iloprost and Pain

Transient osteoporosis (TO) or bone marrow edema syndrome (BMES) is a self-limited clinical condition, which affects middle-aged men and women. It can be treated with miscellaneous conservative and surgical measures, which are analyzed in this systematic review.. BMES/TO is a transient clinical entity, which can be treated with various therapeutic modalities. The aim of our study was to assess the efficacy of different therapeutic options for the alleviation of pain and reduction of bone marrow edema (BME) in patients with BMES/TO, as well as to propose a therapeutic algorithm.. PubMed, Scopus, Cochrane, and Google Scholar were searched. Eligibility and extraction of studies were conducted by two authors. Methodological quality assessment was carried out with the modified Delphi technique, Methodological Index for Non-Randomized Studies (MINORS) criteria, and Cochrane Collaboration's risk of bias tool. Outcomes that were compared were time of pain resolution, VAS pain scores, and BME regression on magnetic resonance imaging (MRI).. A total of 36 articles (880 patients) were included. Bisphosphonates had higher efficiency in less than 1-month outcomes on pain resolution compared with core decompression (CD), while iloprost was more efficient at 1-3 months compared with bisphosphonates and CD. At 3-6 months, all three of the aforementioned showed equal results on pain resolution, and at a period of 6-12 months, CD and extracorporeal shockwave therapy (ESWT) showed excellent results followed by bisphosphonates and the conservative group (CG) consisting of non-steroidal anti-inflammatory drugs (NSAIDs) and/or analgesics and/or restricted weight bearing. On MRI at 1-3 months, bisphosphonates, iloprost, and CD had relatively the same outcomes on BME resolution, with the least promising being the CG. At 3-6 months, CD seemed to have achieved the best results on the resolution of BME, followed by ESWT, CG, and bisphosphonates group. At 6-12 months, ESWT had the best outcomes compared with the conservative, bisphosphonates, and iloprost groups.. BMES/TO has been treated with many non-standardized measures due to the low number of highly reliable studies. Current literature shows promising results with regard to the reduction of the clinical course of BMES/TO, but further large multicenter randomized controlled trials, as well as standardized radiological and clinical scores, are warranted to acquire evidence-based recommendations on the therapeutic algorithm.

Topics: Bone Marrow; Bone Marrow Diseases; Diphosphonates; Edema; Female; Humans; Iloprost; Male; Middle Aged; Multicenter Studies as Topic; Osteoporosis; Pain; Syndrome

For many years, the only pharmacological option for patients with critical limb ischemia (CLI) unsuitable for revascularization has been prostanoids; however, some recent guidelines have become very restrictive regarding their use. We review the available evidence on the use of prostanoids and analyze the guideline positions as well as the possible reasons for changes over time. In most placebo-controlled trials and meta-analyses, prostanoids showed a significant effect in improving rest pain, promoting ulcer healing and reducing major amputations. Results for iloprost were especially consistent. Different prostanoid drugs have different evidence of efficacy, thus using a generic term "prostanoids" is misleading. Unfortunately, the available evidence is often of low quality and probably not sufficient to support an extensive use of prostanoids in all patients, and further high-quality randomized trials are needed. Consequently, some recent guidelines do not recommend treatment with prostanoids in this setting. However, in our opinion, pending definitive evidence, patients with CLI who have a viable limb in whom revascularization is unfeasible or has a poor chance of success, without alternative to amputation, may benefit from treatment with iloprost, balancing harms and benefits in each case.

Topics: Alprostadil; Amputation, Surgical; Humans; Iloprost; Ischemia; Pain; Prostaglandins; Treatment Outcome; Vasodilator Agents

