Comparison of gastric and intestinal antisecretory and protective effects of prostacyclin and its stable thia-amino-analogue (HOE 892) in consious rats

The effects of prostacyclin (PGI₂) and its stable thia-thimo-analogue (Hoe 892) on gastric and intestinal secretions and gastric mucosal lesions have been determined in conscious rats. Both PGI₂ and Hoe 892 given subcutaneously (s.c.) reduced dose-dependent gastric acid secretion, the ID₅₀ (dose producing 50% inhibition) being about 48.6 and 11.8 gmg/kg, respectively. In contrast, intragastric (i.g.) PGI₂ and Hoe 892 did not cause any change in gastric acid secretion at doses ranging from 1 to 100 gmg/kg. Both PGI₂ and Hoe 892 reduced significantly intestinal fluid secretion (antienteropooling activity). PGI₂ and Hoe 892 given i.g. or s.c. reduced dose-dependent gastric ulcer formation induced by acidified aspirin (ASA), Hoe 892 being somewhat less potent than PGI₂. Both PGI₂ and Hoe 892 were equally effective against mucosal necrosis induced by absolute ethanol and this effect was observed both after i.g. and s.c. administration of these agents. We conclude that stable thia-amino-PGI₂ analogue, Hoe 892, has similar gastric and intestinal antisecretory and protective activity as PGI₂ and may be useful in the prevention of gastric damage by various noxious agents.     

Inhibition of platelet thromboxane A2 synthase activity by sodium 5-(3′-pyridinylmethyl)benzofuran-2-carboxylate

This report outlines the activity of a new thromboxane synthase inhibitor sodium, 5-(3-pyridinymethyl)-2-benzofurancarboxylate, (U-63557A). U-63557A is a potent inhibitor of the thromboxane synthase in human platelets $\text{in}$$\text{vitro}$, as well as in rhesus monkey platelets $\text{ex vivo}$. A single oral dose of 3.0 mg/kg U-63557A inhibits the platelet thromboxane synthase in rhesus monkeys approximately 80% for at least 12 hrs. U-63557A has been administered to monkeys twice a day, (10 mg/kg) for 14 days, without evidence of drug tachyphylaxis or rebound. U-63557A does not inhibit thrombin-stimulated PGI₂ biosynthesis in human endothelial cells, the 5-lipoxygenase in human neutrophils, or the cyclo-oxygenase in a variety of test systems. In anesthetized dogs, U-63557A injected i.v. at 0.1 at 5 mg/kg prevented the blockage of stenosed coronary arteries caused platelet aggregation,. Similar effects were obtained by oral administration of 1–5 mg/kg. The thromboxane synthase inhibitor was more efficacious than cyclooxgenase inhibitors and equal to PGI₂ in efficacy. Under appropriate conditions the protective effects of U-63557A could be reversed by i.v. cylooxygenase inhibitors suggesting that its efficacy dependened in part of endogenous PGI₂ formation. Due to its specificity, oral activity, and extended duration of action, U-63557A is a promising compound for the evaluation of the role of thromboxane synthase in a variety of patho[hysiological states.     

Comparison of gastric and intestinal antisecretory and protective effects of prostacyclin and its stable thia-imino-analogue (Hoe 892) in conscious rats

The effects of prostacyclin (PGI2) and its stable thia-thimo-analogue (Hoe 892) on gastric and intestinal secretions and gastric mucosal lesions have been determined in conscious rats. Both PGI2 and Hoe 892 given subcutaneously (s.c.) reduced dose-dependent gastric acid secretion, the ID50 (dose producing 50% inhibition) being about 48.6 and 11.8 micrograms/kg, respectively. In contrast, intragastric (i.g.) PGI2 and Hoe 892 did not cause any change in gastric acid secretion at doses ranging from 1 to 100 micrograms/kg. Both PGI2 and Hoe 892 reduced significantly intestinal fluid secretion (antienteropooling activity). PGI2 and Hoe 892 given i.g. or s.c. reduced dose-dependent gastric ulcer formation induced by acidified aspirin (ASA), Hoe 892 being somewhat less potent than PGI2. Both PGI2 and Hoe 892 were equally effective against gastric mucosal necrosis induced by absolute ethanol and this effect was observed both after i.g. and s.c. administration of these agents. We conclude that stable thia-imino-PGI2 analogue, Hoe 892, has similar gastric and intestinal antisecretory and protective activity as PGI2 and may be useful in the prevention of gastric damage by various noxious agents.     

