Jay Lichter

Vanadium treatment of type 2 diabetes: a view to the future.

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.

Dose-Dependent Sustained Release of Dexamethasone in Inner Ear Cochlear Fluids Using a Novel Local Delivery Approach

The thermo-reversible triblock copolymer poloxamer 407 was investigated as a drug delivery vehicle for micronized dexamethasone into the middle and inner ears of guinea pigs. The study characterized the gelation and in vitro release kinetics of poloxamer formulations. In vivo, the pharmacokinetic profile of formulations containing varying concentrations of poloxamer and dexamethasone was examined following intratympanic administration. Significant drug levels within the perilymph were observed for at least 10 days, while systemic exposure was minimal. The sustained-release kinetics profile could be significantly modulated by varying the concentrations of both poloxamer and dexamethasone. Assessment of auditory function revealed a small transient shift in hearing threshold, most probably of conductive nature, which resolved itself within a week. No significant histological changes of the round window membrane or cochlea could be noted. Poloxamer 407 thus represents an effective and safe delivery system to achieve sustained release of dexamethasone to the inner ear.

OTO-104: a sustained-release dexamethasone hydrogel for the treatment of otic disorders.

Hypothesis: To investigate whether OTO-104, a poloxamer-based hydrogel containing micronized dexamethasone for intratympanic delivery, can provide long-lasting inner ear exposure and be well tolerated. Methods: OTO-104 was administered intratympanically to guinea pigs and sheep, and its pharmacokinetic and toxicity profiles were examined. Results: After a single intratympanic injection of OTO-104 (from 0.6% to 20%, w/w), significant and prolonged exposure to dexamethasone in the inner ear was observed. Increasing the concentration of OTO-104 resulted in higher perilymph drug levels as well as a more prolonged duration of exposure. At the highest dose, therapeutic perilymph levels of dexamethasone could be sustained over 3 months in guinea pigs and more than 1 month in sheep. A toxicologic evaluation was conducted, including assessments of middle and inner ear function and physiology, as well as appraisal of local and systemic toxicity. A small and transient shift in hearing threshold was observed, most probably conductive in nature. No significant histologic changes in middle or inner ear tissues were noted. Although macroscopically mild erythema/inflammation was documented in a subset of guinea pigs treated with 20% OTO-104, the nature and the severity of these changes were not different between the poloxamer vehicle, saline, and 20% OTO-104 groups. No evidence of acute dermal toxicity, delayed hypersensitivity, or systemic adverse effects was found. Conclusion: OTO-104 is a novel proprietary therapeutic delivery system that can achieve prolonged, sustained release of dexamethasone within the inner ear fluids. The administration of this clinical candidate formulation via intratympanic injection is expected to be well tolerated both locally and systemically.

Pharmacokinetics of Dexamethasone Solution following Intratympanic Injection in Guinea Pig and Sheep

Information on inner ear pharmacokinetics is limited in the literature, especially in large animals and in humans. A preliminary study was designed to explore the differences in inner ear exposure between guinea pigs and sheep following a single intratympanic injection of a 2% dexamethasone sodium phosphate solution. In both species, significant levels of dexamethasone were observed in the perilymph within 1 h, and decreasing by 50- to 100-fold within 12 h. Overall, the exposure to dexamethasone in the inner ear was significantly lower in sheep by 17- to 27-fold than in guinea pigs. Systemic and CNS exposure were minimal in both species as indicated by the low drug levels observed in plasma and CSF. Altogether, the preliminary evidence presented herein suggests the sheep as a practical and acceptable animal model to study the inner ear pharmacokinetics of drug candidates in large mammals and its potential towards extrapolation to human exposure.

Contents Vol. 14, 2009

Maurizio Barbara, Rome Olivier Bertrand, Bron F. Owen Black, Portland Th omas Brandt, München Barbara Canlon, Stockholm John P. Carey, Baltimore Douglas A. Cotanche, Boston Cor W.R.J. Cremers, Nijmegen Norbert Dillier, Zürich Robert Dobie, Sacramento Manuel Don, Los Angeles Jill B. Firszt, St. Louis Andrew Forge, London Bernard Fraysse, Toulouse Rick Friedman, Los Angeles Bruce J. Gantz, Iowa City Pablo Gil-Loyzaga, Madrid Anthony W. Gummer, Tübingen James W. Hall III, Gainesville Joseph W. Hall III, Chapel Hill Michael Halmagyi, Camperdown Rudolf Häusler, Bern Vicente Honrubia, Los Angeles Gary D. Housley, Auckland Karl-Bernd Hüttenbrink, Köln Pawel J. Jastreboff , Atlanta Margaret A. Kenna, Boston Philippe P. Lefebvre, Liège Bernd Lütkenhöner, Münster Linda L. Luxon, London Geoff rey A. Manley, Freising Alessandro Martini, Ferrara Jennifer R. Melcher, Boston Saumil N. Merchant, Boston Brian C.J. Moore, Cambridge David R. Moore, Nottingham Cynthia C. Morton, Boston Donata Oertel, Madison Kaoru Ogawa, Tokyo Stephen J. O’Leary, Parkville Alan R. Palmer, Nottingham Lorne S. Parnes, London, Ont. Jean-Luc Puel, Montpellier Ramesh Rajan, Monash Yehoash Raphael, Ann Arbor J. Th omas Roland, New York John J. Rosowski, Boston Rudolf Rübsamen, Leipzig Mario A. Ruggero, Evanston Leonard P. Rybak, Springfi eld Richard J. Salvi, Buff alo Robert V. Shannon, Los Angeles Guido F. Smoorenburg, Besse sur Issole Haim Sohmer, Jerusalem Olivier Sterkers, Clichy Istvan Sziklai, Debrecen Peter R. Th orne, Auckland Shin-ichi Usami, Matsumoto P. Ashley Wackym, Milwaukee Tatsuya Yamasoba, Tokyo Fan-Gang Zeng, Irvine Basic Science and Clinical Research in the Auditory and Vestibular Systems and Diseases of the Ear