Buerger's disease (thromboangiitis obliterans) is a non-atherosclerotic, segmental inflammatory pathology that most commonly affects the small and medium sized arteries, veins, and nerves in the upper and lower extremities. The aetiology is unknown, but involves hereditary susceptibility, tobacco exposure, immune and coagulation responses. In many cases, there is no possibility of revascularisation to improve the condition. Pharmacological treatment is an option for patients with severe complications, such as ischaemic ulcers or rest pain.This is an update of the review first published in 2016.. To assess the effectiveness of any pharmacological agent (intravenous or oral) compared with placebo or any other pharmacological agent in patients with Buerger's disease.. The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, AMED, the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials register to 15 October 2019. The review authors searched LILACS, ISRCTN, Australian New Zealand Clinical Trials Registry, EU Clinical Trials Register, clincialtrials.gov and the OpenGrey Database to 5 January 2020.. We included randomised controlled trials (RCTs) involving pharmacological agents used in the treatment of Buerger's disease.. Two review authors, independently assessed the studies, extracted data and performed data analysis.. No new studies were identified for this update. Five randomised controlled trials (total 602 participants) compared prostacyclin analogue with placebo, aspirin, or a prostaglandin analogue, and folic acid with placebo. No studies assessed other pharmacological agents such as cilostazol, clopidogrel and pentoxifylline or compared oral versus intravenous prostanoid. Compared with aspirin, intravenous prostacyclin analogue iloprost improved ulcer healing (risk ratio (RR) 2.65; 95% confidence interval (CI) 1.15 to 6.11; 98 participants; 1 study; moderate-certainty evidence), and helped to eradicate rest pain after 28 days (RR 2.28; 95% CI 1.48 to 3.52; 133 participants; 1 study; moderate-certainty evidence), although amputation rates were similar six months after treatment (RR 0.32; 95% CI 0.09 to 1.15; 95 participants; 1 study; moderate-certainty evidence). When comparing prostacyclin (iloprost and clinprost) with prostaglandin (alprostadil) analogues, ulcer healing was similar (RR 1.13; 95% CI 0.76 to 1.69; 89 participants; 2 studies; I² = 0%; very low-certainty evidence), as was the eradication of rest pain after 28 days (RR 1.57; 95% CI 0.72 to 3.44; 38 participants; 1 study; low-certainty evidence), while amputation rates were not measured. Compared with placebo, the effects of oral prostacyclin analogue iloprost were similar for: healing ischaemic ulcers (iloprost 200 mcg: RR 1.11; 95% CI 0.54 to 2.29; 133 participants; 1 study; moderate-certainty evidence, and iloprost 400 mcg: RR 0.90; 95% CI 0.42 to 1.93; 135 participants; 1 study; moderate-certainty evidence), eradication of rest pain after eight weeks (iloprost 200 mcg: RR 1.14; 95% CI 0.79 to 1.63; 207 participants; 1 study; moderate-certainty evidence, and iloprost 400 mcg: RR 1.11; 95% CI 0.77 to 1.59; 201 participants; 1 study; moderate-certainty evidence), and amputation rates after six months (iloprost 200 mcg: RR 0.54; 95% CI 0.19 to 1.56; 209 participants; 1 study, and iloprost 400 mcg: RR 0.42; 95% CI 0.13 to 1.31; 213 participants; 1 study). When comparing folic acid with placebo in patients with Buerger's disease and hyperhomocysteinaemia, pain scores were similar, there were no new cases of amputation in either group, and ulcer healing was not assessed (very low-certainty evidence). Treatment side effects such as headaches, flushing or nausea were not associated with treatment interruptions or more serious consequences. Outcomes such as amputation-free survival, walking distance or pain. Moderate-certainty evidence suggests that intravenous iloprost (prostacyclin analogue) is more effective than aspirin for eradicating rest pain and healing ischaemic ulcers in Buerger's disease, but oral iloprost is not more effective than placebo. Very low and low-certainty evidence suggests there is no clear difference between prostacyclin (iloprost and clinprost) and the prostaglandin analogue alprostadil for healing ulcers and relieving pain respectively in severe Buerger's disease. Very low-certainty evidence suggests there is no clear difference in pain scores and amputation rates between folic acid and placebo, in people with Buerger's disease and hyperhomocysteinaemia. Further well designed RCTs assessing the effectiveness of pharmacological agents (intravenous or oral) in people with Buerger's disease are needed.