Comparison of the vasodepressor action of ZK 36 374, a stable prostacyclin derivative,PGI2 and PGE1 with their effect on platelet aggregation and bleeding time in rats

ZK 36 374, a new, chemically stable prostacyclin derivative, was compared with PGE₁ and PGI₂ with respect to its action on platelet aggregation in vitro, on bleeding time and on arterial blood pressure in conscious rats. The time of occlusion of a hole in a polyethylene (PE) tube of an AV-shunt between the left carotid artery and the right jugular vein by a microthrombus was considered as an index of bleeding time. All three substances inhibited the ADP-induced aggregation of human and rat platelets. In human PRP, ZK 36 374 was 17 times more active than PGE₁ and 2 – 5 times as potent as PGI₂. In contrast, in rat PRP, PGI₂ was 9.2 and 3.4 times as potent as PGE₁ and ZK 36 374, respectively. Similar differences in potency were found in the in vivo experiments where these substances given by an intravenous infusion to conscious rats prolonged bleeding time and depressed mean arterial pressure in a dose-dependent manner. ZK 36 374 was also orally active. At oral doses of 1, 2 and 3 mg/kg this new compound caused a dose-dependent prolongation of bleeding time and a fall in arterial blood pressure. In conclusion, the results show that ZK 36 374 is an intravenously and orally active prostacyclin derivative which may be of therapeutic value for occlusive peripheral vascular diseases.     

Anti-platelet aggregating and disaggregating activities of 6,9-methano PGI2

Anti-platelet aggregating and disaggregating activities of the chemically stable 6,9-methano prostaglandin I₂ (6,9-methano PGI₂) were investigated. 6,9-Methano PGI₂ inhibited ADP-induced platelet aggregation in PRP from humans, rabbits and rats. 6,9-Methano PGI₂ also inhibited rabbit platelet aggregation induced by ADP, collagen, thrombin, arachidonic acid and 11,9-epoxy-methano PGH₂. Antiaggregating activities of 6,9-methano PGI₂ were 0.3 to 2.0 times greater than those of PGE₁. 6,9-Methano PGI₂ facilitated platelet disaggregation in a dose related manner. Antiaggregating and disaggregating activities of 6,9-methano PGI₂ were markedly enhanced by incubation with the phosphodiesterase inhibitor, theophylline.     

Circulatory and platelet actions of 6,9-thiaprostacyclin (PGI2-S) in the cat.

A new analog of prostacyclin, 6,9-Thiaprostacyclin was infused intravenously in pentobarbital anesthetized cats in order to determine its hemodynamic and anti-platelet aggregating properties. At an infusion rate of 0.01 μmoles/kg/min, PGI₂-S moderately decreased arterial blood pressure without altering heart rate of superior mesenteric artery flow or platelet aggregation responses to ADP. However, at 0.05 μmoles/kg/min, PGI₂-S significantly reduced arterial blood pressure and significantly increased heart rate, and superior mesenteric artery flow. Moreover, at 0.05 μmoles/kg/min, PGI₂-S inhibited ADP platelet aggregation by 80%. PGI₂-S may be a useful agent in circulatory shock.     

Prostacyclin (PGI2) effets on anterior pituitary hormones in the rat in vivo

Intravenous injection of 600 μg PGE₂ or PGI₂ significantly increased serum LH and prolactin levels in estradiol treated ovariectomized rats. There was no effect on serum FSH concentration. PGE₂ and PGI₂ stimulated LH release in a non-dose dependent manner, while prolactin levels were positively correlated with the dose administered following PGI₂ treatment. 6-keto-PGF_1α at a comparable dose had no effect on pituitary hormone levels. Subcutaneous administration of 1 mg/kg or 60 mg/kg PGI₂ for seven days significantly depressed serum LH level both in male and female rats. These doses had no effect on serum FSH or prolactin levels.     

