documented in 64.3%, 85.7%, and 31.2% of the 100-micrograms arbaprostil, 50-micrograms arbaprostil, and placebo treatment groups (p value vs. placebo = 0.003 and 0.002, respectively). No difference in side effects or changes in laboratory parameters were found between the treatment groups except that diarrhea, usually mild, was found more often in the 100-micrograms arbaprostil group (60.0%) than in the 50-micrograms arbaprostil (31.8%) or placebo groups (23.5%) (p value 100 micrograms arbaprostil vs. placebo = 0.02). A single nighttime administration of arbaprostil seems to be a safe and efficacious agent for the treatment of acute duodenal ulcer.

Failure of a cytoprotective dose of Arbacet to heal acute gastric ulcers.

Twenty outpatients with an endoscopic diagnosis of gastric ulcer were evaluated for 6 wk in a randomized, double-blind trial comparing 15(R)-15-methyl prostaglandin E2 (Arbacet) (10 micrograms, 0.5 h before each meal and at bedtime) with placebo. Endoscopy was performed at 3 wk and 6 wk during the study period. Five of nine patients (56%) taking Arbacet and seven of 11 patients (64%) in the placebo group had complete healing of their gastric ulcer. Healing occurred in four patients from the Arbacet group and three patients in the placebo group at 3 wk. A cytoprotective dose of Arbacet (40 micrograms daily) is not significantly better than placebo in healing gastric ulcers.

Isolation and characterization of the urinary metabolites of arbaprostil in the male dog after intravenous administration.

The profile of urinary metabolites of 3H-arbaprostil was characterized in the male dog after intravenous administration. The major metabolites were purified and their structures deduced by gas chromatography/mass spectrometry (GC/MS) studies after conversion to the methyl ester-methoxime-trimethylsilyl ether derivatives, aided by GC with simultaneous radioactivity monitoring. The identified metabolites accounted for 96% of the urinary excretion products. beta-Oxidation of the carboxy side-chain of arbaprostil to 15-methyl-2,3,4,5-tetranor PGE1, via the 15-methyl-2,3-dinor PGE2 intermediate, appeared to be the most significant metabolic pathway. In contrast to the rat, the following were observed in the dog: glucuronic acid conjugation of the 15-methyl-2,3,4,5-tetranor PGE, and PGA metabolites; detection of the 15-methyl-2,3-dinor PGE2 intermediate; absence of 19-hydroxyl-15-methyl-2,3,4,5-tetranor PGA, and PGB metabolites; oxidation at C-20; and excretion of some parent drug.

Cytoprotective doses of arbacet with minimal antisecretory properties are not effective in duodenal ulcer healing.

The efficacy of arbacet (a synthetic analog of prostaglandin E2) in definite cytoprotective but minimal antisecretory dose was evaluated in the treatment of duodenal ulcer. One hundred five patients with endoscopically proven duodenal ulcer were randomized in a double-blind manner to receive four times daily either arbacet 25 micrograms or placebo. Ulcer healing was assessed endoscopically after two and four weeks of treatment. The mean age, sex distribution, and tobacco and alcohol consumption were similar in the two treatment groups. The ulcers of 16 patients in both the placebo and the arbacet-treated group healed after 14 days of treatment. At the end of the study, healing of the ulcer was observed in 69.2% of the arbacet-treated patients and in 60.4% of patients in the placebo treated group. (Difference was not statistically significant). We conclude that cytoprotective doses of arbacet with minimal antisecretory properties are not effective in duodenal ulcer healing.

Failure of a cytoprotective dose of arbaprostil to heal acute duodenal ulcers. Results of a multiclinic trial.

Previous therapeutic trials with prostaglandins have shown them to be effective in healing duodenal ulcers when used at doses that are highly effective suppressors of gastric acid secretion. We undertook this trial to determine if a cytoprotective dose of arbaprostil (10 micrograms q.i.d. for 4 wk) would also be efficacious in this disease state. Eighty-two patients between the ages of 19 and 72 yr with endoscopically documented duodenal ulcers were entered into this randomized double-blind placebo-controlled trial. The patients were monitored with biweekly endoscopies and laboratory examinations, weekly interviews during the period when drug was administered, and a follow-up interview plus laboratory examinations 1 wk after drug administration was completed. No statistically significant differences between the arbaprostil and placebo treatment groups were found for ulcer healing rates, pain relief, antacid consumption, side effects, or laboratory examinations. It is presumed that this prostaglandin may not have sufficient duodenal cytoprotective capacity to effectively heal duodenal ulcers, or that some suppression of gastric acid secretion may be required to achieve significant clinical efficacy.

