Iloprost

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{{DrugProjectFormSinglePage |authorTag=Sheng Shi, M.D. [1]; Adeel Jamil, M.D. [2] |genericName=Iloprost |aOrAn=a |drugClass=Prostaglandin Analog |indicationType=treatment |indication=pulmonary arterial hypertension (PAH) (WHO Group 1) |adverseReactions=vasodilatation, flushing, nausea, trismus, headache, increasing frequency of cough, and influenza-like symptoms |blackBoxWarningTitle=TITLE |blackBoxWarningBody=Condition Name: (Content)

|fdaLIADAdult=

Pulmonary arterial hypertension

  • Indication
  • Dosing information
  • Iloprost is intended to be inhaled using the I-neb® AAD® System. The first inhaled dose should be 2.5 mcg (as delivered at the mouthpiece).
  • If this dose is well tolerated, dosing should be increased to 5.0 mcg and maintained at that dose;
  • otherwise maintain the dose at 2.5 mcg.
  • Frequency: 6 to 9 times per day (no more than once every 2 hours) during waking hours, according to individual need and tolerability.
  • The maximum daily dose evaluated in clinical studies was 45 mcg (5 mcg 9 times per day).
  • Direct mixing of Iloprost with other medications in the I-neb® AAD® System has not been evaluated; do not mix with other medications.
  • To avoid potential interruptions in drug delivery due to equipment malfunctions, the patient should have easy access to a back-up I-neb®AAD® System.
  • Iloprost is supplied in 1 mL ampules in two concentrations: 10 mcg/mL and 20 mcg/mL.

Use in Patients with Pre-existing Hepatic Impairment

  • Dosing information
  • Because iloprost elimination is reduced in patients with impaired liver function , consider increasing the dosing interval (e.g., 3-4 hours between doses depending on the patient's response at the end of the dose interval) in patients with Child-Pugh Class B or C hepatic impairment.

Use in Patients with Pre-existing Renal Impairment

  • Dosing information
  • Dose adjustment is not required in patients who are not on dialysis. The effect of dialysis on iloprost is unknown

|offLabelAdultGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Iloprost in adult patients.

|offLabelAdultNoGuideSupport=

Radiographic contrast agent nephropathy

  • Dosing information
  • 0.5 nanograms/kg/min (ng/kg/min) 30 to 90 minutes prior to contrast administration [1]

Transient osteoporosis

  • Dosing information
  • 50 mcg (reduced to 25 mcg and then 20 mcg due to adverse effects) in 500 mL of sodium chloride solution administered IV over 6 hours on 5 consecutive days. [2]
  • 50 mcg 3 times daily for 3 days [3]

|fdaLIADPed=Safety and efficacy in pediatric patients have not been established. |offLabelPedGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Iloprost in pediatric patients. |offLabelPedNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Iloprost in pediatric patients. |contraindications=None |warnings=Iloprost solution should not be allowed to come into contact with the skin or eyes; oral ingestion of Iloprost solution should be avoided.

Risk of Syncope

Monitor vital signs while initiating Iloprost. Do not initiate Iloprost in patients with systolic blood pressure below 85 mmHg. Syncope can also occur in association with pulmonary arterial hypertension, particularly in association with physical exertion. The occurrence of exertional syncope may reflect a therapeutic gap or insufficient efficacy, and the need to adjust dose or change therapy should be considered.

Pulmonary Venous Hypertension

Should signs of pulmonary edema occur when inhaled Iloprost is administered in patients with pulmonary hypertension, stop treatment immediately, as this may be a sign of pulmonary venous hypertension.

Bronchospasm

Iloprost inhalation can induce bronchospasm. Bronchospasm may be more severe or frequent in patients with a history of hyperreactive airways. Iloprost has not been evaluated in patients with chronic obstructive pulmonary disease (COPD), severe asthma, or with acute pulmonary infections. |clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Pre-marketing safety data on Iloprost were obtained from 215 patients with pulmonary arterial hypertension receiving iloprost in two 12-week clinical trials and two long-term extensions. Patients received inhaled Iloprost for periods of from 1 day to more than 3 years. The median number of weeks of exposure was 15. Forty patients completed 12 months of open-label treatment with iloprost. The following table shows adverse events reported by at least 4 Iloprost patients and reported at least 3% more frequently for Iloprost patients than placebo patients in the 12-week placebo-controlled study.