Potentiation of anti-aggregating activity of PGI2 by 7-ethoxycarbonyl-6,8-dimethyl-4-hydroxymethyl-1(2H)-phthalazinone (EG-626) in rabbit platelets in vitro

Anti-aggregating activity of 7-ethoxycarbonyl-6,8-dimethyl-4-hydroxymethyl-1(2H)-phthalazinone (EG-626) was tested using rabbit platelets in vitro. EG-626 alone, when added before, prevented platelet aggregation induced by ADP, as did PGI₂, papaverine and dipyridamole. Spontaneous disaggregation was also accelerated when EG-626 was added after the maximal aggregation induced by ADP. EG-626 alone also inhibited platelet aggregation induced by collagen and arachidonic acid. ID₅₀s of these agents in ADP-induced aggregation were 7–9 nM for PGI₂, 223 μM for EG-626, 266 μM for papaverine and 957 μM for dipyridamole. When EG-626 was used in combination with PGI₂, a threshold dose (50 μM) of EG-626 potentiated the anti-aggregating effect of subthreshold dose (3 nM) of PGI₂ upto 100% inhibition in collagen-induced platelet aggregation. The marked potentiating effect of EG-626 was accompanied by an accumulation of cyclic AMP in the platelets. These effects might be due to inhibition of phosphodiesterase. Papaverine and dipyridamole, other phosphodiesterase inhibitors, also potentiated the anti-aggregating activity of PGI₂. The activity of papaverine, however, was one eighth of EG-626 and that of dipyridamole was much less. The most effective combination of PGI₂ and EG-626 to induce 50% inhibition was obtained with 20% of ID₅₀ of each agent, whereas that of PGI₂ and papaverine or dipyridamole was 39 or 41%, respectively.     

Antiplatelet activity of the long-acting thromboxane receptor antagonist BMS 180,291 in monkeys

The effects of the novel TxA₂/prostaglandin endoperoxide (TP) receptor antagonist BMS 180,291 on platelet reactivity was determined ex vivo in conscious African green monkeys. Platelet aggregation responses to U-46,619 were decreased 50% and 100% at 23 to 24 hrs after BMS 180,291 oral doses of 1 and 3 mg/kg, respectively. In addition to inhibiting aggregation, a 3 mg/kg oral dose of BMS 180,291 also produced an 11±3-fold shift to the right in the U-46,619 concentration-response relationship for platelet shape change at 24 hrs after dosing. When the 3 mg/kg oral dose was continued for 11 days, the shift in this concentration-response relationship increased to 26±10- and 93±30-fold at 24 hrs after the 8th and 11th doses, respectively. This progressive inhibition corresponds to 93±3 and 99±1% blockade of platelet TP-receptors responsible for shape change, respectively. Comparable levels of TP-receptor blockade have been previously correlated with antithrombotic and antiischemic activities of TP-receptor antagonists in vivo. Platelet reactivity to U-46,619 had completely recovered on the 7th day after the final dose of BMS 180,291, indicating effective elimination from the circulation over this interval. In separate experiments, a 3-mg/kg i.v. dose of BMS 180,291 produced only marginal and transient hemodynamic effects in anesthetized African green monkeys. Overall, these data demonstrate that BMS 180,291 given orally once a day produces a sustained and therapeutically-relevant level of TP-receptor antagonism.     