Topics: Adult; Alprostadil; Amputation, Surgical; Aspirin; Epoprostenol; Folic Acid; Hematinics; Humans; Iloprost; Male; Middle Aged; Pain; Placebos; Platelet Aggregation Inhibitors; Prostaglandins; Randomized Controlled Trials as Topic; Thromboangiitis Obliterans; Ulcer

Prostanoids (alprostadil and iloprost) are used for the treatment of patients with critical limb ischemia in whom revascularization procedure is inadequate or proved to be unsuccessful. According to a Cochrane analysis (CD006544) prostanoids differ in their effects on rest-pain relief and ulcer healing.. To study the efficacy and safety of prostanoids for critical limb ischemia.. Systematic literature search and meta-analysis (mixed treatment comparison) was performed.. Seven randomized controlled trials including 964 patients were analyzed. Compared to placebo, both alprostadil (OR: 3.2 95% CI: 1.7-5.5 and OR: 1.8 95% CI: 0.6-4.3) and iloprost (OR: 2.7 95% CI: 1.7-4.2 and OR: 2.5 95% CI: 1.0-5.4) were more efficacious with regard to rest-pain relief and ulcer healing and the difference between the two prostanoids was not significant (OR: 1.2 95% CI: 0.7-1.9 and OR: 0.74 95% CI: 0.3-1.5). Adverse events occurred significantly more often with both drugs compared to placebo, however, they were less frequent with alprostadil than with iloprost (OR 0.2 95% CI: 0.1-0.3).. Prostanoids have favorable effect on rest-pain relief and ulcer healing in critical limb ischemia, without statistically significant difference between the two available drugs. The Cochrane study (CD006544) reported mistaken results due to defaults in the analysis.

Topics: Alprostadil; Humans; Iloprost; Ischemia; Leg; Pain; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Rest; Skin Ulcer; Vasodilator Agents

Rheumatoid arthritis is a chronic inflammatory autoimmune disease with proinflammatory cytokines involved in its pathogenesis. Recently in vitro as well as in vivo studies have shown that iloprost, a stable prostacyclin analogue, can reduce the release of these cytokines. This study was performed to further investigate the anti-inflammatory effects of iloprost by determining plasma adhesion molecules as markers of endothelial cell activation, and plasma thrombomodulin as a parameter of endothelial cell injury in patients with rheumatoid arthritis receiving oral iloprost therapy.. Plasma thrombomodulin levels and the values of the plasma adhesion molecules VCAM-1 (vascular cell adhesion molecule 1), E-selectin (CD62E), and ICAM-1 (intercellular adhesion molecule 1, CD 54) were measured by ELISA during a 7-day period of treatment with orally-administered iloprost in 14 patients with active rheumatoid arthritis. Finally, the same parameters were determined at the end of the observation period (1 week after the end of therapy). In addition, the disease activity was measured using the DAS (disease activity score) as well as the patients' self-assessed pain severity, and correlated with the changes of plasma adhesion molecule and thrombomodulin levels.. The plasma levels of all three adhesion molecules as well as of thrombomodulin significantly decreased under therapy with oral iloprost. After 1 week (day 7 of therapy), the mean percent changes from day 0 were -20.1% for VCAM-1 (p = 0.008), -21.2 for ICAM-1 (p = 0.003), -24.6% for E-selectin (p = 0.001), and -21.7% for thrombomodulin (p = 0.003). This decrease lasted up to 1 week after the end of therapy in the case of VCAM-1 (p = 0.023) and ICAM-1 (p = 0.001). Further analysis of the results revealed additional significant correlations between different parameters of clinical disease activity, thrombomodulin and adhesion molecules.. This study showed hints towards clinical effects in patients with rheumatoid arthritis receiving oral iloprost therapy. Pathophysiologically, the decrease of adhesion molecules points at an immunomodulating effect of iloprost. The observed thrombomodulin-lowering effect of iloprost may indicate stabilisation of endothelial cell function by diminishing endothelial cell injury.

