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At least 19 recordsLinked to original sources
PubMed1987

Developmental toxicity of alprostadil in rats after subcutaneous administration or intravenous infusion.

Timed-pregnant Upj:TUC(SD)spf (Sprague-Dawley) rats were dosed with alprostadil (prostaglandin E1), either subcutaneously on Days 6-15 of gestation at 0.0, 0.5, 1.0, or 2.0 mg/kg/day or by iv infusion into the jugular vein (24 hr/day) on Days 7-15 at 0.0, 0.5, 1.0, 2.0, 4.0, or 6.0 mg/kg/day. Maternal toxicity was observed in all dams receiving alprostadil subcutaneously, the severity of which increased in a dose-related manner. Toxicity also was evident in the offspring in the 2.0 mg/kg/day group as evidenced by a significant increase in the percentage of resorptions and a significant decrease in the percentage of live fetuses. Mean fetal weight was significantly depressed in all three alprostadil-treated groups and several skeletal and visceral variations were significantly higher in the 1.0 and 2.0 mg/kg/day groups than in the vehicle control group; in addition, there were two instances of significantly increased frequencies of skeletal variations in the 0.5 mg/kg/day group. Gross, visceral, and skeletal malformations were significantly increased in the high-dose group. During iv infusion of alprostadil more than 50% of the dams in the 6.0 mg/kg/day group died and there was one death in the 4.0 mg/kg/day group. Significant decreases in maternal weight gain between Days 7 and 11 of gestation were observed at doses of 1.0 mg/kg/day and above. However, continuous iv infusion of this prostaglandin, at dosages which were not severely toxic to the dams, was judged not to be teratogenic or otherwise embryotoxic in rats. The increase in uterine contractions, observed at 1.0 and 2.0 mg/kg after sc administration to rats implanted with chronic uterine microballoons, was consistent with the hypothesis that the developmental toxicity observed after bolus sc administration was the consequence of decreased blood flow in the uterus and/or placenta and/or embryos.

Abnormalities, Drug-Induced↗
PubMed1992

Influence of alprostadil on pulmonary dysfunction after a cardiac operation.

To test the effects of alprostadil on pulmonary dysfunction after cardiac operations, we studied 24 male patients undergoing aortocoronary bypass. Twelve were given an intravenous infusion of alprostadil (synthetic prostaglandin E1), 20 ng.kg-1.min-1, in a double-blind manner during operation; the other 12 were controls. Duration of artificial respirator use and frequent blood gas analyses were used to assess postoperative pulmonary function. Use of the artificial respirator postoperatively was significantly lower in the prostaglandin group (mean time. 5.25 +/- 1.81 hours) compared with the controls (mean time, 8.34 +/- 4.35 hours) (p = 0.047). The proportion of patients with hypercapnia and with hypoxia determined every 4 hours for the first 24 hours after extubation was significantly lower in the prostaglandin group compared with the controls (p less than 0.0001). These results indicate that synthetic prostaglandin E1 may play a role in protecting lung tissue during extracorporeal circulation.

Adult↗
PubMed1989

An alprostadil analogue and human gastric secretion. A double-blind placebo-controlled study of the effects of a capsule and tablet formulation.

The effects of single oral doses of 800 and 1200 micrograms of the new alprostadil analogue mexiprostil (prostaglandin E1 16-methyl-16-methoxy derivative, MDL 646), presented as tablet and capsule formulation, on basal and pentagastrin-stimulated acid secretion, were studied in 10 healthy volunteers, using a randomized, double-blind, placebo-controlled, 5-way crossover design. Compared to placebo, administration of mexiprostil resulted in a significant inhibition of basal gastric acid secretion, at both doses and formulations. Pentagastrin-stimulated gastric secretion was reduced to a lesser degree and the differences compared to placebo did not achieve statistical significance when adjustments were made for basal effects present before starting stimulation. Total volume of gastric secretion, under basal conditions, was decreased by both doses and formulations, though the changes were significant only at 1200 micrograms for both formulation. The decrease in volume of gastric secretion during pentagastrin infusion did not reach statistical significance. Basal intragastric pH was increased by both doses and formulation, but the changes were significant only for the capsule formulation, at either dose. Neither dose of mexiprostil prevented the decrease in intragastric pH produced by pentagastrin infusion. Tolerability of mexiprostil was excellent with no unwanted effects reported either during or after the study. No changes in heart rate and systemic blood pressure were observed. Laboratory safety parameters were not altered by mexiprostil. There was no significant difference between the effects of both formulations of mexiprostil on any pharmacodynamic parameter.

