Platelet aggregation inhibitory activity and vasodepressor activity of a series of bicyclo[3.2.0]hept-6-ylidene iminoxy alkanoic acids with modified lower side chains

Prostacyclin analogues derived from modification of the lower side chain of the bicyclo[3.2.0]hept-6-ylidene iminoxyacetic acid (1) were studied in inhibition of in vitro and ex vivo platelet aggregation and in the spontaneously hypertensive rat. Iminoxyacetic acids (13a), (13b), (13c) and iminoxypropionic acid (14b) were 2.9, 3.0, 1.9 and 2.0 times respectively more potent than PGE1 in inhibiting ADP-induced aggregation of human platelets in vitro. Following intravenous administration at a dose of 90-110 micrograms/kg in the guinea pig, iminoxyacetic acids (13a), (13c) and iminoxypropionic acid (14b) showed a maximum inhibition of 82-92% with a half life in the range of 14-22 min. Following oral administration at a dose of 1 mg/kg in the guinea pig, iminoxyacetic acids (13a) and (13b) inhibited heterologous platelet aggregation for 4.5 h. Following intravenous administration in spontaneously hypertensive rats, acids (13a)-(13c) and (14b) lowered the mean blood pressure in a dose dependent manner. At a dose of 100 micrograms/kg, the effect lasted for 20-40 min.     

Pharmacological profile of a novel carbacyclin derivative with high metabolic stability and oral activity in the rat

A novel carbacyclin derivative (16S)-13,14-dehydro-16,20-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I₂ (3-oxa-analogue) has been synthesized in order to find chemically and metabolically stable prostacyclin-memetics with a potency equal or even superior to PGI₂.The 3-oxa-analogue was found to be stabilized against β-oxidation, a main metabolic degradation step also for chemically stable PGI₂-analogues. The compound is orally available and displays a long duration of 4,5 – 48 h of antiaggregatory and hypotensive action. The 3-oxa-analogue inhibits ADP-induced platelet aggregation with an IC₅₀ of 3.0 nM. Following intravenous application the 3-oxa-analogue lowers diastolic blood pressure in a dose dependent manner, the ED₂₀ being 0.1 – 0.2 μg/kg after injection and ≤ 0.05 μg/kg/min after infusion respectively. In vivo platelet aggregation is inhibited after i.v. infusion of the 3-oxa-analogue with an IC₅₀ of 0.037 μg/kg/min. As compared to Iloprost, the 3-oxa-analogue is 5 – 12 fold more potent with respect to in vivo hypotensive and anti-aggregatory effects.The results of the present studies indicate that the 3-oxa-analogue has a pharmacological profile comparable to prostacyclin (PGI₂) and Iloprost. Due to the fact that the 3-oxa-analogue is chemically and metabolically stable, long term oral treatment can be achieved in clinical conditions in which PGI₂ and Iloprost have already been shown to be therapeutically useful principles.     

Pulmonary and anti-platelet effects of intravenous and inhaled prostacyclin in man

Prostacyclin in aerosol was inhaled by three healthy volunteers (0.3 – 30 μg) and by twelve patients with bronchial asthma (200 or 400 μg). Essentially, no changes in pulmonary function were noticed. Intravenous infusion of prostacyclin (2 – 20 ng/kg/min) into six healthy volunteers also remained without effects on respiratory indices studied. Inhaled prostacyclin impaired platelet aggregability to ADP, dispersed circulating platelet aggregates and produced vasodilation comparable to those observed following intravenous administration of the hormone. We suggest that aerosols of prostacyclin might be used in future in treatment of arterial thrombo-embolism.     

