Prostacyclin (PGI2) Pathway to Enhance Wound Healing in Diabetic Foot Ulcers

Exclusion Criteria

• •Groups 1, 2 and 3:
• •Unstable diabetes that has resulted in hyperosmolar coma or ketoacidosis, and/or documented increase or decrease in HbA1c of more than 2.0% within the previous 3 months.
• •Presence of diabetic peripheral neuropathy above the ankle, defined as a scoring \>3 of at least two of the four stimuli of the Neuropathy Disability Score (i.e. pinprick sensation, light touch, vibration, and temperature perception) (37).
• •Infected wound, treated with antibiotics in the past 15 days.
• •Critical ischemia of the lower limb, defined as leg pain at rest associated with ankle pressure \<70 mmHg.
• •History of hypersensitivity reaction to treprostinil, fluconazole, other azole compounds, L-NMMA, ketorolac, meloxicam, or any NSAIDs or acetylsalicylic acid, lidocaine (or any local anesthetic with an amide bond), or their excipients
• •History of asthma, rhinitis, nasal polyps, angioedema, hives rash, or any other allergic reaction due to acetylsalicylic acid or any NSAID taking
• •Pulmonary veno-occlusive disease (PVOD)
• •Porphyria
• •Hyperkalemia
• •Active or uncontrolled cardiovascular disease as follows: Myocardial infarction, or angina within the previous 6 months; Severe ischemic heart disease; Arrhythmia (uncontrolled, symptomatic, requiring treatment or life-threatening); Congestive heart failure, or decompensated heart failure not medically controlled; Stroke or transient ischemic attack within the previous 3 months; Uncontrolled hypertension: systolic blood pressure (SBP)\> 180 mmHg or diastolic blood pressure (DBP)\> 105 mmHg (2 abnormal readings during visit) Valvular heart disease
• •Severe liver disease (Child-Pugh C) at the time of enrollment
• •Renal disease (creatinine \>2 mg/dL and/or estimated glomerular filtration rate (GFR) \<30 mL/min, history of dialysis)
• •Active peptic ulcer disease, recent gastrointestinal bleeding or perforation, or history of peptic ulcer disease or gastrointestinal bleeding or perforation with NSAIDs
• •Intracerebral or gastrointestinal hemorrhage, hemostasis disorder or every clinical status that may lead to bleeding
• •Chronic venous disease defined as stage 4a and 4b of the Clinical-Etiological-Anatomical-Pathophysiological (CEAP) classification
• •Cutaneous condition deemed incompatible with skin biopsy and dermal microdialysis by the investigator
• •History of necrotic angiodermatitis
• •Trauma or any clinical event susceptible to be responsible for hemorrhage within the previous 6 months
• •Concomitant treatment with pentoxifylline, anticoagulants, probenecid, medicinal products known to prolong the QT interval or anti-inflammatory or analgesic dose of acetylsalicylic acid
• •If concomitant treatment with NSAIDs, participants have to be stopped 1 week before the inclusion
• •Pregnancy or Lactation
• •Females with childbearing potential, defined as a premenopausal female capable of becoming pregnant, and not using an highly effective form of birth control. Effective birth control methods include: oral, implant or patch hormone contraception; intrauterine device; abstinence and outercourse; tubal ligation; vasectomy.
• •Groups 1,2,3 and 4:
• •Participant involved in another interventional clinical study
• •Person deprived of liberty by judicial order
• •Person under guardianship or curatorship