Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-15
2001-06-26
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06251935
ABSTRACT:
This application claims priority from German Application No. 199 41 217.0, filed on Aug. 30, 1999, the subject matter of which is hereby incorporated herein by reference.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to the use of racemic &agr;-lipoic acid or its enantiomers or pharmaceutically acceptable salts, amides, esters or thioesters thereof, in reduced or oxidized form, as active ingredient in the prevention of the acute or chronic treatment of migraine.
2. Background Information
Migraine is one of the most commonly occurring disorders. Migraine is defined by the International Headache Society (IHS) as a disorder characterized by episodic attacks of headache combined with autonomic symptoms. The painful episodes occur acutely and episodically, but the disorder itself must be regarded as chronic. In some patients without the so-called aura, the attacks of pain last for about 4 to 72 hours, are often unilateral and are associated with nausea and vomiting, and photo- and phonophobia. In patients with the so-called aura, reversible neurological signs such as aphasia, paresis, ataxia and dizziness occur a few minutes before an attack of pain. Epidemiological studies have shown that about 8 to 15% of the population suffer occasionally or frequently from mild to severe episodes of migraine. Women are usually affected more than men. Migraine normally appears for the first time at an age of 20 to 35, and is less common in children than in adults. The diagnosis is made by the physician only on the basis of the history and clinical data. There are no technical or biochemical methods providing a reliable diagnosis.
The pathophysiology and pathobiochemistry of migraine is underdeveloped. In the past, migraine has been regarded as a psychosomatic disorder without biological substrate, and it was unclear whether migraine is a physical disorder or a psychological health impairment. However, most experts no longer regard this as in doubt. It must, however, always be taken into account that psychological changes may induce migraine, and many other diverse factors such as hormonal (menstruation), nutritional (alcohol and malnutrition), medical (pharmaceuticals), environmental (noise) and psychological (stress) contribute to migraine. Patients still seek semi-professional assistance such as homeopathy or cell therapy.
In some patients, a reduction in the cerebral blood flow in isolated regions of the brain was associated with episodes of migraine (Lauritzen & Hansen, 1988). Perivascular changes stimulating afferent pain-conducting nerve fibres have been regarded, at least in some patients, as contributing to migraine (Moskowitz A. M. et al., Rev Neurol 145: 181-195; 1989), as have changes in various neurotransmitters (noradrenaline, serotonin, tachykinins etc.) (Edvinsson L. et al., in: Olesen J. Edvinsson L (ed.) Basic mechanisms of headache. Elsevier Science Publishers, Amsterdam 129-144; 1988). A reduction in the mitochondrial phosphorylation potential in the brain of migraine patients has been discussed recently, but it is still unclear whether this observation indicates primary deficits or represents only a secondary event in the pathophysiology of migraine (Schoenen et al., Neurology 50: 466-470; 1998).
Migraine is still treated only symptomatically. Some medications are used to modulate (&bgr; blockers) the so-called trigger factors for the episodes of migraine. Other compounds have vasoactivity (serotonin antagonists such as sumatriptan, non-steroidal anti-inflammatory drugs such as acetylsalicylic acid, anticonvulsants such as valproic acid). The vasoactivity of ergotamine does not, however, contribute to its clinical effects. Vitamin B2 is an important cofactor in the mitochondrial respiratory chain and, according to reports, reduces the occurrence of episodes of migraine in 68% of patients (Schoenen J. et al., loc. cit.). However, no vitamin B
2
deficiency has been observed in migraine patients, nor do patients with a vitamin B
2
deficiency show a clinical picture comparable with migraine.