Effect of indomethacin, tiaprofenic acid and dicrofenac on rat gastric mucosal damage and content of prostacyclin and prostaglandin E2

Gastric ulcerogenicity and depletion of endogenous prostaglandins (PGs) content induced by tiaprofenic acid, dicrofenac and indomethacin were examined using the same antiinflammatory effective doses. Male Wistar rats were given each of these drugs intragasrically 24, 18, and 3 hrs before sacrifice in the following doses (mg/kg): indomethacin (0.8, 4 and 20); tiaprofenic acid (1.2, 6 and 30); dicrofenac (0.8, 4 and 20). Endogenous prostacyclin (PGI₂) and PGE₂ in fundic mucosa were determined by radioimmunoassay. The three compounds produced fundic mucosal lesions in a dose-dependent manner. However, tiaprofenic acid and dicrofenac were both less potent than indomethacin in producing gastric mucosal lesions at similar antiinflammatory doses. Mucosal PGE₂ content was abolished by the three compounds in the following doses (mg/kg): indomethacin (4 and 20); tiaprofenic acid (6 and 30); dicrofenac (20). Mucosal PGI₂ was maintained around 50% of the control value in rats given tiaprofenic acid in a dose of 6 mg/kg or dicrofenac in a dose of 4 mg/kg, while indomethacin in a dose of 4 mg/kg markedly reduced mucosal PGI₂ to 17% of the control value. In larger doses, tiaprofenic acid and dicrofenac were also significantly less potent in reducing mucosal PGI₂ than idomethacin. These results suggest that the difference in ulcerogenicity between idomethacin and the other two compounds was closely related to their potency in decreasing PGI₂ in the gastric (fundic) mucosa.     

Prevention of blockage of partially obstructed coronary arteries with prostacyclin correlates with inhibition of platelet aggregation

Coronary arteries (circumflex or left anterior descending) of anesthetized dogs were partially obstructed to approximately 5% of the normal lumen size by fitting a plastic cylinder around the vessel. Under these conditions, blood flow in the artery was not maintained but, instead, gradually declined over a few minutes until the vessel was completely blocked. Shaking the plastic obstructor restored blood flow temporarily, however, flow gradually declined again to zero. Sometimes flow was spontaneously restored by immediate increases that occurred at irregular intervals while, on other occasions, blood flow had to be restored by shaking the obstructor every time the rate declined to near zero. Intravenous infusion of prostacyclin (PGI₂) at 15 to 150 ng/kg/min reversed and prevented the blockage of the coronary arteries. The efficacy of PGI₂ in preventing blockage correlated with inhibition of ADP-induced platelet aggregation in platelet rich plasma prepared from blood samples withdrawn from the dogs during PGI₂ infusion. Other coronary vasodilators, nitroglycerin and PGE₂, that have no antiaggregatory effects, failed to prevent blockage whereas PGE₁ and indomethacin, which do block aggregation, also prevented blockage of the vessels. PGI₂ or its precursor, PGH₂, dripped topically on the obstructed site prevented the blockage of the artery. This local effect of PGI₂ could be obtained with amounts too small to cause systemic inhibition of platelet aggregation. The results show that PGI₂ prevents blockage of partially obstructed coronary arteries and this effect correlates with inhibition of platelet aggregation. Furthermore, the data suggest that locally produced PGI₂ may have a local antiaggregatory effect without inhibiting platelet aggregation in the general circulation.     

The Clinically-tested S1P Receptor Agonists,FTY720 and BAF312, Demonstrate Subtype-Specific Bradycardia (S1P1) and Hypertension (S1P3) in Rat