This image is provided by the National Library of Medicine.

Pre-marketing serious adverse events reported with the use of inhaled Iloprost and not shown in Table 1 include congestive heart failure, chest pain, supraventricular tachycardia, dyspnea, peripheral edema, and kidney failure. In a small clinical trial (the STEP trial) , safety trends in patients receiving concomitant bosentan and Iloprost were consistent with those observed in the larger experience of the Phase 3 study in patients receiving only Iloprost or bosentan.

Adverse events with higher doses

In a study in healthy subjects (n=160), inhaled doses of iloprost solution were given every 2 hours, beginning with 5 mcg and increasing up to 20 mcg for a total of 6 dose inhalations (total cumulative dose of 70 mcg) or up to the highest dose tolerated in a subgroup of 40 subjects. There were 13 subjects (32%) who failed to reach the highest scheduled dose (20 mcg). Five were unable to increase the dose because of (mild to moderate) transient chest pain/discomfort/tightness, usually accompanied by headache, nausea, and dizziness. The remaining 8 subjects discontinued for other reasons. |postmarketing=The following adverse reactions have been identified during the postapproval use of Iloprost. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cases of bronchospasm and wheezing have been reported, particularly in patients with a history of hyperreactive airways . Bleeding events most commonly reported as epistaxis and hemoptysis were observed on Iloprost treatment . Cases of thrombocytopenia, dizziness, diarrhea, mouth and tongue irritation, nasal congestion, dysgeusia, hypersensitivity, and rash have also been reported with the use of Iloprost. |drugInteractions=During clinical trials, iloprost was used concurrently with anticoagulants, diuretics, cardiac glycosides, calcium channel blockers, analgesics, antipyretics, nonsteroidal anti-inflammatory drugs, corticosteroids, and other medications. Intravenous infusion of iloprost had no effect on the pharmacokinetics of digoxin. Acetylsalicylic acid did not alter the clearance (pharmacokinetics) of iloprost.

Cytochrome P450

Although clinical studies have not been conducted with Iloprost (inhaled iloprost), in vitro studies of iloprost indicate that no relevant inhibition of cytochrome P450 drug metabolism would be expected.

Antihypertensives and Vasodilators

In studies in normal subjects, there was no pharmacodynamic interaction between intravenous iloprost and either nifedipine, diltiazem, or captopril. However, Iloprost has the potential to increase the hypotensive effect of vasodilators and antihypertensive agents.

