bis(maltolato)oxovanadium(iv) and maltol

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.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Organometallic Compounds; Pyrones; Vanadates

Syntheses of vanadium complexes using the naturally occurring ligands isomaltol (Hima) and allomaltol (Hama), as well as a newly synthesized, potentially tetradentate diaminodipyrone [H(2)(en(ama)(2)], are reported. Complete characterization of the resulting compounds [trans-VO(ima)(2)(H(2)O), VO(ama)(2), V(ima)(3), V(ama)(3) and VO(en(ama)(2))], including X-ray crystallography analyses for trans-VO(ima)(2)(H(2)O) and V(ima)(3), are presented herein. Potentiometric titrations (25 degrees C, I = 0.16 M NaCl) were used to measure stability constants in the V(IV)-Hima system; these data were compared to previous data collected on the V(IV)-L (L = Hma, Hama) systems. The in vivo efficacy of these compounds to lower the blood glucose levels of STZ-diabetic rats was tested; all but VO(en(ama)(2)) produced significant decreases in plasma glucose levels. The results were compared to those of the benchmark compound BMOV [VO(ma)(2), bis(maltolato)oxovanadium(IV)], a known insulin-enhancing agent.

Topics: Animals; Blood Glucose; Crystallography, X-Ray; Diabetes Mellitus, Experimental; Hydrogen-Ion Concentration; Hypoglycemic Agents; Insulin; Isomerism; Ligands; Pyrones; Rats; Time Factors; Vanadates; Vanadium Compounds

Twenty years ago, we detected the interdependence between structure and function of rat liver Golgi complexes that are characteristic for streptozotocin diabetes, which served us in further investigations as a useful indicator of the effectiveness of drugs we were testing. This work presented results obtained in eight groups of rats (four control and four diabetic) that were administered orally either bis(maltolato)oxovanadium(IV) [BMOV] or maltol alone. The activities of the rat liver Golgi marker enzyme, galactosyltransferase [GalT], as well as the morphology of Golgi complexes were studied in situ using an electron microscope; parallel estimations of vanadium concentration and phospholipid percentage were made in Golgi-rich preparations isolated from the liver. Our main findings were normalization in diabetic animals orally treated with 1.8 mmol BMOV in 0.09 mol NaCl solutions over seven days, which demonstrated an accompanying increase in phosphatidic acid (PA) percentage (p < 0.05) compared to controls. In the diabetic groups, Pearson's test showed a positive double correlation between GalT activity, vanadium concentration, and PA percentage in Golgi-rich membrane preparations from the liver. Additionally, a negative correlation was found between vanadium concentration and phosphatidylcholine percentage in the fractions.

Topics: Animals; Diabetes Mellitus, Experimental; Female; Galactosyltransferases; Golgi Apparatus; Hypoglycemic Agents; Liver; Microscopy, Electron; Osmolar Concentration; Phospholipids; Pyrones; Rats; Rats, Wistar; Sodium Chloride; Vanadates; Vanadium

A wide variety of vanadium-containing complexes have been tested, both in vivo and in vitro, as possible therapeutic agents for the oral treatment of type 2 diabetes mellitus. None so far has surpassed bis(maltolato)oxovanadium(IV) (BMOV) for glucose- and lipid-lowering in an orally available formulation. Ligand choice is clearly an important factor in pharmacological efficacy of vanadium compounds as insulin enhancing agents. In this study, we kept the ligand and dose the same, varying instead the metal ion bound to the maltolato ligand in a series of binary complexes of neutral charge. A requirement for vanadyl ion as the metal ion of choice was apparent; no other metal ion tested served as a suitable substitute. Amongst [MoO(2)](2+), Co(II), Cu(II), Cr(III), and Zn(II), only [MoO(2)](2+) and Co(II) showed any hypoglycemic activity at the ED(50) dose for bis(maltolato)oxovanadium(IV), 0.6 mmolkg(-1) by oral gavage in streptozotocin (STZ)-diabetic rats within 72 h of administration of compound.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Hypoglycemic Agents; Male; Molybdenum; Organometallic Compounds; Pyrones; Rats; Rats, Wistar; Vanadates; Vanadium

Oral treatment with maltol or bis(maltolato)oxovanadium(IV) [BMOV] alters the biochemical activity of the rat liver Golgi marker enzyme, i.e., galactosyltransferase (GalT), and the organelle morphology in a relatively short time. Four groups of rats were investigated: control (C), treated with BMOV for 2 days (pVC), treated with BMOV for 7 days (C+V), and treated with maltol alone for 7 days (C+M). All drugs were administered as drinking solutions. These conditions were used, because normalization of galactosyltransferase activity (GalT) and morphology of rat liver Golgi complexes were previously found by us in streptozotocin-induced diabetes. In this paper, we present the influence of BMOV or maltol alone (as a vanadium ligand in BMOV compound) on rat liver Golgi complexes. The lowest statistically significant enzyme activity, in comparison with three other groups of rats (p < 0.01), was found in rats treated with BMOV solution for two days (pVC). Liver Golgi complexes in these rats showed relatively slight changes as compared with controls. The activity of GalT was similar to controls of the C+V and C+M groups. Morphological examinations of the Golgi apparatus in rats treated with vanadium salts revealed a slightly increased secretory activity. In response to various agents used in experiments, the Golgi complexes were generally reduced in size, except for the (C+M) group. Not only cisternae, but also vacuoles and associated vesicles on both sides of stacks were reduced in almost all Golgi structures. Ultrastructural findings were generally in agreement (except for pVC group) with biochemical results (yields of liver Golgi-rich fractions, activity of galactosyltransferase) obtained in the same rats.

Topics: Administration, Oral; Animals; Female; Golgi Apparatus; Liver; Pyrones; Rats; Rats, Wistar; Vanadates