WO1997026887A1

WO1997026887A1 - Use of galanthamine in the preparation of novel drugs

Info

Publication number: WO1997026887A1
Application number: PCT/AT1997/000011
Authority: WO
Inventors: Martin Alois Hermann Mucke; Werner Frantsits
Original assignee: Sanochemia Ltd.
Priority date: 1996-01-26
Filing date: 1997-01-27
Publication date: 1997-07-31
Also published as: AT402691B; EP0876147A1; ATA14996A; AU1432897A

Abstract

Described is the use of galanthamine or one of its acid addition salts in the preparation of a drug for the treatment of trisomia 21 and related syndromes, glaucoma, myasthenia gravis and neuromuscular auto-immune illnesses and/or nerve-compression trauma.

Description

Use of galanthamine to manufacture new medicines

The invention relates to the new use of galanthamine or an analog or a pharmaceutically acceptable acid addition salt thereof for the manufacture of medicaments for the treatment of Lang-don-Down syndrome (Mongolism, Trisomy 21), for the treatment of glaucoma, for the treatment of myasthenia gravis and the related Eaton-Lambert syndrome and / or for the treatment of nerve compression trauma.

Down syndrome is due to a tripling of chromosome 21, i.e. the patients have a set of 47 instead of 46 chromosomes, which is relatively easy to detect cytologically. Trisomie 21 is associated with moderate to severe intellectual disability and a number of physical signs of dysmorphism. Causal therapy is currently not possible. Existing disabilities can be influenced by targeted therapeutic measures, but the need for help usually remains.

Taken together, the different types of glaucoma are responsible worldwide for the majority of disease-related cases of blindness. In the USA and Europe, the number of people affected is estimated to be at least 2-3 million each. Since glaucoma usually does not cause pain or other striking symptoms before a clear loss of vision has occurred, it is assumed that about half of the cases are not correctly diagnosed.

Glaucoma is an optical neuropathy that is characterized by optic nerve damage and associated visual impairment. It is the common end stage of a number of different diseases affecting the eye. As soon as a critical number of optic nerve neurons are destroyed, "blind spots" initially develop on the periphery of the visual field, which increasingly extend to the central visual field. As soon as the optic nerve can no longer correctly transmit the signals from the retina to the brain, an irreversible there is a loss of vision.

Since about one percent of the aqueous humor is exchanged per minute, the fluid balance of the eye must be exactly balanced. The most important risk factor for the development of glaucoma due to mechanical damage to the optic nerve is an intraocular pressure above the upper limit of the normal value of 20 mm Hg.

The subspecies of glaucoma are classified based on the angle enclosed by the lens and iris and the intraocular pressure:

1. In the open-angle glaucoma there is a normal anatomy of the eye, but the drainage of the aqueous humor through the trabecular network is obstructed, so that the intraocular pressure rises.

2. In narrow-angle glaucoma (angular block glaucoma), the iris is pressed by the primarily increased intraocular pressure against the intact trabecular system, whereupon the outflow of the aqueous humor is hindered.

3. In low-pressure glaucoma there is primary damage to the lens with moderately elevated or normal intraocular pressure. Inadequate blood supply to the eye is considered the main risk factor, but lower blood pressure or cranial pressure, primary degeneration of the ganglia, autoimmune symptoms, abnormalities of the connective tissue and neurotoxins are also discussed as cofactors.

There are also clear genetic risk factors for developing glaucoma. An intensive search for the corresponding gene loci is currently underway.

Myasthenia gravis (MG) is an autoimmune disease in which the immune system forms antibodies against the acetylcholine receptors at the junctures between nerves and muscles (the so-called neuromuscular end plates) of the body. In the Eaton-Lambert syndrome, which is closely related to MG, these autoantibodies are not directed against the post-synaptic receptors, but against proteins of the presynaptic, calcium-controlled channels, which allow acetylcholine to escape into the synaptic cleft. This inactivates or destroys the respective antibody targets, making it increasingly difficult to trigger muscle contractions, which first leads to a feeling of insurmountable fatigue and finally to a state of paralysis. The first manifestations often appear in the muscles of the eyes, and subsequently the pharynx and larynx and finally the entire skeletal muscles are affected.

The main forms of MG are:

1. Spontaneous adult MG, which usually occurs in the third decade in women and in the fifth decade in men without a known trigger and whose symptoms are fully manifested within three years of the first manifestation.

2. Infection-related MG can (possibly caused by a process of molecular mimicry) after herpes or bacterial infections.

3. Medically induced MG is a risk factor for treatment with penicillamine and related antibiotics.

4. Transient neonatal MG occurs in newborns who receive pathogenic immunoglobulins (with or without receptor antibodies) from the maternal circulation in the course of pregnancy. It manifests itself in about 12% of all children of MG patients within the first three days post partum and is self-limiting within 1-4 weeks.