Anticoagulants and Platelet Inhibitors

Since Iloprost inhibits platelet function, there is a potential for increased risk of bleeding, particularly in patients maintained on anticoagulants or platelet inhibitors. |FDAPregCat=C |useInPregnancyFDA=Iloprost has been shown to be teratogenic in rats as described below. There are no adequate and well controlled studies in pregnant women. Iloprost should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In developmental toxicity studies in pregnant Han-Wistar rats, continuous intravenous administration of iloprost at a dosage of 0.01 mg/kg daily (serum levels not available) led to shortened digits of the thoracic extremity in fetuses and pups. In comparable studies in pregnant Sprague-Dawley rats which received iloprost clathrate (13% iloprost by weight) orally at dosages of up to 50 mg/kg/day (Cmax of 90 ng/mL), in pregnant rabbits at intravenous dosages of up to 0.5 mg/kg/day (Cmax of 86 ng/mL), and in pregnant monkeys at dosages of up to 0.04 mg/kg/day (serum levels of 1 ng/mL), no such digital anomalies or other gross-structural abnormalities were observed in the fetuses/pups. However, in gravid Sprague-Dawley rats, iloprost clathrate (13% iloprost) significantly increased the number of non-viable fetuses at a maternally toxic oral dosage of 250 mg/kg/day and in Han-Wistar rats was found to be embryolethal in 15 of 44 litters at an intravenous dosage of 1 mg/kg/day. |useInNursing=It is not known whether Iloprost is excreted in human milk. In studies with Han-Wistar rats, higher mortality was observed in pups of lactating dams receiving iloprost intravenously at 1 mg/kg daily. In Sprague-Dawley rats, higher mortality was also observed in nursing pups at a maternally toxic oral dose of 250 mg/kg/day of iloprost clathrate (13% iloprost by weight). In rats a passage of low levels of iloprost or metabolites in to the milk was observed (less than 1% of iloprost dose given intravenously). No disturbance of post-natal development and reproductive performance was seen in animals exposed during lactation. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Iloprost, a decision to discontinue nursing should be made, taking into account the importance of the drug to the mother. |useInPed=Safety and efficacy in pediatric patients have not been established. |useInGeri=Clinical studies of Iloprost did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. |useInRenalImpair=Iloprost has not been evaluated in subjects with impaired renal function. However, in a study with intravenous infusion of iloprost in patients with end-stage renal failure requiring intermittent dialysis treatment (n=7), the mean AUC0-4h was 230 pg*h/mL compared to 54 pg*h/mL in patients with renal failure (n=8) not requiring intermittent dialysis and 48 pg*h/mL in normals. The half-life was similar in both groups. The effect of dialysis on iloprost exposure has not been evaluated. |useInHepaticImpair=Iloprost has not been evaluated in subjects with impaired hepatic function. However, in an intravenous iloprost study in patients with liver cirrhosis, the mean clearance in Child- Pugh Class B subjects (n=5) was approximately 10 mL/min/kg (half that of healthy subjects). Following oral administration, the mean AUC0-8h in Child-Pugh Class B subjects (n=3) was 1725 pg*h/mL compared to 117 pg*h/mL in normal subjects (n=4) receiving the same oral iloprost dose. In Child-Pugh Class A subjects (n=5), the mean AUC0-8h was 639 pg*h/mL. Although exposure increased with hepatic impairment, there was no effect on half-life. |administration=Inhale |monitoring=Vital signs should be monitored while initiating Iloprost |IVCompat=There is limited information about the IV Compatibility. |overdose=In clinical trials of Iloprost, no case of overdose was reported. Signs and symptoms to be anticipated are extensions of the dose-limiting pharmacological effects, including hypotension, headache, flushing, nausea, vomiting, and diarrhea. A specific antidote is not known. Interruption of the inhalation session, monitoring, and symptomatic measures are recommended. |drugBox={{Drugbox2 | Watchedfields = changed | verifiedrevid = 443868674 | IUPAC_name = 5-{(E)-(1S,5S,6R,7R)-7-hydroxy-6[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octen-6-inyl]-bicyclo[3.3.0]octan-3-ylidene}pentanoic acid | image = Iloprost 2D structure.png | width = 300 | image2 = Iloprost ball-and-stick animation.gif

| tradename = Iloprost, Ilomedine | Drugs.com = Monograph | licence_EU = Iloprost (inhalation) or Ilomedine (intravenous) | licence_US = Iloprost | pregnancy_category = C | legal_status = Rx-only | routes_of_administration = Inhaled Intravenous

| bioavailability = The absolute bioavailability of inhaled iloprost has not been determined. | metabolism = Iloprost is metabolized principally via β-oxidation of the carboxyl side chain. The main metabolite is tetranor-iloprost, which is found in the urine in free and conjugated form. In animal experiments, tetranor-iloprost was pharmacologically inactive. | elimination_half-life = 20–30 minutes | excretion = ?

