The role of prostaglandins E1 and E2, dinoprostone, and misoprostol in cervical ripening and the induction of labor: a mechanistic approach.

PURPOSE: Prostaglandins play a critical role in cervical ripening by increasing inflammatory mediators in the cervix and inducing cervical remodeling. Prostaglandin E1 (PGE1) and prostaglandin E2 (PGE2) exert different effects on these processes and on myometrial contractility. These mechanistic differences may affect outcomes in women treated with dinoprostone, a formulation identical to endogenous PGE2, compared with misoprostol, a PGE1 analog. The objective of this review is to evaluate existing evidence regarding mechanistic differences between PGE1 and PGE2, and consider the clinical implications of these differences in patients requiring cervical ripening for labor induction. METHODS: We conducted a critical narrative review of peer-reviewed articles identified using PubMed and other online databases. RESULTS: While both dinoprostone and misoprostol are effective in cervical ripening and labor induction, they differ in their clinical and pharmacological profiles. PGE2 has been shown to stimulate interleukin-8, an inflammatory cytokine that promotes the influx of neutrophils and induces remodeling of the cervical extracellular matrix, and to induce functional progesterone withdrawal. Misoprostol has been shown to elicit a dose-dependent effect on myometrial contractility, which may affect rates of uterine tachysystole in clinical practice. CONCLUSIONS: Differences in the mechanism of action between misoprostol and PGE2 may contribute to their variable effects in the cervix and myometrium, and should be considered to optimize outcomes.

Epidural blood flow during prostaglandin E1 or trimethaphan induced hypotension.

To evaluate the effect of prostaglandin E1 (PGE1) or trimethaphan (TMP) induced hypotension on epidural blood flow (EBF) during spinal surgery, EBF was measured using the heat clearance method in 30 patients who underwent postero-lateral interbody fusion under isoflurane anaesthesia. An initial dose of 0.1 microgram.kg-1.min-1 of PGE1 (15 patients), or 10 micrograms.kg-1.min-1 of TMP (15 patients) was administered intravenously after the dural opening and the dose was adjusted to maintain the mean arterial blood pressure (MAP) at about 60 mmHg. The hypotensive drug was discontinued at the completion of the operative procedure. After starting PGE1 or TMP, MAP and rate pressure product (RPP) decreased significantly compared with preinfusion values (P < 0.01), and the degree of hypotension due to PGE1 remained constant until 60 min after its discontinuation. Heart rate (HR) did not change in either group. EBFF did not change during PGE1 infusion whereas in the TMP group, EBF decreased significantly at 30 and 60 min after the start of TMP (preinfusion: 45.9 +/- 13.9 ml/100g/min. 30 min: 32.3 +/- 9.9 ml/100 g/min (P < 0.05). 60 min: 30 +/- 7.5 ml/100 g/min (P < 0.05)). These results suggest that PGE1 may be preferable to TMP for hypotensive anaesthesia in spinal surgery because TMP decreased EBF.

Effect of prostaglandin E1 analogue administration on peripheral skin temperature at high altitude.

The effect of prostaglandin E1 analogue on peripheral skin temperature was examined at high altitude, where local cold injuries are common owing to severe environmental conditions. The peripheral skin temperature at rest was significantly lower at higher altitudes. Oral administration of the prostaglandin E1 analogue limaprost reversed this temperature decrease, probably by enhancement of peripheral circulation. The temperature recovery rate after a cold water challenge was also improved after the administration of limaprost. This oral type of prostaglandin E1 analogue is strongly recommended as an effective prophylactic and therapeutic vasodilator for local cold injuries at high altitudes.

["Responders and non-responders" to PGE1 and alpha-cyclodextrin]. / "Responders e non-responders" alla PGE1 alpha-ciclodestrina.

