Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-03-04
2002-01-01
Geist, Gary (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S043000, C514S210030, C514S213010, C514S217000, C514S646000
Reexamination Certificate
active
06335323
ABSTRACT:
TECHNICAL FIELD
The present invention relates to the use of a combined medicament in the treatment of various forms of peripheral neuropathy, especially painful neuropathies and diabetic neuropathy, including diabetic amyotrophy, mononeuritis, mononeuritis multiplex, cranial nerve palsies and autonomic neuropathy. The invention also relates to the preparation of medicaments for such treatments.
BACKGROUND OF THE INVENTION AND PRIOR ART
Diabetes mellitus is a metabolic disorder resulting in hyperglycaemia (raised blood sugar), polyuria (increased output of urine) and glycosuria (appearance of sugars (e.g. glucose) in the urine). Diabetes has been recognised as a major disease for centuries. In addition to defective carbohydrate metabolism, it can also lead to altered metabolism of lipids and proteins and patients are at risk of complications from microvascular and macrovascular diseases which are serious and may be fatal.
Insulin dependent diabetes results from failure of the islets of Langerhans (&bgr;) cells of the pancreas to produce sufficient insulin. This often arises as a result of auto-immunity directed against islet tissue. Non-insulin-dependent diabetes may in part arise from altered efficiency of insulin receptor signalling (insulin resistance) or from a relative deficiency of insulin.
Detectable diabetic neuropathy occurs in approximately 60% of diabetic patients. Some 20% of diabetic patients show moderate to severe symptoms, the severity is generally thought to be linked to the duration of diabetic symptoms and the level of control using e.g. insulin, or oral hypoglycaemic agents such as the sulphonylureas.
Diabetic neuropathy may be mild, for example taking the form of “burning” or tingling in the feet or numbness and/or loss of vibration sense in the extremities, especially the feet. Moderate to severe symptoms of neuropathy include pain and spasm in the extremities (painful neuropathy with spasm). Diabetic amyotrophy is indicated by pain over the thigh and loss of quadriceps power, sometimes also loss of power in the lower leg resulting in foot drop. Autonomic neuropathy principally affects the nerves supplying the heart and viscera. Mononeuritis is usually caused by a single peripheral nerve palsy.
Other peripheral neuropathies include the following:
HIV associated neuropathy;
B
12
-deficiency associated neuropathy;
cranial nerve palsies;
drug-induced neuropathy;
industrial neuropathy;
lymphomatous neuropathy;
myelomatous neuropathy;
multi-focal motor neuropathy;
chronic idiopathic sensory neuropathy;
carcinomatous neuropathy;
acute pan autonomic neuropathy;
alcoholic neuropathy;
compressive neuropathy;
vasculitic/ischaemic neuropathy;
mono- and poly- neuropathies.
Both type I (insulin dependent) diabetes and type II (non-insulin dependent) diabetes are associated with neuropathy. Type I diabetes commonly presents in relatively young adults, often with diabetic ketoacidosis, type II diabetes (also know as maturity onset diabetes) often occurs in middle age or in elderly patients. Type II diabetes is particularly associated with the relatively late and severe onset of neuropathy.
Previous treatments for diabetic neuropathy have included tricyclic antidepressants on their own, the antiepileptic drug carbemazepine, and the antiarrythmic drug mexilitene. However these seem only to be mildly effective, and not in all cases. Long term good diabetic control has also shown to be a benefit in the prevention of diabetic neuropathy and in control of the symptoms, presumably controlling the agents which cause the damage to the nerves. There is little indication that long term control of diabetes can reverse symptoms i.e. the damage, once done, appears not to be reversible by treatment of the underlying diabetes.
Recent clinical trials have shown that gamolenic acid may reduce symptoms, and prevent the progression of abnormalities in nerve conduction studies in diabetic neuropathy.
WO 96/11009 discloses treatment of multiple sclerosis by some of the combinations of components employed in the present invention.
Vitamin B
12
has been proposed for the treatment of B
12
-deficiency associated neuropathy.
DISCLOSURE OF THE INVENTION
The present inventor has surprisingly found that a combination of an antidepressant or a monamine oxidase inhibitor (MAOI) with an inducer or a precursor of a neurotransmitter can be effective in the treatment of peripheral neuropathies, and in particular painful neuropathy. The components of this medicament may be presented as a combined preparation for simultaneous, separate or sequential use in the treatment of various peripheral neuropathies. It has also been observed that a parallel or simultaneous administration of vitamin B
12
treatment, for example orally or by injection, may enhance the therapeutic effect of this combination.
It has also been found that combinations (i) vitamin B
12
with an inducer or a precursor of a neurotransmitter and (ii) vitamin B
12
with an antidepressant, are effective in treatment of peripheral neuropathies.
Accordingly, in a first aspect the present invention provides the use of any one of the following components or combinations of components:
C,
A and B,
A and C,
B and C,
A, B and C,
wherein
A is an antidepressant or a monoamine oxidase inhibitor,
B is vitamin B
12
, and
C is a precursor or inducer of a neurotransmitter, in the manufacture of a medicament for the treatment of at least one form of peripheral neuropathy.
In another aspect the invention provides a method of making a medicament for the treatment of a patient suffering from a peripheral neuropathy, comprising admixing any one of the following components:
C,
A and B,
A and C,
B and C,
A, B and C,
wherein
A is an antidepressant or a monoamine oxidase inhibitor,
B is vitamin B
12
, and
C is a precursor or inducer of a neurotransmitter, with at least one pharmaceutically acceptable component or vehicle to prepare a medicament suitable for administration to a patient.
In yet another aspect the invention provides a method of treatment of a patient suffering from a form of peripheral neuropathy, comprising administering to the patient any one of the following combinations of components:
I. A, B and C
II. A and B
III. B and C
IV. A and C
wherein
A is an antidepressant or a monoamine oxidase inhibitor,
B is vitamin B
12
, and
C is a precursor or inducer of a neurotransmitter,
said components being administered simultaneously or separately, in amounts which in combination have the effect of ameliorating the peripheral neuropathy.
In a further aspect the invention provides a pharmaceutical composition containing as the only pharmaceutically active components vitamin B
12
and a precursor or inducer of a neurotransmitter.
Treatment may be simultaneous or separate including sequential administration of the components.
In the medicaments of the invention, there may be included at least one pharmaceutically acceptable component or vehicle such as an incipient, carrier, buffer, stabiliser or other material, as discussed below.
Also provided is a kit or pack containing components A and B, or A and C, or A and B and C, or B and C, wherein component A the components being formulated for simultaneous, separate or sequential delivery in the treatment of peripheral neuropathy. Particularly components A and C may be combined, and component B separate .
The diabetic neuropathy with which the present invention is concerned may be characterised by degeneration of the long nerves (the nerves of the peripheral nervous system) as a result of the metabolic disturbances of diabetes. This can be contrasted with other neurodegenerative disorders such as multiple sclerosis, the effects of which are concentrated in the central nervous system. Whilst multiple sclerosis leads to demyelination of the neurons of the central nervous system (that is, degeneration of the myelin sheath which surrounds the neurons), the toxic effects of diabetes occur in the body of the peripheral neuron, possibly due to the toxic effect of metabolites arising through the underlying diabetic disturbance o
Geist Gary
Larson & Taylor PLC
Owens, Jr. Howard V.
The WWK Trust
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