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BACKGROUND OF THE INVENTION
The present invention relates to dysfunctional energy metabolism of both
glucose and lipids in animals and humans. More particularly, a novel
combination of metabolic cofactors, L-carnitine combined with
acetyl-L-carnitine, restores normal mental and physical activity to aged
patients with dysfunctional energy metabolism and, when employed
prophylactically, prevents development of related syndromes.
In the normal course of aging an organism's ability to synthesize,
conserve, and absorb crucial metabolic cofactors declines. Conversion of
nutrients to useful energy within cells involves highly specific enzymatic
processes which are sensitive to presence or absence of these cofactors.
In the higher order of animals, especially with respect to humans, as well
as laboratory rodents, enzyme pathways of energy metabolism are known with
relative precision. Despite extensive research efforts, however,
interrelationship of many metabolic processes and enzymatic cofactors
remain imprecisely known. Indeed, metabolic interrelationships of
enzymatic cofactors L-carnitine and acetyl-L-carnitine in cardiac and
skeletal muscle have not been completely defined. The same is true in
nervous tissue, especially the brain, where available research data
concerning function of these cofactors are often contradictory and
inconclusive owing to the inordinate difficulty in establishing truly
controlled experimental formats. Much of what is known has been gained
from the organ's response to traumatic, toxic, and ischemic insults as
well as investigations of these cofactors' effects in chronically diseased
brains. Such information provides little or no guidance to those concerned
with psychophysiologic and psychomotor disturbances or confronting
syndromes affecting multiple tissues. The following brief notations are
believed to illustrate the complexity of the state of the art knowledge of
diseases of energy metabolism.
The study of disease of energy metabolism commonly referred to as
mitochondrial diseases is an emerging specialty in human medicine. Most of
these diseases arise from mutation of the mitochondrial genomes and, to a
lesser extent, nuclear genes. Such mutations result in specific
dysfunctional enzymes in metabolic pathways and in structural changes of
mitochondria which disrupt enzyme orientation in metabolic pathways
thereby impairing their efficiency. Mitochondrial genome mutations may
exist at birth but typically occur over time as base dilutions,
substitutions, and insertions during the course of replication; or in
response to environmental factors, disease, and accumulation of toxic
metabolites. Clinical syndromes presented depend upon the metabolic
pathway affected and the proportion of dysfunctional mitochondria that has
been attained. Organs normally effected by disease of energy metabolism
are highly differentiated, nonregenerating tissues requiring high levels
of oxygen and energy, such as brain and skeletal and heart muscle.
Treatment of these diseases is directed to sustaining life by
supplementing high levels of metabolic cofactors in an effort to skew
metabolism along specific pathways and to providing substrates for the
pathways. Rarely, in human medicine, do deficiencies of cofactors or
substrates cause diseases of energy metabolism. In veterinary medicine
only a few genetically based diseases of energy metabolism are recognized.
Among them are dilated cardiomyopathy in dogs and stress syndrome in
swine. However, deficiencies of metabolic cofactors in dogs have been
investigated. A study of commonly encountered age-related syndromes in old
dogs, examples of which are included in this application, revealed them to
be due to dysfunctional energy metabolism. More specially, syndromes
involving heart and skeletal muscle were relieved by L-carnitine
supplemention while a syndrome affecting the brain was relieved by
increased acetyl-L-carnitine intake. However, complex interrelationships
exist. For example, a treatment for a psychotic syndrome with
acetyl-L-carnitine was successful but resulted in emergence of a heart
failure syndrome and both cofactors were required to normalize the dog. In
another case, synergistic effects were realized with the two cofactors
combined as opposed to their individual use in treating a syndrome
involving skeletal muscle. And, in yet another case, a dog that heretofore
had required heavy sedation to control an epileptic syndrome, experienced
unexpected improvement in after it had been treated with combined
L-carnitine and acetyl-L-carnitine for several weeks.
L-carnitine as well as acetyl-L-carnitine are natural constituents of
higher organisms, particularly animal heart and muscle tissue and can be
synthesized by the body or obtained from red meat, poultry, fish, and
dietary products. L-carnitine is absorbed from the small intestine into
systemic circulation at a rate of about 2 to 5 mg per pound body weight
which is compatible with normal physiologic function and the basis for
dosages in the accompanying studies. In standard medical treatment of
syndromes related to deficiency of L-carnitine or L-carnitine-dependent
enzymes dosage of L-carnitine employed may be 10 to 50 times higher than
rate of physiologic intestinal absorption. This affords passive diffusion
of carnitine into systemic circulation but such high dosages have the risk
of causing diarrhea.
