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Nature Reviews. Rheumatology Apr 2023Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease with multi-organ involvement, fibrosis and vasculopathy. Treatment in SSc, including early... (Review)
Review
Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease with multi-organ involvement, fibrosis and vasculopathy. Treatment in SSc, including early diffuse cutaneous SSc (dcSSc) and the use of organ-specific therapies, has improved, as evident from randomized clinical trials. Treatments for early dcSSc include immunosuppressive agents such as mycophenolate mofetil, methotrexate, cyclophosphamide, rituximab and tocilizumab. Patients with rapidly progressive early dcSSc might be eligible for autologous haematopoietic stem cell transplantation, which can improve survival. Morbidity from interstitial lung disease and pulmonary arterial hypertension is improving with the use of proven therapies. Mycophenolate mofetil has surpassed cyclophosphamide as the initial treatment for SSc-interstitial lung disease. Nintedanib and possibly perfinidone can be considered in SSc pulmonary fibrosis. Pulmonary arterial hypertension is frequently treated with initial combination therapy (for example, with phosphodiesterase 5 inhibitors and endothelin receptor antagonists) and, if necessary, the addition of a prostacyclin analogue. Raynaud phenomenon and digital ulcers are treated with dihydropyridine calcium channel blockers (especially nifedipine), then phosphodiesterase 5 inhibitors or intravenous iloprost. Bosentan can reduce the development of new digital ulcers. Trial data for other manifestations are mostly lacking. Research is needed to develop targeted and highly effective treatments, best practices for organ-specific screening and early intervention, and sensitive outcome measurements.
Topics: Humans; Mycophenolic Acid; Pulmonary Arterial Hypertension; Phosphodiesterase 5 Inhibitors; Scleroderma, Systemic; Cyclophosphamide; Lung Diseases, Interstitial
PubMed: 36849541
DOI: 10.1038/s41584-023-00909-5 -
CMAJ : Canadian Medical Association... Nov 2021
Topics: Fluorescence; Frostbite; Humans; Iloprost
PubMed: 34810170
DOI: 10.1503/cmaj.202258-f -
Cureus Sep 2023Raynaud's phenomenon (RP) is a vasospastic disorder characterized by an exaggerated vasoconstrictive response to cold or emotional stress. It can be classified as...
Raynaud's phenomenon (RP) is a vasospastic disorder characterized by an exaggerated vasoconstrictive response to cold or emotional stress. It can be classified as primary (PRP) or secondary (SRP) depending on its association with an underlying condition. We present a case of a young female with severe RP, with trophic changes and abnormal capillaroscopy. After a detailed investigation, a diagnosis of secondary RP due to solvent exposure was made. The patient was treated with calcium channel blocker in low doses, due to hypotension, without improvement of symptoms. Vitamin C and pentoxifylline were added with an unsatisfactory response. Given the progressive worsening of RP and the appearance of trophic lesions, the patient's treatment was reviewed, and continuous intravenous iloprost infusion through an elastomeric pump was started. This resulted in significant symptom improvement and normalization on the capillaroscopic examination.
PubMed: 37829986
DOI: 10.7759/cureus.45004 -
Annals of Translational Medicine Apr 2021Pulmonary hypertension (PH) is a severe disease that affects people of all ages. It can occur as an idiopathic disorder at birth or as part of a variety of... (Review)
Review
Pulmonary hypertension (PH) is a severe disease that affects people of all ages. It can occur as an idiopathic disorder at birth or as part of a variety of cardiovascular and pulmonary disorders. Inhaled pulmonary vasodilators (IPV) can reduce pulmonary vascular resistance (PVR) and improve RV function with minimal systemic effects. IPV includes inhaled nitric oxide (iNO), inhaled aerosolized prostacyclin, or analogs, including epoprostenol, iloprost, treprostinil, and other vasodilators. In addition to pulmonary vasodilating effects, IPV can also be used to improve oxygenation, reduce inflammation, and protect cell. Off-label use of IPV is common in daily clinical practice. However, evidence supporting the inhalational administration of these medications is limited, inconclusive, and controversial regarding their safety and efficacy. We conducted a search for relevant papers published up to May 2020 in four databases: PubMed, Google Scholar, EMBASE and Web of Science. This review demonstrates that the clinical using and updated evidence of IPV. iNO is widely used in neonates, pediatrics, and adults with different cardiopulmonary diseases. The limitations of iNO include high cost, flat dose-response, risk of significant rebound PH after withdrawal, and the requirement of complex technology for monitoring. The literature suggests that inhaled aerosolized epoprostenol, iloprost, treprostinil and others such as milrinone and levosimendan may be similar to iNO. More research of IPV is needed to determine acceptable inclusion criteria, long-term outcomes, and management strategies including time, dose, and duration.