| CASNo_Ref =  ☑Y | CAS_number_Ref =  ☑Y | CAS_number = 78919-13-8 | CAS_supplemental = 73873-87-7 | ATC_prefix = B01 | ATC_suffix = AC11 | PubChem = 6435378 | DrugBank_Ref =  ☑Y | DrugBank = DB01088 | ChemSpiderID_Ref =  ☑Y | ChemSpiderID = 4940161 | UNII_Ref =  ☑Y | UNII = JED5K35YGL | KEGG_Ref =  ☑Y | KEGG = D02721 | ChEMBL_Ref =  ☑Y | ChEMBL = 236025

| C=22 | H=32 | O=4 | molecular_weight = 360.48 g/mol | smiles = O=C(O)CCC/C=C1/C[C@@H]2C(/C=C/[C@@H](O)C(C)CC#CC)[C@H](O)C[C@@H]2C1 | InChI = 1/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 | InChIKey = HIFJCPQKFCZDDL-SGSAMSKHBK | StdInChI_Ref =  ☑Y | StdInChI = 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 | StdInChIKey_Ref =  ☑Y | StdInChIKey = HIFJCPQKFCZDDL-SGSAMSKHSA-N }} |mechAction=Iloprost is a synthetic analog of prostacyclin PGI2. Iloprost dilates systemic and pulmonary arterial vascular beds. It also affects platelet aggregation but the relevance of this effect to the treatment of pulmonary hypertension is unknown. The two diastereo- isomers of iloprost differ in their potency in dilating blood vessels, with the 4S isomer substantially more potent than the 4R isomer. |structure=Iloprost (iloprost) Inhalation Solution is a clear, colorless, sterile solution containing iloprost formulated for inhalation via the I-neb® AAD® (Adaptive Aerosol Delivery) System. Iloprost is supplied in 1 mL single-use glass ampules containing either 10 mcg/mL or 20 mcg/mL. For the 10 mcg/mL solution, one mL of the solution contains 0.01 mg iloprost, 0.81 mg ethanol, 0.121 mg tromethamine, 9.0 mg sodium chloride, and approximately 0.51 mg hydrochloric acid (for pH adjustment to 8.1) in water for injection. For the 20 mcg/mL solution, one mL of the solution contains 0.02 mg iloprost, 1.62 mg ethanol, 0.242 mg tromethamine, 9.0 mg sodium chloride, and approximately 0.76 mg hydrochloric acid (for pH adjustment to 8.4) in water for injection. The solution contains no preservatives. The chemical name for iloprost is (E)-(3aS, 4R, 5R, 6aS)-hexahydro-5-hydroxy-4-[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octen-6-ynyl]-Δ2(1H),Δ-pentalenevaleric acid. Iloprost consists of a mixture of the 4R and 4S diastereoisomers at a ratio of approximately 53:47. Iloprost is an oily substance, which is soluble in methanol, ethanol, ethyl acetate, acetone, and pH 7 buffer, sparingly soluble in buffer pH 9, and very slightly soluble in distilled water, buffer pH 3, and buffer pH 5. The molecular formula of iloprost is C22H32O4. Its relative molecular weight is 360.49. The structural formula is shown below:

This image is provided by the National Library of Medicine.

|PD=There is limited information about the pharmacokinetic. |PK=General: In pharmacokinetic studies in animals, there was no evidence of interconversion of the two diastereoisomers of iloprost. In human pharmacokinetic studies, the two diastereoisomers were not individually assayed. Iloprost administered intravenously has linear pharmacokinetics over the dose range of 1 to 3 ng/kg/min. The half-life of iloprost is 20 to 30 minutes. 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 1 hour after inhalation. Absorption and Distribution: The absolute bioavailability of inhaled iloprost has not been determined. Following intravenous infusion, the apparent steady-state volume of distribution was 0.7 to 0.8 L/kg in healthy subjects. Iloprost is approximately 60% protein-bound, mainly to albumin, and this ratio is concentration-independent in the range of 30 to 3000 pg/mL. Metabolism and Excretion: 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 is found in the urine in free and conjugated form. In animal experiments, tetranor-iloprost was pharmacologically inactive. Clearance in normal subjects was approximately 20 mL/min/kg. A mass-balance study using intravenously and orally administered [3H]-iloprost in healthy subjects (n=8) showed recovery of 81% of total radioactivity over 14 hours post-dose, with 68% and 12% recoveries in urine and feces, respectively. |nonClinToxic=====Carcinogenesis, Mutagenesis, Impairment of Fertility====