L-carnitine (3-hypodroxy-4-N-trimethylaminobutyric acid) has two main
functions, both critical to energy metabolism. The first is translocation
of long-chain fatty acids from the cytosol across the outer and inner
mitochondrial membranes and intervening space into the mitochondrial
matrix. The second function is to modulate intracellular CoA homeostasis
within the mitochondrial matrix by transesterifation of acyl-CoA esters
produced in B-oxidation which regenerates CoA and acylcarnitine.
Accumulation of long chain acyl-CoA esters is a consequence of enzyme
disfunction and metabolic impairment or stasis in the B-oxidation system.
Resulting shortage of available CoA then limits transfer of acetyl groups
to the Krebs cycle for energy production. Acylcarnitine, produced during
homeostasis, can be exchanged across the mitochondrial membrane for free
carnitine and eventually transported out of the cell to be excreted in
urine. Canids are unique in the fact that their liver and kidneys
synthesize carnitine but they lack an enzyme in skeletal and cardiac
muscle which is crucial to the last stage of L-carnitine synthesis. In
dogs L-carnitine is synthesized in the liver and transported to muscle
tissue.
Acetyl-L-carnitine (-trimethyl-B-acetylbutyrobetaine) shares intracellular
CoA homeostatic function with carnitine. It is the prevalent ester of
carnitine in tissue, freely exchangeable across subcellular membranes, and
can serve as a pool of acetyl groups to regenerate acetyl-CoA. This
property comes into play in instances of excessive exercise where
glycolysis has resulted in accumulation of lactic acid in muscle cells.
Studies with rat brain tissue show acetyl-L-carnitine to be associated
with increased glycolysis and oxygen metabolism. Other studies indicate
acetyl-L-carnitine enhances ketone-body metabolism in rat brains. In
experimentation with rats acetyl-L-carnitine has been shown to maximize
energy production, promote membrane stability, restore membrane changes
that are age-related, and serve as precursor to acetylcholine. Cholinergic
effects enhance nerve impulse transmission and have been demonstrated to
counter or delay age-changes and dementia in brains of rodents and humans.
In addition to depleted available energy and concomitant depression of cell
and organ function another consequence of impaired energy metabolism is
formation of free oxygen radicals and their destructive effects on
proteins and other large molecules, mitochondrial membranes, and
especially mitochondrial DNA. Environmental sources of free radicals are
infection, drugs, hypoxia, chemicals, and food. These destructive effects
are cumulative leading to development of physiologic dysfunctions with
increasing age, and along with mitochondrial genome mutation from other
causes, must be considered as contributors to the etiology of syndromes
seen with the dogs in this report. Normally, cell and organ function
deteriorates with age resulting in reduced biosynthesis of metabolites and
cofactors, reduced digestive function and enteral absorption, and impaired
renal tubule resorption from glomerular filtrate. In elderly dogs any or
all of the above can lead to depletion of tissue reserves of L-carnitine
and acetyl-L-carnitine to the extent that energy metabolism is impaired.
Four syndromes, psychosis, skeletal muscle weakness and atrophy,
epileptiform convulsions, and cardiomyopathy were observed in dogs in this
study. Syndromes presented as singular entities as in the skeletal muscle
syndrome or as complex of syndromes. Psychosis, in the form of extreme
anxiety with trembling, hiding and panicky flight are common in old dogs
exposed to sharp noises such as fireworks discharges. Even a mild
stimulant such as the sound of cellophane being crumbed into a ball will
illicit a panic response in some dogs. Management of most such cases is
with tranquilizers during periods when stimuli are most prevalent (e.g.
New Years Eve and The Fourth of July). Tranquilizers do nothing to cure
the patient, their effect is psychological depression. When patients
become extremely debilitated by the psychosis mood altering drugs such as
doxepin and fluoxetine can be employed. Here again a cure will not be
forth coming. At best the animal will be so heavily sedated as to not pose
a threat to itself, property, or the public. Pharmacologically-active
mind-depressions do not correct any metabolic imbalances in the brain,
hence do not effect a cure. In some cases psychotic episodes progress to
grand mal seizures. Depressant drugs are the common means employed for
their control. Phenobarbital, primidone, and/or KBr are consumed once to
several times a day. The drugs do not correct the underlying metabolic
dysfunction in the brain but they do stop the seizures at the expense of
greatly depressing the patient. Psychotic and seizuring dogs are not
demented in the sense that there is large-seal neuronal dysfunction with
loss of inelegance, memory, or awareness of surroundings. Psychoses are
almost the opposite, with heightened awareness of sounds and events in the
environment. They may precipitate seizures.
