Title: Treatment of multiple sclerosis (MS) and other
demyelinating conditions using lofepramine in combination with
L-phenylalanine, tyrosine or tyrptophan and possibly a vitamin B12
United States Patent: 6,569,850
Issued: May 27, 2003
Inventors: Loder; Cari (127 Russell Court, Woburn Place,
London WC1H 0LP, GB)
Appl. No.: 584401
Filed: June 1, 2000
Method for treating multiple sclerosis or encephalomyelitis by
administering to a patient a combination of a tricyclic antidepressant drug
and tyrosine or phenylalanine or both.
Description of the Invention
This invention relates to the treatment of Multiple Sclerosis (MS) and
other Demyelinating Conditions.
Multiple sclerosis is a common and well known neurological disorder. It is
characterised by episodic patches of inflammation and demyelination which
can occur anywhere in the central nervous system (CNS) almost always without
any involvement of the peripheral nerves. The occurrence of the patches is
disseminated in time and space, hence the older alternative name of
disseminated sclerosis. It is believed that the pathogenesis involves local
disruption of the blood brain barrier, a local immune and inflammatory
response, with consequent damage to myelin and hence to neurons.
Clinically, MS can present in both sexes and at any age. However, its most
common presentation is in relatively young adults, often with a single focal
lesion such as damage to the optic nerve (optic neuritis), an area of
anaesthesia or paraesthesia or muscular weakness. Vertigo, nystagmus double
vision, pain, incontinence, cerebellar signs, L'Hermitte's sign (paraesthesia
or pain in the arms and legs on flexing the neck) and a large variety of
less common symptoms may occur. The initial attack is often transient and it
may be weeks, months or years before a further attack occurs. Some fortunate
individuals may have a stable condition, while other unfortunate ones may
have an unrelenting downhill course ending in complete paralysis. More
commonly there is a long series of remissions and relapses, each relapse
leaving the patient somewhat worse than before. Relapses may be triggered by
stressful events or viral infections. Elevated body temperature almost
invariably makes the condition worse whereas a reduced temperature, for
example induced by a cold bath, may make the condition better. There are no
satisfactory treatments for MS. Steroids may produce a temporary improvement
but any beneficial effect invariably wears off. Recent clinical trials have
shown that interferon may somewhat reduce the risk of relapse. However, the
effect is modest and most patients still deteriorate.
I have now developed a new and highly effective treatment for compensating
for the effects of nerve damage caused by MS and other demyelinating
My invention is based on the use of a combination of an antidepressant or a
mono-amine oxidase inhibitor in combination with an inducer or precursor of
a neurotransmitter. The two compounds may be administered in the same dosage
form, or may be in separate dosage forms but a combined pack may be in
separate packs for administration at separate times but so as to be
effective together in the body.
Lofepramine and related tricyclic and tetracyclic antidepressants work by
interfering with the inactivation of substances called neurotransmitters
which are required for the normal transmission of nerve impulses from one
nerve cell to the next. Such neurotransmitters, among them substances called
noradrenaline and serotonin, are released from one nerve cell and activate
the next one. They are inactivated by various mechanisms including rapidly
being taken up into nerve cells and also enzymic destruction by enzymes
known as monoamine oxidase inhibitors (MAOI). Lofepramine is a drug which
inhibits neurotransmitter uptake and which is in the class of tricyclic
antidepressants and which also has some MAOI activity. Newer drugs to treat
depression are more active against serotonin and are known as selective
serotonin reuptake inhibitors (SSRIs).
I have discovered that the use of L-phenylalanine (LPA), the precursor of
noradrenaline, contributes to the therapeutic effect. In some individuals,
however, an alternative may be L-tryptophan which is a precursor of the
neurotransmitter, serotonin. Several different antidepressants including
tricyclic antidepressants, SSRIs and MAOIs have beneficial effects but have
consistently obtained the best results with lofepramine. Detailed
information on lofepramine is given in the Merck Index. I have also noted
that when the patient receives regular injections of vitamin B12 the
treatment works best.
As an example, a regime of 70 mg lofepramine and 500 mg LPA per day for over
a year in my own case completely resolved severe unequivocally diagnosed MS.
Over 100 other patients have done well on a similar regime, although some
have been given other antidepressants either of the traditional tricyclic
class, such as amitriptyline or imipramine, or the newer specialist
serotonin uptake inhibitors or monoamine oxidase inhibitors. Four particular
instances are given in the appendix. Most have done best on lofepramine. The
doses of LPA have also varied from about 100 mg to up to 5 g per day, but
best results are obtained with doses in the region of 500-2000 mg/day. The
doses of antidepressants (with the proviso that minimum effective and
maximum safe levels are determined according to the drug), lie broadly in
the range 10 mg to 200 mg per day.