Sphingosine-1-phospate (S1P) and S1P receptor agonists elicit mechanism-based effects on cardiovascular function in vivo. Indeed, FTY720 (non-selective S1P_X receptor agonist) produces modest hypertension in patients (2–3 mmHg in 1-yr trial) as well as acute bradycardia independent of changes in blood pressure. However, the precise receptor subtypes responsible is controversial, likely dependent upon the cardiovascular response in question (e.g. bradycardia, hypertension), and perhaps even species-dependent since functional differences in rodent, rabbit, and human have been suggested. Thus, we characterized the S1P receptor subtype specificity for each compound in vitro and, in vivo, the cardiovascular effects of FTY720 and the more selective S1P_1,5 agonist, BAF312, were tested during acute i.v. infusion in anesthetized rats and after oral administration for 10 days in telemetry-instrumented conscious rats. Acute i.v. infusion of FTY720 (0.1, 0.3, 1.0 mg/kg/20 min) or BAF312 (0.5, 1.5, 5.0 mg/kg/20 min) elicited acute bradycardia in anesthetized rats demonstrating an S1P₁ mediated mechanism-of-action. However, while FTY720 (0.5, 1.5, 5.0 mg/kg/d) elicited dose-dependent hypertension after multiple days of oral administration in rat at clinically relevant plasma concentrations (24-hr mean blood pressure = 8.4, 12.8, 16.2 mmHg above baseline vs. 3 mmHg in vehicle controls), BAF312 (0.3, 3.0, 30.0 mg/kg/d) had no significant effect on blood pressure at any dose tested suggesting that hypertension produced by FTY720 is mediated S1P₃ receptors. In summary, in vitro selectivity results in combination with studies performed in anesthetized and conscious rats administered two clinically tested S1P agonists, FTY720 or BAF312, suggest that S1P₁ receptors mediate bradycardia while hypertension is mediated by S1P₃ receptor activation.     

Effects of prostaglandins E2, I2 and F2α, arachidonic acid and indomethacin on pressor responses to norepinephrine in conscious rats

The effects of prostaglandins E₂ (PGE₂), I₂ (PGI₂) and F₂α (PGF₂α), arachidonic acid and indomethacin on pressor responses to norepinephrine were examined in conscious rats. Intravenously infused PGE₂ (0.3, 1.25 μg/kg/min), PGI₂ (50, 100 ng/kg/min), PGF₂α (1.8, 5.4 μg/kg/min) and arachidonic acid (0.7, 1.4 mg/kg/min) did not change the basal blood pressure. Both PGE₂ and PGI₂ significantly attenuated pressor responses to norepinephrine, whereas PGF₂α significantly potentiated them. Arachidonic acid, a precursor of the prostaglandins (PGs), significantly attenuated pressor responses to norepinephrine. Since the attenuating effect of arachidonic acid was completely abolished by the pretreatment with indomethacin (5 mg/kg), arachidonic acid is thought to exert an effect through its conversion to PGs. On the contrary, intravenously injected indomethacin (0.2–5.0 mg/kg) facilitated pressor responses to norepinephrine in a dose-related manner without any direct effect on the basal blood pressure. These results suggest that endogenous PGs may participate in the regulation of blood pressure by modulating pressor responses to norepinephrine in conscious rats.     

De-aggregatory action of prostacyclin in vivo and its enhancement by theophylline

In the mixed venous blood of anaesthetized, heparinized cats prostacyclin de-aggregated platelet thrombi, which were formed on the surface of blood-superfused collagen strips or on the surface of blood-superfused aortic strips from atherosclerotic rabbits. The reversal of platelet aggregation by prostacyclin was still achieved 3 hrs after the formation of platelet clumps. After an intravenous injection of prostacyclin the ID₅₀ for its de-aggregatory action was 7.5 μg/kg. Theophylline ethyldiamine (aminophylline), at a dose of 3 mg/kg i.v., did not reverse platelet aggregation but it enhanced the duration of the de-aggregatory action of prostacyclin; it had little effect on the hypotensive action of prostacyclin. It is concluded that prostacyclin disintegrates platelet clumps long after they are formed in heparinized blood $\text{in vivo}$ and that its anti-platelet action, but not hypotensive action, is selectively potentiated by a phosphodiesterase inhibitor. The above experimental data indicate the possibility of the combined use of theophylline and prostacyclin in arterial thrombosis.     

