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Biomedical subjects

Gary S Tilbrook

Publications and source records attributed to Gary S Tilbrook.

4 recordsLinked to original sources

Drug development in anaesthesia: industrial perspective.

PURPOSE OF REVIEW: In this review, we summarize the new drugs in development in the anaesthesia field. RECENT FINDINGS: There are some interesting approaches, including pro-drugs of propofol such as Aquavan (MGI Pharma, Bloomington, Minnesota, USA) and novel 'soft-drug' sedatives and hypnotics (e.g. CNS-7259X and TD-4756) as well as a novel approach to terminate the action of steroidal neuromuscular blockers (sugammadex). There is also significant activity in the field of novel analgesics. Particularly addressing the fields of sedatives, hypnotics and neuromuscular blockers, however, there is relatively little drug discovery activity currently. Part of the reason for this may be that the mechanisms of action of anaesthetics are not fully understood. This cannot be the whole story, however, since attractive new targets have recently been identified. For example, an agent with selective actions at the beta3-containing subunit of the gamma-amino butyric acid-A receptor is likely to have the hypnotic effects of propofol without the cardiac depressant side-effects. SUMMARY: We consider the main reason for low activity is the perception in industry that there is little need for new drugs in anaesthesia because the needs are well addressed by existing agents. If this is not the case then anaesthesiologists need to be more effective in communicating their requirements.

Analgesics↗

The effect of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') and its metabolites on neurohypophysial hormone release from the isolated rat hypothalamus.

Methylenedioxymethamphetamine (MDMA, 'ecstasy'), widely used as a recreational drug, can produce hyponatraemia. The possibility that this could result from stimulation of vasopressin by MDMA or one of its metabolites has been investigated in vitro. Release of both oxytocin and vasopressin from isolated hypothalami obtained from male Wistar rats was determined under basal conditions and following potassium (40 mM) stimulation. The results were compared with those obtained for basal and stimulated release in the presence of MDMA or metabolites in the dose range 1 microM to 100 pM (n=5 - 8) using Student's t-test with Dunnett's correction for multiple comparisons. All compounds tested affected neurohypophysial hormone release, HMMA (4-hydroxy-3-methoxymethamphetamine) and DHA (3,4-dihydroxyamphetamine) being more active than MDMA, and DHMA (3,4-dihydroxymethamphetamine) being the least active. The effect on vasopressin release was greater than that on oxytocin. In the presence of HMMA the ratio test:control for basal release increased for vasopressin from 1.1+/-0.16 to 2.7+/-0.44 (s.e.m., P<0.05) at 10 nM and for oxytocin from 1.0+/-0.05 to 1.6+/-0.12 in the same hypothalami. For MDMA the ratio increased to 1.5+/-0.27 for vasopressin and to 1.28+/-0.04 for oxytocin for 10 nM. MDMA and its metabolites can stimulate both oxytocin and vasopressin release in vitro, the response being dose dependent for each drug with HMMA being the most potent.

Adrenergic Uptake Inhibitors↗

Synthesis and physicochemical assessment of novel 2-substituted 3-hydroxypyridin-4-ones, novel iron chelators.

Novel 3-hydroxypyridin-4-one containing tridentate ligands were synthesised and their physicochemical properties characterised, including ionisation constants and stoichiometric titration with Fe(III). There is an urgent demand for orally active iron chelators with potential for the treatment of thalassaemia. In principle, tridentate ligands are likely to be more kinetically stable than bidentate molecules, but to date no satisfactory molecules have been identified. Fe(III) stability constants were assessed by competition with the hexadentate ligand EDTA. In all cases no evidence was found for a tridentate mode of iron chelation; instead the ligands behaved as bidentate hydroxypyridinones. As a consequence they provide no advantage over the more simple alkyl hydroxypyridinones.

Iron Chelating Agents↗

Memantine. Merz.

Memantine hydrochloride, an NMDA antagonist, was launched in Germany by Merz in 1989 for the treatment of dementia, an indication for which development was continuing in other markets. It is also under development by Merz, Lundbeck, Neurobiological Technologies Inc (NTI) Forest Laboratories and Suntory for the potential treatment of Alzheimer's disease (AD), AIDS-related dementia and pain in patients with neuropathy, and by Allergan for the potential treatment of ocular disease. By July 2001, a regulatory filing for neuropathic pain was expected in 2003. In February 2002, the CPMP recommended to the EU commission to approve memantine for the treatment of moderately severe-to-severe Alzheimer's disease. At this time, marketing authorization was expected late in the first half of 2002, and Lundbeck planned to launch memantine under the brand name Ebixa during the second half of 2002. Merz and Lundbeck, filed memantine for AD in the EU in September 2000 and an NDA was submitted in November of that year. The compound was in phase H trials in the US for the treatment of AIDS-related dementia and pain by August 1996 and phase III trials for glaucoma and neuroprotection by 1999. Analysts at Merrill Lynch predicted in October 2001 that Allergan would make regulatory filings in the US for memantine in glaucoma and ocular hypertension in 2005, and that Forest Laboratories would file for memantine in the US as a supplement to Alzheimer's disease data in early 2002, and for the treatment of neuropathic pain in 2003. Sales of $25 million in 2004, rising to $75 million in 2005, were predicted by Merrill Lynch for this product.

Animals↗