Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-06-14
2002-05-07
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S660000, C514S661000
Reexamination Certificate
active
06384083
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to adamantane amines or structurally similar compounds for combating the Borna disease virus and for the prevention and treatment of emotional diseases and other disorders associated with BDV infections in humans and animals.
Emotional diseases, in general, and depressions of different severities, in particular, are among the most widespread syndromes at the present time, at least in industrialized countries. It is estimated that, for example in Germany, approximately 5% up to possible 10% of the population suffer at least occasionally from depressive disease conditions. These conditions are not merely mild emotional upsets; they are diseases, which severely affect the afflicted and can make them unable to work and this, not only if the condition exists for a longer time. The suicide rate for endogenous, depressive patients at the present time is of the order of 20%, if medical help is not sought. Frequently therefore, prolonged in-patient treatments are unavoidable which, in turn, is a problem for the patient as well as for the general public.
In the case of a longer in-patient treatment, the danger of hospitalization exists for the patient. Moreover, society must make sufficient therapy places available, including suitable clinics and specially trained personnel. All this is also associated with high costs for the general public.
It is now known that not only man, but also animals can suffer from emotional disorders in a similar manner. Such disorders are known, for example, for horses, in which the syndrome expresses itself as a listless phase, which is associated with drowsiness, loss of energy and frequently with disorders of muscular coordination. This horse disease is associated with an activated Borna disease virus infection. In the extreme case, the diseased animal must be put to sleep in order to bring an end to its suffering.
Depressions are also treated with drugs. On the basis of different theories, an attempt is made to influence the nervous system and to improve the depressive symptoms. Various anti-depressive drugs can have a mood-elevating, psychomotor-activating, calming or anxiety reducing, etc. effect to different degrees. The mode of action of most of the drugs has been clarified only inadequately.
For example, tricyclic and tetracyclic drugs are in use. According to other therapeutic attempts, selective seratonin reuptake inhibitors (SSRI), monoamino oxidase inhibitors or noradrenalin reuptake inhibitors are administered therapeutically. Many drugs have relatively severe side effects, such as the danger of convulsions, tremors, nausea and vomiting, headaches, anxiety states, severe liver and kidney disorders, anemia, etc. Moreover, the anti-depressive effect is limited or subjectively not present in a number of patients.
There is therefore a great need for a more effective medicinal treatment, and moreover for one with fewer side effects, for the treatment of emotional disorders of different origin.
Recently, the Applicants were able to find virus proteins and genetic material of the Borna disease virus (BDV) in the blood samples of emotionally sick patients during an acute depressive phase. This genetic material comprised sheathed, non-segmented, single-strand RNA virus of negative polarity, which is known to initiate emotional and, in some cases, depression-like symptoms in animals. It was possible to isolate the infectious human BDV from the blood of patients with different intensities of emotional diseases (L. Bode in Curr. Topics Microbiol. Immun. 1995, 190, 103-130; L. Bode, W. Zimmermann, R. Ferszt, F. Steinbach, H. Ludwig, Nature Med. 1995, 1, 232-236; L. Bode, R. Dürrwald, F. A. Rantam, R. Ferszt, H. Ludwig, Mol. Psychiatry 1996, 1 (3): 200-212).
It may be assumed that a BDV infection, aside from other factors, such as possibly a genetic predisposition, could represent a factor in the initiation of emotional diseases, which are characterized, for example, by changes in the messenger material area of the limbic system and could represent other, especially cerebral, disorders.
The problem, on which the invention is based, consists therein that depressions in man and animals are to be treated medicinally, as effectively as possible, without significant compromising side effects. At the same time, any BDV infection present should, if possible, be suppressed effectively or eliminated. Moreover, BDV infections in man and animal in general are to be controlled.
SUMMARY OF THE INVENTION
In order to solve this problem, the invention provides for the use of adamantane amines or compounds of a similar structure.
The inventive use is indicated for the prevention and control of viruses of the Bornaviridiae family, especially Borna disease virus (BDV) infections and for the treatment of emotional disorders and other disorders associated with Borna disease virus infections in humans and animals.
The inventive use may also be indicated for the prevention and control of infections in humans and animals with other viruses of the order of Mononegavirales.
A negative antibody finding does not exclude a BDV infection and, with that, an indication for the inventive treatment.
Since the mechanism of the adamantane action has not yet been clarified, it cannot be stated with certainty whether the action is causative or indirect.
1-Adamantane amine belongs to the group of adamantanes. These are stable, colorless, crystalline, tricyclic compounds with a “cage-like” structure. In its spatial structure, adamantane (tricyclo(3.3.1.1
3,7
)decane itself is similar to a diamond, is water insoluble and, for that reason already, pharmaceutically not usable.
There are, however, certain pharmaceutically usable adamantane derivatives.
From the PCT WO 94/28885, a plurality of adamantane derivatives are known, which are substituted in different positions. These derivatives are, in particular, alcohols and ketones but do not include amino-substituted derivatives. Numerous antiviral, antibacterial, antimycotic and antitumor properties, which are not quantified in greater detail, are ascribed to these adamantane derivatives. Certain ketones are said to be usable against HIV and possibly other retroviruses.
The water-soluble salts of 1-adamantane amine or of 1-aminoadamantane (international name (INN): amantadine, C
10
H
17
N, MW 151.26), amantadine sulfate (II) and amantadine hydrochloride (III) have been known for about 30 years as pharmaceutical active materials.
Amantadine sulfate or hydrochloride is still used at the present time for the treatment of Parkinson's disease and in the further area of the Parkinson syndrome in the case of an akinetic crisis, extrapyramidal disorders and reduced vigilance. As far as it is known, the pharmacological effect is based, among other things, on an increase in the availability of dopamine at the dopaminergic synapses. Details of the mechanism have not yet been clarified. On the basis of this effect on the nervous system, the use for the prophylactic treatment of migraines has also already being proposed (DE 19510189 A1).
Water-soluble amantadine derivatives were originally approved for the prophylaxis and treatment of certain influenza A strains. W. L. Davies, R. R. Grunert et al. (Science 1964, vol. 144, 862/863) discovered that amantadine hydrochloride inhibits the replication of viruses of four strains of influenza A and one of the C type. On the other hand, the closely related influenza B strains, mumps and a large number of other RNA and DNA viruses were not sensitive. In the case of the A strains, it was possible to push back the virus production by a power of 10, but it was not possible actually to suppress it. Amantadine sulfate and amantadine hydrochloride were thereupon approved internationally as a drug for the prophylaxis of influenza A infections and for the treatment of acute influenza diseases caused by influenza A viruses.
The specific activity of amantadine against influenza A virus is documented in vitro (cell culture) and on patients. The mechanism of action is based on th
Bode Liv
Dietrich Detlef
Emrich Hinderk M.
Ludwig Hanns
Ludwig Hanns
Norris & McLaughlin & Marcus
Travers Russell
Wang Shengjun
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