BACKGROUND: In this study we evaluated a group of 76 patients (mean age 66 +/- 12) treated with the short-term PGE1 alpha-ciclodestrina protocol (60 micrograms/die for 2 days). Responders to PGE1 alpha-ciclodestrina treatment were considered patients with an increase in flow/perfusion and an associated improvement in signs/symptoms. Moderate responders were considered patients with only flow/perfusion increase or only sign/symptoms improvement. Non-responders were characterised by no increase in flow/perfusion and no clinical improvement. METHODS: Signs/symptoms variations were measured on an analogue scale line. Perfusion measurements (laser Doppler, transcutaneous PO2, arterial inflow with straingauge plethysmography) were recorded after the two days of the short term treatment. RESULTS: In the group of 38 patient with claudication (200-600 m) 54% were considered responders, 12% non responders and 34% moderate responders. In the more severe claudication group (distance < 200 m) including 18 patients, 66% were responders, 8% non responders and 26% were considered moderate responders. In the rest pain group (13 patients) there were 63% responders, 9% non-responders and 28% moderate responders. In the gangrene group (10 patients) 60% were considered responders, 10% non-responders and 3% moderate responders. The overall percentages were 61.25% of responders, 10% of non-responders and 28.75% moderate responders. CONCLUSIONS: The evaluation of the response to PGE1 alpha-ciclodestrina treatment may indicate which group of patients will benefit from the treatment and which group will have no benefits or only limited benefits. This may induce changes in treatment (i.e. increasing doses, more prolonged treatment) or other solutions (revascularisation if possible, arterial infusion or amputation).

Determination of candidates for adjunctive 'gastroprotective' prostaglandins.

Long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) is now recognized as being frequently associated with asymptomatic gastric ulceration and its complications. Such adverse effects on the gastric mucosa have recently been found to occur with even greater frequency in certain NSAID-treated patients. Synthetic prostaglandin analogues have been shown to be cytoprotective of the gastric mucosa. This benefit has been evidenced by the reduced risk of gastric ulceration and gastric bleeding in patients taking NSAIDs on a prolonged basis. The first synthetic prostaglandin to be approved for this indication is misoprostol (Cytotec). To determine which and how many patients receiving NSAIDs should be treated adjunctively with a cytoprotective prostaglandin to reduce risk of NSAID-induced gastropathy, a clinical study of 100 consecutive patients seen in a rheumatology practice was undertaken. Patients were assessed by interview and chart review. Of these patients, 19% to 30% were considered potential candidates for adjunctive prostaglandin therapy. The rationale for use of the "gastroprotective" prostaglandins appears to lie in the identification of those patients who are especially at high risk for gastric ulcers.

[Effect of prostaglandin E1 on arterial ketone body ratio during and after hepatectomy].

We evaluated the effect of prostaglandin E1 (PGE1) on arterial ketone body ratio (AKBR) in patients undergoing hepatectomy. Sixteen patients were divided into two groups. In the PGE1 group (n = 8), 0.02-0.05 micrograms.kg-1.min-1 of PGE1 was administrated intravenously throughout the operation. In the control group (n = 8) patients were not given PGE1. AKBR decreased significantly during the operation; the decrease was in the same degree in both groups. Although AKBR rose in both groups after the operation, it returned more rapidly to the normal level in the PGE1 group compared with the control group. On the third postoperative day, the value of AKBR in the PGE1 group was significantly higher than that of the control group. These findings suggest that the intraoperative administration of PGE1 is valuable for protection against postoperative hepatic dysfunction induced by hepatectomy.

[The effect of low-rose prostaglandin E1 on circulation, respiration and body temperature during surgical anesthesia].

We investigated the effects of low-dose prostaglandin E1 (PGE1) on circulation, respiration, and body temperature during surgical anesthesia. We studied 109 adult patients undergoing upper abdominal operations under thoracic epidural combined with inhalational anesthesia. Patients were divided into 2 groups; Control group (n = 42) and PGE1 group (n = 67). In PGE1 group, PGE1 infusion was started at the rate of 0.02 microgram.kg-1.min-1 before the induction of anesthesia and was terminated at the end of surgery. There were no differences between the groups in demographic, anesthetic and surgical characteristics. After treatment with PGE1, arterial pressure decreased slightly but significantly, resulting in lower arterial pressure in PGE1 group than in control group before the induction of anesthesia. After the induction of anesthesia, however, arterial pressure decreased significantly in both groups, and the differences in arterial pressure between the groups were not observed any more during surgery. Heart rate was not different between the groups throughout the study period. Intraoperative urine output was greater in PGE1 group than in control group. PaO2/FIO2 ratio was not different between the groups both before and during anesthesia. Rectal temperature remained slightly but significantly lower in PGE1 group throughout surgery. Rectal-to-palm temperature gradient tended to be smaller in PGE1 group 1 hour after the induction of anesthesia. Low-dose PGE1 reduced arterial pressure. However, the difference in arterial pressure between the groups was so small that the difference disappeared during surgery. Meanwhile, low-dose PGE1 increased urine output, suggesting that renal blood flow was better-maintained with PGE1. In spite of several investigations reporting an unfavorable effect of PGE1 on PaO2, low dose PGE1 did not affect PaO2 in this study. Finally low-dose PGE1 reduced core temperature, though slightly, probably through redistribution of the body heat.