PubMed: 33987295
DOI: 10.21037/atm-20-4895 -
European Review For Medical and... Jan 2022Despite its low incidence, pulmonary hypertension in children places a substantial burden on families and society because survival can be shorter than 10 months and... (Review)
Review
OBJECTIVE
Despite its low incidence, pulmonary hypertension in children places a substantial burden on families and society because survival can be shorter than 10 months and treatment options are limited and ineffective. Drugs to treat pulmonary hypertension include endothelin antagonists, phosphodiesterase type 5 inhibitors and prostacyclin, which is the most widely used to treat pediatric pulmonary hypertension. The main aim of this study was to provide a comprehensive overview of the advantages and disadvantages of prostacyclin and its analogs for treating pulmonary hypertension in children.
MATERIALS AND METHODS
To retrieve a thorough collection of studies, we performed a search in PubMed using the following combination of keywords: (Prostacyclins) or (Epoprostenol) or (Iloprost) or (Treprostinil) or (Beraprost), (children) and (pulmonary arterial hypertension). The time limits used for the search were December 1983 to May 2021.
RESULTS
The search retrieved a total of 238 articles. Titles and abstracts of articles were screened for relevance, and all relevant articles published in English were included.
CONCLUSIONS
Epoprostenol can be effective against severe pulmonary hypertension. Iloprost can treat severe persistent pulmonary hypertension in newborns and inhaled iloprost can be used in pulmonary vasoreactivity testing. Treprostinil is a long-acting prostacyclin analog, and it shows the highest antiproliferative activity among prostacyclins. Beraprost may be effective in premature infants, but available evidence comes from only one patient, so more clinical testing is needed.
Topics: Antihypertensive Agents; Child; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Iloprost; Infant, Newborn; Prostaglandins I; Pulmonary Arterial Hypertension
PubMed: 35049017
DOI: 10.26355/eurrev_202201_27745 -
International Journal of Circumpolar... Dec 2023We performed a scoping review to identify the extent of the literature describing the use of iloprost in the treatment of frostbite. Iloprost is a stable synthetic... (Review)
Review
We performed a scoping review to identify the extent of the literature describing the use of iloprost in the treatment of frostbite. Iloprost is a stable synthetic analog of prostaglandin I. As a potent inhibitor of platelet aggregation and vasodilator, it has been used to address the post-rewarming reperfusion injury in frostbite. The search using iloprost and frostbite as key words and MeSH terms yielded 200 articles. We included in our review the literature examining iloprost for the treatment of frostbite in humans in the form of primary research, conference proceedings and abstracts. Twenty studies published from 1994 to 2022 were selected for analysis. The majority were retrospective case series consisting of a homogeneous population of mountain sport enthusiasts. A total of 254 patients and over 1000 frostbitten digits were included among the 20 studies. The larger case series demonstrated a decrease in amputation rates relative to untreated patients. Primary gaps in the literature include a paucity of randomised trials and relatively limited study populations to date. While the case evidence is promising, a multi-centre collaboration would be crucial to adequately power prospective randomised studies to definitively determine if iloprost has a role in the treatment of frostbite.
Topics: Humans; Iloprost; Prospective Studies; Retrospective Studies; Epoprostenol; Frostbite
PubMed: 36966492
DOI: 10.1080/22423982.2023.2189552 -
Pulmonary Circulation 2020This manuscript on drug repurposing incorporates the broad experience of members of the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative as... (Review)
Review
This manuscript on drug repurposing incorporates the broad experience of members of the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative as an open debate platform for academia, the pharmaceutical industry and regulatory experts surrounding the future design of clinical trials in pulmonary hypertension. Drug repurposing, use of a drug in a disease for which it was not originally developed, in pulmonary arterial hypertension has been a remarkable success story, as highlighted by positive large phase 3 clinical trials using epoprostenol, bosentan, iloprost, and sildenafil. Despite the availability of multiple therapies for pulmonary arterial hypertension, mortality rates have modestly changed. Moreover, pulmonary arterial hypertension patients are highly symptomatic and frequently end up on parental therapy and lung transplant waiting lists. Therefore, an unmet need for new treatments exists and drug repurposing may be an important avenue to address this problem.
PubMed: 33282182
DOI: 10.1177/2045894020941494 -
The Cochrane Database of Systematic... Dec 2020Frostbite is a thermal injury caused when tissue is exposed to sub-zero temperatures (in degrees Celsius) long enough for ice crystals to form in the affected tissue....
BACKGROUND
Frostbite is a thermal injury caused when tissue is exposed to sub-zero temperatures (in degrees Celsius) long enough for ice crystals to form in the affected tissue. Depending on the degree of tissue damage, thrombosis, ischaemia, necrosis (tissue death), gangrene and ultimately amputation may occur. Several interventions for frostbite injuries have been proposed, such as hyperbaric oxygen therapy, sympathectomy (nerve block), thrombolytic (blood-thinning) therapy and vasodilating agents such as iloprost, reserpine, pentoxifylline and buflomedil, but the benefits and harms of these interventions are unclear.
OBJECTIVES
To assess the benefits and harms of the different management options for frostbite injuries.