Myasthenia gravis can be associated with other autoimmune diseases, whereby an existing thyroid disease can worsen the symptoms. Thymectomy usually improves symptoms within one year and is therefore recommended for all post-pubertal MG patients up to the age of 60.

The much rarer Eatσn-Lambert syndrome also manifests itself in progressive, sometimes painful muscle weakness, especially in the lower abdomen and thighs, and in dryness of the mouth and various paresthesias.

Mechanical damage to the central or peripheral nervous system can result from a variety of different traumatic events, is mostly painful and often results in paralysis. Even if the mechanical integrity of the affected nerve is preserved, it can be affected by compression. Acute transient compression trauma can be a consequence of the shock wave propagating through the tissue after a stroke, while chronic compression is triggered by congenital malformations, displacements, bleeding or space-consuming processes when the nerve is pressed against a bone. The irritation caused by the compression trauma leads to uncontrolled firing of the affected neurons, a process which triggers sensation of pain, interferes with normal nerve function, and can lead to permanent damage if left untreated. Frequent causes of transient or chronic nerve compression are shock or pressure on the skull or spine, tooth extraction, tumors, innate or proximity of nerves to larger blood vessels or aneurisms caused by displacement, and in the case of glaucoma increased intraocular pressure.

As mentioned, there are currently no effective means of improving the causal disability of people with trisomy 21. Medicinal interventions are limited to the administration of growth hormones (somatotropin), anabolic steroids (eg oxandrolone), serotonin, and high-dose vitamins and minerals .

Drug treatment for glaucoma focuses on reducing the intraocular pressure by topical application to the anterior part of the eye:

Miotics such as pilocarpine (an alkaloid) and carbachol (carbamylcholine, a choline ester) are parasympathomimetics which have been used for decades in narrow-angle glaucoma because they promote the outflow of the aqueous humor by contraction of the pupil. Echothiophate (phospholine iodide, a phosphate ester) and physostigmine (eserine) exert an indirect parasympathomimetic effect by inhibiting acetylcholinesterase. Epinephrine (adrenaline), its precursors (such as dipivefrin, which are metabolized to adrenaline in the eye) and alpha2-agonists (eg brominide) also promote the drainage of aqueous humor and thus lower intraocular pressure due to the adrenergic effect.

Beta blockers (e.g. Timolol, Levobunolol and Betaxolol) work by reducing the formation of aqueous humor. Various oral beta blockers (propanolol, atenolol, nadolol) for lowering blood pressure also do this.

Carbonic anhydrase inhibitors (dorzolamide) also reduce the formation of aqueous humor.

Ophthalmic formulated steroids (e.g. the selective FP receptor agent Latanoprost).

New findings suggest that optic nerve damage continues even after successful reduction of intraocular pressure. Direct treatment of the optic nerve is therefore sought in order to prevent further degradation of damaged neurons.

For myasthenia gravis and related syndromes, e.g. Eaton-Lambert syndrome, three different types of drug therapy are currently being carried out:

Acetylcholinesterase inhibitors (AChEI) accelerate the cholinergic neuromuscular conduction and can achieve rapid symptomatic improvement. Pyridostigmine, a short-acting AChEI, has been in use since 1934 and is still considered the treatment of first choice. Distigmine and tetrastigmine (essentially dimers or tetramers of pyridostigmine) and organic phosphate esters have long been effective, but have been discredited because of their often unpredictable profile of effects, cumulative systemic effects and muscarinic side effects. It is also AChEI with poor selectivity in relation to acetylcholinesterase compared to butyrylcholinesterase. Immunosuppressants (eg prednisone, azathioprine and cyclosporin) are indicated if the symptoms cannot be adequately controlled with AChEI and these are pronounced enough to justify the risks of the considerable side effects associated with these drugs.

Ablative immunotherapy aims at a short-term reduction of the autoantibodies directed against the acetylcholine receptor or calcium channel through complexation and neutralization. This is achieved by intravenous administration of immunoglobulin or a soluble peptide which mimics the epitopes recognized by the autoantibodies. These processes are usually supported by frequent plasma exchange.

The causal therapy of chronic compression trauma is surgical decompression, which, however, is not always necessary or feasible and does not always result in the immediate elimination of the symptoms. In these cases, analgesics are used topically or instilled. Antiepileptics are sometimes also used, the anticonvulsive effects of which are based on the prevention of repeated discharge of the action potentials of depolarized nerves.