A background course of vitamin B12 for example by injection, is also
preferred and does have a beneficial effect. Daily amounts may for example
be the conventional daily requirement for the vitamin.
Four case histories of patients other than myself illustrating the
beneficial effects of my invention are given later herein. A total of 126
patients have now been tested and almost all have received benefit. This
benefit has reached varying degrees with some only showing a small
improvement and others a complete resolution of all symptoms such as I
observed in myself.
A specific example of the use of the treatment is 70 mgs (half the
therapeutic starting dose for depression) of lofepramine taken each morning
with 500 mgs of L-phenylalanine, and 500 mgs of L-phenylalanine taken mid
afternoon. For patients with the regular MS attacks of chronic progressive
MS it is desirable to include an 8-10 week course of 1000 micrograms of
hydroxocobalamin (intra muscular) per week at the start of treatment and
then 1000 micrograms every ten days thereafter.
Other TCADs or MAOIs may be substituted for lofepramine and higher doses of
antidepressants, L-phenylalanine may be indicated in individuals who fail to
respond to the suggested levels. It is not advised to exceed the usual
maximum prescribing dose of lofepramine (or another TCAD or MAOI) but doses
between 70 mg and 210 mg of lofepramine can be prescribed. The doses of
L-phenylalanine can then be increased in proportion to the dose of the TCAD
70 mg lofepramine+500 mg L-phenylalanine twice per day.
120 mg lofepramine+1000 mg L-phenylalanine twice per day.
210 mg lofepramine+1500 mg L-phenylalanine twice per day.
This drug treatment is not appropriate for individuals with a history of
cardiac problems, high blood pressure or for those suffering from PKU.
1. Tablets of 500 mg L-tryptophan, or L-phenylalanine or the two combined to
be taken at a dose of 1-10/day in accordance with an appropriate daily dose
of an antidepressant chosen from the classes of tricyclic or tetracyclic
antidepressants, monoamine oxidase inhibitors or serotonin reuptake
inhibitors. Examples of such drugs and some typical doses per day include
lofepramine (70 mg), imipramine (100 mg), clomipramine (50 mg),
amitriptyline (150 mg), nortriptyline (75 mg), mianserin, protriptyline (40
mg), venlafaxine, fluvoxamine (150 mg), fluoxetine (20 mg), maprotiline (75
mg), sertraline, pargyline, moclopemide, triazolopyridine, phenelzine (45
mg), tranylcypromine (20 mg), desipramine, dothiepin (70 mg), doxepin (100
mg), paroxetine, trimipramine, oxazine or viloxazine (500 mg). However, any
other member of these classes of drugs not listed here may be used in this
way, in doses indicated in standard texts.
2. Tablets as in (1) in which an appropriate dose of the amino acid is
combined with an appropriate dose of the chosen antidepressant in the same
dosage form so that an adequate daily dose of each can be provided.
3. Tablets containing 25-100 mg of lofepramine, together with 500 mg of
phenylalanine, or 500 mg of tryptophan, or 250 mg of each. Normally such
tablets would be used so as to provide a daily dose of 50-200 mg lofepramine
together with 500-1000 mg of the amino acids.
4-6 Other appropriate dosage forms for 1-3 such as soft or hard gelatin
capsules, emulsions, creams, whips, solutions, or any dosage form known to
those skilled in the art.
Patient A 49 y female. MS for 20 years. Symptoms on starting treatment: weak
legs; rapid fatigue on exercise; bladder urgency and frequency with
incontinence; arms too weak to allow self dressing; right hip pain. After 12
weeks treatment: complete disappearance of all symptoms.
Patient B 45 y male. MS for 12 years. Symptoms on starting treatment:
confined to wheelchair; legs spastic and weak; arms weak and rapidly
fatigued; hands numb; bladder urgency and incontinence. After 8 weeks
treatment: fatigue and weakness of arms and legs greatly improved;
spasticity less; bladder improved; walking on crutches instead of
Patient C 38 y male. MS for 2 years. Symptoms on starting treatment: badly
slurred speech; fatigue; bladder urgency and frequency; limited to half a
mile walking even with a stick; poor hand control and writing. After 6 weeks
treatment: fatigue better; speech much less slurred; eyesight and writing
improved; can walk half a mile without a stick.
Patient D 40 y female. MS for 3 years. Symptoms on starting treatment: poor
balance; optic neuritis; spasticity and spasms with pain in legs and feet;
bladder urgency; "shimmering" sight. After 3 weeks treatment: spasms,
spasticity and pain completely relieved; bladder function better; balance
better; "shimmering" sensation disappeared.
Claim 1 of 14 Claims
1. A method for treating multiple sclerosis or encephalomyelitis in a
patient in need therefore, comprising administering to a patient in need
thereof a pharmaceutically effective amount of a combination of a tricyclic
antidepressant drug; and, at least one noradrenaline precursor selected from
tyrosine and phenylalanine.
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