Among the causes of skeletal muscle weakness and reduction of mass are
nutritional deficiency, in particular deficiency of SE and vitamin E. In
cases of nutritional myopathy, refined to as white muscle disease, the
vitamin E interrelates metabolically with SE and can be a valuable adjust
to therapy. This condition is common to herbivorous and omnivorous but not
carnivorous. A myopathy common in dogs is denervation myopathy, a
condition that develops secondary to herniation of intervertebral dises
and ankylosing spondyloarthropathy. Where spinal nerves are damaged
reduced impulse stimulation to the innervated muscle leads to weakness,
degeneration, and atrophy. This form of muscle disease is managed by
attempting to reduce trauma to the spinal nerve by controlling chronic
inflammation and bone formation along the nerve's course from the spine
with drugs classified as non-steroidal anti-inflammatory agents. If
skeletal muscle is not exercised it will become weak and degenerate and
eventually atrophy. This condition, common to traumatic injuries,
precludes normal function after extended periods of time. There are
auto-immune myopathies where the body produces an immune reaction, usually
to some infectious agent, that cross reacts with skeletal muscle.
Management of these conditions is based upon suppression of the immune
reaction for an undetermined period of time. Eventually, the reaction
subsides and the immune depressant drugs can be with drawn. There are
other causes of skeletal muscle weakness and atrophy. Clinically they are
morphologically similar to one and other and require biopsy for definitive
diagnosis.
Heart failure secondary to dilated cardiomyopathy has been treated with
high dosages of L-carnitine, 100 mg per pound body weight. Such massive
therapy is only moderately successful, at best. In most cases prognosis is
very guarded. One reason for the poor response may be that diagnosis is
not forthcoming until pathology is so advanced it cannot be reversed.
Another consideration is that L-carnitine therapy only addresses lipid
metabolism in the heart ignoring the part glycolysis may contribute.
Cardiac arrhythmias are part of heart failure and evidence of pathology of
heart muscle. Arrhythmias are treated with pharmachologically active drugs
which may stabilize the heart. Drugs such as lidocaine, propanalol,
digoxin, and procainamide all are useful in stabilizing the heart beat
which may be critical at times but such drugs do not address the metabolic
disturbance that caused the pathology. It is common for dogs with cardiac
arrhythmias to die suddenly or, at best, be forced to remain on medication
for extended periods, even for life.
As a consequence of above-noted complexities in identifying and treating
syndromes related to dysfunctional energy metabolism as well as
understanding their interrelationships little progress has been achieved
in prevention and therapy. The following examples of U.S. Patents relating
to carnitine and acetyl-L-carnitine are illustrative of the existing state
of the art.
U.S. Pat. No. 4,346,107 relates specifically to the use of acylcarnitine in
treating dementia of human patients particularly when mental dysfunction
is related to impaired cerebral blood flow. Typifying numerous approaches
to management of dementias, is does not investigate psychoses and
epileptiform seizures as being associated with deficits of energy
metabolism, their connection with deficiencies of L-carnitine and
acetyl-1-carnitine, the possibility of precipitating other energy deficit
syndromes as a consequence of therapy with a single metabolic cofactor,
and the need for therapy that modulates both glycolyses and lipid
metabolism.
U.S. Pat. No. 4,599,232 relates to combination of carnitine or
acetylcarnitine and coenzye Q10 for tissue metabolic disorders involving
circulatory function. The patent's use of coenzymes Q10 directs its
effects towards control of free radical excess and facilitation of
oxidative phosphorylation, the final stage of energy metabolism. It does
not address the observed synergistic effects of combined L-carnitine and
acetyl-L-carnitine on glycolysis and lipid metabolism nor does it
recognize the need of both metabolic cofactors when treating dysfunctional
energy metabolism related to deficit of L-carnitine or acetyl-L-carnitine
as discovered in the present patent.
U.S. Pat. No. 5,576,384 relates to the general use of acylcarnitine for
therapy of patients with Acylcarnitine Metabolic Dysfunction Syndrome. It
excludes consideration of carnitine metabolism disorders and the combined
therapy for disorders where both deficiencies may exist.