The acid addition salts of galanthamine, which has the chemical structural formula

has been known for many years as active pharmaceutical ingredients with an inhibitory effect on the synaptic enzyme acetylcholinesterase. Galanthamine is therefore used pharmacologically for paralysis symptoms following poliomyelitis and for various diseases of the nervous system. Galanthamine and some of its derivatives are also used in the symptomatic treatment of Alzheimer's disease and related dementia.

Chemically speaking, galanthamine is an alkaloid of the morphine group, which can be obtained from snowdrops (Galanthus woronowii, G. nivalis, etc.) and other amaryllidaceae.

In addition to the production of galanthamine from plant sources, chemical synthesis processes for galanthamine and its analogs including their acid addition salts have also recently been proposed, reference being made to WO 95/27715 A (= US Pat. No. 5,428,159 A) and to WO 96/12692 A. published international patent application PCT / AT 95/00208.

The use of galanthamine for producing a medicament for the treatment of Alzheimer's disease and related dementias is known from EP 236 684 A.

The invention is based on the object of providing a medicament with which the functional status of patients suffering from trisomy 21 and related syndromes, in particular adolescents, can be improved and with which the effective treatment of glaucoma, myasthemia gravis and Eaton-Lambert syndrome and / or nerve compression trauma is possible.

According to the invention, this is achieved by a medicament containing galanthamine or an acid addition salt.

The invention therefore relates to the use of galanthamine or a pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicament for the treatment of trisomy 21 and related syndromes, glaucoma, myasthemia gravis as well as related autoimmune diseases and / or nerve compression trauma.

Mongoloids are substantially activated by administration of galanthamine or an acid addition salt of the medicament containing the same. The cognitive performance and learning ability of these patients increases sharply, so that improved accessibility for learning therapy etc. is given. For the patient, the chances of increased integration into society thus increase considerably, since not only are the necessary social activities much better mastered, but also much better information processing and memory are provided.

So far, it has been assumed that with intensive treatment and care of patients suffering from trisomy 21 (Mongoloids), a limited learning outcome, which is usually not directly proportional to the effort, can be achieved. Treatment of the down patient with a medicament containing galanthamine achieved according to the invention can, however, increase the learning success considerably.

Outpatient trials on adolescent Langdon-Down patients whose intellectual and social developmental age roughly corresponded to that of an elementary school pupil led to significant improvements in the following areas when oral administration of galanthamine hydrobromide with unchanged other medication and treatment: Daily practical skills ( esp. Eating and hygiene behavior), cognitive performance, as well as openness and manageability by parents and therapists.

It was not foreseeable that the administration of a medicament containing galanthamine would improve the possibilities and the success of the treatment of Mongoloid patients, especially adolescents, to such an extent that a previously unimaginable improvement in the brain performance of these people is achieved.

The short-acting inhibitors of acetylcholinesterase, physostigmine and neostigmine, are used alone and in combination with pilocarpine for the topical treatment of glaucoma. Because of their unfavorable pharmacological properties, however, in order to achieve a reasonably constant intraocular active ingredient level, they must be applied into the tear sac several times a day, which is always accompanied by acute eye irritation and impaired vision. In addition, these are non-specific inhibitors that do not have a good ability to differentiate between acetyl and butyryl cholinesterase. The potential for side effects of simultaneous inhibition of butyrycholinesterase is currently unknown. On the other hand, the long-acting miotics are, from a pharmacological point of view, consistently irreversible and also non-selective inhibitors of cholinesterases, which makes it difficult to control their effects. In addition, they have a denaturing effect on the protein of the eye lens and can therefore cause clouding (cataracts) as the most important side effect. The permanent narrowing of the pupil complicates the removal of the lens that may become necessary, since the pupil muscle tears frequently. The use of echothiophate, isofluorophate and other alkylated miotics is therefore only recommended after cataract surgery.

Galanthamine combines the complete reversibility of the inhibitory effect with a half-life that is an order of magnitude higher than that of physostigmine and neostigmine. If necessary, its effect can be completely and at any time neutralized by parasympatholytics, such as atropine. The selectivity of galanthamine for acetylcholinesterase is also almost a power of ten higher than for physostigmine, which results in a reduced potential for side effects. Ophthalmic formulations can be created in the form of drops for twice a day use, or as an emulsion for application once a day, just as a membrane bag to be carried in a tear bag can release the active ingredient over several days.