Topics: Administration, Oral; Adult; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Biomarkers; Cell Adhesion Molecules; E-Selectin; Enzyme-Linked Immunosorbent Assay; Female; Humans; Iloprost; Intercellular Adhesion Molecule-1; Male; Middle Aged; Pain; Pain Measurement; Platelet Aggregation Inhibitors; Severity of Illness Index; Thrombomodulin; Vascular Cell Adhesion Molecule-1

In an open study the clinical efficacy and tolerability of the stable prostacyclin (PGI2) analogue iloprost in the treatment of 900 patients with advanced peripheral arterial occlusive disease (Fontaine stage III and IV), enrolled by 169 centres, were investigated. Of these patients, treated with infusions over 6 h daily up to 42 days, 853 could be evaluated: four were excluded because of wrong diagnosis. The responder rates, defined as pain relief, no or reduced use of analgesics (stage III and IV), improvement of trophic lesions, i.e. complete or > or = 50% healing of ulcers, demarcation of necroses (stage IV), and global improvement, were 75.0% and 66.0% in stage III and 46.3% and 41.8% in stage IV patients in the valid case and intention-to-treat group, respectively. A complete healing of ulcers was observed in 12.3% of those patients (n = 375) presenting with ulcerations at the beginning of treatment. Diabetic and non-diabetic patients were comparable with regard to efficacy of iloprost. 71.4% and 66.2% (stage III and IV) of initial responders at 6 months follow-up were still free from rest pain and showing complete or partial healing of trophic lesions. 7.9% of stage III and 16.9% of stage IV patients underwent major amputation during the whole study period with a reduced amputation rate in responders compared to non-responders in stage IV. 7.9% stage III and 13.2% stage IV patients died. 83.2% and 86.0% of stage III and IV patients presented with adverse events at any time of treatment, mainly headache, nausea and flush as well as gastrointestinal symptoms, occurring mostly during the titration phase. The investigators' judgement, however, revealed a very good and good tolerability in 74.8% of stage III and in 73.7% of stage IV patients.

Topics: Adult; Aged; Aged, 80 and over; Amputation, Surgical; Arterial Occlusive Diseases; Female; Humans; Iloprost; Infusions, Intravenous; Leukocyte Count; Male; Middle Aged; Pain; Platelet Aggregation Inhibitors; Risk Factors; Treatment Outcome; Vasodilator Agents

Topics: Adenosine Diphosphate; Blood Platelets; Cardiovascular Agents; Clinical Trials as Topic; Collagen; Epoprostenol; Humans; Iloprost; Male; Pain; Platelet Aggregation; Random Allocation; Vascular Diseases

The effects of iloprost, a chemically stable compound with prostacyclin mimetic activity, on exercise capacity and platelet aggregation were assessed in 24 patients with effort angina and proved critical (at least 70% diameter narrowing) coronary artery disease. Upright bicycle ergometer testing (25-W increments every 2 minutes) was performed during drug and placebo infusions using a crossover, randomized, single-blind protocol. Samples for measurements of adenosine diphosphate-induced platelet aggregation in platelet-rich plasma were obtained in all patients before and during the study. Compared with placebo, intravenous iloprost consistently (p less than 0.001) prolonged exercise duration and time to onset of significant (0.1 mV) ST depression. Angina and ST depression occurred at a greater heart rate and rate-pressure product. Benefits were remarkable in some patients (67%) and not in others. Iloprost administration resulted in reduced platelet aggregation at peak exercise in all patients, whether they had consistent or little response to the drug. Thus, iloprost administration may improve exercise capacity in patients with stable exertional angina pectoris. Improvements are independent of changes in the major determinants of myocardial oxygen demand and associated with markedly reduced platelet aggregation, which may account for increased myocardial perfusion in patients with high sensitivity to coronary constriction.

Topics: Angina Pectoris; Cardiovascular Agents; Clinical Trials as Topic; Electrocardiography; Epoprostenol; Exercise Test; Female; Humans; Iloprost; Male; Middle Aged; Pain; Platelet Aggregation; Random Allocation

Non-freezing cold injury (NFCI) remains largely under-reported, and is of particular importance in the armed forces where its prevalence is greatest. Iloprost, a synthetic prostaglandin I. An Iloprost infusion was used to treat the long-term sequelae of an ex-soldier suffering with ongoing pedal pain and loss of function 20 years after the initial NFCI insult sustained on military exercise. Following 5 days of iloprost infusion, he reported 4 weeks of markedly reduced pain and increased mobility before symptom relapse. A second infusion was thus given 3 months later, which resulted in increased pain and analgesic requirements.. The use of iloprost in the treatment of NFCI is discussed and its use in a condition which physicians consistently struggle to treat effectively is considered. Careful counselling is recommended as symptoms may be worsened.

