Ischemic Ulcers In Patients Research Articles

Baiying qingmai formulation ameliorates thromboangiitis obliterans by inhibiting HMGB1/RAGE/NF-κB signaling pathways.

Baiying Qingmai Formulation (BF) is a classical clinical prescription used for decades to treat thromboangiitis obliterans (TAO). Although it effectively relieves pain and ischemic ulcers in patients with TAO, its anti-TAO mechanisms remain unclear. The chemical components of BF were analyzed using high-performance liquid chromatography and the potential targets of the compounds identified in BF were analyzed using molecular docking. Further, the signaling pathways and molecular mechanism of BF in treating TAO were studied using a rat model of TAO. Seven compounds (gallic acid, catechin, chlorogenic acid, caffeic acid, paeoniflorin, quercetin, and paeonol) were identified in BF, and molecular docking predicted their high affinities with HMGB1/RAGE/NF-κB proteins. In in vivo studies, BF not only inhibited the protein expression of HMGB1, RAGE, ICAM-1, and VCAM-1; mRNA levels of HMGB1 and RAGE; and the phosphorylation of NF-κB, ERK, Janus kinase (JNK) and p38 MAPK in the femoral artery, but also reduced the levels of inflammatory cytokines (IL-6, TNF-α, IL-1β, HMGB1) and stable metabolite (TXB2) of cytokine promoting thrombosis (TXA2) in the plasma. Moreover, BF stimulated the secretion of stable metabolite (6-keto-PGF1α) of cytokine inhibiting thrombosis (PGI2) in the plasma. BF inhibited the inflammatory response and thrombosis in the femoral artery, thus reducing the degree of vascular occlusion, which alleviated the symptoms in rats with TAO. Our findings suggest that BF ameliorates TAO by inhibiting the activation of the ERK, JNK, p38 MAPK and HMGB1/RAGE/NF-κB signaling pathways, thereby providing novel ideas for the treatment of TAO and essential information for the further development and utilization of BF as a promising drug to treat TAO.

Combined Analysis of Clinical Data on HGF Gene Therapy to Treat Critical Limb Ischemia in Japan.

The objective of this combined analysis of data from clinical trials in Japan, using naked plasmid DNA encoding hepatocyte growth factor (HGF), was to document the safety and efficacy of intramuscular HGF gene therapy in patients with critical limb ischemia (CLI). HGF gene transfer was performed in 22 patients with CLI in a single-center open trial at Osaka University; 39 patients in a randomized, placebo-controlled, multi-center phase III trial, 10 patients with Buerger's disease in a multi-center open trial; and 6 patients with CLI in a multi-center open trial using 2 or 3 intramuscular injections of naked HGF plasmid at 2 or 4 mg. Resting pain on a visual analogue scale (VAS) and wound healing as primary endpoints were evaluated at 12 weeks after the initial injection. Serious adverse events caused by gene transfer were detected in 7 out of 77 patients (9.09%). Only one patient experienced peripheral edema (1.30%), in contrast to those who had undergone treatment with VEGF. At 12 weeks after gene transfer, combined evaluation of VAS and ischemic ulcer size demonstrated a significant improvement in HGF gene therapy group as compared to the placebo group (P=0.020). The long-term analysis revealed a sustained decrease in the size of ischemic ulcer in HGF gene therapy group. In addition, VAS score over 50 mm at baseline (total 27 patients) demonstrated a tendency (P=0.059), but not significant enough, to improve VAS score in HGF gene therapy as compared to the placebo group. The findings indicated that intramuscular injection of naked HGF plasmid tended to improve the resting pain and significantly decreased the size of the ischemic ulcer in the patients with CLI who did not have any alternative therapy, such as endovascular treatment (EVT) or bypass graft surgery. An HGF gene therapy product, CollategeneTM, was recently launched with conditional and time-limited approval in Japan to treat ischemic ulcer in patients with CLI. Further clinical trials would provide new therapeutic options for patients with CLI.

Efficacité de l’oxygénothérapie hyperbare dans le traitement d’un ulcère nécrotique d’orteil au cours d’une sclérodermie systémique

The medical treatment of ischemic ulcers in patients with systemic sclerosis remains difficult. Despite the major help provided by vasodilator treatments, the risk of spontaneous or surgical amputation remains high. A 48-year-old female patient from Guadeloupe was treated in our department for diffuse systemic sclerosis present for 15years complicated by lung, joint and digestive involvement, and associated with severe Raynaud's phenomenon. The clinical course was marked by the occurrence of multiple ischemic ulcers, which were resistant to conventional medical treatment and resulted in two surgical amputations (to the 2nd and 3rd interphalangeal joints of the toes of the left foot). Treatment with an endothelin-receptor antagonist and a calcium inhibitor was then introduced for secondary prevention. Two years later, the patient consulted for a further ischemic ulcer of the left 4th toe. She refused the proposed treatment with iloprost. Because of the unfavorable outcome and the absence of therapeutic alternative to amputation, hyperbaric oxygen therapy was initiated. Thirty 90-minutes sessions of pure oxygen at 2.5 ATA were conducted over a 10-week period. Complete healing was obtained after 8 months. We report herein a clinical case illustrating the efficacy of hyperbaric oxygen therapy for the treatment of ischemic ulcers of the toes in systemic sclerosis. It could offer an alternative therapeutic option, in particular for patients presenting resistant ischemic ulcers and a contraindication for or intolerance to the conventional medical treatment.