A review of mucosal protection by synthetic prostaglandin E analogs against injury by non-steroidal anti-inflammatory agents.

Non-steroidal anti-inflammatory agents (NSAIDs) damage the gastric mucosa both in normal volunteers and in arthritic patients. Four large studies have been done in our laboratory comparing the prostaglandin E analog misoprostol against placebo, cimetidine, and sucralfate. These studies showed that misoprostol protected the stomach significantly better than cimetidine or sucralfate. In the duodenum, misoprostol and cimetidine were equally effective. Comparison of secretory and anti-secretory doses of misoprostol reveal duodenal protection with the former but not with the latter, but gastric protection with both doses, suggesting that cytoprotective mechanisms other than acid suppression exist in the stomach in subjects taking prostaglandins. Adequately controlled and blind studies reported in the literature in arthritic patients are also reviewed, and it would appear that prostaglandins offer the best currently available method of providing mucosal protection for patients taking NSAIDs.

Misoprostol: a prostaglandin for peptic ulcer.

Misoprostol, an E1 prostaglandin analog, protects gastric mucosa against the ulcerogenic effects of a wide variety of noxious agents, including aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). This synthetic prostaglandin was recently approved by the Food and Drug Administration for use in patients at high risk of gastric ulceration because of chronic NSAID therapy for osteoarthritis, rheumatoid arthritis and related conditions. Side effects of misoprostol are minimal, but the drug is relatively expensive. Protection against gastrointestinal bleeding has not been established.

Overview of the mucosal protective effects of misoprostol in man.

Misoprostol, a novel synthetic analog of prostaglandin E1 has been evaluated for its potential mucosal protective properties in healthy human subjects using randomized, double-blind, placebo-controlled studies. Misoprostol significantly reduced established aspirin-induced gastric microbleeding. Likewise, misoprostol significantly inhibited aspirin-induced fecal blood loss when administered concurrently with aspirin. The reduction of gastrointestinal blood loss was neither a consequence of the inhibition of gastric secretion, nor a change in aspirin absorption. In addition, misoprostol effectively attenuated the transmucosal potential difference drop induced by sodium taurocholate. In endoscopic studies, misoprostol significantly inhibited damage to the gastroduodenal mucosa induced by aspirin, tolmetin and ethanol. In the ethanol study, the protective effects of misoprostol were significantly and profoundly greater than that afforded by cimetidine administered at an effective gastric antisecretory dose. These studies indicate that misoprostol has mucosal protective property in man. The basis for this mucosal protective effect is not fully known, but laboratory and clinical evidence indicate a direct effect on the barrier functions of the stomach, an increased or maintenance of gastric mucosal blood flow and an enhanced mucus and bicarbonate secretion. The implications of these findings suggest that misoprostol may be useful in the prevention and treatment of acute gastroduodenal mucosal lesions and inflammation.

The effect of prostaglandin E1 during cardiopulmonary bypass on renal function after cardiac surgery.

We have evaluated the effect of prostaglandin E1 (PGE1) on renal function after cardiac surgery with cardiopulmonary bypass in 20 patients, ten of whom received 0.02 microgram.kg-1.min-1 of PGE1 by infusion into the oxygenator during bypass; ten patients served as controls. Serum beta 2-microglobulin fell significantly and urine beta 2-microglobulin increased significantly after surgery in both groups. Urine N-acetyl-beta-D-glucosaminidase was high after surgery in both groups, but it was significantly lower in the PGE1 group. Free water clearance fell significantly on the 1st, 3rd, and 5th postoperative days compared with preoperative values in the control but not in the PGE1 group. These results suggest that PGE1 may prevent renal dysfunction after cardiopulmonary bypass.