Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-07-11
2002-10-15
Pak, John (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S251000, C514S276000, C514S458000, C514S474000, C514S547000, C514S556000, C514S561000, C514S565000, C514S578000, C514S665000, C514S690000, C514S706000, C514S904000, C514S905000, C424S670000, C424S679000, C424S681000, C424S682000, C424S683000, C424S686000, C424S688000, C424S692000, C424S697000, C424S702000, C424S722000, C424S756000, C424S764000, C426S072000, C426S074000
Reexamination Certificate
active
06465517
ABSTRACT:
FIELD OF THE INVENTION
The present invention pertains to a nutritional composition and a method for the treatment of migraine.
BACKGROUND
Migraine is a neurological multifactorial syndrome, of which headache is only one of the many ways the disease manifests itself. Migraine is characterised by recurrent attacks of severe, pulsating and disabling headache, vomitting, photo- and phonofobia and malaise, which worsens with movement. In 20% of the patients additional transient focal neurological (aura) symptoms may occur. The exact mechanism is unknown, but generic factors might be involved in the disease. Patients may suffer from a defect in ion channels and have a disturbed energy metabolism in brain and skeletal muscle. These above described features are not observed with ordinary headache such as for example tension headache. The prevalence or migraine is 17.6% for women and 6% for men. The disease is characterised by attacks of severe headache and autonomic or neurological symptoms. The attacks occur in two forms, migraine without aura (common migraine), which occurs in 75% of the patients and with aura (classic migraine), occur in about 30% of the migraineurs. Both types however are experienced in one third of the subjects.
Enhanced central neuronal excitability and susceptibility to spontaneous neuronal depolarisation characterise migraine with aura and possibly without aura. The mechanism behind a migraine attack is still not completely unravelled, due to the diversity of the complaints and the lack of good animal models for migraine. However, there is increasing evidence that a wide range of mechanisms is involved in the pathogenesis of migraine, of which the phenomenon of spreading depression (SD) plays an obligate part. A wave of hyperexcitability spreads out and passes over the cortical surface at a rate of 2-3 mm per minute. In the wake of the wave of excitation, the previously hyperactive cortical neurons become depolarised and electrically quiescent—or depressed—for some minutes. The loss of proper ionic gradients across the membrane following hyperexcitation is associated with marked changes in ion levels of the cortical extracellular fluid, including a remarkable increase in extracellular potassium.
Electrical excitability of skeletal and cardiac muscle cells and neurons results from a balance of inhibitory and excitatory influences. A large number of voltage-gated ion channels, ligand-gated channels, transporters and ATP-dependent pumps are involved in maintaining this balance. Ionic concentration gradients across the membrane can be established and maintained because the lipid bilayer is an extremely good insulator. Establishment of the gradient is highly ATP-dependent and achieved by ATP-dependent pumps. Once the ionic gradient is achieved, movement of one or more ions down their respective concentration gradients results in signaling voltage differences across a membrane. Normal membrane excitability is tightly regulated by the balance of these opposing influences and dependent on cellular energy metabolism for the delivery of appropriate amounts of ATP. Mitochondrial dysfunctioning therefore may result in disruption of the delicate balance, by limiting proper functioning of the ATP-dependent pumps. This results in a change of the excitability of various cells. Large changes in excitability of muscle or nerve may well be lethal, but subtle changes in some ion channels can lead to a slight increase in membrane excitability that may result in seizures, epilepsy or migraine headache (Ptacek, L. J. (1999) Semin. Neurol. 19, 363-369). Usually these diseases are episodic, and nerve or muscle may function properly under many circumstances. However, during stress (or other ATP consuming circumstances for example) a precipitating event can lead to periodically abnormal excitability.
Different neurophysiological, cerebral blood flow (CBF) and brain metabolic measures confirm the hypothesis that a disturbed cellular energy metabolism is associated with and may lead to changes in neuronal excitability and susceptibility to spreading depression or activation in migraine. Positron Emission Tomography (PET) measurements in several centers have shown increased mitochondrial oxygen consumption in the brains of patients with migraine. Studies using
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P-MRS have provided evidence of mitochondrial abnormality in platelets and in muscle tissue and have shown a disordered cerebral energy metabolism in patients with migraine. Barbiroli, B., et a. (1992) Neurology 42, 1209-1214 studied brain and muscle energy metabolism by
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P MRS in 12 patients affected by migraine with aura (classic migraine) in distinct periods. Brain
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P-MRS disclosed a low phosphocreatine content in all patients, accompanied by high ADP concentrations, a high percentage of V/Vmax (ATP), and low phosphorylation potential-features showing an unstable state of metabolism in classic migraine. Abnormal muscle mitochondrial function, in the absence of clinical signs of muscle impairment, was present in nine of the 12 patients examined. In another study conducted with migraine patients, brain energy phosphate metabolism and intracellular pH (pHi) was studied in a cross-sectional study by in vivo
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P NMR spectroscopy as well. During a migraine attack the ratio ATP/total phosphate signal (mole % ATP) was preserved, but there was a decrease in mole % phosphocreatine (PCr) and an increase in mole % inorganic phosphate (Pi), resulting in a decrease of the PCr/Pi ratio, an index of brain phosphorylation potential. This was found in classic but not common migraine. Mole % Pi was also increased in combined brain regions between attacks. There was no alteration in brain pHi during or between attacks. Energy phosphate metabolism but not pHi appears disordered during a migraine attack in this study (Welch, K. M., et al. (1989) Neurology 39, 538-541). Lodi et al. (1997) J. Neurol. Sci. 146, 73-80 also used
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P-MRS to quantify skeletal muscle bioenergetics and proton efflux in 63 patients with migraine (23 with migraine without aura, MwoA, 22 with migraine with aura, MwA, and 18 with prolonged aura or stroke, CM) and in 14 patients with cluster headache (CH), all in an attack-free period. At rest, mitochondrial function was abnormal only in CM, as shown by a low phosphocreatine (PCr) concentration. At the end of a mixed glycolytic/aerobic exercise all three migraine groups showed a significantly smaller decrease of cytosolic pH compared to controls with a similar end-exercise PCr breakdown, while end-exercise pH was normal in cluster headache patients. The normal rate of proton efflux in all headache groups suggests that the reduced end-exercise acidification was due to a reduction of glycolytic flux in migraine patients. The maximum rate of mitochondrial ATP production (Qmax), calculated from the rate of post-exercise PCr recovery and the end-exercise [ADP], was low in cluster headache patients as well as in migraine patients, except in MwoA patients. In conclusion, the study by Lodi et al. shows that the muscle mitochondrial failure, present in migraine as well as cluster headache patients, is in the former associated with a reduced glycolytic flux, while in the latter the glycolytic flux is normal.
The disturbed energy metabolism is not restricted to migraine type of headache. In a study by Montagna P. et al., (1997) Neurology 48, 113-119,
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P MRS on the brain and skeletal muscles of 14 patients affected with cluster headache (CH) was performed. Patients were examined in various periods and nine of them also during the cluster period, although not during the attack. Brain 31P MRS showed reduced phosphocreatine (PCr) levels, an in creased ADP concentration (calculated from the creatine kinase equilibrium), a reduced phosphorylation potential, and a high relative rate of ATP biosynthesis (% of V/Vmax). The inorganic phosphate (Pi) content was increased during the cluster period. Ten of 13 patients also showed a slow rate of PCr recovery in muscle after the exercise.
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P-MRS in CH patients showed abnormalit
N.V. Nutricia
Pak John
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