Adult↗
PubMed1987

An alprostadil analogue and human gastric secretion. A double-blind placebo-controlled study of the effects of a tablet and lyovial formulation.

The effects of single doses of 800 micrograms and 1200 micrograms of the new alprostadil analogue (prostaglandin E1 16-methyl-16-methoxy derivative) MDL 646, presented as tablet and lyovial formulations, on basal and pentagastrin-stimulated gastric acid secretion, were studied in 10 normal male volunteers using a randomised, double-blind placebo-controlled cross-over design. Compared to placebo, both doses of MDL 646 significantly decreased acid output during the basal and pentagastrin-stimulated periods. No difference between the tablet and lyovial formulations was found. Total basal output (tablet and lyovial data pooled) was reduced by 58% and 68% following 800 micrograms and 1200 micrograms MDL 646, respectively. Stimulated output was reduced to a lesser degree (15% and 27%). Inhibition of the stimulated acid secretion was observed up to 1.5 to 1.75 h after drug administration. Tolerance was good with only one subject reporting nocturnal abdominal pain following each dose of the drug and placebo.

Adult↗
PubMed1992

Effect of intravenous cimetidine, ranitidine and pentagastrin and intragastric prostaglandin E1 treatments on gastric transmucosal potential difference in the rat.

Effects of intravenous cimetidine, ranitidine and intragastric prostaglandin E1 (alprostadil) treatments on the transmucosal potential difference (PD) of the stomach were compared. It was also investigated whether the above-mentioned drugs influenced the decrease of PD which followed both intragastric administration of 30% alcohol or Ca++ solution in 5 Mm final concentration and intravenous administration of pentagastrin. Both cimetidine and ranitidine treatments led to significant (p < 0.05) increase of PD, the effect of ranitidine was dose dependent. Prostaglandin E1 in a dose of 40 micrograms/kg led to significant decrease of PD (< 0.05). Both intragastric administration of prostaglandin E1 in a dose of 40 micrograms/kg and intravenous administration of ranitidine in a dose of 10 mg/kg significantly diminish the effect of Ca++ and alcohol to decrease PD. Neither prostaglandin E1, nor ranitidine pretreatment had any effect on the rapid and highly significant (p < 0.01) decrease of PD following i.v. pentagastrin administration. It is hypothesized that transmucosal PD of the stomach provides information not only on the actual condition of the mucosal barrier but on the electrophysiology of gastric secretion as well.

Alprostadil↗
PubMed1987

Effect of heparin and dihydroergotamine on platelet adenosine-3',5'-cyclic monophosphate.

Human platelet adenosine-3',5'-cyclic monophosphate (cAMP) levels were determined in platelet rich plasma (PRP) and in washed platelets by a modification of the protein binding assay; the validation of the method is described. Dihydroergotamine (DHE) inhibited epinephrine induced platelet aggregation (ID50 = 2.5 X 10(-7) mol/l), and increased cAMP levels in platelets by an alpha-adrenergic receptor blocking effect, since phentolamine but not propranolol, behaved similarly. The DHE induced cAMP accumulation was correlated to the inhibitory effect on aggregation and showed a characteristic alpha-adrenergic receptor pattern in the presence of alprostadil (PGE1) and epinephrine but not collagen or adenosine diphosphate (ADP). Thrombin induced aggregation was similarly affected by DHE but with 100 times higher concentration. Heparin was found to increase slightly ADP and epinephrine induced aggregation and to decrease cAMP. Also, heparin was found to inhibit thrombin induced platelet aggregation. In washed platelets, the inhibitory effect of thrombin on PGE1 induced cAMP accumulation was counteracted by heparin. This indicates that the binding site of thrombin on platelets is important in the control of adenyl cyclase. Evidence is presented that some of the beneficial synergistic effect of DHE and heparin may consist in the ability of those compounds to produce opposite effects on cAMP system in platelets.