Effect of oral prostaglandin E2 on DNA turnover in gastric and intestinal epithelia of the rat.

The mucosal incorporation and clearance of a DNA precursor was examined in the rat stomach and intestine following oral treatment with natural prostaglandin E2 (PGE2) or 15(R) 15 methyl prostaglandin E2 (Me PGE2). Control groups received vehicle or pentagastrin. After five days of treatment animals were labelled with methyl-3H-thymidine. Groups of rats were killed at 0.75, 24, 72, 96 and 120 h after labelling. Treatments continued until killed. Mucosal scrapings were analysed for radioactivity and DNA. Morphometric measurements were performed and plasma levels of gastrin and somatostatin determined. PGE2 and its stable analogue produced hyperplasia within one week of treatment, in particular of the gastric antrum and changed the incorporation and clearance of radioactive thymidine from gastric and intestinal epithelia. The most consistent finding was a delayed elimination of thymidine from the mucosa, indicating a slowing of the DNA turnover. The DNA synthesis was differently affected along the gastrointestinal tract, being unchanged or reduced in the stomach and moderately increased in the intestine. Prostaglandin treatment was associated with a three- to ten-fold increase of the gastric acid contents and with elevated plasma levels of gastrin and somatostatin. It is concluded that E2 prostaglandins produce hyperplasia of gastric and intestinal epithelia in the rat by prolonging the cell survival time rather than by increasing new cell production. Hypergastrinemia is not a likely mediator of trophic actions of E2 prostaglandins, which develop despite elevated plasma levels of somatostatin.

Plasma levels of the prodrug, arbaprostil, [(15R)-15-methylprostaglandin E2], and its active, antiulcer (15S) epimer in humans after single dose oral administration.

Arbaprostil [(15R)-15-methylprostaglandin E2] is an antiulcer prodrug being evaluated for the treatment of gastric and duodenal ulcers in humans. It epimerizes in acidic gastric fluid to produce the biologically active form, (15S)-15-methyl-PGE2, which acts directly on the gastric mucosa and possesses both gastric acid antisecretory and cytoprotective properties. Because of its local mode of action, plasma levels of the two epimers may have greater relevance to drug safety than to therapeutic efficacy. In the present study, plasma concentrations of both 15-methyl-PGE2 epimers resulting from a gastric acid antisecretory dose of arbaprostil oral solution (50 micrograms) were measured in eight male volunteers having sufficient gastric acidity for prodrug activation (pH less than 3). Arbaprostil was determined with a newly developed RIA having a sensitivity of 10 pg X mL-1. The accuracy of the RIA was confirmed by parallel analysis of plasma samples by HPLC. (15S)-15-Methyl-PGE2 was also determined by HPLC. Arbaprostil was both rapidly absorbed and eliminated (tmax of 15-30 min and plasma t1/2 of 20 min), but there was large intersubject variability in its observed maximum plasma concentration (38 to 348 pg X mL-1). The concentration of (15S)-15-methyl-PGE2 did not exceed 25 pg X mL-1 In six subjects and 50 pg X mL-1 in the remaining two subjects. The significance of these results is discussed.

Pregnancy termination: techniques, risks, and complications and their management.

