NZ614375A - Cyanocobalamin, methylcobalamin, and/or adenosylcobalamin to help maintain a pain-free head and pain-free body and provide defense against headaches and body pain - Google Patents
Cyanocobalamin, methylcobalamin, and/or adenosylcobalamin to help maintain a pain-free head and pain-free body and provide defense against headaches and body pain Download PDFInfo
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Abstract
The disclosure relates to use of an active vitamin B12 analogue selected from cyanocobalamin, methylcobalamin, adenosylcobalamin or a combination thereof in the manufacture of a medicament for treating headache, wherein the medicament is adapted for oral administration to the mouth, preferably on top of the tongue and/or under the tongue, in a form selected from the group consisting of a dissolving strip, a lozenge, a spray, a tablet, a capsule, a dot, a solution, an emulsion, an encapsulated microsphere and a suspension.
Description
TITLE OF THE INVENTION
CYANOCOBALAMIN, METHYLCOBALAMIN, AND/OR ADENOSYLCOBALAMIN
TO HELP MAINTAIN A PAIN-FREE HEAD AND PAIN-FREE BODY AND
PROVIDE DEFENSE AGAINST HEADACHES AND BODY PAIN
INVENTOR
Ernest Timothy Armstrong of Palm Desert, CA, USA
CROSS REFERENCE TO RELATED APPLICATION
This application claims the priority right from the U.S. provisional patent
application 61/695,540 that was filed on August 31, 2012, the content of which is
herewith incorporated in its entirety by reference.
FIELD OF THE INVENTION
The present invention generally relates to cyanocobalamin containing
medications that are placed in the mouth, dissolved and swallowed for the
prevention and treatment of headaches and body pains in humans and for
enhancing the normal functioning of the human body by boosting the human
defense against headaches and body pains.
BACKGROUND OF THE INVENTION
Any discussion of the prior art throughout the specification should in no way be
considered as an admission that such prior art is widely known or forms part of common
general knowledge in the field.
Human brains are one fiftieth of our body’s weight, and yet consume up to one fifth of the
body’s energy. Two thirds of the brain’s energy consumption goes into making nerve
cells fire, and one third into cell maintenance. Most of the brain’s energy is chemical
energy manufactured in the mitochondria and stored in the form of ATP. Mitochondria
live as organelles within cells, including brain cells. The number of mitochondria per cell
can range from one to thousands, depending on the energy needs of the cell. Energy-
hungry brain cells contain thousands of mitochondria. Once inside the body
cyanocobalamin is converted to adenosylcobalamin and methylcobalamin.
Adenosylcobalamin is critical to the health and functioning of the brain’s mitochondria
while methylcobalamin is critical to the health and functioning of the rest of the brain’s
and body’s cells.
Muscle cells have a large energy demand and require lots of ATP. Muscle cells also
have a correspondingly high number of mitochondria, and are often the site of the
body’s soreness and pain. The current invention focuses on musculoskeletal pain.
The current invention discloses novel approaches to prevent and treat the
malfunctioning or underperformance of the body’s mitochondria and cells with
methylcobalamin, and adenosylcobalamin, and their chemical precursor,
cyanocobalamin, especially in the central and peripheral nervous systems. The
inventor of the current invention puts forth the theory that by providing cyanocobalamin,
methylcobalamin, and/or adenosylcobalamin in therapeutic doses to headache and
body pain sufferers that their mitochondria will attain sufficient therapeutic
concentrations of these essential micronutrients to survive, increase in number and
function properly, thereby not creating the symptoms of certain types of headache and
body pain.
The current invention differs substantially from prior uses of cobalamins, such as
hydroxycobalamin to take up excess nitric oxide, or cobalamins to prevent IgE-mediated
allergic diseases, neurogenic inflammation or cobalamins to repair nerve cell-insulating
myelin sheath.
Cyanocobalamin, methylcobalamin, adenosylcobalamin and hydroxocobalamin each
contain a biologically rare cobalt metal atom as a central feature. Around that cobalt is
the active part of each molecule (i.e. the moiety) which is the location responsible for
the unique type of chemical reactions that molecule causes to make happen. Attached
to their central cobalt atoms; cyanocobalamin has a cyano group, methylcobalamin has
a methyl group, adenosylcobalamin has an adeno group, and hydroxocobalamin has a
hydroxyl (OH) group. Because of these distinct electromagnetic properties, each of
these compounds plays a distinct biochemical role.
