Re:Treating chronic pain, migraine & muscle spasticity through inhibiti

[Guest guest]

An interesting adjunct to the above article.

http://www.patentstorm.us/patents/6455553/fulltext.html*

*

US Patent 6455553 - Method for treating a demyelinating condition

US Patent Issued on September 24, 2002

<http://www.patentstorm.us/patents-by-date/2002/0924/1.html>

he present invention provides a method for treating a demyelinating

condition in a subject in need of treatment, by administering to the

subject an amount of a Ca^2+ -channel blocker effective to treat the

demyelinating condition. The present invention is also directed to a

method for treating a demyelinating condition in a subject in need of

treatment, by administering to the subject a Ca^2+ -channel blocker in

combination with a glutamate inhibitor, in amounts effective to treat the

demyelinating condition. Also disclosed is a pharmaceutical composition

comprising a Ca^2+ -channel blocker, a glutamate inhibitor, and a

pharmaceutically-acceptable carrier. Additionally, the present invention

provides a method for treating a demyelinating condition in a subject in

need of treatment, by administering to the subject a Ca^2+ -channel

blocker in combination with a hypertensive agent, in amounts effective to

treat the demyelinating condition. Finally, the present invention

discloses a pharmaceutical composition comprising a Ca^2+ -channel

blocker, a hypertensive agent, and a pharmaceutically-acceptable carrier.

Demyelination is a feature of many neurologic disorders. Demyelinating

conditions are manifested in loss of myelin--the multiple dense layers of

lipids and protein which cover many nerve fibers. These layers are

provided by oligodendroglia in the central nervous system (CNS), and

Schwann cells in the peripheral nervous system (PNS). In patients with

demyelinating conditions, demyelination may be irreversible; it is usually

accompanied or followed by axonal degeneration, and often by cellular

degeneration. Demyelination can occur as a result o

neuronal damage or

damage to the myelin itself--whether due to aberrant immune responses,

local injury, ischemia, metabolic disorders, toxic agents, or viral

infections [1, 23].

Central demyelination (demyelination of the CNS) occurs in several

conditions, often of uncertain etiology, that have come to be known as the

primary demyelinating diseases. Of these, multiple sclerosis is the most

prevalent. Other primary demyelinating diseases include

adrenoleukodystrophy (ALD), adrenomyeloneuropathy, AIDS-vacuolar

myelopathy, HTLV-associated myelopathy, Leber's hereditary optic atrophy,

progressive multifocal leukoencephalopathy (PML), subacute sclerosing

panencephalitis, and tropical spastic paraparesis. In addition, there are

acute conditions in which demyelination can occur in the CNS, e.g., acute

disseminated encephalomyelitis (ADEM) and acute viral encephalitis.

Furthermore, acute transverse myelitis, a syndrome in which an acute

spinal cord transection of unknown cause affects both gray and white

matter in one or more adjacent thoracic segments, can also result in

demyelination. Finally, there are animal models which mimic features of

human demyelinating diseases [23]. Examples include experimental

autoimmune neuritis (EAN), demyelination induced by Theiler's virus, and

experimental autoimmune encephalomyelitis (EAE)--an autoimmune disease

which is experimentally induced in a variety of species and which

resembles MS in its clinical and neuropathological aspects [15, 21].

Multiple sclerosis (MS) is the most prevalent demyelinating condition. In

Europe and North America, an average of 40-100 people out of every 100,000

have MS. The disease affects approximately 250,000 people in the United

States alone. MS is a chronic, devastating neurological disease that

affects mostly young adults. The pathogenesis of MS is a complex process

that leads to destruction of myelin and oligodendroglia, as well as axonal

damage, in the brain and spinal cord [1, 16]. Histopathologically, MS is

characterized by inflammation, plaques of demyelination infiltrating cells

in the CNS tissue, loss of oligodendroglia, and focal axonal injury [1].

The disease is thought to result from aberrant immune responses to myelin,

and possibly non-myelin, self-antigens [17, 18]. Clinically, MS may follow

a relapsing-remitting, or it may take a chronically progressive course

with increasing physical disability [15]. Typically, the symptoms of MS

include lack of co-ordination, paresthesias, speech and visual

disturbances, and weakness [23].

Current treatments for the various demyelinating conditions are often

expensive, symptomatic, and only partially effective, and may cause

undesirable secondary effects. Corticosteroids (oral prednisone at 60-100

mg/day, tapered over 2-3 weeks, or intravenous methylprednisolone at

500-1000 mg/day, for 3-5 days) represent the main form of therapy for MS.

While these may shorten the symptomatic period during attacks, they may

not affect eventual long-term disability. Long-term corticosteroid

treatment is rarely justified, and can cause numerous medical

complications, including osteoporosis, ulcers, and diabetes [23].

Immunomodulatory therapy with recombinant human interferon-β

(Betaseron and Avonex) and with co-polymer (Copaxon) slightly reduces the

frequency of relapses in MS, and may help delay eventual disability [23].

Both forms of interferon-β and co-polymer are currently used as

treatment modalities for MS, but all are exceedingly expensive.

Immunosuppressive drugs (azathioprine, cladribine, cyclophosphamide, and

methotrexate) are used for more severe progressive forms. However, they

are not uniformly beneficial, and have significant toxic side-effects.

Several drugs (e.g., baclofen at 30-60 mg/day in divided doses) may reduce

spasticity by inhibiting the spinal cord reflexes. Cautious and judicious

use is required, though, because the drug-induced reduction in spasticity

in MS patients often exacerbates weakness, thereby further incapacitating

the patient [23].

Similarly, current treatment for ALD, another devastating demyelinating

disease, is relatively ineffective. Symptoms of ALD may include cortical

blindness, corticospinal tract dysfunction, mental deterioration, and

spasticity. Therapy to control the course of ALD may include bone marrow

transplantation and dietary treatment [19], but inexorable neurological

deterioration invariably occurs, ultimately leading to death [20, 23].

Some progress has been realized in the treatment of animals with EAE and

EAN, by using glial cell transplants and growth factors, and by inhibiting

adhesion molecules, autoantibodies, and cytokines [21]. However, none of

these treatments has been shown to be beneficial in humans, and some

require extensive neurosurgical intervention. Thus, it is clear from the

foregoing that there exists a need for more effective, and less expensive

and invasive, methods to treat the varied array of demyelinating

conditions, without producing undesirable secondary effects.

Calcium-channel blockers are a class of pharmacological agents which

inhibit the transmembrane flux of calcium (Ca^2+ ) ions into cells,

particularly vascular smooth muscle cells and cardiac muscle cells. They

have been indicated for the treatment of angina, arrhythmias, atrial

fibrillation, hypertension, and paroxysmal supraventricular tachycardia

[14]. Amlodipine, a potent Ca^2+ -channel blocker, is a long-acting

dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel

blocker). Amlodipine selectively inhibits Ca^2+ -ion influx across

cell membranes, with a greater effect on vascular smooth muscle cells than

on cardiac muscle cells. In particular, amlodipine is a peripheral

arterial vasodilator that acts directly on vascular smooth muscle to cause

a reduction in peripheral vascular resistance and a reduction in blood

pressure. Amlodipine has been demonstrated to be effective in treating

chronic stable angina, vasospastic angina, and hypertension [14], and it

may also have neuroprotective activity [12]. Other Ca^2+ -channel

blockers include bepridil, diltiazem, felodipine, flunarizine, isradipine,

mibefradil, nicardipine, nifedipine, nimodipine, nisoldipine, nivaldipine,

and verapamil [14].

--

Larry Shield

011-39-06-321-4114

shieldlp@...