Prostacyclin inhibits 5-hydroxytryptamine release but stimulates thromboxane synthesis during cardiopulmonary bypass

The antiaggregating agent prostacyclin (PGI₂) was infused into ten dogs during cardiopulmonary bypass (CPB) to minimize thrombocytopenia and platelet dysfunction. The animals were anesthetized, placed on mechanical ventilation and underwent thoracotomy. After heparinization with 300 u/kg, animals were assigned to control (n=5) or PGI₂ treated groups (n=5). Thoracotomy and then CPB decreased platelet numbers to below 30, 000/mm³ (p < 0.05) and fibrinogen to less than 150 mg/dl (p < 0.05). PGI₂ at 100 ng/kg·min was infused for the 2 h period of CPB. PGI₂ infusion did not prevent these changes, but did prevent platelet serotonin release. In the control group after CPB, platelet serotonin fell from the baseline value of 1.11 μg/10⁹ to 0.35 μg/10⁹ platelets (p < 0.05). In contrast, PGI₂ treatment resulted in a serotonin increase to 2.27 μg/10⁹ platelets (p < 0.05). Thromboxane B₂ concentrations of platelets and plasma rose during CPB (p < 0.05). Surprisingly, PGI₂ infusion accentuated this rise in platelet and plasma thromboxane B₂ (p < 0.05). These data indicate that during CPB, an infusion of PGI₂: 1) does not prevent thrombocytopenia; 2) increases platelet serotonin uptake despite, 3) an associated rise in platelet and plasma thromboxane B₂.     

Release of prostaglandin I2-like activity from the rat aorta: Effect of captopril,furosemide, and sodium

The effect of captopril, furosemide, indomethacine and intake of sodium on the production of PGI₂-like material was studied in the rat aorta. Release of PGI₂-like material from these vessels was estimated by its ability to inhibit ADP-induced vessels was estimated by its ability to inhibit ADP-induced platelet aggregation. Pretreatment with indomethacin (15 mg/kg/day) reduced the capacity of the aorta to release PGI₂-like material. Pretreatment with captopril (10 mg/kg/day) had no effect. Intravenous furosemide (60 μg/ml plasma volume) increased the capacity of the aorta to inhibit by 28% (p<.025). The inhibitory capacity of aorta removed from rats on a low sodium diet did not differ from those on a high sodium diet. We conclude that the action of furosemide in reducing vascular tone may be related to stimulation of PGI₂ synthesis in blood vessels whereas the effect of captopril and sodiumin in reducing vascular tone may involve a mechanism unrelated to PGI₂ synthesis or may involve the synthesis of a prostaglandin other than PGI₂.     

Inhibition of prostaglandin biosynthesis by SQ 28,852, A 7-oxabicyclo-[2.2.1]heptane analog

7-Oxabicyclo[2.2.1]heptane analogs of prostaglandin (PG) H₂ can act as thromboxane (Tx) A₂ receptor antagonists or agonists, PGI₂ and/rr PGD₂ receptor agonists, or exhibit a mixture of the above activities. SQ 28,852, a new analog with a hexyloxymethyl omega side chain, is a potent inhibitor of PG synthesis. SQ 28,852 inhibited collagen and arachidonic acid (AA)-induced platelet aggregation and TxB₂ and PGE₂ formation, but did not block platelet aggregation induced by ADP or the TxA₂ mimics, 9,11-azoPGH₂, SQ 26,655, and U-46,619. It also blocked conversion of AA to TxB₂, PGE₂, and 6-ketoPGF₁α by microsomal preparations of human platelets, bovine seminal vesicles, and bovine aortas, respectively, but did not inhibit the conversion of PGH₂ to TxA₂ by the platelet microsomal preparation. SQ 28,852 (p.o.) protected mice against the lethal effects of AA (75 mg/kg, i.v.). The I₅₀ values for SQ 28,852, indomethacin and aspirin were 0.025, 0.05 and 15 mg/kg, respectively. Neither SQ 28.852 nor indomethacin protected mice from death caused by 9,11-azoPGH₂. SQ 28,852 (0.01 to 1 mg/kg, i.v.) inhibited AA-induced bronchoconstriction in anesthetized guinea pigs for at least 60 min. As an inhibitor of AA-induced bronchoconstriction, SQ 28,852 was 16- and 45-times more potent than indomethacin at 3 and 60 min after i.v. administration, respectively. SQ 28,852 did not inhibit brochoconstriction induced by histamine or 9.11-azoPGH₂, indicating its specificity of action . SQ 28,852 is the first example of a new class of cyclooxygenase inhibitors whose structure is similar to that of the naturally occurring endoperoxide, PGH₂.     