Topics: Adult; Cold Injury; Foot Injuries; Humans; Iloprost; Infusions, Intravenous; Male; Military Personnel; Pain; United Kingdom; Vasodilator Agents

To assess the efficacy and of iloprost in the treatment of Buerger's disease.. In this prospective study, 158 patients with rest pain and/or ischemic ulcers from 17 clinics were administered 1 ng/kg/min intravenous iloprost for 28-days. The primary endpoint was complete healing without pain or major amputation at 24 weeks. The secondary endpoints were pain assessment, reduction in ulcer area, 50% reduction of the ulcer size, shift in the modified SVS/ISCVS clinical status grading scale, global assessment by the investigator and an independent observer at 4 and 24 weeks. The comparisons were carried out with the initial values. The final evaluation was carried out in 150 patients.. Complete healing rate was significantly better with iloprost treatment in comparison to the initial values at 24 weeks (<0.001). The secondary endpoints; complete healing rate, pain, the size of the ulcer, 50% reduction of the ulcer size, SVS/ISCVS grading scale, assessment by investigator, assessment by observer parameters were significantly better at 4 and 24 weeks (<0.001). The reduction of the ulcer size was significantly better when comparing 4th and 24th week values (<0.05).. The results of this independent study indicate that intravenous iloprost relieves ischemic symptoms efficiently in the acute phase Buerger's disease patients. Considering unsatisfactory results following surgical revascularisation and sympathectomy in Buerger's disease, prostacyclin analogues might be the first line treatment as long as complete abstinence from smoking is achieved.

Topics: Adult; Amputation, Surgical; Analysis of Variance; Chi-Square Distribution; Critical Illness; Female; Humans; Iloprost; Infusions, Intravenous; Ischemia; Male; Middle Aged; Pain; Prospective Studies; Smoking; Smoking Cessation; Smoking Prevention; Thromboangiitis Obliterans; Time Factors; Treatment Outcome; Turkey; Wound Healing

The writhing response to acute nociception has been used to test the analgesic activity of drugs in rodents. Dilute acetic acid is the most frequently used irritant to induce writhing behaviour. The administration of acetic acid intraperitoneally activates both peripheral and central mechanisms of nociception. It releases nociceptive mediators such as prostaglandins (PG) E(2)and I(2)at the site of noxious stimulation, the peritoneal cavity, and at central sites such as the dorsal horn of the spinal cord and some brain regions. We have used the PGI(2)mimetic, iloprost, an agonist at the IP receptor, to induce the writhing response in mice. Iloprost activates the IP receptors on peripheral nociceptors directly and thus does not release nociceptive prostaglandins into the peritoneal cavity. However, prostaglandins are still involved in nociceptive transmission at the spinal and supraspinal levels. Using this model of nociception, it is possible to identify the site of action of analgesic drugs which reduce prostaglandin release in central tissues through inhibition of cyclooxygenase. Thus, a drug that inhibits the iloprost-induced writhing response and reduces release of prostaglandins in the central nervous system is likely to be a centrally acting analgesic drug. This chapter compares the iloprost- and acetic acid-induced writhing responses in mice and describes a method for measuring central prostaglandin levels. Part of this work has been published previously.

Topics: Acetic Acid; Analgesics; Animals; Cyclooxygenase Inhibitors; Dinoprostone; Female; Iloprost; Mice; Mice, Inbred C57BL; Models, Animal; Pain; Pain Measurement; Prostaglandin-Endoperoxide Synthases

The risk of developing avascular osteonecrosis (AVN) after chemotherapy is age related and, at up to 17% of all treated patients, relatively high.. In a prospective study, 8 patients (4 male, 4 female, 14.3+/-4.9 years old) were treated for symptomatic chemotherapy-associated AVN with intravenous infusion of iloprost. Association Research Circulation Osseus (ARCO) stages I-IV in 37 bones (25 joints) were treated.. Follow-up was 20.8+/-17 months (range: 6-53 months). No serious adverse reactions due to the infusion with iloprost were recorded. Pain levels were lower and functional outcome measured as Harris Hip and Knee Society Scores improved by the latest follow up.. Our current data confirm the findings of other investigators that healing of advanced stages of AVN is not possible, but that in early stages of AVN, pain relief and an improvement of joint function can be achieved by iloprost.

