Long-acting PGE2 and Lisinopril Mitigate H-ARS.

Thrombocytopenia is a major complication in hematopoietic-acute radiation syndrome (H-ARS) that increases the risk of mortality from uncontrolled hemorrhage. There is a great demand for new therapies to improve survival and mitigate bleeding in H-ARS. Thrombopoiesis requires interactions between megakaryocytes (MKs) and endothelial cells. 16, 16-dimethyl prostaglandin E2 (dmPGE2), a longer-acting analogue of PGE2, promotes hematopoietic recovery after total-body irradiation (TBI), and various angiotensin-converting enzyme (ACE) inhibitors mitigate endothelial injury after radiation exposure. Here, we tested a combination therapy of dmPGE2 and lisinopril to mitigate thrombocytopenia in murine models of H-ARS following TBI. After 7.75 Gy TBI, dmPGE2 and lisinopril each increased survival relative to vehicle controls. Importantly, combined dmPGE2 and lisinopril therapy enhanced survival greater than either individual agent. Studies performed after 4 Gy TBI revealed reduced numbers of marrow MKs and circulating platelets. In addition, sublethal TBI induced abnormalities both in MK maturation and in in vitro and in vivo platelet function. dmPGE2, alone and in combination with lisinopril, improved recovery of marrow MKs and peripheral platelets. Finally, sublethal TBI transiently reduced the number of marrow Lin-CD45-CD31+Sca-1- sinusoidal endothelial cells, while combined dmPGE2 and lisinopril treatment, but not single-agent treatment, accelerated their recovery. Taken together, these data support the concept that combined dmPGE2 and lisinopril therapy improves thrombocytopenia and survival by promoting recovery of the MK lineage, as well as the MK niche, in the setting of H-ARS.

Mucosal ulcerogenic action of monochloramine in rat stomachs: effects of polaprezinc and sucralfate.

Effects of a novel zinc compound polaprezinc [N-(3-aminopropionyl)-L-histidinatozinc] and sucralfate on the mucosal ulcerogenic responses induced by monochloramine (NH2Cl) were examined in rat stomachs. Oral administration of NH2Cl (>60 mM) produced severe lesions in unanesthetized rat stomachs, with concomitant increase of lipid peroxidation. These lesions were aggravated by sensory deafferentation but not affected by pretreatment with indomethacin or L-NAME. The mucosal ulcerogenic response to NH2Cl was significantly inhibited by oral pretreatment with either dmPGE2 (10 microg/kg), capsaicin (30 mg/kg), or NOR-3 (3 mg/kg), the NO donor. Gastric lesions induced by NH2Cl were also inhibited by prior oral administration of polaprezinc (3-30 mg/kg) as well as sucralfate (30 and 100 mg/kg). The protective effect of polaprezinc was not affected by any pretreatments such as indomethacin, L-NAME, or sensory deafferentation, while that of sucralfate was significantly mitigated in the presence of either indomethacin or L-NAME. On the other hand, mucosal exposure to NH4OH (60 mM) caused a marked PD reduction in ex vivo stomachs made ischemic by bleeding from the carotid artery, followed by severe gastric lesions. These ulcerogenic and PD responses caused by NH4OH plus ischemia were also attenuated by prior application of polaprezinc, while dmPGE2 and sucralfate prevented such lesions without affecting the reduced PD response. These results suggest that: (1) NH2Cl generated either exogenously or endogenously damages the gastric mucosa, (2) both polaprezinc and sucralfate protect the stomach against injury caused by NH2Cl, and (3) the mechanisms underlying the protective action of sucralfate may be partly mediated by both endogenous PGs and NO but may be different from those of polaprezinc.

Repair of rat gastric mucosa: effect of 16,16-dimethyl prostaglandin E2.

