United States Patent: 6,841,551
Issued: January 11, 2005
Inventors: Nimmo; Alan John (Townsville, AU); Vink; Robert (Pas adena, AU)
Assignee: Hoffmann-La Roche Inc. (Nutley, NJ)
Appl. No.: 181323
Filed: October 15, 2002
PCT Filed: January 18, 2001
PCT NO: PCT/AU01/00046
371 Date: October 15, 2002
102(e) Date: October 15, 2002
PCT PUB.NO.: WO01/52844
PCT PUB. Date: July 26, 2001
A treatment for brain, spinal and nerve injury comprising use of a substance P receptor antagonist optionally in combination with a magnesium compound. There is also provided a formulation for use in this treatment comprising a substance P receptor antagonist and a magnesium compound.
Description of the Invention
FIELD OF THE INVENTION
THIS INVENTION relates to a method of therapy of brain, spinal and nerve injury. There is also provided a formulation which is particularly useful in the method.
Injury to the brain results in the development of motor and cognitive deficits that contribute to the significant morbidity experienced by survivors of brain injury. Moreover, it is an occurrence that has the highest incidence in younger members of society. Accordingly, injury to the brain is responsible for the greatest loss of productive life as compared to any other disease process. Despite this, there is no effective therapy to improve outcome after brain injury. We disclose the use of a method of therapy as a robust pharmacologic intervention for the treatment of brain injury. Use of this therapy significantly improves both motor and cognitive outcome in mild to severe experimental brain injury and has also been found to have beneficial effect also for the treatment of spinal cord and nerve injuries.
BACKGROUND OF THE INVENTION
It is well known that brain injury results in the development of neurologic deficits through two mechanisms. The first of these is known as primary mechanisms. These occur at the time of the injurious event and include mechanical processes such as laceration, tearing, stretching and compression of nerve fibres. Little can be done for this type of injury once it has occurred. The second mechanism is secondary injury, which includes biochemical and physiological processes, initiated by a primary injury but which manifest with time after the injury. It has been demonstrated that much of the morbidity after brain injury is associated with the development of this secondary injury. Given that the secondary injury develops from minutes to days after the primary event, there exists a window of opportunity to pharmacologically prevent this type of injury and significantly improve resultant outcome. However, the factors that make up secondary injury must first be identified and then "antifactors" developed to inhibit the injury process.
Our studies have concentrated on identifying secondary injury factors after brain injury and developing interventional therapies. One of the factors that we had previously identified1-4 as critical to determining outcome after injury was brain magnesium ion concentration. This ion is a regulatory factor in a number of biochemical and physiological processes that are activated after brain injury. Indeed, a decrease in the magnesium ion concentration was observed to exacerbate the injury process while an increase in the concentration of magnesium ion was noted to attenuate the injury process and result in an improved outcome5. The treatment of brain injury with magnesium has since been shown to be effective1,6-10 even when administered up to 24 hours after the primary event, and the success of the treatment in experimental animal studies has subsequently led to clinical trials in human brain injury.
Despite the attenuation of deficits after brain injury with magnesium administration, it was clear that there were still motor and cognitive deficits that persisted after the treatment. Our attention was particularly drawn to the fact that in younger animals, the accumulation of water in the brain (ie. cerebral oedema or brain swelling) was still present and that this may present a significant risk factor. Indeed, in a recent clinical study11, delayed brain swelling was responsible for 50% of all deaths recorded in young victims of brain injury.
STATEMENT OF INVENTION
It therefore is an object of the invention to provide a method of therapy in relation to brain injury and a formulation for use in the method.
The formulation in one aspect of the invention comprises a substance P receptor antagonist and a magnesium compound, wherein the combined use of the magnesium compound and the substance P receptor antagonist results in greater protection against injury than either of the magnesium compound or the substance P receptor antagonist used alone.
The method of the invention includes the step of administration of the formulation to the patient suffering from brain injury. Alternatively, each of the components of the formulation are administered separately or separated by a time delay that does not affect the effectiveness of the therapy, e.g. 1-30 minutes and up to 24 hours as discussed above.
Substance P is an excitatory neurotransmitter and has a role in pain transmission and is a peptide having the structure RPKPEEFFGLM-NH2. It is from the hypothalamus, CSN and intestine and increases smooth muscle contraction of the G1 tract.
It is known that substance P binds to a number of receptors inclusive of the NK1 receptor (i.e. neurokinin 1 receptor), the NK2 receptor and the NK3 receptor. These receptors are believed to have a role in blood travelling to the brain.
Therefore, a substance P antagonist is a substance that inhibits binding of substance P to any one of the receptors referred to above. A list of suitable substance P antagonists is referred to in Tables 1, 2 and 3 attached herewith.