Duration of activity of the acid, methyl ester and amide of an orally active platelet aggregation inhibitory prostanoid in the rat

The prostanoid 3-oxa-4,5,6-trinor-3,7-inter- -phenylene PGE₁ (OI-PGE₁) has been shown to be a more potent inhibitor of ADP-induced human platelet aggregation than PGE₁. OI-PGE₁ inhibits ex vivo ADP-induced platelet aggregation for 60 minutes after an oral dose of 20 mg/kg to rats. Present studies compare duration of ex vivo inhibition to ADP-induced platelet aggregation in the rat by OI-PGE₁, its methyl ester and amide after administration by various routes. All oral (p.o.) and intraduodenal (i.d.) doses were 20 mg/kg and all intravenous (i.v.) doses were 1 mg/kg. OI-PGE₁ and its methyl ester had the same duration of activity after i.v. (60 min.) and p.o. (60 min.) administration, however, the methyl ester, when administered i.d., had a longer duration of activity than the free acid i.d. (>90 min. vs. 60 min.). OI-PGE₁-amide had significantly longer duration than the acid or methyl ester after i.v. (>120 min.), p.o. (>240 min.) or i.d. (>240 min.) administration. Present data suggest that in the rat (1) intestinal absorption of OI-PGE₁-methyl ester is more efficient than it is for the free acid and (2) due to metabolic and/or distributional differences between OI-PGE₁ and its amide, the amide has a much greater duration of activity.     

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.     

Ciprostene, a stable prostacyclin analog, produces peripheral vasodilation, platelet inhibition and increased clot dissolution in the cat

The effect of the stable prostacyclin analog ciprostene on hemodynamic parameters, platelet aggregation and clot dissolution was examined in the sodium pentobarbital anesthetized cat. Hemodynamic and platelet aggregation effects were measured in 5 cats following infusion of 5, 10, 20, 40 and 80 μg/kg/min of ciprostene. Drug was dissolved in Tyrode's buffer (pH 7.4) and all doses were infused for 20 minute intervals in ascending order. The hemodynamic data were consistent with peripheral vasodilation. The total peripheral resistance and mean aortic pressure decreased with incresing dose. No change in heart rate, cardiac index, or left ventricle dP/dt (contractility) was observed. All doses infused produced inhibition of ADP induced platelet aggregation. In vivo fibrinolytic activity was assessed with an aortic thrombus positioned at the bifurcation of the aorta. Five cats were infused with vehicle and 5 cats each were infused with 8 and 20 μg/kg/min ciprostene respectively. All infusions were via a 4F catheter positioned in the aorta proximal to the thrombus. Infusion time was 3 hours. Infusion of 8 μg/kg/min did not enhance dissolution of the aortic thrombus. However, the 20 μg/kg/min infusion significantly reduced the thrombus weight (mean = 13.2 mg) compared to vehicle (mean = 38.7 mg) (p < 0.03). The results suggest that ciprostene is a potent vasodilator and platelet inhibitor with clot dissolution properties.     

Prostacyclin-like activity in rat vascular tissues. fast, long-lasting inhibition by treatment with lysine acetylsalicylate

Both arterial and venous tissues obtained from normal rats released prostacyclin (PGI₂)-like activity, as marked by its potent inhibitory effect on platelet aggregation. Intraperitoneal or intravenous administration of a single dose of a soluble lysine salt of acetylsalicylic acid (L-ASA, 1–400 mg/kg) resulted in abolition or substantial reduction of prostacyclin-like activity released from rat vasculature. The inhibitory effect of L-ASA was evident one minute after its i.v. administration to the animals, persisted for at least 24 hours and was still detectable (in venous tissues only) 168 hours later. Venous tissues were inhibited by doses of L-ASA as low as 1 mg/kg, whereas arterial tissues were not inhibited by doses of L-ASA lower than 10 mg/kg. This difference may possibly be related to the lower prostacyclin-like activity shown by rat venous tissues compared to arterial ones.It is suggested that L-ASA or part of its molecule may bind to and inhibit cyclo-oxygenase in the blood vessel wall in a manner similar to the acetylation of platelet cyclo-oxygenase.     