Alprostadil↗
PubMed1988

Prostaglandin E1 treatment in ductus dependent congenital cardiac malformation. A review of the treatment of 34 neonates.

Thirty-four sick neonates with major duct dependent cardiac defects were given short term (1 h-408 h) intravenous infusions of prostaglandin E1 (alprostadil) in doses varying between 0.1 micrograms/kg/min (starting dose) and 0.01 micrograms/kg/min. The aim of the study was to establish an effective and safe regiment that could be initiated after clinical diagnosis of a severe duct dependent cardiac defect, whose clinical course would be adversely affected by ductus closure. After an initial dosage of 0.1 micrograms/kg/min, effective clinical improvement was achieved in 28 infants (82%). In all 28 responders, the effect was maintained at a reduced dosage of 0.05 micrograms/kg/min, and in 21 a low dosage of 0.01 micrograms/kg/min was effective. Side effects, which occurred in 21 infants (62%), were reversible and dose related, and no serious side effects were noted at a dosage of less than 0.05 micrograms/kg/min. A starting dose of 0.05 micrograms/kg/min with subsequent reduction is recommended, but in case of institution of treatment before transfer to a pediatric cardiac centre a lower starting dose of 0.01 micrograms/kg/min may be preferred.

Acidosis↗
PubMed1985

[Use of series E prostaglandins in the treatment of essential hypertension].

Fifty-four hypertensive patients with the average BP level of 208 +/- 3.2/125 +/- 2.4 mm Hg were infused 2 doses of PGE. Forty patients received PGE2 in the form of protein (USA) and 14 patients were administered PGE1 in the form of alprostadil (USA). Each patient received on the average 3.5 mg of PGE2 or 0.7 mg of PGE1 during 48 hours. PGE infusion by the devised scheme induced no significant side-effects, was attended by an increase in the diuresis and natriuresis as well as a BP decrease (more pronounced with PGE1) not only in the period of the infusion but also during the 2-3 days following it. The hypotensive effect and BP fall in the orthostatic position were more marked following PGE2 infusion. PGE enhanced the sensitivity of the patients to obsidan, clophelin, hydrochlorothiazide and to a lesser degree to corinfar. Infusion of PGE2 to patients with essential hypertension resistant to hypotensive agents reduced the BP and made it possible to diminish the number of the drugs prescribed and their doses. The hypotensive effect of the drugs administered persisted for up to 5-7 months. It can be expected that repeated infusions of PGE2 every 6 months, will contribute to an alleviation of arterial hypertension, the patient's clinical improvement and the lowering of doses of hypotensive drugs.

Adult↗
PubMed1988

Gossypol attenuates selectively the blood pressure lowering effect of endothelium-dependent vasodilators in the rabbit in vivo.

The in vivo blood pressure lowering effect of three vasodilators whose in vitro effects are endothelium-dependent (acetylcholine, substance P and adenosine triphosphate) was reduced by 40-60% after systemic treatment of the animals with gossypol. In vitro, gossypol is an inhibitor of the production and/or release of endothelium-derived relaxing factor. Systemically administered gossypol had no effect on blood pressure decreases produced by the endothelium-independent agents prostaglandin E1 (alprostadil) and glyceryl trinitrate. These results suggest that endothelium-mediated vasodilator mechanisms could participate in blood pressure regulation.

Acetylcholine↗
PubMed1990

New drug approaches to the treatment of heart failure in infants and children.

