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Title:  Treatment of fatigue, head injury and stroke

United States Patent:  6,441,038

Issued:  August 27, 2002

Inventors:  Loder; Cari (Farncombe, GB); Horrobin; David F. (Stirling, GB)

Assignee:  Laxdale Limited (Sterling, GB)

Appl. No.:  686629

Filed:  October 12, 2000

Abstract

A method of treatment of disorders of neurological origin and drug formulations for use in the method are disclosed. These conditions comprise fatigue and associated syndromes of pain, weakness and depressed mood which are associated with chronic fatigue syndrome, brain injury and stroke, stress, fibromyalgia, and irritable bowel syndrome. The treatment comprises administering to a patient in need thereof a selective inhibitor of noradrenaline reuptake combined with either phenylalanine or tyrosine in the same dosage form or the same pack.# The noradrenergic drug may be selected from lofepramine, desipramine or reboxetine. The selective inhibitor may be a combined inhibitor of both noradrenaline and serotonin reuptake such as venlafaxine, duloxetine or milnacipran, or an inhibitor of both noradrenaline and dopamine reuptake such as bupropion.

DETAILED DESCRIPTION OF THE INVENTION

Because of the anecdotal evidence of the benefits of lofepramine and phenylalanine, reported in earlier patent applications, we have conducted a substantial, randomised, placebo-controlled, double blind trial in 138 patients with multiple sclerosis (MS). Half the patients received 70 mg lofepramine and 500mg I-phenylalanine twice a day, while the other half received identical-appearing placebos. All patients in both groups received regular injections of vitamin B12. 44 patients had the relapsing/remitting type of MS, 35 had primary progressive disease, and 59 had secondary progressive disease. A wide range of disease severeites was exhibited by the patients: on the Kurtzke Extended Disability Symptom Scale (EDSS) about half the patients had seventies of 6.5 or more, with the other half 6.0 or less. Patients were assessed on various scales, but particularly the Kurtzke scale, and the Gulick MS Patient Symptom scale. The Kurtzke scale aims to provide a relatively objective assessment of the degree of disability as assessed by the neurologist. The Gulick scale assesses a range of symptoms assessed by the patient. These symptoms can be grouped into six factors (Gulick E E, Model confirmation of the MS-related symptom checklist. Nursing Res 1989; 38: 147-153): musculoskeletal (including weakness, spasms and balance problems): elimination (bowel and bladder): emotions (depression, anxiety and loneliness): sensory (pain, numbness, paraesthesia): head symptoms (visual, swallowing and memory): and fatigue. The trial lasted for six months and patients were assessed at baseline, 2 weeks, 4 weeks, 3 months and 6 months.

The results were clear cut and surprising and showed the best evidence ever obtained for a treatment for MS, especially given the relatively short duration of the trial. Interferons slow down the rate of deterioration in MS but do not produce any actual improvements in symptoms. As a result trials have to be two or three years long in order to show differences between active and placebo groups: those differences depend not on improvement in the interferon group but on deterioration in the placebo group. In contrast, lofepramine + phenylalanine produced actual improvements both on the Gulick and the Kurtzke scales. The placebo group showed a deterioration in the Kurtzke scale, and a small improvement on the Gulick scale. The results are summarised in table 1.

Table 1. The results of the trial for the Kurtzke disability and Gulick symptom scales. In the change from baseline line, a + sign indicates improvement and a - sign indicates deterioration. In the difference between the two groups, a + sign indicates that active treatment with lofepramine and phenylalanine was better than placebo. There were 69 patients in each group.

        Parameter                          Kurtzke    Gulick
        Baseline score                        6.07      20.02
        Change from baseline on active       +0.107     +10.63
        Change from baseline on placebo      -0.132      +3.68
        Difference between active and placebo   +0.239      +6.95
        P for difference                      0.042       0.017


Three particularly surprising and striking findings emerged from the results obtained with the Gulick scale. First, the effect was very rapid: there was a clear difference between active and placebo by 2 weeks, which reached a peak at 4 weeks and then stayed stable for the remaining five months of the trial. Second, the improvement was seen across all the sub-scales of the Gulick scale (overall 20.5% from baseline, musculoskeletal 15%, elimination 27%, emotions 31%, sensory 23%, head 27% and fatigue 21%): these are large and important effects which have a major impact on the quality of life of patients. Third, the effect on fatigue was particularly important to the patients since it was quick, substantial and a contrast to the interferons which often increase fatigue initially. Patients with MS consistently state that fatigue is the single most important symptom which affects their quality of life (J D Fisk et al. The impact of fatigue on patients with multiple sclerosis. Canadian Journal of Neurological Science 1994; 21: 9-14). We had previously noted an effect on fatigue in a few patients with MS (PCT/GB95/02361) but had not drawn particular attention to this, nor claimed treatment of fatigue, nor expected to see such a large, consistent and statistically significant effect on this important and difficult to manage symptom.