Effects of a synthetic prostaglandin analogue, cloprostenol, on the corpus luteum of the guinea pig

The effects of a synthetic prostaglandin analogue, cloprostenol, on luteal function in a guinea pig were studied. At a dose of 250μg, cloprostenol administered I-P on day 9 of the oestrous cycle caused a reduction in the length of the oestrous cycle from 17.4±s.d. 0.9 to 14.5±1.1 days (p<0.01). Lower doses were ineffective, and post-treatment cycles were not different in length from pre-treatment cycles. Cloprostenol also caused a dose-dependent reduction in luteal weight, which fell from 3.52±0.82 to 1.82±0.4mg (<0.01) 48 h after administation of a 250μg dose on day 9. Plasma progesterone, measured by radioimmunoassay, was reduced from 4.67±0.59 to 2.69±0.66 ng ml⁻¹(p<0.01) 48 h after administration of 250μg cloprostenol on day 9. 250μg cloprostenol also reduced blood flow per corpus luteum, measured by ⁸⁵Sr-labelled 15μm microspheres, both at 3 h (20.20±10.36 to 9.40±4.2μ1 min⁻¹; p0.05) and at 48 h 18.47±8.27 to 5.23±1.90μl min⁻¹; p<0.01) after administration on day 9. No adverse side-effects were observed at any dose level of cloprostenol used. It was concluded that cloprostenol is a useful experimental luteolysin in the guinea pig.     

Application of high-performance liquid chromatography of plasma fatty acids as their phenacyl esters to evaluate splanchnic and renal fatty acid balance in vivo

Plasma fatty acids from renal and hepatic veins, and arterialized hand vein obtained in 20 subjects before and after insulin infusion were separated by reversed-phase high-performance liquid chromatography following phenacyl esterification. Separation and quantification over the range 1.0–100 nmol per injection of nine fatty acids was achieved within 60 min using [²H₃₁]palmitic acid as internal standard. Analytical recoveries were greater than 90% and the intra- and inter-assay coefficients of variation were less than 2.5 and 4.0%, respectively. Following insulin infusion, net splanchnic uptake of total fatty acids decreased from 3.0±0.3 to 1.0±0.1 μmol/kg min (p<0.01), whereas net renal balance remained neutral (−0.04±0.04 vs. −0.06±0.03 μmol/kg min, p=N.S.). Individual fatty acid balance varied from a low of 0.012±0.005 (myristic acid) to a high of 0.95±0.08 (oleic acid) μmol/kg min across the splanchnic tissues and from 0.005±0.002 (stearic acid) to 0.21±0.1 (oleic acid) μmol/kg min across the kidney. There is a substantial diversity in changes in plasma concentration and regional balance of individual fatty acid during short-term fasting and hyperinsulinemia. This method is simple, accurate, and can be applied to assess individual fatty acid metabolism in vivo.     

The pharmacology of L-670,596, a potent and selective thromboxane/prostaglandin endoperoxide receptor antagonist

L-670,596 ((-)6,8-difluoro-9-rho-methylsulfonyl benzyl-1,2,3,4- tetrahydrocarbazol-1-yl-acetic acid) has been shown to be a potent receptor antagonist as evidenced by the inhibition of the binding of 125I-labeled PTA-OH to human platelets (IC50, 5.5 x 10(-9) M), inhibition of U-44069 induced aggregation of human platelet rich plasma (IC50, 1.1 x 10(-7) M), and competitive inhibition of contractions of the guinea pig tracheal chain induced by U-44069 (pA2,9.0). The compound was also active in vivo as shown by inhibition of arachidonic acid and U-44069 induced bronchoconstriction in the guinea pig (ED50 values, 0.04 and 0.03 mg/kg i.v., respectively), U44069 induced renal vasoconstriction in the pig (ED50, 0.02 mg/kg i.v.), and inhibition of ex vivo aggregation of rhesus monkey platelets to U-44069 (active 1-5 mg/kg p.o.). The selectivity of the compound was indicated by the failure to inhibit, first, ADP-induced human or primate platelet aggregation and, second, bronchoconstriction in the guinea pig in vivo and contraction of the guinea pig tracheal chain in vitro to a variety of agonists. It is concluded that L-670,596 is a potent, selective, orally active thromboxane A2/prostaglandin endoperoxide receptor antagonist.     