Topics: Adolescent; Adult; Age Factors; Child; Female; Hodgkin Disease; Humans; Iloprost; Male; Osteonecrosis; Pain; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Prospective Studies; Treatment Outcome; Vasodilator Agents; Young Adult

cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine, 4 (A-987306) is a new histamine H(4) antagonist. The compound is potent in H(4) receptor binding assays (rat H(4), K(i) = 3.4 nM, human H(4) K(i) = 5.8 nM) and demonstrated potent functional antagonism in vitro at human, rat, and mouse H(4) receptors in cell-based FLIPR assays. Compound 4 also demonstrated H(4) antagonism in vivo in mice, blocking H(4)-agonist induced scratch responses, and showed anti-inflammatory activity in mice in a peritonitis model. Most interesting was the high potency and efficacy of this compound in blocking pain responses, where it showed an ED(50) of 42 mumol/kg (ip) in a rat post-carrageenan thermal hyperalgesia model of inflammatory pain.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzofurans; Carrageenan; Disease Models, Animal; Drug Design; Drug Evaluation, Preclinical; Humans; Hyperalgesia; Ligands; Mice; Molecular Structure; Pain; Peritonitis; Quinazolines; Rats; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Stereoisomerism; Structure-Activity Relationship

Bone marrow edema (BME) is a common cause of pain of the musculoskeletal system. The aim of the study was to assess the efficacy of iloprost in the treatment of BME of different localizations and etiologies.. We reviewed 104 patients (54 male, 50 female) with BME. Their mean age was 52.8 +/- 14.7 years. BME was located 50 times in the knee, 19 times in the talus, 18 times in the femoral head and 17 times in other bones. Patients were allocated to three distinct etiological groups: 27 cases were estimated to have idiopathic BME, 16 post-traumatic BME and the other 61 BME secondary to activated osteoarthritis or mechanical stress. Therapy consisted of a series of five iloprost infusions with either 20, 25 or 50 microg of iloprost given over 6 hours on 5 consecutive days each.. At the clinical follow-up four months after therapy, the pain level of the 104 patients at rest had diminished by a mean of 73% (p<0.0001): 64% of patients reported a reduction, 34% no change and 2% an increase in pain at rest. Pain under stress decreased by a mean of 59%, (p<0.0001): 76% of patients had less pain during activity, 22% no change from baseline and 2% an increased pain level. On MRI, 65% had significant reduction of BME size or complete normalization and 20% showed no change. Worsening of the MRI pattern was found in 2%. 13% were lost to MRI follow-up. Side effects were significantly reduced by lowering the daily dose from 50 to 20 microg, without impairment of therapeutic effect.. The authors conclude that the use of parenteral iloprost might be a viable method in the treatment of BME of different etiologies.

Topics: Adult; Aged; Bone Marrow Diseases; Dose-Response Relationship, Drug; Edema; Female; Follow-Up Studies; Humans; Iloprost; Magnetic Resonance Imaging; Male; Middle Aged; Osteoarthritis; Osteonecrosis; Pain; Retrospective Studies; Stress, Mechanical; Time Factors; Vasodilator Agents

Recent studies on prostanoids showed that some of prostanoid receptors are expressed in rat dorsal root ganglion (DRG) neurons. These facts suggest that prostanoid receptors might be involved in the excitation mechanism of DRG neurons. In the present study, PCR experiments revealed that one of prostanoid receptor, prostacyclin receptor (IP receptor) was expressed in L6 and S1 rat DRG neurons and that the expression of IP receptor was not changed in DRG neurons obtained from the cyclophosphamide (CYP)-induced cystitis rat. We examined the functional role of IP receptor agonist and other prostanoids by measuring cyclic AMP (cAMP) accumulation and substance P (SP) release in primary cultured DRG neurons. The pretreatment of DRG neurons with prostanoid agonists such as iloprost (IP), butaprost (EP(2)), misoprostol (EP(2-4)), PGE(2) (EP(1-4)) or PGD(2) (DP and CRTH2) sensitized the DRG neurons and hence potentiated the lys-bradykinin-induced SP release. The increase of SP release by lys-BK plus prostanoid agonists was proportion to cAMP accumulation. Iloprost was the most potent agonist to induce cAMP accumulation and SP release among prostanoid agonists evaluated in this study and its effect is mediated by IP receptor. Moreover, capsaicin-, ATP- and KCl-induced SP release was also enhanced by iloprost although iloprost did not change intracellular Ca(2+) and membrane depolarization induced by these chemical stimuli. These results strongly indicate that IP receptor play an important role in the sensitization of rat sensory neuron.