General considerations in planning therapy of heart failure include identification of the cause, rapidity of onset, and the age of the patient. Neonates and young infants with acute onset heart failure frequently develop acidaemia, respiratory compromise or failure, and metabolic derangements such as hypoglycaemia, hypocalcaemia or hypomagnesaemia. These complications require early recognition and urgent therapy. The diagnosis of heart failure in neonates with ductal dependent congenital cardiac lesions (such as coarctation of the aorta, hypoplastic left heart syndrome or pulmonary valve atresia) allows the early institution of alprostadil (prostaglandin E1) therapy to maintain patency of the ductus arteriosus, which stabilises these infants before surgical therapy. Classic therapy for infants with heart failure due to a large left-to-right shunt consists of salt restriction, diuretics and digoxin. If this treatment is inadequate an angiotensin converting enzyme (ACE) inhibitor (e.g. captopril) is added to therapy. The question then arises whether captopril and diuretics should be the initial therapy and digoxin added if this treatment fails. Acute heart failure may occur in the immediate postoperative period after cardiac surgery or may complicate acute overwhelming infections. Therapy consists of volume loading, vasodilator or inotropic agents. Heart failure due to various forms of chronic dilated cardiomyopathy usually responds to treatment with salt restriction, diuretics, digoxin and captopril. Acute deterioration requires treatment with vasodilators and/or inotropic agents. Heart failure in fetuses may occur from sustained supraventricular tachyarrhythmias, and may respond to treatment of the mother with antiarrhythmic agents such as digoxin or procainamide.

Arrhythmias, Cardiac↗
PubMed1990

Self-administration in the pharmacological treatment of impotence.

Recent innovative research into the physiology and pharmacology of erection and the introduction of intracavernous injection of vasoactive agents have revolutionised our approach to the diagnosis and treatment of impotence. A thorough understanding of the rationale, indications, precautions and potential complications of intracavernous self-injection is essential for successful management. The commonly used drugs for injection are papaverine, either alone or in combination with phentolamine, and alprostadil (prostaglandin E1). The major adverse effects include priapism, prolonged erection, and fibrosis of the erectile tissue. With the proper technique and appropriate dosage, this is a safe, minimally invasive, and highly effective treatment.

Animals↗
PubMed1989

Protection of rat spinal cord against contusion injury by new prostaglandin derivatives.

Two prostaglandin oligomeric compounds, an acid-form compound and an ester-form compound, were synthesized from alprostadil (prostaglandin E1). They were found to provide significant protection to the rat spinal cord against contusion injury. After laminectomy at the T-11 segment of the spinal cord, a weight drop (10 g x 5 cm) caused a "dynamic" injury. The degree of recovery was estimated by several neurologic deficit indices; the Tarlov score, inclined plane test and hot plate test. In the control group (no drug), animals were still paralyzed 4 weeks after injury (Tarlov score 1 to 2). By administering these prostaglandin oligomers, either pre-injury (30 min before injury; one dose of 6 mg/kg i.p.) or post-injury (3 doses, each of 6 mg/kg i.p. at 30 min, 6 h, and 12 h after injury), the Tarlov scores recovered to 3.5 to 4.5 by 4 weeks, and animals were able to either support body weight or to walk with a slight deficit. Although both acid- and ester-forms of the compound demonstrated efficacy, the ester-form provided greater protection to the spinal cord. Other neurologic deficit indices also supported these observations.

Animals↗
PubMed1986

Antithrombotic effects of sodium salt of 17(R)-methyl-20-isopropylidenecarbacyclin in the arteriole of the hamster cheek pouch.

Antithrombotic effects of sodium salt of 17(R)-methyl-20-isopropylidenecarbacyclin (CS-570), a chemically stable prostaglandin I2 (PGI2, epoprostenol, prostacyclin) derivative, were investigated in the arteriole of the hamster cheek pouch. A microthrombus was produced by a slight mechanical injury followed by iontophoretic application of adenosine diphosphate (ADP) to an arteriole of 70 to 100 micron in diameter. The platelet thrombus size was determined with a video image processor. With this technique, a reproducible and quantitatively measurable periodical thrombus was obtained. CS-570 inhibited the thrombus formation dose-dependently. The potency of CS-570 was about 1/8 that of PGI2 and 6 times that of carbacyclin when infused i.v. CS-570 also decomposed an established thrombus. Alprostadil (PGE1), dipyridamole and ticlopidine failed to show inhibitory effects. The antithrombotic effect of CS-570 was definitely demonstrated.

Adenosine Diphosphate↗