Sensitive high-performance liquid chromatographic assay for norfloxacin utilizing fluorescence detection

A rapid, sensitive and reproducible reversed-phase high-performance liquid chromatographic assay was developed for the determination of norfloxacin. Following protein precipitation with 10% trichloroacetic acid, norfloxacin and the internal standard enoxacin were extracted from plasma with chloroform, dried and reconstituted in the mobile phase. The chromatographic separation of norfloxacin and the internal standard enoxacin was achieved on a C₈ column with fluorescence detection set at 280 and 418 nm for excitation and emission, respectively. The peaks with a resolution factor greater than 1.5 were free from interferences. Excellent linearity (r² 0.998) was observed over the concentration range 0.025–5.0 μg/ml in plasma. The inter-assay variability was 13.6% or less at all concentrations examined. The suitability of the assay for pharmacokinetic studies was determined by measuring norfloxacin concentration in rat plasma after administration of a single intravenous 10 mg/kg dose.     

Metabolic energy is required in human platelets at any stage during optical aggregation and secretion

The relationship between metabolic energy and platelet aggregation and secretion was investigated by sudden exhaustion of the cell energy content after these platelet responses had been initiated. In normal platelets, optical aggregation was at any stage susceptible to energy exhaustion, whereas single platelet disappearance and secretion were hardly affected. Prelowering the platelet energy content, while preserving the adenylate energy charge, made both optical aggregation and the secretion from dense, α- and acid hydrolase-containing granules susceptible to energy exhaustion, but single platelet disappearance was not affected. Complete arrest of secretion occurred when the energy content had fallen below 3–3.5 μmol ATP equivalents (ATPeq)/10¹¹ platelets, while optical aggregation was interrupted below 2–2.5 μmol ATPeq/10¹¹ platelets. At any stage of optical aggregation and the three secretion responses, the dependence on energy remained the same, indicating a tight coupling between these functions and metabolic energy, which held during the entire responses.     

Cytoprotective and antisecretory properties of a non-diarrheogenic and non-uterotonic prostacyclin analog: U-68, 215

U-68,215 [15-Cyclohexyl-9-deoxo-13, 14-dihydro-2′, 9a-methano-4,5,6,16,17,18,19,20-octanor-3-oxa-3,7-(′1,′3-interphenylene)-PGE₁] is a stable prostacyclin analog. When given orally to rats, it is cytoprotective for the stomach (ED₅₀: 0.8 μg/kg) and the intestine (ED₅₀: 22 μg/kg), is gastric antisecretory (ED₅₀: 35 μg/kg) and antiulcer (aspirin) (ED_{50: 5 μg/kg}). The oral antisecretory ED₅₀ in dogs in 50 μg/kg. It has a long duration of gastric cytoprotection: 8–10 hours compared to 3 hours for 16, 16-dimethyl PGE₂ Unlike most prostaglandins of the E type, it is not diarrheogenic (not enteropooling), it does not induced cellular proliferation of the gastroeintestinal mucosa, when given twice a day for eight days, it is not uterotonic (in monkeys), and it does not prevent embryo implantation in hamsters. It ihibits platelet aggregation (ED₅₀: 300 μg/kg), but does not promote bleeding from cut vessels nor from gastric ulcers. U-68,215 lowers blood pressure at a n oral dose correponding to 1–5 time the antisecretory ED₅₀ in rats and dogs, and to 150 times the cytoprotective ED₅₀ in rats. It may be of therapeutic value in the treatment of conditions where inhibition of gastric acid secretion is desirable, e.g., gastric and duodenal ulcer, and in conditions responding to cytoprotection, e.g., stress ulcers, hemorrhagic gastritis and gastric erosions associated with nonsteroidal antiinflammatory drugs.     

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.     

