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  Use of chemical chelators as reversal agents for drug-induced neuromuscular blockUSPTO Application #: 20070299035Title: Use of chemical chelators as reversal agents for drug-induced neuromuscular block Abstract: or a pharmaceutically acceptable salt thereof. wherein X is the general formula B wherein R is The invention relates to the use of chemical chelators for the preparation of a medicament for the reversal of drug-induced neuromuscular block, to a kit for providing neuromuscular block and its reversal, and to cyclophane derivatives having the general formula A (end of abstract) Agent: Organon Usa, Inc. Patent Department - Roseland, NJ, US Inventors: Antonius Helena Adolf Bom, Alan William Muir, David Rees USPTO Applicaton #: 20070299035 - Class: 514058000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, Polysaccharide, Dextrin Or Derivative The Patent Description & Claims data below is from USPTO Patent Application 20070299035. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The invention relates to the use of chemical chelators for the preparation of a medicament for the reversal of drug-induced neuromuscular block, and to a kit for providing neuromuscular block and its reversal. [0002] A neuromuscular blocking agent (NMBA, also called a muscle relaxant) is routinely used during the administration of anaesthesia to facilitate endotracheal intubation and to allow surgical access to body cavities, in particular the abdomen and thorax, without hindrance from voluntary or reflex muscle movement. NMBAs are also used in the care of critically-ill patients undergoing intensive therapy, to facilitate compliance with mechanical ventilation when sedation and analgesia alone have proved inadequate. [0003] Based on their mechanisms of action, NMBAs are divided into two categories: depolarizing and non-depolarizing. Depolarizing neuromuscular blocking agents bind to nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction in a way similar to that of the endogenous neurotransmitter acetylcholine. They stimulate an initial opening of the ion channel, producing contractions known as fasciculations. However, since these drugs are broken down only relatively slowly by cholinesterase enzymes, compared to the very rapid hydrolysis of acetylcholine by acetylcholinesterases, they bind for a much longer period than acetylcholine, causing persistent depolarization of the end-plate and hence a neuromuscular block. Succinylcholine (suxamethonium) is the best known example of a depolarizing NMBA. [0004] Non-depolarizing neuromuscular blocking agents compete with acetylcholine for binding to muscle nAChRs, but unlike depolarizing NMBAs, they do not activate the channel. They block the activation of the channel by acetylcholine and hence prevent cell membrane depolarization, and as a result, the muscle will become flaccid. Most clinically-used NMBAs belong to the non-depolarizing category. These include tubocurarine, atracurium, (cis)atracurium, mivacurium, pancuronium, vecuronium, rocuronium and rapacuronium (Org 9487). [0005] At the end of surgery or a period of intensive care, a reversal agent of NMBAs is often given to the patient to assist the recovery of muscle function. Most commonly used reversal agents are inhibitors of acetylcholinesterase (AChE), such as neostigmine, edrophonium and pyridostigmine. Because the mechanism of action of these drugs is to increase the level of acetylcholine at the neuromuscular junction by inhibiting the breakdown of acetylcholine, they are not suitable for reversal of depolarizing NMBAs such as succinylcholine. The use of AChE inhibitors as reversal agents leads to problems with selectivity, since neurotransmission to all synapses (both somatic and autonomic) involving the neurotransmitter acetylcholine is potentiated by is these agents. This non-selectivity may lead to many side-effects due to the non-selective activation of muscarinic and nicotinic acetylcholine receptors, including bradycardia, hypotension, increased salivation, nausea, vomiting, abdominal cramps, diarrhea and bronchoconstriction. Therefore in practice, these agents can be used only after or together with the administration of atropine (or glycopyrrolate) to antagonize the muscarinic effects of acetylcholine at the muscarinic receptors in the autonomic parasympathetic neuro-effector junctions (e.g. the heart).The use of a muscarinic acetylcholine receptor (mAChR) antagonist such as atropine causes a number of side-effects, e.g., tachycardia, dry mouth, blurred vision, and furthermore may affect cardiac conduction. [0006] A further problem with anticholinesterase agents is that residual neuromuscular activity must be present (>10% twitch activity) to allow the rapid recovery of neuromuscular function. Occasionally, either due to hyper-sensitivity of the patient or accidental overdose, administration of NMBAs can cause complete blockade of