PIP: This article outlines the current modalities of pregnancy termination, as well as their risks and complications, in 3 phases of pregnancy: 1) up to 49 days past the last menstrual period, 2) 8-15 weeks, and 3) 16-24 weeks. Before 8 weeks of pregnancy, suction dilatation and curettage (D and C) is the preferred method. However, a medical approach, possibly self-administered, is viewed as more satisfactory and requires only an improvement in side effects. From 8-15 weeks' gestation, suction D and C and dilatation and evacuation (D and E) are the methods of choice. The use of laminaria tents improves both the facility and safety of these procedures in nulliparous patients and perhaps in multiparous patients. Priming of the cervix with prostaglandin could further decrease the difficulty and risks of these procedures. The use of a hydrogel compound is especially worthy of consideration. There is controversy about the preferred method between 16-20 weeks' gestation. D and E appears to have fewer complications and to be more cost-effective than hypertonic saline injection. Urea-prostaglandin has fewer and less severe complications than saline injection, and seems to be more cost-effective than saline injection in terms of duration of hospitalization. The high frequency of failure and side effects, combined with the possibility of expulsion of a live fetus, make prostaglandin-only injection less desirable. After 20 weeks' gestation, urea-prostaglandin injection is probably the safer method. Given the rapid increase in complications with passing weeks, any delay in providing late abortion services should be avoided. 2nd trimester pregnancy terminations, especially those after 18 weeks' gestation, are associated with increased mortality and morbidity and should be performed at specialized centers where providers are better equipped to manage complications.^ieng

The influence of 15(R)-15 methyl PGE2, methyl ester, on Nd:YAG laser-induced gastric ulcers.

The effect of 15(R)-15 methyl PGE2 on the evolution of gastric ulcers induced by endoscopic Nd:YAG laser photocoagulation was studied. By continuous application of 50 to 70 watt power for 4 sec at a distance of 15 mm from the gastric mucosa, reproducible ulcers can be induced. The effect of the drug in nonantisecretory doses (10 micrograms/kg) on the acute ulcer formation and on the healing rate was evaluated in mongrel dogs by light microscopy. Local administration or oral pretreatment did not influence the size or depth of acute ulcers (7.4 mm in diameter) as compared to a control series (7.2 mm). Pretreatment for several days, however, had a marked beneficial effect on the healing rate of the ulcers (1.71 mm after 7 days compared to 2.76 mm for the control series). From these data it may be concluded that 15(R)-15 methyl PGE2 has a beneficial effect on ulcer healing, even in nonantisecretory doses.

15 (R)-15-methyl prostaglandin E2 does not prevent gastrointestinal bleeding in seriously ill patients.

A prospective, randomized trial was designed to compare the relative efficacy of 15 (R)-15-methyl prostaglandin E2 with antacid (usually Mylanta II) in 46 patients admitted to a respiratory-surgical intensive care unit. Bleeding was assessed by a modification of the Hemoccult slide test. Three of 22 patients in the antacid group bled, and 12 of 24 patients in the prostaglandin group bled, for a highly significant difference (p = 0.008). Patients in whom prophylaxis failed tended to have a greater number of risk factors. Other prostaglandin analogues that do not require conversion from an inactive to an active form, may be more useful than the agent we studied. Based on currently available data, the hourly titration of the gastric juice to a pH of greater than 3.5 remains the preferred method of prophylaxis for acute bleeding from the stomach in seriously ill patients.

Treatment of hemorrhagic gastritis with 15(R)-15 methyl prostaglandin E2: report of a case.

A 19-yr-old male developed severe hemorrhagic gastritis following three abdominal operations. Treatment with intravenous cimetidine and hourly antacids to maintain his gastric pH above 5 failed to affect gastrointestinal bleeding. Also, peripheral venous vasopressin, propantheline bromide, and glucagon were without effect. Total gastrectomy was considered to control his bleeding. However, since a number of prostaglandin analogs prevent gastric lesions produced by many noxious agents (e.g., aspirin, alcohol, strong acid or alkali, etc.) in animals and humans, the patient was treated with 50 micrograms of 15(R)-15 methyl prostaglandin E2 intragastrically every 6 h for 10 days. To epimerize the 15(R) form to the more active 15(S) form, 50-100 ml of 50-mN HCl was placed into the patient's stomach immediately before each dose. Bleeding ceased within 24 h of the onset of 15(R)-15 methyl prostaglandin E2 therapy and did not recur. The prompt response to 15(R)-15 methyl prostaglandin E2 in combination with hourly antacids in this patient with persistent and severe hemorrhagic gastritis suggests a therapeutic effect and the need for a prospective double-blind clinical trial.