9α-homo-9,11-epoxy-5,13-prostadienoic acid analogues: Specific stable agonist (SQ 26,538) and antagonist (SQ 26,536) of the human platelet thromboxane receptor

A newly synthesized 9α-homo-9,11-epoxy-5,13-prostadienoic acid analogue, SQ 26,536, (8(R)9(S)11(R)12(S)-9α-homo-9,11-epoxy-5(Z), 13(E)-15S-hydroxyprostadienoic acid) inhibited arachidonic acid (AA)-induced platelet aggregation with an I₅₀ value of 1.7 μ . SQ 26,536 did not inhibit prostaglandin (PG) synthetase activity of bovine seminal vesicle microsomes or thromboxane (Tx) synthetase activity of lysed human blood platelets. SQ 26,536 also inhibited platelet aggregation induced by epinephrine (secondary phase), 9,11-azoPGH₂ and collagen but did not inhibit the primary phase of epinephrine-induced aggregation or ADP-induced platelet aggregation. SQ 26,538 (8(R)9(S)11(R)12(S)-9α-homo-9-, 11-epoxy-5(Z),13(E)-15R-hydroxyprostadienoic acid), a 15-epimer of SQ 26,536, induced platelet aggregation with an A₅₀ value of 2.5 μ . SQ 26,536 competitively inhibited SQ 26,538-induced platelet aggregation with a K_i value of 3 μ . Neither indomethacin, a PG synthetase inhibitor, nor SQ 80,338 (1-(3-phenyl-2-propenyl)-1H-imidazole), a Tx synthetase inhibitor, inhibited SQ 26,538- or 9,11-azoPGH₂-induced platelet aggregation. These data indicate that SQ 26,536 and SQ 26,538 are stable antagonist and agonist, respectively, of the human blood platelet thromboxane receptor.     

Hydrolysis of an orally active platelet inhibitory prostanoid amide in the plasma of several species

The prostanoid 3-oxa-4,5,6-trinor-3,7-inter-m-phenylene-PPGE₁-amide (OI-PGE₁-amide) has a prolonged duration of oral platelet aggregation inhibitory activity when compared to the parent free acid (OI-PGE₁) in the rat. When incubated in rat plasma at 1μg/ml for 30 seconds prior to addition of ADP, OI-PGE₁-amide inhibits in vitro rat platelet aggregation ≈50%. OI-PGE₁ inhibits at 1 ng/ml. Inhibition of platelet aggregation by plasma incubated with OI-PGE₁-amide (1μg/ml) increases with time and the rate of this increase differs with species. Incubation of OI-PGE₁ in plasma does not result in an increase of platelet inhibitory activity with time. The increase of platelet inhibitory activity was assumed to indicate hydrolysis of OI-PGE₁-amide to the more active OI-PGE₁. A compound, different from OI-PGE₁-amide, was isolated by an ion exchange/silica gel separation sequence from an incubation of OI-PGE₁-amide in rat plasma. It had potent platelet aggregation inhibitory activity. This material was shown to be OI-PGE₁ by thin-layer chromatography, gas chromatography and mass spectral analysis. Studies with [³H]-OI-PGE₁-amide confirmed the formation of OI-PGE₁ in plasma incubations. Amide hydrolytic activity was significantly different between species, the rank order being: rat > guinea pig > monkey human > dog. This relationship corresponded with that determined by measuring the increase in platelet inhibitory activity with time in plasma incubations of OI-PGE₁-amide reported above. Present data indicate that (a) OI-PGE₁-amide is hydrolyzed to the parent acid by plasma enzymes of several species and (b) hydrolytic activity of plasma varies widely between species.     

Differing mechanisms for leukotriene D4-induced bronchoconstriction in guinea pigs following intravenous and aerosol administration

Leukotriene D₄ (LTD₄) when administered intravenously or by aerosol to guinea pigs produced changes in pulmonary mechanics including a decrease in dynamic compliance and an increase in pulmonary resistance. The effects of intravenous LTD₄ (0.5 μg kg⁻¹) were short lived and abolished by pretreatment of the animal with either cyclooxygenase inhibitors, a thromboxane synthetase inhibitor (OKY 1555) or an SRS-A antagonist (FPL 55712). These findings suggest that bronchoconstriction produced by the intravenous infusion of LTD₄ at 0.5 μg kg⁻¹ is due to the release of thromboxane A₂. However, in animals treated with indomethacin, LTD₄ at higher doses (>0.8 μg kg⁻¹) still elicited a bronchoconstriction which could be blocked by FPL 557112. Nebulization of 0.1 – 1.0 μg of LTD₄ into the lung produced prolonged changes in pulmonary mechanics which were inhibited by FPL 55712 and were potentiated indomethacin. LTD₄, therefore, when administered by aerosol produced effects on the lung which were not mediated by cyclooxygenase products. Responses to nebulized rather than intravenous LTD₄ in the guinea pig may more closely resemble those seen in human tissues.     

