piperidines and Diabetic-Foot

Chronic wounds (e.g. diabetic foot ulcers) reduce the quality of life, yet treatments remain limited. Glucocorticoids (activated by the enzyme 11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1) impair wound healing.. Efficacy, safety, and feasibility of 11β-HSD1 inhibition for skin function and wound healing.. Investigator-initiated, double-blind, randomized, placebo-controlled, parallel-group phase 2b pilot trial.. Single-center secondary care setting. Adults with type 2 diabetes mellitus without foot ulcers were administered 400 mg oral 11β-HSD1 inhibitor AZD4017 (n = 14) or placebo (n = 14) bi-daily for 35 days. Participants underwent 3-mm full-thickness punch skin biopsies at baseline and on day 28; wound healing was monitored after 2 and 7 days. Computer-generated 1:1 randomization was pharmacy-administered. Analysis was descriptive and focused on CI estimation. Of the 36 participants screened, 28 were randomized.. Exploratory proof-of-concept efficacy analysis suggested AZD4017 did not inhibit 24-h ex vivoskin 11β-HSD1 activity (primary outcome; difference in percentage conversion per 24 h 1.1% (90% CI: -3.4 to 5.5) but reduced systemic 11β-HSD1 activity by 87% (69-104%). Wound diameter was 34% (7-63%) smaller with AZD4017 at day 2, and 48% (12-85%) smaller after repeat wounding at day 30. AZD4017 improved epidermal integrity but modestly impaired barrier function. Minimal adverse events were comparable to placebo. Recruitment rate, retention, and data completeness were 2.9/month, 27/28, and 95.3%, respectively.. A phase 2 trial is feasible, and preliminary proof-of-concept data suggests AZD4017 warrants further investigation in conditions of delayed healing, for example in diabetic foot ulcers.. Stress hormone activation by the enzyme 11β-HSD type 1 impairs skin function (e.g. integrity) and delays wound healing in animal models of diabetes, but effects in human skin were previously unknown. Skin function was evaluated in response to treatment with a 11β-HSD type 1 inhibitor (AZD4017), or placebo, in people with type 2 diabetes. Importantly, AZD4017 was safe and well tolerated. This first-in-human randomized, controlled, clinical trial found novel evidence that 11β-HSD type 1 regulates skin function in humans, including improved wound healing, epidermal integrity, and increased water loss. Results warrant further studies in conditions of impaired wound healing, for example, diabetic foot ulcers to evaluate 11β-HSD type 1 as a novel therapeutic target forchronic wounds.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Adult; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Diabetic Foot; Double-Blind Method; Epidermis; Female; Humans; Male; Middle Aged; Niacinamide; Pilot Projects; Piperidines; Quality of Life; Skin; Treatment Outcome; Wound Healing

BACKGROUND Diabetes causes damage to the soft tissue and bone structure of the foot, referred to as "diabetic foot". Ibrutinib is a Bruton tyrosine kinase (Btk) inhibitor, and the role and mechanism of ibrutinib on the diabetic foot have not been elucidated. MATERIAL AND METHODS Male Wister rats were randomly divided into 3 groups: control group, model group, and ibrutinib group. After 14 days, the ulcer wound size of each group was measured, and the ulcer healing rate was calculated. The level of inflammatory factors interleukin (IL)-1ß, tumor necrosis factor (TNF)-alpha, and IL-6 was detected by enzyme-linked immunosorbent assay (ELISA). Real-time polymerase chain reaction (PCR) was used to analyze the changes of Toll-like receptor 2 (TLR2) and TLR4. The expression of vascular endothelial growth factor (VEGF) and the RAGE (receptor for advanced glycation end product/NF-kappaB (nuclear factor-kappa B) pathway was detected by western blot. RESULTS Blood glucose, blood lipids, serum creatinine, and urea nitrogen (BUN) levels were increased in the model group, together with increased levels of IL-1ß, TNF-alpha, IL-6, as well as TLR2 and TLR4 expression, and there were significant differences compared with the control group (P<0.05). Meanwhile, the model group showed decreased VEGF expression and increased expression of RAGE and NF-kappaB. However, ibrutinib reduced blood sugar, blood lipids, creatinine, and urea nitrogen levels, inhibited the secretion of inflammatory factors, promoted ulcer healing, improved ulcer healing rate, decreased the expression of TLR2, TLR4, RAGE, and NF-kappaB, and increased VEGF expression; there were significant differences in the ibrutinib group compared with the model group (P<0.05). CONCLUSIONS The Btk inhibitor ibrutinib can upregulate VEGF expression, inhibit the expression of TLRs, inhibit the secretion of inflammatory factors, and promote the healing of diabetic foot ulcer possibly by regulating the RAGE/NF-kappaB pathway.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Cytokines; Diabetes Mellitus; Diabetic Foot; Disease Models, Animal; Male; NF-kappa B; Piperidines; Pyrazoles; Pyrimidines; Rats; Rats, Wistar; Receptor for Advanced Glycation End Products; Signal Transduction; Toll-Like Receptors; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Diabetic foot ulcer is the most common cause of diabetes-associated nontraumatic lower extremity amputation. Most patients who undergo lower extremity amputation for a diabetic foot have had diabetes for a long time and suffer from multiorgan disorder; thus, it can be a challenge to ensure sufficient anesthetic and analgesic effects while maintaining stable hemodynamics. Recently, peripheral nerve block has gained popularity owing to its attenuating effects of systemic concerns. This retrospective observational study aimed to compare the effects of remifentanil-based general anesthesia (GEA) and popliteal nerve block (PNB) on postoperative pain and hemodynamic stability in diabetic patients undergoing distal foot amputation.A total of 59 consecutive patients with a diabetic foot who underwent distal foot amputation between January 2012 and May 2014 were retrospectively reviewed. Patients received remifentanil-based GEA (GEA group, n = 32) or PNB (PNB group, n = 27). The primary outcomes were to evaluate postoperative analgesic effects and perioperative hemodynamics. Also, postoperative pulmonary complications and 6-month mortality were assessed as secondary outcomes.Significant differences in pain scores using numeric rating scale were observed between the groups in a linear mixed model analysis (PGroup×Time = 0.044). Even after post hoc analysis with the Bonferroni correction, the numeric rating scale scores were significantly lower in the PNB group. Furthermore, patients in the PNB group required less pethidine during the first 6 hours after surgery (27 ± 28 vs 9 ± 18 mg; P = 0.013). The GEA group had a lower mean blood pressure (Bonferroni-corrected P < 0.01), despite receiving more ephedrine (P < 0.001). Significantly more patients in the GEA group suffered from postoperative pneumonia and required the management in intensive care unit (P = 0.030 and 0.038, respectively). However, the groups did not differ in terms of 6-month mortality.This study demonstrated that compared with remifentanil-based GEA, PNB might be a favorable option for diabetic patients undergoing distal foot amputation, despite the lack of significant mortality benefits, as PNB was associated with improved postoperative analgesia, hemodynamic stability, and a low incidence of pulmonary complications during the immediate postoperative period, especially in high-risk patients.

Topics: Aged; Amputation, Surgical; Anesthesia, General; Diabetic Foot; Female; Hemodynamics; Humans; Male; Middle Aged; Pain Measurement; Pain, Postoperative; Peripheral Nerves; Piperidines; Remifentanil; Retrospective Studies

Topics: Animals; Cell Line; Diabetes Mellitus, Experimental; Diabetic Foot; Estrogen Receptor alpha; Estrogen Receptor Antagonists; Estrogen Receptor beta; Humans; Mice, Knockout; Piperidines; Pyrazoles; Pyrimidines; Wound Healing