Iloprost was not mutagenic in bacterial and mammalian cells in the presence or absence of extrinsic metabolic activation. Iloprost did not cause chromosomal aberrations in vitro in human lymphocytes and was not clastogenic in vivo in NMRI/SPF mice. There was no evidence of a tumorigenic effect of iloprost clathrate (13% iloprost by weight) in Sprague-Dawley rats dosed orally for up to 8 months at doses of up to 125 mg/kg/day (Cmax of 45 ng/mL serum), followed by 16 months at 100 mg/kg/day, or in Crl:CD-1®(ICR)BR albino mice dosed orally for up to 24 months at doses of up to 125 mg/kg/day (Cmax of 156 ng/mL serum). The recommended clinical dosage regimen for iloprost (5 mcg) affords a serum Cmax of 0.16 ng/mL. Fertility of males or females was not impaired in Han-Wistar rats at intravenous doses up to 1 mg/kg/day. |clinicalStudies=A randomized, double-blind, multi-center, placebo-controlled trial was conducted in 203 adult patients (inhaled iloprost: n=101; placebo: n=102) with NYHA Class III or IV pulmonary arterial hypertension (PAH, WHO Group 1; idiopathic in 53%, associated with connective tissue disease, including CREST and scleroderma, in 17%, or associated with anorexigen use in 2%) or PAH related to chronic thromboembolic disease (WHO Group 4; 28%). Inhaled iloprost (or placebo) was added to patients' current therapy, which could have included anticoagulants, vasodilators (e.g., calcium channel blockers), diuretics, oxygen, and digoxin, but not PGI2 (prostacyclin or its analogs) or endothelin receptor antagonists. Patients received 2.5 or 5.0 mcg of iloprost by repeated inhalations 6 to 9 times per day during waking hours. The mean age of the entire study population was 52 years and 68% of the patients were female. The majority of patients (59%) were NYHA Class III. The baseline 6-minute walk test values reflected a moderate exercise limitation (the mean was 332 meters for the iloprost group and 315 meters for the placebo group). In the iloprost group, the median daily inhaled dose was 30 mcg (range of 12.5 to 45 mcg/day). The mean number of inhalations per day was 7.3. Ninety percent of patients in the iloprost group never inhaled study medication during the nighttime. The primary efficacy endpoint was clinical response at 12 weeks, a composite endpoint defined by: a) improvement in exercise ability (6-minute walk test) by at least 10% versus baseline evaluated 30 minutes after dosing, b) improvement by at least one NYHA class versus baseline, and c) no death or deterioration of pulmonary hypertension. Deterioration required two or more of the following criteria: 1) refractory systolic blood pressure < 85 mmHg, 2) worsening of right heart failure with cardiac edema, ascites, or pleural effusion despite adequate background therapy, 3) rapidly progressive cardiogenic hepatic failure (e.g., leading to an increase of GOT or GPT to > 100 U/L, or total bilirubin ≥ 5 mg/dL), 4) rapidly progressive cardiogenic renal failure (e.g., decrease of estimated creatinine clearance to ≤ 50% of baseline), 5) decrease in 6-minute walking distance by ≥ 30% of baseline value, 6) new long-term need for i.v. catecholamines or diuretics, 7) cardiac index ≤ 1.3 L/min/m2, 8) CVP ≥ 22 mmHg despite adequate diuretic therapy, and 9) SVO2 ≤ 45% despite nasal O2 therapy. Although effectiveness was seen in the full population (response rates for the primary composite endpoint of 17% and 5%; p=0.007), there was inadequate evidence of benefit in patients with pulmonary hypertension associated with chronic thromboembolic disease (WHO Group 4); the results presented are therefore those related to patients with PAH (WHO Group 1). The response rate for the primary efficacy endpoint among PAH patients was 19% for the iloprost group, compared with 4% for the placebo group (p=0.0033). All three components of the composite endpoint favored iloprost (Figure 1).