Determination of norepinephrine in small volume plasma samples by stable-isotope dilution gas chromatography–tandem mass spectrometry with negative ion chemical ionization

A stable-isotope based gas chromatography–tandem mass spectrometry–negative ion chemical ionization method was developed for the determination of norepinephrine (NE) levels in small volumes (25–100 μl) of plasma. NE was stabilized in plasma by the addition of semicarbazide and spiked with deuterium-labeled norepinephrine internal standard. The analytes were isolated from the plasma by solid-phase extraction using phenylboronic acid columns and derivatized using pentafluoropropionic anhydride. The derivatized analytes were chromatographed on a capillary column and detected by tandem mass spectrometry with negative ion chemical ionization. Unparalleled sensitivity and selectivity were obtained using this detection scheme, allowing the unambiguous analysis of trace levels of NE in small-volume plasma samples. Linear standard curves were obtained for NE over a mass range from 1 to 200 pg per sample. The method had a limit of quantitation of 10 pg NE/ml plasma when using a 100-μl sample aliquot (1 pg/sample). Accuracy for the analysis of plasma samples spiked with 10 to 200 pg NE/ml typically ranged from 100±10%, with RSD values of less than 10%. The methodology was applied to determine the effect of clonidine on plasma NE levels in conscious spontaneously hypertensive rats. Administration of clonidine (30 μg/kg) produced an 80% reduction in plasma NE accompanied by a 30% reduction in heart and mean arterial pressure that persisted >90 min after drug administration. The ability to take multiple samples from individual rats allowed the time course for the effect of clonidine to be mapped out using only one group of animals.     

Clinical efficacy of a stable prostacyclin analog, iloprost, in diabetic neuropathy

Iloprost, a stable prostacyclin analog, was evaluated clinically for its ability to ameliorate the symptoms of peripheral neuropathy associated with diabetes. In an open, nonrandomized trial, 13 diabetic patients with neuropathy but without proliferative retinopathy received an intravenous infusion of iloprost at a dose of 10 μg, at a rate of 0.1 μg/kg/h, twice daily for two weeks.The administration of Iloprost relieved the majority of such subjective symptoms as pain, numbness or sensation of cold and to a lesser extent, such autonomic symptoms as dizziness. In contrast, there was little evidence of objective improvement, e.g., in motor nerve conduction velocity. Iloprost treatment significantly inhibited the platelet aggregation rate stimulated by collagen . In the one patient tested, thermography revealed an increase in skin temperature by more than 2°C.Side effects associated with Iloprost included headache (3 patients) or aggravation of pain in the extremities (2 patients) and could be ameliorated by slowing the infusion rate or by discontinuing the drug (one patient). Iloprost appears to be safe and effective for relieving the symptoms of diabetic neuropathy. Our results provide the rationale for a double-blind, clinical trial in larger populations of diabetics with peripheral neuropathy.     

A new prostaglandin E1 analogue (CL-115,574) II. Effects on gastric acid secretion in the dog

The efficacy of CL-115,574, a prostaglandin E₁ analogue, as an acid antisecretory agent was evaluated in dogs. CL-115,574 inhibited acid secretion maximally at an oral dose of 20 μg/kg causing 100% inhibition of acid secretion up to one hour after administration, with significant inhibition of secretion (30%) still present nearly four hours after drug administration. The wide disparity between the maximally effective antisecretory dose 20 μg/kg and the dose at which reproducible side effects occurred (1 mg/kg) suggests that this compound may be developed as an antisecretory compound for use in man.