Pilot studies have shown that all forms of glaucoma with increased intraocular pressure can cause galanthamine HBr to reduce its by 5-50 mm Hg if 1-2 drops of a 0.5 l, 0% ophthalmic solution in the eye sac twice a day be introduced. These doses do not affect the internal pressure of the healthy eye, so that preventive treatment is possible. In acute angular block glaucoma, the described administration can take place at hourly intervals until the pain subsides, so that the eye is accessible to the surgical intervention after the internal pressure has been reduced to a maximum of 25 mm Hg. Preliminary data indicate that long-term therapy of moderate chronic glaucoma with galanthamine through a mechanism that has not yet been clarified can delay further damage to the optic nerve or even reactivate some of its neurons. Galanthamine can be used advantageously for glaucoma with increased intraocular pressure and has a protective or regenerative effect on the optic nerve.

In contrast to the AChEI described above, galanthamine has excellent pharmacological properties. After oral ingestion as a tablet or solution, it is quickly and completely absorbed through the gastrointestinal tract and, because of its high distribution volume, reaches the entire skeletal muscles in sufficient concentration. It combines the good uptake and the reversibility of the AChEI action of pyridostigmine and neostigmine with the prolonged activity of the alkylated pyridostigmine oligomers, but avoids their cumulative effects.

Pilot studies have shown that 10-30 mg of galanthamine HBr per day, given orally as a tablet or drinking solution for a few months, has an advantageous effect on mild to moderate myasthenia gravis in the sense of symptomatic relief. There were indications that in purely ocular manifestations this effect can be brought about by topical application to the eye (in a similar way to glaucoma).

Galanthamine, alone and in combination with immunotherapy, is suitable for the symptomatic treatment of myasthenia gravis and Eaton-Lambert syndrome.

Although the analgesic effect of galanthamine is too low to be of therapeutic significance, it can contribute to the restoration of normal stimulus conduction in mild or moderate compression trauma when used locally or systemically, especially with trigeminal neuralgia and facial paresis as well as with conditions after removal of medullary tumors . This may be due to the inhibitory effect of galanthamine on synaptic acetylcholinesterase, or to another mechanism that has not yet been characterized.

In pilot studies, up to 50 days of local infiltration or subcutaneous injection of 1-5 mg of galanthamine HBr per Day, with or without supplemental oral administration of 10-30 mg of the same substance per day, has been shown to be effective. Such a treatment cycle can be repeated if necessary after a break of 30-50 days.

Galanthamine is suitable for the treatment of nerve compression trauma and supports the restoration of normal nerve function after surgical decompression.

Galanthamine or an acid addition salt thereof can be administered in any suitable chemical or physical form.

For example, it can be administered as the hydrobromide, hydrochloride, methyl sulfate or methiodide.

Galanthamine or its pharmaceutically acceptable acid addition salts can be administered to patients orally or by subcutaneous or intravenous injection or intracerebroventricularly using an implanted container.

It may be necessary to start with lower doses than they are effective.

Typical dosing rates when administering galanthamine or its acid addition salts depend on the nature of the compound used and on the condition of the patient. Typical treatment rates for treatment with galantamine or with galanthamine hydrobromide are in the range from 0.2 to 1.0 mg per day and kilogram of body mass, depending on the age, physical condition and other medication of the patient.

The following specific formulations can be used in the treatment of trisomy 21:

Tablets or capsules containing 5 or 10 mg galanthamine Parenteral solution containing 1 mg / ml galanthamine.

Liquid formulation for oral administration, in one concentration of 1 or 5 mg / ml galanthamine / ml.

The following specific formulations can be used in the treatment of glaucoma:

Ophthalmic aqueous solution, 0.5% or 1.0%

Ophthalmic emulsion

Bags or comparable aids with a semi-permeable membrane for delayed release of the active ingredient, for insertion in the lacrimal sac

The following specific formulations can be used in the treatment of myasthenia gravis and Eaton-Lambert syndrome:

Film-coated tablet, 5 mg and 10 mg drinking solution, 1 mg / ml parenteral solution, 1 mg / ml ophthalmic solution, 0.5% and 1.0%

The following specific formulations can be used in the treatment of nerve compression trauma:

Film-coated tablet, 5 mg and 10 mg drinking solution, 1 mg / ml parenteral solution, 1 mg / ml

Claims

Claims:

1. Use of galanthamine or a pharmaceutically acceptable acid addition salt thereof, for the manufacture of a medicament for the treatment of trisomy 21 or related trisomy syndromes, for the treatment of glaucoma, for the treatment of myasthenia gravis and of the Eaton-Lambert syndrome and related neuromuscular autoimmune diseases and / or for the treatment of nerve compression trauma.

2. Use of galanthamine hydrobromide for the manufacture of a medicament for the treatment of trisomy 21 or related trisomy syndromes, for the treatment of glaucoma, for the treatment of myasthenia gravis as well as related neuromuscular autoimmune diseases and / or for the treatment of the nerve com pression traumas.