Carl Lebel

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.

Distribution of Dexamethasone and Preservation of Inner Ear Function following Intratympanic Delivery of a Gel-Based Formulation

Intratympanic (IT) delivery of drugs to the ear is increasingly used for both clinical and research purposes. One limitation of IT delivery is that drugs are rapidly lost from the middle ear by a number of processes, so that prolonged delivery of drug is technically difficult. In the present study, the delivery characteristics of a poloxamer hydrogel formulation containing dexamethasone (dex) were evaluated. The gel is liquid at room temperature, allowing IT injection, but transitions to a gel at body temperature, providing a prolonged residence time in the middle ear. A 50-µl volume of control or dex-containing gel (dex-gel) was injected through the tympanic membrane of guinea pigs. Cochlear function was assessed with cochlear action potential and acoustic emission thresholds measured immediately, 6 or 24 h after IT gel injection. After 6- or 24-hour treatment with dex-gel, perilymph drug gradients along the cochlea were assessed by taking samples sequentially from the apex, and endolymph was sampled from the basal turn. Control gel injections caused small changes in sound field calibrations and functional measures for low-frequency stimuli, consistent with an induced conductive loss. Within 24 h, responses returned to normal. Twenty-four hours after dex-gel injection, low-frequency changes remained as the dex-gel was retained better in the middle ear, but there was no indication of high-frequency loss. While perilymph sample data showed that dex gradients were substantially lower than after single injections of dex solution, quantitative analysis of this result suggests that some dex may have entered the perilymph through the thin bone in the apical region of the cochlea. Endolymph levels of dex remained lower than those in the perilymph. This study confirms that a poloxamer hydrogel-based dex formulation provides an effective method for a prolonged delivery, providing a more uniform distribution of drug in the inner ear.

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.

Principles of inner ear sustained release following intratympanic administration

Previous studies revealed that intratympanic administration of the steroid dexamethasone in poloxamer 407 hydrogel, a class of thermoreversible polymers, resulted in significant and durable exposure in the inner ear. Interestingly, varying the concentrations of the poloxamer vehicle and of the steroid impacted the pharmacokinetic profile of dexamethasone in the perilymphatic compartment. Here, the respective contributions of different vehicles (aqueous solution, poloxamer hydrogel) and steroid drugs (dexamethasone, methylprednisolone) were investigated. In particular, various forms of the steroids, discriminated by their aqueous solubility, were compared.

The Sustained-Exposure Dexamethasone Formulation OTO-104 Offers Effective Protection against Noise-Induced Hearing Loss.

The otoprotective effects of OTO-104 were investigated following both acute and chronic administration of cisplatin. The acute administration of cisplatin to guinea pigs resulted in profound hearing loss (70-80 dB SPL) across all frequencies tested. A single intratympanic injection of 6% OTO-104, but not of lower doses, almost completely protected against cisplatin ototoxicity. In contrast, a dexamethasone solution administered under the same experimental conditions offered no otoprotection. OTO-104 was also very effective in protecting against the progressive hearing loss observed with the chronic administration of cisplatin (3 injections at a weekly interval). The otoprotection was found to be dependent upon the activation of dexamethasone-dependent classical nuclear receptor pathways.

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