The anecdotal evidence indicating that noradrenaline precursors and noradrenergic drugs like lofepramine and desipramine are particularly effective, and the new and unexpected clinical trial evidence which clearly proves the efficacy, and shows that the effect on fatigue is very important, and that the effects on symptoms are astonishingly rapid and effective across all the symptom groups, has led us to extend our ideas and new applications of those ideas. In particular, the combination of the noradrenaline precursors, phenylalanine and tyrosine, coupled with a drug which either has as its sole action or a component of its action the inhibition of noradrenaline reuptake, is now seen to be valuable in the treatment of fatigue in any form, in the management of rehabilitation after stroke, in the treatment of stress in any form, and in the treatment of fibromyalgia and related disorders such as irritable bowel syndrome.

We can now, as a result of these entirely novel clinical trial findings, draw conclusions about mechanisms of action which lead to these novel applications. First, it is apparent that the system involved is dependent on noradrenaline and to a much smaller extent on serotonin: the greater impact of noradrenergic as opposed to serotoninergic drugs, and the greater effect of phenylalanine as opposed to tryptophan, indicate this. Second, the mechanism is extremely rapid and is too quick to involve any major neuroregeneration which is likely to take months or years if it occurs: the mechanism is therefore likely to involve changes in the function of an existing neuronal system within the brain and spinal cord. Third, the wide range of systems improved by the treatment includes neuronal systems supplying the head and neck, the skeletal muscles, the sensory system, the autonomic nervous system and higher cortical functions: the nerve cells involved in the therapeutic effect must therefore interact with almost all parts of the brain and spinal cord.

What parts of the central nervous system might fulfil the criteria required to explain the effects of lofepramine and phenylalanine? There are two closely related systems which precisely fit our entirely novel and unexpected observations. These are the Locus Coeruleus (LC) and the Lateral Tegmentum (LT) (R Y Moore and F E Bloom, Central catecholamine neuron systems: anatomy and physiology of the norepinephrine and epinephrine systems. Annual Review of Neuroscience 1979; 2: 113-168. B H Smith and W H Sweet, Monoaminergic regulation of central nervous system function: I. Noradrenergic systems. Neurosurgery 1978; 3: 109-119).

The LT and the LC are unique systems. They are both dependent on noradrenaline (NA, also known as norepinephrine) as their main neurotransmitter. The LC is a neuronal nucleus located in the brainstem reticular formation. The LT is a more diffuse system including a number of nuclei such as the dorsal motor vagus, the nucleus tractus solitarius and adjacent tegmentum, and the lateral tegmentum itself. The nerve fibres of the LC travel virtually throughout the whole central nervous system, including to the spinal cord, brainstem, cerebellum, thalamus, hypothalamus, basal telencephalon and the entire cortex. The LT neurons are somewhat less widely distributed but even so go to the spinal cord, brainstem, hypothalamus and basal telencephalon.

The real peculiarity of these systems, however, relates to (a) their astonishingly frequent neuronal branching so that a single LT or LC nerve cell may have axons which connect with millions of other nerve cells, (b) the diverse endings of branches from a single nerve cell so that one branch may go to the cerebellum, for example, while another goes to the cortex, (c) their lack of clear cut synaptic end targets, with each nerve cell making diffuse contact with millions of other cells, and (d) their release of noradrenaline from sites along all the branches of the axons and not just from the synaptic endings. Smith and Sweet vividly state "single axons may traverse several regions of the brain, making no specific synaptic connections in any one area, but spraying transmitter (noradrenaline) over several areas".

The axons of the LT and LC systems are very widely distributed, making contact with motor nerve systems, sensory nerve systems, pain systems and autonomic systems such as those regulating cardiovascular and respiratory functions, bladder and bowel functions, reproductive functions and stress responses.