neuromuscular function ("deep block"). At present, there is no reliable treatment to reverse such a `deep block`. Attempts to overcome a `deep block` with high doses of AChE inhibitors has the risk of inducing a "cholinergic crisis", resulting in a broad range of symptoms related to enhanced stimulation of nicotinic and muscarinic receptors. [0007] There is thus a reed for an alternative method for reversing the action of NMBAs, i.e. to restore the muscular contractions. [0008] The present invention provides for the use of chemical chelators (or sequestrants) as reversal agents. In one aspect the invention pertains to the use of a chemical chelator capable of forming a guest-host complex for the manufacture of a medicament for the reversal of drug-induced neuromuscular block. [0009] The use of chemical chelators as reversal agents for NMBAs has the advantage that they are effective in reversing the action of both depolarizing and non-depolarizing NMBAs, since chemical chelators do not compete with the NMBA for binding to nAChRs. Their use does not increase the level of acetylcholine and therefore they produce fewer side effects than AChE-based reversal agents. In addition, there is no need for the combined use of a AChE inhibitor and a mAChR antagonist (e.g., atropine). The chemical chelators of the invention may further be safely employed for the reversal of `deep block`. [0010] The term chemical chelator (or sequestrant), as used in the present invention, means any organic compound which can engage in host-guest complex formation with a neuromuscular blocking agent. The chemical chelator acts as the host molecule, the neuromuscular blocking agent being the guest molecule. The specific molecular complex, the guest-host complex, is defined as an organised chemical entity resulting from the association of two or more components held together by noncovalent intermolecular forces. [0011] The chemical chelators (or sequestrants), according to the invention, are host molecules selected from various classes of, mostly cyclic, organic compounds which are known for their ability to form inclusion complexes with various organic compounds in aqueous solution, e.g. cyclic oligosaccharides, cyclophanes, cyclic peptides, calixarenes, crown ethers and aza crown ethers. Formation of inclusion complexes (also called encapsulation, or chemical chelation) is part of the well-known area of `supramolecular chemistry` or `host-guest chemistry`. Many cyclic organic compounds are known to be capable of forming an inclusion complex with another molecule, organic or inorganic. The structures and chemistry of these compounds are well documented (Comprehensive Supramolecular Chemistry, Volumes 1-11, Atwood J. L., Davies J. E. D., MacNicol D. D., Vogtle F., eds; Elsevier Science Ltd., Oxford, UK, 1996). [0012] Preferred chemical chelators for use with the present invention are cyclic oligosaccharides, cyclophanes and calixarenes. [0013] Examples of cyclic oligosaccharides suitable for use with the invention are the cyclodextrins, a catagory of naturally occurring cyclomaltooligosaccharides, the cyclomannins (5 or more .alpha.-D-mannopyranose units linked at the 1,4 positions by .alpha. linkages), the cyclogalactins (5 or more .beta.-D-galactopyranose units linked at the 1,4 positions by .beta. linkages), the cycloaltrins (5 or more .alpha.-D-altropyranose units linked at the 1,4 positions by .alpha. linkages), each of which are capable of forming guest-host complexes. Cyclic oligosaccharides of different monosaccharide compositions, accessible through total chemical synthesis, represent further chemical chelators capable of interaction with a neuromuscular blocking agent. For example, cyclo-[(1-4)-.alpha.-L-rhamnopyranosyl-(1-4)-.alpha.-D-mannopyra- nosyl]tetraoside, was found to be effective in reversal of the action of the neuromuscular blocking agent rocuronium bromide. [0014] A particularly preferred class of cyclic oligosaccharide chelators according to the invention is formed by the cyclodextrins: [0015] Cyclodextrins are cyclic molecules containing six or more .alpha.-D-glucopyranose units linked at the 1,4 positions by .alpha. linkages as in amylose. As a con-sequence of this cyclic arrangement, the cyclodextrins exist as conical shaped molecules with a lipophilic cavity which can attract guest molecules whilst the outside is more hydrophilic and water-soluble. Cyclodextrins composed of six, seven, eight and nine glucopyranose units are commonly known as .alpha.-, .beta.-, .gamma.- and .delta.