Topics: Animals; Animals, Newborn; Capsaicin; Cells, Cultured; Cyclic AMP; Cystitis, Interstitial; Disease Models, Animal; Female; Ganglia, Spinal; Iloprost; Inflammation Mediators; Membrane Potentials; Neurons, Afferent; Nociceptors; Pain; Potassium Chloride; Prostaglandins; Rats; Rats, Sprague-Dawley; Receptors, Epoprostenol; Substance P; Vasodilator Agents

Topics: Adult; Anemia, Sickle Cell; Epoprostenol; Humans; Iloprost; Male; Osteonecrosis; Pain; Platelet Aggregation Inhibitors; Treatment Outcome

The antihyperalgesic effect of pentoxifylline was investigated in three experimental pain models. Pentoxifylline (0.5-1.6 mg kg(-1)) given 30 min before the stimulus significantly inhibited the writhing response induced by the intraperitoneal (i.p.) administration of either acetic acid (-90%) or zymosan (-83%), but not that of iloprost, in mice, as well as the zymosan-induced articular hyperalgesia in the zymosan arthritis in rats (-50%). Pentoxifylline also inhibited the mechanical hypernociception in rats induced by the intraplantar injection of either carrageenin (-81%), bradykinin (-56%) or tumor necrosis factor alpha (TNF-alpha; -46%), but not that induced by interleukin-1beta (IL-1beta) or prostaglandin E(2) (PGE(2)). Pentoxifylline did not inhibit the nociceptive response in the hot plate test in mice. Further, the antinociceptive effect of pentoxifylline in the writhing test in mice and the zymosan-induced articular hyperalgesia were not reversed by the coadministration of the opioid receptor antagonist naloxone. Thus, pentoxifylline antinociceptive effect is probably not mediated at a central level. Pentoxifylline significantly reduced TNF-alpha (-43%) and IL-1beta (-42%) concentrations in the joint exudates of rats stimulated by intra-articular injection of zymosan and the production of both cytokines (-66 and -86%, respectively) by mouse peritoneal macrophages stimulated in vivo with zymosan as well as the expression of TNF-alpha at the tissue level in carrageenin-injected rat paws. In conclusion, the antinociceptive activity of pentoxifylline is associated with the inhibition of the release of both TNF-alpha and IL-1beta.

Topics: Acetic Acid; Animals; Arthritis, Experimental; Carrageenan; Hot Temperature; Hyperalgesia; Iloprost; Immunohistochemistry; Inflammation; Interleukin-1; Joints; Male; Mice; Pain; Pain Measurement; Pentoxifylline; Peritoneal Cavity; Phosphodiesterase Inhibitors; Physical Stimulation; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha; Zymosan

Treatment options of bone marrow edema syndrome, which is associated with vascular disturbances, are protracted nonoperative treatment or core decompression which still demands several weeks until complete recovery. We obtained excellent results by the use of the vasoactive drug iloprost, a stable prostacyclin analogue, leading to a complete relief of symptoms in cases of bone marrow edema which had initially suggested early avascular necrosis of the second metatarsal head. The bone marrow edema of the second metatarsal bone was thought to be due to altered biomechanics following a distal first metatarsal chevron osteotomy. During the five days of iloprost infusion, the patient reported relief of rest pain. After therapy, the pedobarogram was normalized. The AOFAS forefoot score improved from 44 to 85 points after one month, and to 95 points after three months. At that time, the marrow showed normal signals. Without additional intervention the patient was able to resume normal activities.