It is therefore apparent that the LT and LC systems are primarily noradrenergic systems which are able to influence almost all parts of the rest of the nervous system simultaneously. They are thus very strong candidates for the rapid and completely generalised relief of symptoms obtained in response to lofepramine and phenylalanine in the trial we have just completed in MS.

One of the well-known and difficult to explain observations in MS is that the symptoms seen in the patients are often poorly correlated with the precise positions of the lesions in the central nervous system which are identified by magnetic resonance imaging. Some of the symptoms can be directly related to the lesions, but many of the more generalised symptoms and especially the autonomic symptoms and the fatigue are difficult to relate precisely to the specific points of damage. This situation is similar to that seen in a substantial number of other central nervous system (CNS) disorders. In stroke, head injury, or any form of specific localised damage to the brain, it has long been recognised that there are two syndromes: the first is localised and clearly related to the specific nerve cells damaged by the lesion: the second is much more generalised and includes widespread impairment of neuronal function and very frequently includes substantial subjective fatigue (J L Ingles et al, Fatigue after stroke, Archives of Physical Medicine and Rehabilitation 1999; 80: 173-177. M G Boyeson et al. Sparing of motor function after cortical injury. Archives of Neurology 1994; 51: 405-413. D M Feeney et al, Noradrenergic pharmacotherapy, intracerebral infusion and adrenal transplantation promote functional recovery after cortical damage. Journal of Neural Transplantation and Plasticity 1993; 4: 199-213.). These syndromes are in many ways similar to those which occur in response to prolonged and uncontrollable stress, and also in the rather mysterious syndrome known as chronic fatigue syndrome which is closely related to fibromyalgia and which is associated with a number of other medical conditions including irritable bowel syndrome, and esophageal reflux and related disorders (J M Weiss et al, Behavioral depression produced by an uncontrollable stressor: relationship to norepinephrine, dopamine and serotonin levels in various regions of rat brain. Brain Research Reviews 1981; 3: 167-205. D J Clauw, Fibromyalgia: more than just a musculoskeletal disease. American Family Physician 1995; 52: 843-851).

In all of these conditions there is emerging evidence that the LC and LT systems are dysfunctional. The reasons for the dysfunction may be various. Because the LT and LC neurons go almost everywhere in the CNS, local damage to any part of the CNS will inevitably damage some axons from LT and LC nerve cells. That damage may then impair the function of the LC and LT themselves, or at the least impair the function of the other parts of the brain innervated by the damaged nerves. For example, many LC neurons have branches going to both the cerebellum and the cerebral cortex. A stroke or injury or an MS lesion affecting the cerebellum may thus alter cortical function and vice versa. Because the LT and LC neurons are an important part of the response to stress, sustained stress may lead to damage to or temporary or permanent exhaustion of the system. Viral infection may damage the LT and LC systems directly and this, with chronic stress, may be related to some chronic fatigue and fibromyalgia syndromes.

We propose that what lofepramine and phenylalanine are doing is activating the LC and LT system. This explains the effects on fatigue and on the whole range of symptoms in MS, involving motor, sensory, autonomic and higher cerebral functions. Activation of the LC and LT systems also explains the relief of pain of all types since the LC and LT noradrenergic systems are particularly involved in the regulation of chronic pain (eg C J Glynn et al, Role of spinal noradrenergic system in transmission of pain in patients with spinal cord injury, Lancet 1986; ii: 1249-51. S V R Reddy et al. Spinal cord pharmacology of adrenergic agonist-mediated antinociception. Journal of Pharmacology and Experimental Therapeutics 1980; 213: 525-533). This mechanism indicates that the treatment will also be effective in chronic stress, chronic fatigue, in fibromyalgia and related conditions, in irritable bowel syndrome and in relieving the general fatigue and neurological symptoms which are seen not just in MS but in almost any illness which involves any form of damage to the brain or spinal cord.

Claim 1 of 12 Claims

What is claimed is:

1. A method of treating a condition of fatigue associated with chronic fatigue syndrome, depression, brain infection strokes, stress, fibromyalgia, or irritable bowel syndrome, which method comprises administering to a patient in need thereof a pharmaceutically effective amount of a composition comprising a selective inhibitor of noradrenaline reuptake and either L-phenylalanine or tyrosine in the same dosage form or the same pack.
 


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