Following are references pertaining to diseases of energy metabolism their
causes and treatments.
Luft, R. The development of mitochondrial medicine. Proc. Natl. Acad. Sci.
USA 1994; 91:8731-8738
Singh P J, Santella R N, Zawada E T. Mitochondrial Genome mutations and
kidney disease. Am. Jour. of Kid. Dis. 1996; 28: 140-146
Shishido F, Uemura K, Inugami A, Tomura N, Higano S, Fujita H, Sasaki H,
Kanno I, Mura Kami M, Watahiki Y, Nagata K. Cerebral oxygen and glucose
metabolism and blood flow in mitochondrial encephalopathy: a PET study.
Neurorad. 1996; 38: 102-107
Pons R, DeVito DC. Primary and secondary carnitine deficiency syndromes.
Jour. Child Neuro. 1995; 10: 258-2524
Castorina M, Ferraris L. Acetyl-Carnitine affects aged brain receptorial
system in rodents. Life Sci. 1994; 54: 1205-1214
Carta A, Calvani M, Bravi D, NiBhuach alla S. Acetyl-L-Carnitine and
Alzeimer's disease: pharmacological considerations beyond the cholinergic
sphere. N.Y. A cad. of Sci. 324-326
Aureli T, Miccheli A, Ricciolini R, DiCocco ME, Ramacci MT, Angelucci L,
Ghirardi O, Cont F. Aging brain: effect of Acetyl-L-Carnitine treatment on
rat brain energy and phospholipid metabolism. A study by 31P and `HNMR
spectroscopy. Brain Res. 1990; 526: 108-112
Stanley C. Carnitine disorders. Adv. in Ped. 1995; 42: 209-242
Shoubridge E A. Mitochondrial DNA disease: Histological and cellular
studies. Jour Bioenerg. and Biomemb. 1994; 28: 301-310
Zeviani M, Amati P, Savoia A. Mitochondrial Myopathies. Curr. Opin. Rheum.
1994; 6: 559-567
Sisson D D, Thomas W P. Myocardial diseases. In: Ettingen S J, Feldman E C,
ed. Textbook of Veterinary Internal Medicine. 4th ed. Philadelphia: W B
Saunders, 1995: 995-1005
BRIEF SUMMARY OF THE INVENTION
The present invention, A novel combination of L-carnitine and
acetyl-L-carnitine, has been discovered to relieve syndromes related to
mutations of mitochondrial genomes and age-related impairment of energy
metabolism due deficiencies of L-carnitine and acetyl-L-carnitine in
domesticated animals.
The invention in its various forms are easy to prepare. Liquids for oral
use are prepared at room temperature by dissolving prescribed quantities
of crystalline forms of the cofactors in water, adding preservative and
coloring and/or flavoring, filter sterilizing, and bottling. Liquid for
injection is prepared at room temperature by dissolving prescribed amounts
of each cofactor in water. If the material is to be dispensed in a
multi-dose vial, preservative is added before the pH is adjusted with NaOH
to neutrality and the solution is filter sterilized and bottled. Dry forms
of the invention are prepared by mixing prescribed amounts of the two
desiccated cofactors. If the invention is to be encapsulated, an
anticaking agent to facilitate production may be added prior to
encapsulation. If the dry preparation is to be dissolved for intravenous
injection the desecrated powder or crystalline mixture is measured into
glass vials, sealed and sterilized.
Specific quantities of L-carnitine and acetyl-L-carnitine provided in the
aqueous solutions of the invention may be varied depending upon projected
use. As an example, it is within the comprehension of the invention that
solutions may be prepared to allow each milliliter thereof to contain:
from about 0.1 to 400 milligrams L-carnitine and 0.1 to 400 milligrams
acetyl-L-carnitine. Similarly, ratios of carnitine to Alcar in powdered
forms can be varied from 1 to 100 depending upon intended usages.
All preparations of the invention are easy, safe and convenient to use. The
liquid for oral consumption can be taken directly into the mouth and
swallowed or measured into it with a spoon, dropper, syringe, or like
device. Similarly, the liquid preparation can be measured into food or
drink for consumption. The usual, standardized techniques for parenteral
injection of drug with hypodermic needle and syringe is to be employed for
administering the injectable format of the invention subcutaneously,
intramuscularly, intravenously, or as an additive to compatible liquid
medicaments designed for intravenous injection.