Prostaglandins protect the gastric mucosa against a variety of injurious agents and may accelerate the recovery of the gastric mucosa following damage. In previous studies prostaglandins were given prior to the injurious agent, so it was not possible to distinguish their potential effects on accelerating repair or reducing initial damage. We have investigated the effect of 16,16-dimethyl prostaglandin E2 (dmPGE2) on the repair of the gastric mucosa after injury induced by several injurious agents. dmPGE2 was given orally 15 min prior to aspirin or sodium salicylate, or 30 min after aspirin, sodium salicylate, or ethanol. dmPGE2 delivered prior to injury reduced the aspirin-induced fall in mucosal potential difference (PD), but had no effect on that induced by sodium salicylate. dmPGE2 administered after ASA injury significantly increased recovery of PD (P < 0.05), but did not alter the rate of recovery of PD with other damaging agents. Histological damage was decreased in rats treated with dmPGE2 after aspirin compared to aspirin-only-treated rats (P < 0.02). Exogenous dmPGE2 protects and restores gastric mucosal integrity after aspirin damage but has no effect on the repair of sodium salicylate and ethanol injured mucosa, suggesting that repair of the gastric mucosa after aspirin damage is enhanced by dmPGE2 due to its ability to prevent ongoing damage, rather than directly enhancing repair processes.

Protective effects of potato extracts and 16,16-dimethyl prostaglandin E2 on the induction of hepatic foci by cotreatment of gamma radiation and diethylnitrosamine.

We investigated the effect of potato extracts and 16,16-dimethyl prostaglandin E2 (DiPGE2) on the induction of glutathione S-transferase P-positive (GST-P+) altered hepatic foci in newborn Sprague-Dawley rats given single treatment with 60Co gamma irradiation and diethylnitrosamine (DEN) alone or in sequential combination. Intraperitoneal injection of 0.15 mumol/g body weight of DEN 1 hour after gamma radiation significantly increased the frequencies of GST-P+ hepatic foci compared to DEN or gamma radiation alone and DEN injection 1 hour before irradiation (p < 0.001). Potato extract was given at a dose of 2 mg/ml in drinking water for 3 weeks and DiPGE2 given at a dose of 10 micrograms/mouse 30 minutes before irradiation. Potato extracts and DiPGE2 decreased significantly the number (p < 0.001), area (p < 0.001) and Dmax (p < 0.05) of GST-P+ hepatic foci compared to the corresponding control. These results suggest that potato extracts and DiPGE2 have radio-protective potential and further studies for underlying mechanisms will be necessary.

Dimethyl-prostaglandin E2 prevents stress ulceration with minimal complications.

Gastric mucosal damage produced by topical application of necrotizing agents is diminished by topical or systemic pretreatment with a variety of E and F prostaglandins. The rat restraint model of gastric mucosal injury is more analogous to clinical stress ulceration than are models using intragastric application of toxic solutions; however, previous use of prostaglandin E1 in the restraint model resulted in a prohibitive incidence of GI morbidity. The current study used the restraint model of stress ulceration to compare the effects of a more potent prostaglandin analogue, 16,16-dimethyl prostaglandin E2, with hyperosmolar glucose and antacids. All three agents afforded significant protection from grossly apparent mucosal lesions, alone and in combination. Although other physiologic effects of each agent differed, the only effect which correlated with prevention of mucosal lesions was suppression of gastric acidity. Since effective doses of cytoprotective prostaglandins did not produce notable morbidity in comparison with other agents, they may prove to be a useful adjunct to stress ulcer prophylaxis in clinical settings.

16,16-Dimethyl prostaglandin E2 delays collagen formation in nutritional injury in rat liver.

Chronic nutritional injury was induced in rats by a high-fat, lipotrope-deficient diet. The hepatoprotective effect of 16,16-dimethyl prostaglandin E2 on the deposition of collagen and fat was assessed by histological evaluation and measurement of hydroxyproline. Dose-response studies established that optimal protection was achieved by the twice daily administration of 16,16-dimethyl prostaglandin E2 at 100 micrograms per kg (subcutaneous) or 250 micrograms per kg (oral). 16,16-Dimethyl prostaglandin E2 and a crystalline analog [(p-acetamidobenzamido)phenyl ester of 16,16-dimethyl prostaglandin E2 significantly delayed both the deposition of collagen and the increase in hepatic hydroxyproline content. There was an excellent correlation between the histological assessment of collagen and the biochemical measurement of hydroxyproline. These data provide a rationale for the evaluation of prostaglandins in the treatment of human liver disease.