SEARCH METHODS
On 25 February 2020, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), Embase (OvidSP), ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED), Conference Proceedings Citation Index-Science (CPCI-S), as well as trials registers. Shortly before publication, we searched Clinicaltrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform, OpenGrey and GreyLit (9 November 2020) again. We investigated references from relevant articles, and corresponded with a trial author.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that compared any medical intervention, e.g. pharmacological therapy, topical treatments or rewarming techniques, for frostbite injuries to another treatment, placebo or no treatment.
DATA COLLECTION AND ANALYSIS
Two authors independently extracted data. We used Review Manager 5 for statistical analysis of dichotomous data with risk ratio (RR) with 95% confidence intervals (CIs). We used the Cochrane 'Risk of bias' tool to assess bias in the included trial. We assessed incidence of amputations, rates of serious and non-serious adverse events, acute pain, chronic pain, ability to perform activities of daily living, quality of life, withdrawal rate from medical therapy due to adverse events, occupational effects and mortality. We used GRADE to assess the quality of the evidence.
MAIN RESULTS
We included one, open-label randomised trial involving 47 participants with severe frostbite injuries. We judged this trial to be at high risk of bias for performance bias, and uncertain risk for attrition bias; all other risk of bias domains we judged as low. All participants underwent rapid rewarming, received 250 mg of aspirin and 400 mg intravascular (IV) buflomedil (since withdrawn from practice), and were then randomised to one of three treatment groups for the following eight days. Group 1 received additional IV buflomedil 400 mg for one hour per day. Group 2 received the prostacyclin, iloprost, 0.5 ng to 2 ng/kg/min IV for six hours per day. Group 3 received IV iloprost 2 ng/kg/min for six hours per day plus fibrinolysis with 100 mg recombinant tissue plasminogen activator (rtPA) for the first day only. The results suggest that iloprost and iloprost plus rtPA may reduce the rate of amputations in people with severe frostbite compared to buflomedil alone, RR 0.05 (95% CI 0.00 to 0.78; P = 0.03; very low-quality evidence) and RR 0.31 (95% CI 0.10 to 0.94; P = 0.04; very low-quality evidence), respectively. Iloprost may be as effective as iloprost plus rtPA at reducing the amputation rate, RR 0.14 (95% CI 0.01 to 2.56; P = 0.19; very low-quality evidence). There were no reported deaths or withdrawals due to adverse events in any of the groups; we assessed evidence for both outcomes as being of very low quality. Adverse events (including flushing, nausea, palpitations and vomiting) were common, but not reported separately by comparator arm (very low-quality evidence). The included study did not measure the outcomes of acute pain, chronic pain, ability to perform activities of daily living, quality of life or occupational effects.
AUTHORS' CONCLUSIONS
There is a paucity of evidence regarding interventions for frostbite injuries. Very low-quality evidence from a single small trial indicates that iloprost, and iloprost plus rtPA, in combination with buflomedil may reduce the need for amputation in people with severe frostbite compared to buflomedil alone. However, buflomedil has been withdrawn from use. High quality randomised trials are needed to establish firm evidence for the treatment of frostbite injuries.
Topics: Amputation, Surgical; Aspirin; Bias; Drug Therapy, Combination; Epoprostenol; Fibrinolytic Agents; Frostbite; Humans; Iloprost; Platelet Aggregation Inhibitors; Pyrrolidines; Recombinant Proteins; Rewarming; Tissue Plasminogen Activator; Vasodilator Agents
PubMed: 33341943
DOI: 10.1002/14651858.CD012980.pub2 -
Scandinavian Journal of Trauma,... Dec 2023Our objective was to perform a systematic review of the outcomes of various frostbite treatments to determine which treatments are effective. We also planned to perform... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Our objective was to perform a systematic review of the outcomes of various frostbite treatments to determine which treatments are effective. We also planned to perform meta-analyses of the outcomes of individual treatments for which suitable data were available.
MAIN BODY
We performed a systematic review and meta-analyses in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. We searched PubMed, Cochrane Trials, and EMBase to identify primary references from January 1, 1900, to June 18, 2022. After eliminating duplicates, we screened abstracts to identify eligible studies containing information on treatment and outcomes of Grade 2 to 4 frostbite. We performed meta-analyses of groups of articles that provided sufficient data. We registered our review in the prospective registry of systematic reviews PROSPERO (Nr. 293,693). We identified 4,835 potentially relevant studies. We excluded 4,610 studies after abstract screening. We evaluated the full text of the remaining 225 studies, excluding 154. Ultimately, we included 71 articles with 978 cases of frostbite originating from 1 randomized controlled trial, 20 cohort studies and 51 case reports. We found wide variations in classifications of treatments and outcomes. The two meta-analyses we performed both found that patients treated with thrombolytics within 24 h had better outcomes than patients treated with other modalities. The one randomized controlled trial found that the prostacyclin analog iloprost was beneficial in severe frostbite if administered within 48 h.
CONCLUSIONS
Iloprost and thrombolysis may be beneficial for treating frostbite. The effectiveness of other commonly used treatments has not been validated. More prospective data from clinical trials or an international registry may help to inform optimal treatment.
Topics: Humans; Iloprost; Cohort Studies
PubMed: 38072923
DOI: 10.1186/s13049-023-01160-3