A muscarinic receptor antagonist reverses multiple indices of diabetic peripheral neuropathy: preclinical and clinical studies using oxybutynin.

Preclinical studies indicate that diverse muscarinic receptor antagonists, acting via the M1 sub-type, promote neuritogenesis from sensory neurons in vitro and prevent and/or reverse both structural and functional indices of neuropathy in rodent models of diabetes. We sought to translate this as a potential therapeutic approach against structural and functional indices of diabetic neuropathy using oxybutynin, a muscarinic antagonist approved for clinical use against overactive bladder. Studies were performed using sensory neurons maintained in vitro, rodent models of type 1 or type 2 diabetes and human subjects with type 2 diabetes and confirmed neuropathy. Oxybutynin promoted significant neurite outgrowth in sensory neuron cultures derived from adult normal rats and STZ-diabetic mice, with maximal efficacy in the 1-100 nmol/l range. This was accompanied by a significantly enhanced mitochondrial energetic profile as reflected by increased basal and maximal respiration and spare respiratory capacity. Systemic (3-10 mg/kg/day s.c.) and topical (3% gel daily) oxybutynin reversed paw heat hypoalgesia in the STZ and db/db mouse models of diabetes and reversed paw tactile allodynia in STZ-diabetic rats. Loss of nerve profiles in the skin and cornea of db/db mice was also prevented by daily topical delivery of 3% oxybutynin for 8 weeks. A randomized, double-blind, placebo-controlled interventional trial was performed in subjects with type 2 diabetes and established peripheral neuropathy. Subjects received daily topical treatment with 3% oxybutynin gel or placebo for 6 months. The a priori designated primary endpoint, significant change in intra-epidermal nerve fibre density (IENFD) in skin biopsies taken before and after 20 weeks of treatments, was met by oxybutynin but not placebo. Secondary endpoints showing significant improvement with oxybutynin treatment included scores on clinical neuropathy, pain and quality of life scales. This proof-of-concept study indicates that muscarinic antagonists suitable for long-term use may offer a novel therapeutic opportunity for treatment of diabetic neuropathy. Trial registry number: NCT03050827.

Therapeutic potentials of curcumin in the treatment of non-small-cell lung carcinoma.

Non-small-cell lung carcinoma (NSCLC) is one of the most lethal malignancies that include more than 80% of lung cancer cases worldwide. During the past decades, plants and plant-derived products have attracted great interest in the treatment of various human diseases. Curcumin, the turmeric isolated natural phenolic compound, has shown a promising chemo-preventive and anticancer agent. Numerous studies have shown that curcumin delays the initiation and progression of NSCLC by affecting a wide range of molecular targets and cell signalling pathways including NF-kB, Akt, MAPKS, BCL-2, ROS and microRNAs (miRNAs). However, the poor oral bioavailability and low chemical stability of curcumin remain as major challenges in the utilisation of this compound as a therapeutic agent. Different analogs of curcumin and new delivery systems (e.g., micelles, nanoparticles and liposomes) provided promising solutions to overcome these obstacles and improve curcumin pharmacokinetic profile. The present review focuses on current reported studies about anti-NSCLC effects of curcumin. NSCLC involved miRNAs whose expression is regulated by curcumin has also been discussed. Furthermore, recent researches on the use of curcumin analogs and delivery systems to enhance the curcumin benefits in NSCLC are also described.