Cyanocobalamin, methylcobalamin, and adenosylcobalamin (the three chemicals
pertaining to the current patent) differ in some important ways from hydroxocobalamin
(which does not pertain to the current patent).
Once inside the body cyanocobalamin is converted to methylcobalamin and
adenosylcobalamin, but not to hydroxocobalamin.
Hydroxocobalamin is known to scavenge nitric oxide (NO) which is associated with
migraine. Hydroxocobalamin does this scavenging by trading its OH group connected
to its central cobalt with the nitric oxide molecule. Because neither cyanocobalamin, nor
methylcobalamin, nor adenosylcobalamin have the ability to scavenge nitric oxide, their
ability to lessen the frequency and severity of headaches cannot be ascribed to nitric
oxide scavenging.
In 1999 Merkus disclosed in US patent 5,925,625 a method and composition for the
prophylaxis and treatment of headaches using intranasal hydroxocobalamin. The
current invention can be distinguished from Merkus’ patent because the current
invention discloses the use of different chemical entities, namely cyanocobalamin,
methylcobalamin, and adenosylcobalamin. The current invention can be distinguished
from Merkus’ patent because Merkus describes a short-term treatment while the current
patent describes a long-term treatment. The current invention can be further
distinguished from US patent 5,925,625 because Merkus states that “Oral, sublingual as
well as nasal administration of vitamin B12 appeared to be ineffective treatments...”
while the current patent teaches away from Merkus because the current patent
discloses that buccal and sublingual administration do indeed yield effective treatments
for headache.
In 2001 Ernest T. Armstrong (the inventor of the current invention) disclosed in US
patent 6,255,294 a method to treat allergy using cobalamins. However, in US
6,255,294 there is no mention of headache or migraine. In US 6,255,294 the invention
relied on a method for treating Immunoglobulin E (IgE) mediated atopic disease
including allergic rhinitis and asthma. Such atopic diseases are a completely different
class of disease and human condition with different causations and modes of action
than the headaches and body pains disclosed in the current invention. The claims of
US 6,255,294 were approved with cyanocobalamin, methylcobalamin, and
hydroxocobalamin, but not with adenosylcobalamin.
In 2002 van der Kuy showed in an unblinded, open-label study on 19 migraine patients
that intranasal hydroxocobalamin can have an effect on migraine. The authors of the
van der Kuy study hypothesise that hydroxocobalamin might be effective in migraine
because of its nitric oxide-scavenging activity. Flaws in the van der Kuy study include
the lack of a placebo group as a comparator, and the lack of any follow up after the last
day the subjects received their last dose of medication which could have demonstrated
(or not demonstrated) a persistence of effect. The current invention can be
distinguished from van der Kuy’s research because van der Kuy used
hydroxocobalamin while the current invention discloses the distinct chemical entities of
cyanocobalamin, methylcobalamin, and adenosylcobalamin. The current invention can
be distinguished from van der Kuy’s research because van der Kuy’s treatment has a
short-term persistence of effect while the current invention has a long-term effect. The
current invention can be distinguished from van der Kuy’s research because for all
subjects van der Kuy showed essentially no reduction in severity (mean of 2.2 at
baseline versus 2.1 at the end of the study, on a 0-3 scale). The current invention can
be further distinguished from van der Kuy’s research because van der Kuy’s mechanism
of action describes hydroxocobalamin as a nitric oxide (NO) scavenger. Nitric oxide is
created and excreted by the body within a matter of hours. The important distinguishing
point is that the current invention’s mechanism of action most certainly is different than
that of van der Kuy’s invention because the scavenging of nitric oxide lasts only hours
while the current invention has a persistence of effect lasts weeks, and perhaps months
or years. (Van der Kuy, H et al. Hydroxocobalamin, a nitric oxide scavenger, in the
prophylaxis of migraine: an open, pilot study. Cephalalgia, 2002, 22, 513-519.)