All these possible interventions are pragmatic approaches to alleviating the symptoms of acute episodes of migraine at least in some patients. Various combinations of pharmaceuticals and other treatments are used in individual cases to achieve a clinical benefit. Pharmaceuticals are used either acutely to alleviate an episode of migraine or chronically to reduce the frequency of the episodes. Elimination of medical or environmental trigger factors is likewise an important attempt to help the patient. However, there is still no treatment of the underlying disease of migraine itself, which can be explained by lack of understanding of the pathophysiology of migraine. The benefit of pragmatic therapies is valuable for many suffering patients, but they still cannot be cured of their disorder.
&agr;-Lipoic acid is a naturally occurring antioxidant and a cofactor of the glucose-metabolizing pyruvate dehydrogenase (Packer L. et al., Free Radicals in Biology & Medicine 19(2): 227-250, 1995) and is widely used for treating diabetic polyneuropathy (Ziegler D. et al., Diabetologia 38: 1425-1433; 1995). In addition, &agr;-lipoic acid has been used for decades for treating liver disorders (Bode J. Ch. et al., DMW 112 (9), 349-352; 1987) and poisoning by fungi (Brunn J. et al., Internist. Prax. 19: 475-478, 1979). The molecular mode of action has recently been characterized as that of the diabetes-specific antioxidant (Nagamatsu M. et al., Diabetes Care 18 (8): 1160-1167; 1995).
The biological and therapeutic effects of &agr;-lipoic acid in oxidized and reduced form are also found with numerous derivatives as metabolites, sometimes in diminished and sometimes in improved form (for example 3-ketolipoic acid, 1,2-diselenolane-3-pentanoic acid, lipoamide, octotiamine, 2-(N,N-dimethylamine)ethylamidolipoate HCl, tocopheryl lipoate and tocotrienyl lipoate, gamma-hydroxybutyrat lipoate, lipoic acid vitamin E ester, N-acetyl-p-aminophenol derivatives of lipoic acid and others (Tirosh O. Sen CK, Roy S, Kobayashi S, Packer L. Neuroprotective effects of &agr;-lipoic acid and ist positively charged amide analogue. Free Rad Biol Med 26 (11/12), 1418-1426, 1999); EP 0 855 396 A1, EP 0 869 126 A1, PCT/GB98/02155, WO 99/06040, DE 43 27 462 A1). These derivatives were proposed in order to improve the metabolism and the distribution in vivo, which may also apply to the distribution into the central nervous system. Some derivatives may also improve the effects (for example affinity and turnover rate) on the biological targets (biological redox systems such as &agr;-ketoacid dehydrogenases, H protein, thioredoxin, glutathione reductase or cellular redox systems such as glutathione, ubiquinone, complex I of the respiratory chain, or redox- and SH-sensitive proteins and enzymes, the NO system, catalase, the cellular cystine/cysteine shuttle, homocysteine, tyrosine kinase, MAP kinase, metal ions (for complexation), alpha-1-antiproteinase, or redox-sensitive transcription factors such as NF-kB or AP1) of &agr;-lipoic acid, or couple other active molecules with &agr;-lipoic acid with the aim of a synergistic or additive pharmacological effect.
The term “&agr;-lipoic acid” is therefore used in this text as a general term which, apart from the enantiomers, the racemate and mixtures of the enantiomers, also covers derivatives (esters, thioesters, ethers, salts, amides, metabolites etc.) as long as the active dithiolane group of the &agr;-lipoic acid continues to be partly responsible for the biological and medical effect of the derivative.
Pharmaceuticals with &agr;-lipoic acid have been obtainable for decades and are well tolerated. In this time, many possible uses have been tested, but a benefit in the treatment of migraine has never been reported.
SUMMARY OF THE INVENTION
The aim of the invention is to improve the state of health of migraine patients.
This object is achieved by the use of racemic &agr;-lipoic acid or its enantiomers or pharmaceutically acceptable salts, amides, esters or thioesters
Borbe Harald
Engel Jurgen
Lobisch Michael
Peukert Manfred
Schoenen Jean
Asta Medica Aktiengesellschaft
Henley III Raymond
Pillsbury & Winthrop LLP
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