Improved agents 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 (Manhatten/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® (Guilford Pharma)[2]. This compound is in Phase III trials for procedural sedation. However, the Phase III trial has recently been halted due to a high level of adverse events (hypoxaemia, hypotension, parasthesias and burning sensations). The company is reported to be reviewing dosing levels. It remains to be seen if development will continue.
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 programmes are focussed on esters of barbiturate (Aryx) and benzodiazepine (CeNeS, NeuroSearch) 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 the liver. 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 7529X has a high affinity for the benzodiazepine site of the human GABAA receptor (Ki 6nM). The acid metabolite of CNS 7529X 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 7529X (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 7529X, 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.