Among the preferred forms of the invention is a solution formulated to
contain 45mg L-carnitine and 45 mg acetyl-L-carnitine per milliliter. Such
a preferred solution is particularly useful for oral administration at a
dosage level to provide from about 2 to 4 milligrams of each cofactor per
pound of body weight. The invention is beneficial in aleaveating symptoms
when added to the food of psychotic domesticated animals, those with
cardiomyopathy or skeletal muscle weakness or atrophy, those with tendency
to have epileptiform seizures or in aged obese or debilitated animals when
these conditions are due to inadequacy of available L-carnitine and/or
acetyl-L-carnitine. This preferred form of the invention is particularly
useful for supplementing the diet at a rate of about 5 milligram per pound
of body weight on a daily basis to prevent development of such as
cardiomyopathy, skeletal muscle weakness or atrophy, psychosis, some forms
of epilepsy, and to generally improve mental and physical activity and
well-being.
The purpose of the invention is to treat or prevent from developing disease
syndromes related to inadequate tissue levels of L-carnitine and/or
acetyl-L-carnitine and to treat or prevent disease syndromes related to
mutations of mitochondrial DNA, changes in mitochondrial structure, and
deterioration of the body's ability to synthesize, conserve, and absorb
L-carnitine and acetyl-L-carnitine. One severely psychotic dog had been
unsuccessfully treated for about one year with two different mood-altering
drugs commonly used for treatment of such mental derangements. The owner,
committed to euthanasia, agreed to a final effort to save the animal; the
novel and untested use of acetyl-L-carnitine to treat psychosis. Response
was prompt, recovery began in two days. The effects of acetyl-carnitine on
brain function appeared to correct the dog's psychosis. But when the dog
became normal mentally, acute circulatory failure developed. L-carnitine
was substituted for acetyl-L-carnitine and the circulatory failure was
resolved. Shortly, however, the psychosis resumed. L-carnitine and
acetyl-L-carnitine were not metabolically interchangeable in this case. A
novel, treatment was initiated. L-carnitine and acetyl-L-carnitine were
combined and administered in the dog's food, 5 mg per pound body weight.
He promptly became normal and remained, so receiving daily supplementation
with the invention. This case demonstrated that, with diseases of energy
metabolism, some syndromes may be subclinical only to be expressed in time
or when a more prominent syndrome is relieved, increased activity may
bring an underlying syndrome to light. Or, when treating a syndrome with
one cofactor, in this case acetyl-L-carnitine, a disturbance in metabolism
may develop in another organ necessitating the other cofactor,
L-carnitine. It is clear that when treating diseases of energy metabolism
in old dogs combined L-carnitine and acetyl-L-carnitine are in order.
This principle was underscored by a dog treated with L-carnitine for
skeletal muscle atrophy, weakness and pain. It responded, functioning
normally in three weeks. Then acetyl-L-carnitine was substituted for
L-carnitine to observe any cross-effectiveness. No cross-effect was
observed. Shortly, symptoms of muscle weakness and pain resumed. The
cofactors were mixed, as in the powdered preparation of the invention, and
added to the dog's food, 5 mg per pound body weight. Within one week she
was normal. This accelerated response compared with the time of response
when treatment was with L-carnitine alone would suggest metabolic
synergism exists between L-carnitine and acetyl-L-carnitine.
A third case demonstrated effectiveness of combined L-carnitine and
acetyl-1-carnitine for treating skeletal muscle weakness and neurologic
symptoms. Both syndromes had been long standing in an old dog that was
presented with acute circulatory failure. The dog's heart disease was
diagnosed as being early cardiomyopathy without marked enlargement. When
treated with procainamide and the invention at a rate of 5 mg of combined
1-carnitine and acetyl-L-carnitine per pound of body weight the initial
arrhythmia was converted over night. After one week the procainamide
therapy was stopped the heart continued to improve as the dog received the
invention on a daily basis and within a month the electrocardiogram was
normal. This was an unprecedented response, for most such cases die within
a few days. It is assumed the invention was instrumental in correcting the
metabolic imbalance causing the cardiomyopathy.
L-carnitine and acetyl-L-carnitine are biochemically interchangeable in
mitochondria through action of the enzyme carnitine acetyl-transferase.