-cyclodextrins, respectively. [0016] Both the native cyclodextrins (.alpha., .beta., .gamma.) which are prepared by enzymatic degradation of starch, and especially a number of chemically modified forms thereof, have already found, by virtue of their ability to form guest-host complexes, numerous applications, especially in the pharmaceutical field. Stella and Rajewski (Pharmaceutical Research, 14, 556-567, 1997) have recently reviewed pharmaceutical applications of the cyclodextrins. The major applications are in the pharmaceutical formulations of drugs in order to solubilize and/or to stabilize a drug for oral, nasal, ophthalmic, dermal, rectal and parenteral administration. [0017] The term cyclodextrin as used in relation to the present invention includes both the native cyclodextrins and chemically modified forms thereof. [0018] An overview on such chemically modified cyclodextrins as drug carriers in drug delivery systems is described by Uekama et al. (Chemical Reviews 1998, 98, 2045-2076). Chemical modification of cyclodextrins can be made directly on the native .alpha.-, .beta.- or .gamma.-cyclodextrin rings by reacting a chemical reagent (nucleophiles or electrophiles) with a properly functionalised cyclodextrin (for an recent overview of methods for the selective modification of cyclodextrins see Khan A. R. et al. Chem. Rev. 1998, 98, 1977-1996). To date, more than 1,500 cyclodextrin derivatives have been made by chemical modification of native cyclodextrins (Jicsinszky L. et al Comprehensive Supramolecular Chemistry, Volume 3. Cyclodextrins, Atwood J. L., Davies J. E. D, MacNicol D. D., Vogtle F., eds; Elsevier Science Ltd., Oxford, UK, 1996, pp 57-188). [0019] Many direct modifications of a native cyclodextrin result in a mixture of isomers without precisely defined positions of substitution. Such a mixture of positional isomers is often referred to as a statistic mixture, the number of substituents attached at each cyclodextrin molecule in such a statistic mixture being expressed as the average degree of substitution (DS). Most cyclodextrin derivatives studied for pharmaceutical applications are statistic mixtures (Szente L. and Szejtli J., Adv. Drug Delivery Rev. 1999, 36, 17-28). Direct modification of a cyclodextrin does not alter the constitution or the configuration of the repeating .alpha.-D-glucopyranosyl units. [0020] Cyclodextrins can also be prepared by de novo synthesis, starting with glucopyranose (Gattuso G. et al Chem. Rev. 1998, 98, 1919-1958). In this way, one can prepare not only the naturally occurring cyclic (1.fwdarw.4)-linked cyclodextrins but also the cyclic (1.fwdarw.3)-, (1.fwdarw.2)-, and (1.fwdarw.6)-linked oligopyranosides. Such a synthesis can be accomplished by using various chemical reagents or biological enzymes such as cyclodextrin transglycosylase. By using different sugar units as the starting materials, one can thereby prepare various homogeneous or heterogeneous cyclic oligosaccharides. Chemical modification of cyclodextrins is thus known to modulate their properties and can be used for the design of reversal agents selective for a specific neuromuscular blocking agent. [0021] It will be clear to the skilled person that for a particular neuromuscular blocking agent a chemical chelator host can be developed having a hydrophobic cavity of a shape and size adapted to the guest molecule, while in addition to the hydrophobic interactions between the host and the guest charge interactions can be of importance for complex formation. Since the chemical chelators of the invention are for parenteral application they will have to be water-soluble. A specific host molecule can be designed and prepared to contain functionalities complementary to those of the guest molecule in such a manner that it results in maximum intermolecular interaction via for example hydrogen-bond, hydrophobic, electrostatic, van der Waals, and .pi.-.pi. interactions. Thus, for example, for a guest molecule containing basic functional groups or positive charge, a host molecule containing acidic functional groups or negative charge could be made to increase ionic interaction between the guest and the host. When such a host-guest complex is formed via inclusion or partial inclusion, the cavity size of the host molecule is also very important [0022] The interaction between a chemical chelator and a neuromuscular blocking agent can be analyzed by physical methods such as nuclear magnetic resonance spectroscopy (nmr) and microcalorimetry. [0023] The most preferred cyclodextrins for use in the invention are .gamma.-cyclodextrin and derivatives thereof. [0024] Many of the commonly used neuromuscular blocking agents, or muscle relaxants, such as rocuronium, pancuronium, vecuronium, mivacurium, atracurium, (cis)atracurium, succinylcholine and tubocurarine, are compounds having 1 or 2 cationic sites when in neutral aqueous medium. Cyclodextrins having anionic sites in their structure are among the preferred chemical chelators according to the invention. Continue reading... Full patent description for Use of chemical chelators as reversal agents for drug-induced neuromuscular block Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Use of chemical chelators as reversal agents for drug-induced neuromuscular block patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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