Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-10-12
2002-08-27
Cook, Rebecca (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S217000, C514S239200, C514S438000, C514S613000, C514S649000
Reexamination Certificate
active
06441038
ABSTRACT:
The present application claims priority to United Kingdom patent application 9924172.1, filed Oct. 12, 1999.
FIELD OF THE INVENTION
This invention relates to the treatment of neurological disorders and more particularly to the treatment of neurologically-related fatigue, brain injury, stress, and related conditions.
BACKGROUND OF THE INVENTION
Some years ago one of us noted that combinations of various types of antidepressants, together with neurotransmitter precursors such as phenylalanine, tyrosine and tryptophan, could improve the symptoms of multiple sclerosis and a patent application covering this invention was filed (PCT/GB95/02361). Subsequently we and various associates also noticed that these same combinations could improve peripheral neuropathy, pain from peripheral neuropathy and pain of any type (PCT/GB97/01822 and PCT/GB97/02295). In each case vitamin B12, folic acid, pyridoxine and other nutrients could be added to the formulations.
SUMMARY OF THE INVENTION
We have continued to make clinical observations on the effects of various drugs and amino acids on multiple sclerosis and on pain and as a result have made new discoveries which extend the inventions disclosed in the above patent applications. In particular, we have found that the range of drugs and amino acid precursors which are most effective are those which specifically affect noradrenaline at nerve endings so activating noradrenergic systems, such as lofepramine, desipramine and reboxetine among the drugs and phenylalanine and tyrosine among the amino acids. Phenylanine and tyrosine are precursors of noradrenaline. Tryptophan, the serotonin precursor, and drugs which act prefentially on serotonin have some actions but are less effective. Other drugs which are effective in combination with phenylalanine or tyrosine are drugs which are combined inhibitors of both noradrenaline and serotonin uptake, such as venlafaxine, duloxetine or milnacipran, and drugs which are combined inhibitors of both dopamine and noradrenaline reuptake such as bupropion.
In addition to refining the list of the most effective drugs, the list of possible uses of the combinations has been expanded to include chronic stress, chronic fatigue syndrome, fibromyalgia, fatigue in association with migraine, fatigue in association with brain injuries or other forms of brain damage including stroke, and illnesses associated with chronic fatigue such as irritable bowel syndrome, and brain infections with any agent including viruses, prions or bacteria. A particularly important new use for the combinations of noradrenergic drug and noradrenaline precursor is the neurological rehabilitation of patients after any form of damage to the brain, including traumatic brain injuries and strokes.
DETAILED DESCRIPTION
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,
Horrobin David F.
Loder Cari
Cook Rebecca
Foley & Lardner
Laxdale Limited
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