Reference may also be made to NK1 receptor antagonists as described in U.S. Pat. No. 5,990,125 which are incorporated herein by reference as constituting substance P antagonists that may be utilized in the formulation of the method of the invention. This has specific reference to compounds of structures Ia, Ib, Ic, Id, Ie, X, XVI, XVII, XVIII, XIX, XX and XXI, as well as other antagonists comprising quinuclidine, piperidine ethylene diamine, pyrrolidine and azabornane derivatives and related compounds that exhibit activity as substance P receptor antagonists as described in column 33 of the U.S. Pat. No. 5,990,125.
Such receptor antagonists may be employed having regard to the dosages referred to in column 34 of U.S. Pat. No. 4,990,125 and in various forms of administration i.e. alone or with various pharmaceutically acceptable carriers or diluents by oral administration or parental administration as referred in column 34 of U.S. Pat. No. 5,990,125.
The activity of various substances as substance P receptor antagonists for use in the invention may also be determined by the assays referred to in columns 35-36 of U.S. Pat. No. 5,990,125.
Reference also may be made to substance P receptor antagonists described in U.S. Pat. No. 5,977,104 including the various dosage forms and dosages referred to in this reference which is also totally incorporated herein by reference.
Reference also may be made to U.S. Pat. No. 4,481,139 which describes various peptide antagonists, which is also totally incorporated herein by reference.
It will also be understood that the term "Substance P" as used herein may also include within its scope various truncated forms or analogues as described in U.S. Pat. No. 4,481,139, which is totally incorporated herein by reference.
Reference also may be made to U.S. Pat. No. 4,985,896 which refers to various piperdine and morpholine derivatives for use as substance P antagonists for use in the present invention or piperazino derivatives as described in U.S. Pat. No. 5,981,520. Each of these references are totally incorporated herein by reference.
Reference also may be made to piperidinyl compounds as NK1 or NK2 antagonists for use in the invention referred to in U.S. Pat. No. 5,998,444 which is also totally incorporated herein by reference.
It will also be appreciated that tachykinin antagonists referred to in U.S. Pat. No. 4,981,744 may also be used as substance P antagonists in the invention and thus, this reference is also totally incorporated herein.
Reference may also be made to EP-A-1035115 which is totally incorporated herein by reference, which refers to N-benzyl-4-tolylnicotinamides and related compounds as NK1 receptor antagonists for use in the invention.
Reference may be made to International Publication WO 0050398 which is totally incorporated herein by reference, which refers to various phenyl and pyridinyl derivatives as NK1 receptor antagonists for use in the invention.
Reference is also made to International Publications WO 0050401, WO 0053572, WO 0073278 and WO 0073279, which refer to 3-phenylpyridines, biphenyl derivatives, 5-phenyl-pyrimidine derivatives and 4-phenyl-pyrimidine derivatives respectively which specifications are also totally incorporated herein by reference. These specifications refer to NK1 receptor antagonists for use in the present invention.
Reference also may be made to the 1998 Sigma Catalogue and more particularly pages 1194-1997 which describe modifications of substance P or substance P fragments, which may be used as substance P antagonists, for use in the invention. This publication is also totally incorporated herein by reference.
In relation to the magnesium compound, this may comprise any suitable source of magnesium ion such as magnesium chloride, magnesium sulphate, magnesium oxalate, magnesium gluconate or other non toxic magnesium salt.
The pharmaceutical preparations in accordance with this invention can in addition also contain preservatives, solubilizers, sabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances. Thus the term "comprising" used in the specification should be interpreted in this context. The dosage can vary within wide limits and can, of course, be fitted to the individual requirements in each particular case. In general, a dosage of 1 to 20000 mg per patient, preferably 10 to 5000 mg and more preferably 50 to 2000 mg of the substance P receptor antagonist should be appropriate.
In relation to the development of the inventive concept, it was established by the present inventors that one reason for acute water accumulation in the brain after injury was the result of vasogenic oedema formation. This is caused by an increased permeability of the blood brain barrier thus permitting vascular proteins and water to enter the extracellular space in the brain and case swelling. Few studies have examined how this increased blood brain barrier permeability contributes to the development of neurological deficits after injury, and no studies have investigated whether inhibition of brain swelling improves outcome. Studies of migraines12, 13 have suggested that the vasculature of the dura matter (outer meningeal layer) becomes more permeable to vascular components as a result of substance P release. We therefore hypothesised that substance P may have a similar effect on the cerebral vasculature, where such an effect could lead to increased bloodbrain barrier permeability and vasogenic cerebral oedema. We further hypothesised that administration of a substance P receptor antagonist may prevent brain swelling and the development of delayed neurologic deficits after injury. This hypothesis was a result of our discovery referred to above, that water accumulated in the brain as a result of vasogenic oedema formation.
Thus, in another aspect of the invention there is provided the use of a substance P receptor antagonist for reducing brain barrier permeability and/or vasogenic cerebral oedema.
Claim 1 of 15 Claims
What is claimed is:
1. A pharmaceutical preparation for the treatment of brain, spinal cord or nerve injury comprising a therapeutically effective amount of a substance P receptor antagonist selected from the group consisting of L 742694, L 758298, and LY 303241, a non-toxic magnesium compound and a pharmaceutically acceptable vehicle.