IP; PGI2 analogue

Prostacyclin (PGI2) is produced in the fluid of the oviduct and promotes the development of the embryo[1].
Iloprost, a PGI2 analog, influences the developmental competence and maturation of bovine oocytes[1].
Iloprost (0.5 μM; 22–24 h) raises the percentage of expanded blastocysts and blastocyst rates in bovine embryos[1].
Iloprost (0.5 μM; 22-24 h) assists maturation rates and cumulus cell expansion of bovine oocytes, and increases the mRNA expression of genes related to cumulus expansion[1].
Iloprost (0.5 μM; 22–24 h) stimulates an anti-apoptotic balance in the transcription of apoptosis-related genes (BCL2 and BAX), thereby decreasing the incidence of apoptosis in COCs [1].

Iloprost (0.3 mg/kg/min; via s.c. mini pumps; 33 d) possesses a strong anti-metastatic effect in a rat tumor model that spontaneously metastasizes[2].
Iloprost (0.2 mg/kg/d; i.p.; 10 d) reduces inflammation and the effects of hyperoxia in the lungs of newborn mice; the impairment caused by hyperoxia is mediated by Cyclooxygenase-2 (COX-2/PTGS2)[3].
Iloprost (0.2 mg/kg; i.v. or i.p.) has a brief half-life and is often used in treatment as a frequent (every 2-4 hours) inhalation[4].

Cell Line: Bovine oocytes: cumulus oocyte complexes (COCs)
Concentration: 0.5 μM
Incubation Time: 22-24 hours
Result: Increased mRNA expression levels of cysteine proteinases cathepsins, including ADAM17, AREG, and TNFAIP6 23 and cathepsin genes (CTSK and CTSS).

Spontaneously metastasizing R 3327 MAT Lu prostate carcinoma in Cop rat
0.3 mg/kg/min
Subcutaneous administration via Alzet mini pumps; continuously for 33 days

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Cyclooxygenase-2 (COX-2/PTGS2) mediates hyperoxia-induced impairment of lung development in newborn animals and is increased in the lungs of human infants with bronchopulmonary dysplasia (BPD). COX-2 catalyzes the production of cytoprotective prostaglandins, such as prostacyclin (PGI2), as well as proinflammatory mediators, such as thromboxane A2. Our objective was to determine whether iloprost, a synthetic analog of PGI2, would attenuate hyperoxia effects in the newborn mouse lung. To test this hypothesis, newborn C57BL/6 mice along with their dams were exposed to normoxia (21% O2) or hyperoxia (85% O2) from 4 to 14 days of age in combination with daily intraperitoneal injections of either iloprost 200 µg·kg-1·day-1, nimesulide (selective COX-2 antagonist) 100 mg·kg-1·day-1, or vehicle. Alveolar development was estimated by radial alveolar counts and mean linear intercepts. Lung function was determined on a flexiVent, and multiple cytokines and myeloperoxidase (MPO) were quantitated in lung homogenates. Lung vascular and microvascular morphometry was performed, and right ventricle/left ventricle ratios were determined. We determined that iloprost (but not nimesulide) administration attenuated hyperoxia-induced inhibition of alveolar development and microvascular density in newborn mice. Iloprost and nimesulide both attenuated hyperoxia-induced, increased lung resistance but did not improve lung compliance that was reduced by hyperoxia. Iloprost and nimesulide reduced hyperoxia-induced increases in MPO and some cytokines (IL-1β and TNF-α) but not others (IL-6 and KC/Gro). There were no changes in pulmonary arterial wall thickness or right ventricle/left ventricle ratios. We conclude that iloprost improves lung development and reduces lung inflammation in a newborn mouse model of BPD.[3]