Dalsgaard-Nielsen performed a double-blind, placebo-controlled study on 29 patients
(active n=15 and placebo n=14). During two months every two weeks 2 mg of
cyanocobalamin were administered intramuscularly. The patients reported a: “Good
result” active n=4 versus placebo n=2, and “Considerable improvement” active n=2
versus placebo n=5. The authors concluded that no therapeutic effect attributable to
cyanocobalamin was demonstrated. (Dalsgaard-Nielsen AT, Trautmann J. Profylaktisk
behandling af migraene med vitamin B12. Almindelige Danske Laegeforening 1970;
132:339–41.)
The authors of the van der Kuy study also hypothesise that since cyanocobalamin has
no nitric oxide-scavenging activity, in contrast to hydroxocobalamin, it is not surprising
that in the Dalsgaard-Nielsen trials on cyanocobalamin no effect was seen in migraine
patients. Van der Kuy was correct about the lack of cyanocobalamin’s nitric oxide-
scavenging activity, but they missed another flaw in the Dalsgaard-Nielsen trials:
Dalsgaard-Nielsen administered cyanocobalamin only once every two weeks. Based
on the current inventor’s original clinical research, the current invention teaches away
from Dalsgaard-Nielsen and discloses a particularly preferred embodiment of daily
administration of cyanocobalamin, with repeated delivery ranging from about 15 days to
about 60 days.
The non-obviousness of the instant claims can be established by considering that oral
(buccal) dissolving strip, sublingual lozenges and other disclosed means of introducing
the headache and body pain opposing medications orally provide significant
improvements over the prior art in that the dissolving strip are more convenient for the
headache patient than a series of injections, or a nasal spray. Compared to an
injection, or nasal spray, a dissolving strip or a sublingual lozenge is much more
convenient because it takes from between one minute and five minutes to inject oneself
or to administer a nasal spray. These few minutes may not seem like much, but to the
headache patient, time is of the essence.
Another advantage is that people in pain do not want something stuffed up their nose or
an injection in the body,
Among the surprising advantages of the dissolving strip and sublingual lozenge over the
injection and nasal spray is that the headache patient would not be further irritated by a
painful injection process or by a nasal spray up a sensitive nostril. This is an
important aspect of the oral strip which comes in an easy to use soft plastic
container because headache patients are often hypersensitive to bright lights
(photophobia), shrill sounds (phonophobia), smells (osmophobia), and metallic
objects touching the body. Such extraneous irritations are the last thing a
headache sufferer would want at the time he or she is experiencing an episode of
headache, thus the strips and sublingual lozenge differ in a significant way.
The significance of the difference between the oral dissolving medication and
other delivery means becomes apparent when one examines the large numbers
of people and money involved. There are between 30 and 50 million headache
sufferers in the United States, thus if only ten percent can be provided an
improvement, then some 3 to 5 million people will be helped. According the
American Academy of Pain Medicine, pain affects more Americans than does
diabetes, heart disease, and cancer combined. Back pain problems in the United
States are reported to cost more than $100,000,000,000 annually.
Many large pharmaceutical companies have spent millions of dollars over many
years investigating new medications for headache sufferers, but none of them
have developed any medication with the safety profile, efficacy and ease of use
afforded by the current invention.
SUMMARY OF THE INVENTION
According to a first aspect, the present invention provides a use of an effective amount of
a compound selected from the group consisting of cyanocobalamin, methylcobalamin
and adenosylcobalamin, or combinations thereof, in the manufacture of a dissolvable oral
medicament for the treatment or prevention of headache in a human in need thereof.
According to a second aspect, the present invention provides a composition for the
treatment and prevention of headache comprising about 0.05 mg to about 6 mg
cyanocobalamin, about 0.05 mg to about 6 mg methylcobalamin, and/or about 0.05 mg to
about 6 mg adenosylcobalamin, and further comprising about 3 mg to about 8 mg
magnesium, about 0.1 mg to about 250 mg L-carnitine, about 5 mg to about 100 mg
coenzyme Q10, and/or about 0.1 mg to about 25 mg riboflavin
EXAMPLE 1
This clinical study was designed and directed by the inventor of the current patent.
Methods: 162 human subjects with demonstrated seasonal allergic rhinitis (hay fever) in
the Pacific Northwest region of the United States were split into two groups with
approximately 50 percent in the active group and 50 percent in the placebo group.
