Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-11
2003-05-13
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S816000, C514S817000, C514S818000, C424S040000
Reexamination Certificate
active
06562855
ABSTRACT:
BACKGROUND
The present invention relates to a novel formulation that is capable of displaying one or more beneficial therapeutic effects. By way of example, the novel formulation can provide any one or more of general anaesthesia, analgesia, conscious sedation and neuroprotection.
The state of general anaesthesia encompasses several elements, namely, analgesia (or insensibility to a noxious stimulus), loss of consciousness (hypnotic response), attenuation of the sympathetic nervous system responses to a noxious stimulus (sympatholysis), interruption of memory formation of untoward events, and muscle relaxation.
The state of general anaesthesia is usually produced by a combination of several drugs from different pharmacological classes, as to date no class of compound alone provides the ideal features which are required. For example, potent volatile anaesthetic agents such as halogenated ethers and haloalkanes, may be biotransformed to potentially toxic agents. Also these agents cause excitation on emergence from anaesthesia. Inhalation agents such as nitrous oxide and xenon are not considered to be potent enough to be used as monotherapy, whereas sedative/hypnotic agents (including propofol, benzodiazepines and barbiturates) lack analgesic properties. Analgesics either produce severe respiratory depression requiring assisted ventilation (in the case of the opioids) or do not produce a hypnotic response (non-opioids), whereas peripherally-acting muscle relaxants (e.g., vecuronium and atracurium) have neither analgesic or hypnotic properties.
In view of the prior art, it is clear that there are a number of drawbacks associated with the drugs currently used for general anaesthesia. Firstly, there is a need for specialised drug delivery systems, particularly for potent volatile anaesthetics. This need is obviated by using the intravenous route (total intravenous anaesthesia, otherwise known as “TIVA”). However, current TIVA regimens invariably include analgesic agents (e.g. opiate narcotics) which cause respiratory depression and hypnotic agents (propofol and barbiturates) which cause cardiac depression, thus requiring equipment for ventilatory and cardiovascular support during its use. Secondly, termination of the clinical effect from TIVA requires either biotransformation and/or elimination of the parent drug and their metabolites which may lead to organ toxicity problems. Other disadvantages of these drugs include prolonged emergence associated with excitation, nausea and vomiting (all except propofol), high addictive potential, together with a narrow window of therapeutic efficacy. Finally, there is also the environmental threat associated with the destruction of the ozone layer by nitrous oxide.
The present invention seeks to provide an improved formulation for general pharmaceutical use, especially for use in anaesthesia.
STATEMENT OF INVENTION
Aspects of the present invention are presented in the accompanying claims and in the following description.
DETAILED DESCRIPTION
In a broad aspect, the present invention provides a pharmaceutical comprising an NMDA antagonist and an alpha-2 adrenergic agonist.
In a preferred embodiment, the present invention provides an anaesthetic comprising an NMDA antagonist and an alpha-2 adrenergic agonist.
Surprisingly, we have found that the co-administration of an NMDA receptor antagonist and an alpha-2 adrenergic agonist, preferably as a single formulation, both enhances the efficacy of the individual compounds through a synergistic mechanism, but also diminishes the likelihood of the adverse and unwanted side effects that these drugs can cause when used alone.
One essential component of the formulation is an NMDA receptor antagonist.
The term “anatagonist” is used in its normal sense in the art, i.e., a chemical compound which prevents functional activation of a receptor by its agonist (NMDA, in this case).
The NMDA (N-methyl-D-aspartate) receptor is a major subclass of glutamate receptor (the most important excitatory neurotransmitter in the mammalian central nervous system). Importantly, activation of the NMDA receptor has been shown to be the central event which leads to excitotoxicity and neuronal death in many disease states, as well as a result of hypoxia and ischaemia following head trauma, stroke and following cardiac arrest.
It is known in the art that the NMDA receptor plays a major role in many higher cognitive functions, such as memory and learning, as well as in certain nociceptive pathways and in the perception of pain (Collingridge et al, The NMDA Receptor, Oxford University Press, 1994). In addition, certain properties of NMDA receptors suggest that they may be involved in the information-processing in the brain which underlies consciousness itself.
NMDA receptor antagonists in the context of the present invention are advantageous for a number of reasons, such as the following three specific reasons. Firstly, NMDA receptor antagonists confer profound analgesia, a highly desirable component of general anaesthesia and sedation. Secondly, NMDA receptor antagonists are neuroprotective under many clinically relevant circumstances (including ischemia, brain trauma, neuropathic pain states, and certain types of convulsions). Thirdly, NMDA receptor antagonists confer a valuable degree of amnesia.
The formulation may comprise one or more NMDA receptor antagonists.
Contrary to the prior art uses of NMDA receptor antagonists in general anaesthetic practice, we have surprisingly found that in the formulation of the present invention they are not severely hampered by their concomitant psychotomimetic effects and other undesirable side-effects. Prior art problems associated with this class of compounds included the production of involuntary movements, stimulation of the sympathetic nervous system, induction of neurotoxicity at high doses (which is pertinent since of NMDA receptor antagonists have low potencies as general anaesthetics), depression of the myocardium, proconvulsions in some epileptogenic paradigms e.g., “kindling” (Wlaz P et al, Eur. J. Neurosci. 1994; 6:1710-1719). Difficulties in developing antagonists that cross the blood-brain barrier had also limited their practical application.
In more detail, the NMDA receptor antagonists of the present invention may be competitive antagonists, such as 2-amino-5-phosphonopentanoate and 2-amino-7-phosphonoheptanoate, or derivatives or structural analogues thereof. The NMDA receptor antagonists may also be non-competitive antagonists, such as dizocilpine, ketamine, HA-966 [(+/−)-3-amino-1-hydroxy-2-pyrrolidone], or derivatives or structural analogues thereof.
Preferably, the NMDA receptor antagonist is xenon.
The advantage of using an inert, volatile gas such as xenon as a general anaesthetic is that the molecule can be rapidly eliminated via respiration.
In this respect, it has recently been discovered that xenon (which rapidly equilibrates with the brain) is an NMDA antagonist (Franks N P et al, Nature 1998; 396:324) making it a particularly attractive candidate in the context of the present invention.
Xenon is a chemically inert gas whose anaesthetic properties have been known for over 50 years (Lawrence J H et al, J. Physiol. 1946; 105:197-204). Since its first use in surgery (Cullen S C et al, Science 1951; 113:580-582), a number of research groups have shown it has an excellent pharmacological profile, including the absence of metabolic by-products, profound analgesia, rapid onset and recovery, and minimal effects on the cardiovascular system (Lachmann B et al, Lancet 1990; 335:1413-1415; Kennedy R R et al, Anaesth. Intens. Care 1992; 20:66-70; Luttropp H H et al, Acta Anaesthesiol. Scand. 1994; 38:121-125; Goto T et al, Anesthesiology 1997; 86:1273-1278; Marx T et al, Br. J. Anaesth. 1997; 78:326-327). Mechanistic studies on cultured hippocampal neurons have shown that 80% xenon, which will maintain surgical anaesthesia, reduces NMDA-activated currents by up to 60%. This powerful inhibition of the NMDA receptor explains some of the important features of the p
Franks Nicholas Peter
Maze Mervyn
Kim Vickie
Spivack Phyllis G.
St. Onge Steward Johnston & Reens LLC
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