This image is provided by the National Library of Medicine.

The absolute change in 6-minute walk distance (Figure 2) measured (using all available data and no imputation) 30 minutes after inhalation among patients with PAH was greater in the iloprost group compared to the placebo group at all time points. At Week 12, the placebo-corrected difference was 40 meters (p<0.01). When walk distance was measured immediately prior to inhalation, the improvement compared to placebo was approximately 60% of the effect seen at 30 minutes after inhalation.

This image is provided by the National Library of Medicine.

The effect of Iloprost in various subgroups is shown in Table 2.

This image is provided by the National Library of Medicine.

Hemodynamic assessments obtained at week 12 before inhalation in both groups (at least 2 hours after a previous dose, trough) and after inhalation in the iloprost group (approximately 15 minutes after a dose, peak), are shown in Table 3. The relationship between hemodynamic changes and clinical effects is unknown.

This image is provided by the National Library of Medicine.

In a small, randomized, double-blind, placebo-controlled study (the STEP trial), 34 patients treated with bosentan 125 mg bid for at least 16 weeks tolerated the addition of inhaled iloprost (up to 5 mcg 6 to 9 times per day during waking hours). The mean daily inhaled dose was 27 mcg and the mean number of inhalations per day was 5.6. |howSupplied=Iloprost (iloprost) Inhalation Solution is supplied in cartons of 30 x 1 mL clear glass single-use ampules as follows: 1 mL ampule containing iloprost 10 mcg per mL, carton of 30 (NDC 66215-302-30) 1 mL ampule containing iloprost 20 mcg per mL, carton of 30 (NDC 66215-303-30) |storage=Store at 20 – 25°C (68 – 77°F) Excursions permitted to 15 – 30°C (59 – 86°F) [See USP Controlled Room Temperature] |fdaPatientInfo=Patients receiving Iloprost should be advised to use the drug only as prescribed with the I-neb® AAD® System, following the manufacturer's instructions. Patients should be trained in proper administration techniques including dosing frequency, ampule dispensing, I-neb® AAD® System operation, and equipment cleaning. Advise patients that they may have a fall in blood pressure with Iloprost, so they may become dizzy or even faint. They should stand up slowly when they get out of a chair or bed. If fainting gets worse, patients should consult their physicians about dose adjustment. Advise patients that Iloprost should be inhaled at intervals of not less than 2 hours and that the acute benefits of Iloprost may not last 2 hours. Thus patients may want to adjust times of administration to cover planned activities. |alcohol=Alcohol-Iloprost interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. |brandNames=Ventavis |lookAlike=There is limited information about the look-alike drugs.

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  1. Spargias K, Adreanides E, Demerouti E, Gkouziouta A, Manginas A, Pavlides G; et al. (2009). "[[contrast-induced nephropathy]] in patients with [[renal dysfunction]] undergoing [[coronary angiography]] or [[coronary intervention|intervention]]". Circulation. 120 (18): 1793–9. doi:10.1161/CIRCULATIONAHA.109.863159. PMID 19841299. URL–wikilink conflict (help)
  2. Meizer R, Radda C, Stolz G, Kotsaris S, Petje G, Krasny C; et al. (2005). "MRI-controlled analysis of 104 patients with painful bone marrow edema in different joint localizations treated with the prostacyclin analogue iloprost". Wien Klin Wochenschr. 117 (7–8): 278–86. PMID 15926619.
  3. Mayerhoefer ME, Kramer J, Breitenseher MJ, Norden C, Vakil-Adli A, Hofmann S; et al. (2007). "Short-term outcome of painful bone marrow oedema of the knee following oral treatment with iloprost or tramadol: results of an exploratory phase II study of 41 patients". Rheumatology (Oxford). 46 (9): 1460–5. doi:10.1093/rheumatology/kem172. PMID 17636179.

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