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Much attention has recently focused on the role of tumor cell-platelet interaction in the metastatic cascade. Prostacyclin and stable prostacyclin analogues have been shown to inhibit specifically the formation of metastases in experimental tumor models. This action is based on their ability to reduce the attachment of tumor cells to platelets and to inhibit adhesion of tumor cells-platelet aggregates to the endothelial lining. To investigate the antimetastatic potential of two prostacyclin analogues (Iloprost and Eptaloprost, Schering AG), we have tested these compounds in the spontaneously metastasizing R 3327 MAT Lu prostate carcinoma of the Cop rat in two types of experiments. Treatment was performed for 33 days, starting one day before s.c. implantation of the tumor. The primary s.c.-implanted tumor remained in situ throughout the experiment. In the first test, Iloprost (0.3 micrograms/kg/min) and Eptaloprost (0.1 micrograms/kg/min) were administered via Alzet mini pumps s.c.. There was a considerable reduction of the number of visible lung metastases by Eptaloprost. In the second test, Eptaloprost was administered p.o. in doses of 0.1 and 0.5 mg/kg daily. The number of lung metastases was significantly reduced. Both compounds had no effect on the growth of the primary tumor in the first as well as in the second test. These data show that the prostacyclin analogue Eptaloprost has a significant antimetastatic activity in a spontaneously metastasizing tumor model and thus merits further investigation.[4]

Absorption, Distribution and Excretion
Following inhalation of iloprost (5 mcg) patients with pulmonary hypertension have iloprost peak plasma levels of approximately 150 pg/mL. Iloprost was generally not detectable in plasma 30 minutes to one hour after inhalation. The absolute bioavailability of inhaled iloprost has not been determined.
Unchanged iloprost and its metabolites are mainly excreted in urine.
Following intravenous infusion, the apparent steady-state volume of distribution was 0.7 to 0.8 L/kg in healthy subjects.
Clearance in normal subjects was approximately 20 mL/min/kg.

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Metabolism / Metabolites
In vitro studies reveal that cytochrome P450-dependent metabolism plays only a minor role in the biotransformation of iloprost. Iloprost is metabolized principally via β-oxidation of the carboxyl side chain. The main metabolite is tetranor-iloprost, which was shown to be pharmacologically inactive in animal experiments. In rabbits, dinor-iloprost has also been identified as a drug metabolite. The chemical structures of iloprost metabolites have not been characterized.

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Biological Half-Life
The half-life of iloprost is 20 to 30 minutes.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of iloprost during breastfeeding. The half-life of iloprost is 20 to 30 minutes and iloprost is generally not detectable in plasma 30 to 60 minutes after inhalation. It is unlikely that clinically important amounts of iloprost are excreted into milk after 1 hour following an inhaled dose.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Iloprost is approximately 60% protein-bound, mainly to albumin, and this ratio is concentration-independent in the range of 30 to 3000 pg/mL.

[1]. Iloprost affects in vitro maturation and developmental competence of bovine oocytes. Theriogenology. 2020 Nov;157:286-296.

[2]. Pharmacokinetics of iloprost and cicaprost in mice. Prostaglandins. 1992 Nov;44(5):431-42.

[3]. Iloprost attenuates hyperoxia-mediated impairment of lung development in newborn mice. Am J Physiol Lung Cell Mol Physiol. 2018 Oct 1;315(4):L535-L544.

[4]. Effects of prostacyclin analogues in in vivo tumor models. Adv Prostaglandin Thromboxane Leukot Res . 1991:21B:901-8.

Iloprost is a carbobicyclic compound that is prostaglandin I2 in which the endocyclic oxygen is replaced by a methylene group and in which the (1E,3S)-3-hydroxyoct-1-en-1-yl side chain is replaced by a (3R)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl group. A synthetic analogue of prostacyclin, it is used as the trometamol salt (generally by intravenous infusion) for the treatment of peripheral vascular disease and pulmonary hypertension. It has a role as a platelet aggregation inhibitor and a vasodilator agent. It is a monocarboxylic acid, a secondary alcohol and a carbobicyclic compound.
Iloprost is a mimetic of prostacyclin (PGI2; epoprostenol). Iloprost consists of a mixture of the 4R and 4S diastereoisomers at a ratio of approximately 53:47. It is a potent vasodilator with reported anti-thrombotic properties.
Iloprost is a Prostacycline.
Iloprost is a prostacyclin analogue with potential chemopreventive activity. Iloprost binds to the prostacyclin receptor in various target cells, thereby causing vasodilation, inhibition of platelet aggregation, and decreased tumor cell adhesion to endothelium among other effects. Prostacyclin is a naturally occurring eicosanoid with anti-inflammatory, antineoplastic, and anti-metastatic properties. (NCI05)
An eicosanoid, derived from the cyclooxygenase pathway of arachidonic acid metabolism. It is a stable and synthetic analog of EPOPROSTENOL, but with a longer half-life than the parent compound. Its actions are similar to prostacyclin. Iloprost produces vasodilation and inhibits platelet aggregation.
See also: Iloprost tromethamine (is active moiety of).