Effects of prostaglandin and indomethacin on diet-induced acute pancreatitis in mice.

This study was performed to determine the effects of exogenous prostaglandin and a prostaglandin synthetase inhibitor on experimental pancreatitis in mice. An ethionine-supplemented choline-deficient diet was used to induce pancreatitis in 4-6-wk-old Swiss Webster mice. Mice were injected subcutaneously with 16,16-dimethyl prostaglandin E2 (0.1, 1.0, 10 micrograms X kg-1 X day-1), indomethacin (0.05, 0.5, 5 mg X kg-1 X day-1), or saline for 7 days. The ethionine-supplemented choline-deficient diet was introduced 24 h after the first injection, and animals ate the test diet for 48 h. A 55% mortality was observed in control animals (n = 100) treated with carrier alone. Treatment with 10 micrograms X kg-1 X day-1 of 16,16-dimethyl prostaglandin E2 significantly decreased (p less than 0.01) mortality to 12% (n = 100). Improved survival was accompanied by a significant (p less than 0.05) decrease in the pancreatic content of free chymotrypsin and a decrease in histologic damage. Treatment with 5 mg X kg-1 X day-1 of indomethacin (n = 30) significantly (p less than 0.01) increased mortality in diet-treated rats from a control rate of 55% to 100%. These studies demonstrate a protective effect of prostaglandin on the pancreas and suggest a role for endogenous prostaglandins in the pathophysiology of pancreatitis.

The use of 16-16 dimethyl trans delta 2 PGE1 methyl ester (ONO 802) vaginal suppositories for the termination of early pregnancy. A comparative study.

Vaginal suppositories containing the 16-16 dimethyl trans delta 2 PGE1 methyl ester (ONO 802) were used for the induction of abortion in early pregnancy, and this non-surgical technique was compared with suction termination performed under local anaesthesia or general anaesthesia. Ninety patients were recruited to the study and divided equally between the three groups. Complete abortion was induced in 87 per cent of the patients treated with ONO 802 suppositories, which compared favourably with 87 and 100 per cent for the patients who had suction terminations under local anaesthesia and general anaesthesia respectively. The vaginal suppositories induced uterine bleeding in all patients and the mean time of onset of lower abdominal pain was 2 hours 55 minutes. The average numbers of episodes of vomiting and diarrhoea for patients given ONO 802 suppositories were 0.9 and 0.7 respectively. Menstrual blood loss was measured objectively in all groups and no significant differences between the three methods could be found. In selected cases, ONO 802 vaginal suppositories would seem to be safe and reasonably effective for the termination of early pregnancy.

PIP: Vaginal suppositories containing the 16-16 dimethyl trans delta 2 PGE1 methyl ester (ONO 802) were used for the induction of abortion in early pregnancy, and this nonsurgical technique was compared with suction termination performed under local anesthesia or general anesthesia. 90 patients were recruited to the study and divided equally between the 3 groups. Complete abortion was induced in 87% of the patients treated with ONO 802 suppositories, which compared favourably with 87 and 100% for the patients who had suction terminations under local anesthesia, and general anesthesia, respectively. The vaginal suppositories induced uterine bleeding in all patients and the mean time of onset of lower abdominal pain was 2 hours 55 minutes. The average numbers of episodes of vomiting and diarrhea for patients given ONO 802 suppositories were 0.9 and 0.7, respectively. Menstrual blood loss was measured objectively in all groups and no significant differences between the 3 methods could be found. In selected cases, ONO 802 vaginal suppositories would seem to be safe and reasonably effective for the termination of early pregnancy.