title: Vanadium treatment of type 2 diabetes: a view to the future.
abstract: 3-Hydroxy-2-methyl-4-pyrone and 2-ethyl-3-hydroxy-4-pyrone (maltol and ethyl maltol, respectively) have proven especially suitable as ligands for vanadyl ions, in potential insulin enhancing agents for diabetes mellitus. Both bis(maltolato)oxovanadium(IV) (BMOV), and the ethylmaltol analog, bis(ethylmaltolato)oxovanadium(IV) (BEOV), have the desired intermediate stability for pro-drug use, and have undergone extensive pre-clinical testing for safety and efficacy. Pharmacokinetic evaluation indicates a pattern of biodistribution consistent with fairly rapid dissociation and uptake, binding to serum transferrin for systemic circulation and transport to tissues, with preferential uptake in bone. These bis-ligand oxovanadium(IV) (VOL(2)) compounds have a clear advantage over inorganic vanadyl sulfate in terms of bioavailability and pharmaceutical efficacy. BEOV has now completed Phase I and has advanced to Phase II clinical trials. In the Phase I trial, a range of doses from 10 mg to 90 mg BEOV, given orally to non-diabetic volunteers, resulted in no adverse effects; all biochemical parameters remained within normal limits. In the Phase IIa trial, BEOV (AKP-020), 20 mg, daily for 28 days, per os, in seven type 2 diabetic subjects, was associated with reductions in fasting blood glucose and %HbA1c; improved responses to oral glucose tolerance testing, versus the observed worsening of diabetic symptoms in the two placebo controls.
authors.affiliation: Medicinal Inorganic Chemistry Group, Chemistry Department, 2036 Main Mall, University of British Columbia, Vancouver, BC, Canada. kthompso@chem.ubc.ca
authors.forename: Katherine H
authors.initials: KH
authors.lastname: Thompson
authors.forename: Jay
authors.initials: J
authors.lastname: Lichter
authors.forename: Carl
authors.initials: C
authors.lastname: LeBel
authors.forename: Michael C
authors.initials: MC
authors.lastname: Scaife
authors.forename: John H
authors.initials: JH
authors.lastname: McNeill
authors.forename: Chris
authors.initials: C
authors.lastname: Orvig
mesh_terms: D002986:Clinical Trials as Topic; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000627:therapeutic use*; D009942:Organometallic Compounds / Q000737:chemistry / Q000627:therapeutic use*; D011753:Pyrones / Q000737:chemistry / Q000627:therapeutic use; D014638:Vanadates / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D007004:Hypoglycemic Agents; D009942:Organometallic Compounds; D011753:Pyrones; C541654:bis(ethylmaltolato)oxovanadium(IV); C074212:bis(maltolato)oxovanadium(IV); C008316:maltol; D014638:Vanadates; C052408:ethyl maltol