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Drug Indication
Iloprost is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve a composite endpoint consisting of exercise tolerance, symptoms (NYHA Class), and lack of deterioration. Studies establishing effectiveness included predominately patients with NYHA Functional Class III–IV symptoms and etiologies of idiopathic or heritable PAH (65%) or PAH associated with connective tissue diseases (23%). It is also indicated for the treatment of severe frostbite in adults to reduce the risk of digit amputations. Effectiveness was established in young, healthy adults who suffered frostbite at high altitudes.
Treatment of patients with primary pulmonary hypertension, classified as New York Heart Association functional class III, to improve exercise capacity and symptoms.

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Mechanism of Action
In pulmonary arterial hypertension, endothelial vasoactive mediators such as nitric oxide and prostacyclin are released to induce vasoconstriction. Iloprost mimics the biological actions of prostacyclin, a prostanoid and potent vasodilator produced in the vascular endothelium.

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Pharmacodynamics
Iloprost is a synthetic analogue of prostacyclin PGI2 that dilates systemic and pulmonary arterial vascular beds. It was shown to inhibit platelet aggregation, but whether this effect contributes to its vasodilatory action has not been elucidated. There are two diastereoisomers of iloprost and the 4S isomer is reported to exhibit a higher potency in dilating blood vessels compared to the 4R isomer. When administered intravenously in patients with peripheral vascular conditions such as critical leg ischemia and delayed amputation, iloprost was shown to promote cytoprotection.

C22H32O4

360.4871

360.23

C, 73.30; H, 8.95; O, 17.75

78919-13-8

Iloprost-d4; 1035094-10-0

5311181

Clear solution in acetone (white Oily or waxy solid in pure form)

1.2±0.1 g/cm3

539.2±50.0 °C at 760 mmHg

115.7ºC

294.0±26.6 °C

0.0±3.3 mmHg at 25°C

1.629

2.94

3

4

8

26

606

5

C(/[C@H]1[C@H](O)C[C@@H]2C/C(/C[C@H]12)=C\CCCC(=O)O)=C\[C@@H](O)C(C)CC#CC

HIFJCPQKFCZDDL-ACWOEMLNSA-N

InChI=1S/C22H32O4/c1-3-4-7-15(2)20(23)11-10-18-19-13-16(8-5-6-9-22(25)26)12-17(19)14-21(18)24/h8,10-11,15,17-21,23-24H,5-7,9,12-14H2,1-2H3,(H,25,26)/b11-10+,16-8+/t15?,17-,18+,19-,20+,21+/m0/s1

(5E)-5-[(3aS,4R,5R,6aS)-5-hydroxy-4-[(E,3S)-3-hydroxy-4-methyloct-1-en-6-ynyl]-3,3a,4,5,6,6a-hexahydro-1H-pentalen-2-ylidene]pentanoic acid

ZK-36374; Endoprost; ZK36374; Iloprost; ZK00036374; ZK 36374; Ilomedin; BAYQ6256; ZK-00036374; BAY-Q6256; Ciloprost; Ventavis; CHEMBL494; 78919-13-8; Endoprost; Ilomedin; Iloprostum; UNII-JED5K35YGL;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~100 mg/mL (~277.4 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.94 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.94 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.94 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)