However, evidence in the studies reported herein indicate distinct
differences in metabolic function of the two cofactors with no apparent
cross reaction or substitution between them. It is well accepted that
L-carnitine effects are primarily on energy metabolism of lipids. However,
metabolic pathways involving acetyl-L-carnitine are not well defined. The
following may explain how the psychotic dog was benefitted: Research
indicates acetyl-L-carnitine enhances glycolysis, oxygen metabolism and
energy production in the brain. Which may partially explain beneficial
effects observed. Studies of humans with a mitochondrial disease, MELAS,
suggest symptoms and lesions are the result of lactic acid accumulation in
the brain with concomitant brain edema. Stressful events lead to increase
demand for energy in the brain but with limited reserves of
acetyl-L-carnitine glycolysis is impeded and lactic acid accumulates. To
measurably increase glycolysis, acetyl-L-carnitine facilitate metabolism
of pyruvate, making more energy available for cell function and limiting
accumulation of lactic acid with its detrimental effects. This same
mechanism, acetyl-L-carnitine facilitated pyruvate metabolism, explains
the synergism elicited by L-carnitine and acetyl-L-carnitine, the
invention was used to treat dogs with skeletal muscle weakness and
pathology. Treatment of cardiomyopathy with the invention at physiological
levels, mg per pound body weight, more successful than when L-carnitine
alone is given even at dosages 20 times higher. Although L-carnitine
dependant lipid metabolism is the major energy source in muscle,
acetyl-L-carnitine dependant glycolysis is essential to normal muscle cell
function.
The invention was superior to conventional therapy for treating the
following syndromes that arose from disturbances of energy metabolism:
Psychotic behavior was eliminated and the affected dog regained demeanor
and activity level similar to three years previously while its diet was
supplemented daily with mg of the invention per pound body weight. It
showed no evidence of depression or sedation associated with conventional
therapy.
Similarly, a dog with long standing epileptiform seizures, controlled by
heavy dosages of KBr had only one mild seizure a month during diet
supplementing with the invention at mg per pound of body weight daily.
Without KBr therapy.
Two dogs with profound skeletal muscle weakness became fully active while
receiving diet supplemention with mg of the invention per pound of body
weight each day. One dog regained the ability to jump into a pickup truck.
This patient had a previously-undescribed myopathy diagnosed from a biopsy
as a degenerative condition probably related to dysfunctional energy
metabolism. Other more traditional therapies for treating the myopathy
were ineffective. The other dog was able to run freely and chase cats,
previous to treatment it had to be supported with a sling under its belly
when walking more than a few feet.
Two dogs with circulatory failure recovered completely during the course of
daily diet supplementation with mg of the invention per pound of body
weight. The dogs had a brief course of oral treatment with procianamide.
The superiority of invention was manifested in the completeness of
recovery without prolonged anti-arrhythmia therapy.
Other aspects and advantages of the present invention will be apparent upon
consideration of the following detailed description thereof.
DETAILED DESCRIPTION OF THE INVENTION
The term "cofactor" in general refers to carnitine, Alcar, other vitamins,
and trace minerals that facilitate chemical reactions with specific
enzymes in cells. "Parenteral" shall mean any administrative mode other
than oral and shall include subcutaneous, intramuscular and intravenous
injection. "Syndrome" is a set of symptoms, or complex of symptoms
occurring together which may or may not characterize a specific disease
entity. "Carnitine and Alcar responsive syndrome" shall represent a
symptom complex which is benefited by amelioration of symptoms toward the
normal through treatment of the patient with carnitine and
acetyl-L-carnitine.
The purpose of the invention is to treat, or prevent from developing,
disease syndromes related to inadequate tissue levels of one or both
metabolic cofactors, and to treat or prevent disease syndromes related
inadequate intake of L-carnitine or acetyl-L-carnitine, or to mutations of
mitochondrial DNA, changes in mitochondrial structure, and deterioration
of the body's ability to synthesize, conserve and absorb L-carnitine and
acetyl-L-carnitine.
EXAMPLE 1
This example relates to the preparation of one liter of a stable acqueous
solution containing, per milliliter, 45 mg L-carnitine and 45 mg
acetyl-L-carnitine. All procedures are carried out at room temperature
unless otherwise indicated.
A solution is prepared by dissolving 45 grams of 1-carnitine in 500 ml
water. To this solution 45 grams of acetyl-1-carnitine are added and
dissolved.