Long-term effects of cyclic therapy with iloprost in systemic sclerosis

To assess the long-term effects of cyclic infusion of iloprost, a derivative of prostacyclin, on Raynaud's phenomenon-related symptoms and ischemic ulcers in patients with Systemic Sclerosis (SSc). A retrospective analysis of prospectively collected parameters in 59 consecutive SSc patients, followed at one institution, who were treated for a median time of 52 months with iloprost for severe Raynaud's phenomenon and ischemic ulcers. Among the 50 patients with ischemic ulcers at the start of therapy, 35 (70%) did not show lesions at the last observation. Despite therapy, four patients underwent amputations (two of forefoot, two of finger distal phalanges). Compared to the pre-treatment point, we observed: decrease of the Raynaud's phenomenon VAS (p<0.001), and, in patients with diffuse cutaneous involvement, of the modified Rodnan skin thickness score (p=0.002). The Health Assessment Questionnaire was not significantly improved. Treatment with cyclic iloprost can control Raynaud's phenomenon-related symptoms and ischemic ulcers in the large majority of patients with SSc. However, a disease-modifying effect of this therapy could not be demonstrated.

Effect of Autologous Bone-Marrow Cell Transplantation on Ischemic Ulcer in Patients With Buerger's Disease

Thromboangiitis obliterans, also known as Buerger's disease, is characterized by peripheral occlusive changes in the arteries of the upper and lower limbs and treatment is often ineffective. Intramuscular transplantation of autologous bone marrow-mononuclear cells (BM-MNC) has been recently reported as improving the symptoms and clinical manifestations in patients with severely ischemic limbs, mostly caused by arteriosclerosis obliterans. The present study focused on the patients with Buerger's disease presenting with rest pain and/or skin ulcer uncontrolled by conventional treatments. Fourteen patients with Buerger's disease (Fontaine III: n=2, Fontaine IV: n=12) underwent transplantation of autologous BM-MNC into ischemic skeletal muscles of either the upper or lower limb. After 4 weeks, rest pain was significantly reduced. In 19 skin ulcers of 9 patients, 8 ulcers were healed and 8 were diminished in the size. These improvements were maintained for 24 weeks without complications. In patients with Buerger's disease, intramuscular transplantation of autologous BM-MNC improved symptoms and clinical manifestations, especially skin ulcer.

Reply to Letter Regarding Article, "Effect of Autologous Bone-marrow Cell Transplantation on Ischemic Ulcer in Patients With Buerger's Disease"

Reply to Letter Regarding Article, "Effect of Autologous Bone-marrow Cell Transplantation on Ischemic Ulcer in Patients With Buerger's Disease"

Letter by Akar et al Regarding Article, "Effect of Autologous Bone-Marrow Cell Transplantation on Ischemic Ulcer in Patients With Buerger's Disease"

Letter by Akar et al Regarding Article, "Effect of Autologous Bone-Marrow Cell Transplantation on Ischemic Ulcer in Patients With Buerger's Disease"

Efficacy of prostaglandin E1 in the treatment of lower extremity ischemic ulcers secondary to peripheral vascular occlusive disease: Results of a prospective randomized, double-blind, multicenter clinical trial

Most previous reports suggesting beneficial effects of prostaglandin E1 (PGE1) have been retrospective and uncontrolled. Therefore, this study was undertaken to assess the efficacy of PGE1 in the treatment of ischemic ulcers in patients with peripheral vascular occlusive disease (PVOD). One hundred twenty patients with one to three ischemic ulcers not healing for 3 weeks with standard care were randomized to receive either PGE1 (20 ng/kg/min) or a placebo for 72 hours through a central venous catheter. Ulcers were measured and photographed, and the rest pain was evaluated before and after infusion and at 1- and 2-month follow-up intervals. Fifty-seven patients with 95 ulcers received PGE1. Seventeen ulcers healed (18%); 22 ulcers decreased in size (23%); 37 ulcers remained unchanged or increased in size (39%); five new ulcers developed during the study (5%); and 14 ulcers had inadequate follow-up (15%). Sixty-three patients with 115 ulcers received a placebo. Nineteen ulcers healed (16%); 38 ulcers decreased in size (33%); 45 ulcers remained unchanged or increased in size (39%); three new ulcers developed during the study (3%); and 10 ulcers had inadequate follow-up (9%). None of the above differences between the drug-treated group and the placebo-treated group was statistically significant. This study did not demonstrate efficacy for intravenously administered PGE1 in the healing of ischemic ulcers in patients with PVOD.