Effect of synthetic estrogen on platelet aggregation and vascular release of PGI2-like material in the rabbit

Treatment of adult female New Zealand white rabbits with ethinyl estradiol, the synthetic estrogen used in many oral contraceptives, results in a significant increase in $\text{in vivo}$ aggregation. This alteration in platelet behavior is accompanied by diminished vascular release of antiaggregatory PGI₂ (prostacyclin)-like material. Addition of a progestin prevents the change in platelet aggregation seen with the estrogen alone. Diminished vascular PGI₂ release may be an important factor in the pathogenesis of thrombotic occurrences experienced by some oral contraceptive users. $\text{In vivo}$ platelet aggregation may be of value in identifying individuals at risk of developing thrombotic disturbances while taking oral contraceptives.     

De-aggregatory action of prostacyclin and its enhancement by theophylline

In the mixed venous blood of anaesthetized, heparinized cats prostacyclin de-aggregated platelet thrombi, which were formed on the surface of blood-superfused collagen strips or on the surface of blood-superfused aortic strips from atherosclerotic rabbits. The reversal of platelet aggregation by prostacyclin was still achieved 3 hrs after the formation of platelet clumps. After an intravenous injection of prostacyclin the ID₅₀ for its de-aggregatory action was 7.5 μg/kg. Theophylline ethyldiamine (aminophylline), at a dose of 3 mg/kg i.v., did not reverse platelet aggregation but it enhanced the duration of the de-aggregatory action of prostacyclin; it had little effect on the hypotensive action of prostacyclin. It is concluded that prostacyclin disintegrates platelet clumps long after they are formed in heparinized blood and that its anti-platelet action, but not hypotensive action, is selectively potentiated by a phosphodiesterase inhibitor. The above experimental data indicate the possibility of the combined use of theophylline and prostacyclin in arterial thrombosis.     

Evaluation of the safety and pharmacokinetics of the multi-targeted receptor tyrosine kinase inhibitor sunitinib during embryo–fetal development in rats and rabbits

BACKGROUND : Angiogenesis plays a key role in embryo–fetal development and, based on nonclinical safety data, the majority of vascular endothelial growth factor (VEGF)-targeted antiangiogenic agents used in cancer therapy are not recommended during pregnancy. We investigated the effects of sunitinib (an oral inhibitor of multiple receptor tyrosine kinases [RTKs] including VEGF-receptors) on embryo–fetal development. METHODS : Presumed-pregnant Sprague-Dawley rats and New Zealand White rabbits received repeated daily oral doses of sunitinib (0–30 mg/kg/day), during the major period of organogenesis. Clinical/physical examinations were performed throughout the gestation phase, and blood samples were collected to determine systemic exposure. Necropsy (including uterine examination) was performed on all animals and fetal morphology was examined. RESULTS : The no-observed-adverse-effect level was 1–5 mg/kg/day for maternal toxicity and 3 mg/kg/day for developmental toxicity in rats; 1 and 0.5 mg/kg/day, respectively, in rabbits. Embryo–fetal toxicity included decreases in the number of live fetuses and increases in the numbers of resorptions and post-implantation/complete litter losses; these were observed at doses of ≥5 mg/kg/day in rats and 5 mg/kg/day in rabbits. Malformations included fetal skeletal malformations (generally thoracic/lumbar vertebral alterations) in rats and cleft lip/palate in rabbits. These developmental effects were observed at ∼5.5- (rats) and ∼0.3-times (rabbits) the human systemic exposure at the approved sunitinib dose (50 mg/day). CONCLUSIONS : Similar effects have been reported with the prototype monoclonal antibody bevacizumab. As is typically observed for potent inhibitors of RTKs involved in angiogenesis, sunitinib was associated with embryo–fetal developmental toxicity in rats and rabbits at clinically relevant dose levels. Birth Defects Res (Part B) 33:204–213, 2009. © 2009 Wiley-Liss, Inc.