A second solution is made by dissolving 1 gram of methyl paraben in 400
milliliters water. Dissolution can be hastened by warming the water to 40
degrees centigrade and stirring constantly. The solutions are cooled to
room temperature and water is added sufficient to bring the final quantity
to 1000 milliliters. The final solution is filtered to remover any and all
bacteria, and like-sized microbes. This sterile solution is dispensed in
sterile bottles.
This solution has a mildly acidic taste that enhances many food flavors it
is intended for oral administration or to be added to the diet or drinking
water of an individual animal at the rate of one milliliter per fifteen
pounds body weight.
EXAMPLE 2
This example relates to preparation of one liter of sterile, neutral,
stable aqueous solution containing, per milliliter, 16.7 mg carnitine and
16.7 mg acetyl-L-carnitine. All procedures are carried out at room
temperature.
A solution is prepared by dissolving 16.7 grams of L-carnitine in 400
milliliters of distilled, pyrogen free water. When it is dissolved 16.7
grams acetyl-L-carnitine is added to the solution and is dissolved.
A second solution is made by dissolving 1 gram of methyl paraben in 400
milliliters water. Dissolution can be hastened by warming the water to 40
degrees centigrade and stirring constantly. The second solution is mixed
with the first solution.
The pH of the mixed solutions is adjusted to neutrality with approximately
2.95 grams NaOH. Sufficient quantity water is added to bring the final
volume to 1000 milliliters and the solution is filtered through sterile
equipment to remove bacteria and like-sized microbes. It is then bottled
in sterile rubber-stopped glass vials.
This solution is intended for subcutaneous, intramuscular or intravenous
injection at the rate of 1 ml per 15 pounds body weight. To provide the
added quality of being useful in animals unable to consume or retain
injested materials and in instances where rapidity of response to therapy
may be critical for the life or well being of the patient.
EXAMPLE 3
This example relates to preparation of desiccated powder containing equal
amounts of the L-carnitine and acetyl-L-carnitine.
The mixture is prepared by combining and uniformly mixing 50 mg of both
desiccated L-carnitine and acetyl-L-carnitine in a low moisture
atmosphere. An anticking agent may be blended into the mixture to
facilitate processing through a capsule filling machine. The choice of
anticaking agent must be compatible with state and federal pure food and
drug regulations. The powdered preparation is placed in gelatin capsules
of a size sufficient to contain 45 mg L-carnitine and 45 mg
acetyl-L-carnitine to be swallowed by a 15 pound dog or the capsule may be
opened and the contents sprinkled onto or mixed with the patient's food.
EXAMPLE 4
This example relates to preparation of sterile desiccated powder containing
equal amounts L-carnitine and acetyl-L-carnitine. The mixture is prepared
by combining and uniformly mixing, in a dry atmosphere, 50 grams amounts
of desiccated L-carnitine and acetyl-L-carnitine. The mixture is measured
in 200 mg amounts into sterile, dry glass ampules which are then sealed.
Powder in vials is to be dissolved with sterile water for intravenous use
in cases of acute circulatory failure related to L-carnitine and
acetyl-L-carnitine responsive cardiopathy or mitochondrial genome
mutations where energy metabolism is compromised.
Consistent with the above, oral administration of preparations defined in
Examples 1 and 3 were found to be useful in treating pet dogs with
cardiomyopathy, skeletal muscle weakness, psychosis and epilepsy. Where
these syndromes were actively manifested the preparation eliminated or
markedly ameliorated symptoms. When the preparations were discontinued or
reduced in amount consumed syndromes recurred. Continued supplementation
prevented syndrome development. The following examples relate to the
effectiveness of the preparations of the invention.
EXAMPLE 5
A twelve year old male Weimaraner was treated for almost one year for
anxiety and trembling. It all began when a minor earthquake one week
previous to initial admittance to the hospital resulted in a fearful
change in the dog's behavior. Normally placid, following the quake he had
trembled uncontrollably when put in his owner's backyard. He was reluctant
to enter the hospital and tried to avoid being handled. However, he was
not aggressive nor did he show any tendency to bite from fear. Cranial
nerve function was normal and clinical examination revealed no physical
ailments. It was assumed the dog had a form of anxiety and he was treated
with 25 mg of the mood-altering antipsychosis drug doxepin HCl orally once
daily. This satisfactorily diminished symptoms for several weeks after
which anxiety gradually returned. Six months after starting treatment he
was as troubled as when first presented. Medication was changed to 20 mg
of another antipsychosis drug fluoxetine HCl orally once daily. Again,
anxiety subsided for a few weeks but in time returned and steadily
increased in severity. In spite of daily behavior-modifying therapy his
mental condition deteriorated to the extent that he voluntarily confined
himself and hid behind a couch in one room of the house. Trembling had
become violent when he was taken out of doors and he was unable to go on
short walks. His food bowl frightened him and he refused to eat unless fed
from the owner's hand.
