2005 Annual Scientific Meeting - CLICK FOR PROGRAMME

New drugs for hypnosis and sedation

Gavin J. Kilpatrick PhD and Gary S. Tilbrook PhD

CeNeS limited, Compass House, Vision Park, Histon, Cambridge CB4 9ZR.

A range of drugs are currently available for hypnosis and sedation. However, all of the preparations have drawbacks. Such drawbacks range from extended duration of action and unwanted cardiovascular and respiratory effects to issues with their vehicle including pain on injection and vulnerability to bacterial growth. Three main strategies are being employed by the pharmaceutical industry in an effort to identify improved drugs. Firstly, re-formulations of existing drugs in order to overcome issues relating to the formulation vehicle. Secondly, the development of pro-drugs of existing agents, to circumvent issues such as poor water solubility. Thirdly, the synthesis of novel ‘soft-drugs’ i.e. active compounds that are broken down rapidly in the body to inactive metabolites. Each of these approaches relies on either existing drugs or known mechanisms. We are unaware of any current development programmes aimed at novel mechanisms.

Re-formulations of currently available drugs are mainly focussed on propofol. The goal here is to overcome the issues of injection pain, hyperlipidaemia resulting from repeat use and microbial growth associated with the lipid vehicle. The most advanced is propofol IDD-D^™ (SkyePharma/Endo), which is a 2% formulation of propofol in a medium-chain triglyceride emulsion with inherent antimicrobial properties[1]. This programme is currently in Phase III clinical trials for long-term sedation. Other reformulations of propofol include a lingual spray (Manhattan/Novadel), a surfactant micelle delivery system (Maelor), an aqueous formulation (Physica Pharma) and a cyclodextrin formulation (CyDex). CyDex is also reported to be working on a cyclodextrin formulation of etomidate.

Pro-drug approaches are again largely focussed on propofol, with the goal of achieving good water solubility. The inherent problem with the pro-drug approach is that, since they need to be rapidly metabolised in order to liberate the active compound, they routinely have a slower onset and offset of action profile than that of the parent compound. Some early programmes are under way (Vyrex and Auspex) but the most advanced is the methyl phosphate pro-drug of propofol, Aquavan^® (MGI Pharma)[2]. This compound is in Phase III trials for procedural sedation. However, the first Phase III trial was halted due to a high level of adverse events (hypoxaemia, hypotension, parasthesias and burning sensations). The company is now reported to be undertaking further dose-ranging studies.

The soft-drug approach has previously been employed in the field of anaesthesia, including the short-acting opiate, remifentanil (Ultiva^®), the anaesthetic propanidid and neuromuscular blockers such as mivacurium. A novel metabolically-labile hypnotic agent, TD-4756, is being developed by Theravance. TD-4756 is reported to be hydrolysed rapidly by blood and tissue esterases. It is reported that the recovery profile in animal studies is very rapid and that the compound is associated with less respiratory depressant activity than propofol[3,4]. Other soft-drug programmes are focussed on esters of benzodiazepine (CeNeS, NeuroSearch) and barbiturate (Aryx) ligands.

The compounds under development by CeNeS were assigned from GSK in 2003. The goal of the programme being to improve upon midazolam. The main clinical disadvantages of midazolam are the prolonged duration of action due to the production of active metabolites and the reliance on the clearance of the compound by cytochrome P450 3A4. Building on the expertise gained with remifentanil, GSK designed a range of benzodiazepine ligands that are rapidly metabolised by non-specific tissue esterases (which are widely distributed in the body) to inactive metabolites. For example, CNS 7259X has a high affinity for the benzodiazepine site of the human GABA_A receptor (Ki 6nM). The acid metabolite of CNS 7259X is more than 400 times less active than the parent ester. In rodents, the recovery from loss of righting reflex is observed in less than half the time of an equivalent dose of midazolam (25-30mg/kg i.v.). In the Yucutan micropig, CNS 7259X (0.05-1mg/kg i.v.) induced sedation with a rapid onset and a markedly shorter offset than midazolam at equi-sedative doses. It is postulated that these novel benzodiazepines, such as CNS 7259X, may provide rapid and more predictable onset and offset of sedative action and, as such, represent a significant advance upon midazolam for use in short- and long-term sedation.

References

1.      Ward, D.S. et al., (2002) Anesthesiology 97, 1401.

2.      Krasowski, M.D. (2005) Curr Opin Investigational Drugs 6, 90.

3.      Beattie, D. et al., (2004) Anaesthesia, 59, 101.

4.      Jenkins, T. et al., (2004) Anaesthesia, 59, 100.