Topics: Adult; Bone Marrow; Edema; Female; Foot Diseases; Forefoot, Human; Humans; Iloprost; Metatarsal Bones; Metatarsus; Osteotomy; Pain; Vasodilator Agents

Livedoid vasculopathy is characterized by early, focal painful purpuric lesions of the lower skin extremities without histologic finding of small vessel vasculitis.. A 38-year-old man was seen in our unit for painful purpuric lesions of both feet localized on toes and external sides. Skin biopsy showed dermic vessel thrombosis and endothelial cell proliferation. Lupus anticogulant antibody was positive in association with a heterozygous factor V (Leiden) gene mutation (G1691A). Anticoagulation failed to relieve pain and cutaneous lesions. Intravenous iloprost, a prostacylcin analogous (Ilomedine) was dramatically and rapidly effective in our patient.. Livedoid vasculopathy is a cutaneous affection related to vascular thrombotic events in which thrombophilia plays a central role. Iloprost might be an interesting alternative treatment of painful purpuric lesions when anticoagulant treatments are ineffective.

Topics: Adult; Anticoagulants; Foot; Humans; Iloprost; Infusions, Intravenous; Male; Pain; Skin Diseases, Vascular; Thrombophilia; Treatment Outcome; Vasodilator Agents

Intraperitoneal administration of zymosan and acetic acid induced a dose-dependent nociceptive writhing response in mice. Lavage of the peritoneal cavities with saline reduced the number of total resident peritoneal cells and caused a proportional decrease in the nociceptive responses induced by these stimuli. Furthermore, the specific reduction of the peritoneal mast cell population by intraperitoneal administration of compound 48/80 also reduced the nociceptive responses induced by zymosan and acetic acid. In contrast, enhancement of the peritoneal macrophage population by pretreatment of the cavities with thioglycollate caused an increase in the number of writhes induced by both stimuli. These data suggest that the nociceptive responses induced by zymosan and acetic acid are dependent upon the peritoneal resident macrophages and mast cells. These cells modulate the nociceptive response induced by zymosan and acetic acid via release of tumour necrosis factor alpha (TNF-alpha), interleukin 1beta and interleukin 8. This suggestion is supported by the following observations: (a) pretreatment of the peritoneal cavities with antisera against these cytokines reduced the nociceptive responses induced by these stimuli; (b) peritoneal cells harvested from cavities injected with zymosan or acetic acid released both interleukin 1beta and TNF-alpha; (c) although individual injection of TNF-alpha, interleukin 1beta or interleukin 8 did not induce the nociceptive effect, intraperitoneal injection of a mixture of these three recombinant cytokines caused a significant nociceptive writhing response. In conclusion, our results suggest that the nociceptive activity of zymosan and acetic acid in the writhing model is due to the release of TNF-alpha, interleukin 1beta and interleukin 8 by resident peritoneal macrophages and mast cells.

Topics: Acetic Acid; Animals; Cell Count; Cytokines; Dose-Response Relationship, Drug; Iloprost; Immune Sera; Interleukin-1; Interleukin-8; Macrophages, Peritoneal; Male; Mast Cells; Mice; Nociceptors; Pain; Tumor Necrosis Factor-alpha; Zymosan

Topics: Aged; CREST Syndrome; Female; Humans; Iloprost; Masseter Muscle; Pain; Platelet Aggregation Inhibitors; Raynaud Disease; Scleroderma, Systemic; Vasodilator Agents

Topics: Adult; Antiphospholipid Syndrome; Female; Follow-Up Studies; Humans; Iloprost; Ischemia; Male; Middle Aged; Necrosis; Pain; Toes

Intraperitoneally (i.p.) administered iloprost produced a writhing response indicating nociception. This effect induced by 4 micrograms/kg iloprost was dose dependently protected by morphine with an ED50 (95% confidence limits) value of 0.039 (0.0018-0.067) mg/kg. On the other hand, indomethacin had no effect on iloprost-induced writhing. Thus, this effect of iloprost seems to be relatively more sensitive than other irritants-induced responses on determining the analgesic potency of narcotic drugs.

Topics: Animals; Cardiovascular Agents; Dose-Response Relationship, Drug; Epoprostenol; Iloprost; Injections, Intraperitoneal; Male; Mice; Morphine; Pain; Time Factors