When again brought to the hospital after almost eleven months of therapy
with antipsychosis drugs he was very psychotic. His owner had to drag the
panicking dog into the waiting room where he trembled and coward under the
owner's chair. Clinical examination was much as it was initially.
Euthanasia was considered but the owners opted for increasing fluoxetine
HCI dosage to 40 mg daily. This gave little relief After two days it was
decided to discontinue treatment of the dog with antipsychosis drugs and
to investigate a novel therapy. The decision was predicated upon the
inventor's personal experience. Having endured depression nightly for more
than two decades. The first time he consumed one 500 mg capsules of
acetyl-L-carnitine in a "pop culture" effort to improve his memory.
Depression ceased| And remained so as long as Alcar was consumed daily. It
was thought, there may be a physiologic similarity between depression in
humans and psychosis in dogs, the dog's owners agreed to add mg per pound
body weight acetyl-L-carnitine orally morning and night to his treatment
regimen for one week. The dog's psychosis began to diminish within two
days. By the end of the week he no longer hid in the house, would eat from
his food bowl, and trembling when he went outside was much less severe.
Acetyl-L-carnitine therapy was continued but fluoxetine HCI dosage was
reduced to 20 mg orally once daily. His fearfulness continued to diminish
and he began to go on short walks. Twenty-one days later symptoms were so
minimal that fluoxetine HCI was discontinued. Within a week his behavior
and activity level were as normal as they had been three years previously.
However, that day, while on a moderately long walk he suddenly collapsed,
temporarily became unconscious and, unable to rise or walk, was carried
home. The owner commented that on the previous day's walk a similar but
less severe episode had taken place.
When examined at the hospital he was conscious but very depressed with no
sign of anxiety. His pulse was weak, 200 beats per minute, and capillary
refill time was four seconds. An electrocardiogram (ECG) tracing showed no
arrhythmia but the T-wave was augmented with negative polarity. Because of
symptoms: syncope, exercise intolerance, weak pulse, tachycardia, and
prolonged capillary refill time the dog was diagnosed as suffering from
cardiac failure. Sustained-release 500 mg procainamide orally morning and
night was added to the acetyl-L-carnitine regimen. The following day, an
ECG showed improvement. Amplitude of the T-wave was less but polarity was
still negative. His demeanor was brighter and he was responsive to owner
and surroundings. Within three days he could again walk for short
distances without signs of distress. However, his exercise tolerance was
sub-normal. It was decided to continue giving him the procainamide, for it
seemed to have helped cardiac function, but replace acetyl-L-carnitine
with L-carnitine, 5 mg per pound body weight orally morning and night, to
see if it might further improve his level of physical activity. Following
seven days of L-carnitine supplement, his level of physical activity was
again normal and he was going for two-mile long walks. In an attempt to
clarify whether the dog's activity level had returned to normal because of
carnitine and its metabolic effects on heart muscle or the procainamide
and its effect on cardiac impulse conduction, the latter was phased out
through the ensuing week. During that time he continued to walk and run
normally with no evidence of cardiac insufficiency. This indicated
disturbed metabolism of myocardial cells must have caused the circulatory
failure for the dog's level of activity improved most when he was given
L-carnitine and it remained normal with deletion of procainamide. Daily
treatment only with L-carnitine was continued. Then after 17 days without
acetyl-L-carnitine, the owner called to report the dog's physical activity
was normal but psychosis had returned. It appeared, on one hand, that
acetyl-L-carnitine had improved the dog's psychic state but cardiac
malfunction developed once his activity level increased. On the other
hand, L-carnitine had corrected the circulatory failure without benefiting
the psychosis. In an effort to correct the resurging psychotic state while
preventing recurrence of heart failure acetyl-L-carnitine and L-carnitine
were given to the dog. To evaluate their compatibility the two nutrients
were mixed together as powders in equal parts as a dietary supplement to
be added as a powder to the dog's food. Dosage was mg per pound body
weight daily. While on the combination anxiety symptoms disappeared within
five days and no further heart failure signs developed. The nutri | | |