Subjects were given their study medication, either Cyanocobalamin, USP or placebo in
the a.m. and p.m. every day for 21 consecutive days. Data on adverse events including
headache was captured throughout the ten-week duration of the study. Week One was a
baseline during which time no medication was administered; Weeks Two, Three and
Four were the weeks during which time the subjects received their study medication;
and Weeks Five through Ten were a post-treatment period during which time no
medication was administered but observations of symptoms and adverse events were
documented. Each time a subject felt a “Headache”, he or she reported its occurrence.
Results: The subjects’ post-treatment reports of “Headache” decreased from baseline in
the following surprising and unexpected results: Week Five -1.4 active vs. -0.9 placebo,
Week Six -1.6 active vs. -2.0 placebo, Week Seven -1.4 active vs. -0.1 placebo, Week
Eight -2.1 active vs. -1.2 placebo, Week Nine -3.4 active vs. -1.8 placebo, and Week
Ten -3.2 active vs. -0.3 placebo.
The results also demonstrated a persistence of effect of at least six weeks after finishing
the treatment. The results also demonstrated that there was a greater reduction in the
frequency of headache in the active group versus placebo in five out of six post-
treatment weeks. Additionally, almost one year later a follow-up questionnaire was
completed by 43 active and 49 placebo subjects, the results of which suggest a
persistence of effect lasting almost one year.
EXAMPLE 2
This clinical study was designed and directed by the inventor of the current patent. A
large, multi-centre, Phase 3, randomised, placebo-controlled clinical study on 1,551
patients was designed and directed by the inventor of the current patent. Methods: The
study was titled: “A Phase 3, randomised, double-blind, placebo-controlled, parallel
group study of the safety and efficacy of pre-seasonal sublingual cyanocobalamin
lozenges on moderate to moderately severe seasonal allergic rhinitis in humans”. The
study took place before and during the ragweed pollen season at 23 study sites in the
Midwest, Northeast and Central Texas regions of the United States. Essentially all of
the 23 investigators were Board Certified in Allergy/Immunology. Qualified subjects
were randomised into an active or placebo group (approximately 50% and 50%) using
an interactive voice recognition system (IVRS). All subjects (or their guardians) signed
an Informed Consent form approved by the IRB. Each subject had three visits to the
clinic. At Visit 1 and at Visit 3, they were given a physical exam (HEENT, chest, lungs,
heart, vital signs, height and weight); and donated blood and urine samples for
laboratory analysis. CBC and chemistry panels were run for safety analyses. The
blood samples were analyzed by chemiluminescent immunoassay for the presence of
ragweed specific immunoglobulin epsilon (IgE), and were assayed for cobalamins
(cyanocobalamin, methylcobalamin and adenosylcobalamin) levels.
Subjects self-rated the severity their allergy symptoms in the morning (a.m.) and in the
evening (p.m.) by entering a numeric score in a keypad of a telephone (IVRS) or in a
computer connected via the Internet to a database.
Subjects were given their study medication, either 3.3mg Cyanocobalamin, USP or
placebo in the a.m. and p.m. Subjects were instructed to let the study drug “dissolve
completely in your mouth, especially under your tongue, then swallow.” Subjects self-
administered the study medications for six consecutive weeks. For the next four weeks
subjects did not take any study medications.
Any adverse event (AE) or serious adverse event (SAE) was documented by the
subject in a paper diary and then transcribed to the appropriate case report form (CRF)
page. All SAEs were attended to by the investigator, and reported to the FDA by the
sponsor. All sites were monitored multiple times by qualified monitors.
Results: There was a total enrollment of 1,551 subjects (RA5555 n=763 and RA3333
n=788). The total number of doses possible was 84 doses. Over 50 percent (n=766) of
the 1474 subjects who reported taking at least one dose, took at least 80 doses of study
medication.
The allergy symptom scores were derived by summing and averaging all a.m. plus all
p.m. scores for the symptoms of sneezing, runny nose, nasal congestion, nasal itch and
eye itch. The primary comparison of interest was the scores across Weeks 4, 5 and 6
(i.e. during the pollen season). All randomised subjects who took at least one dose
were included in this intent-to-treat (ITT) analysis. The reduction in symptom severity
from baseline was greater for the active group than the placebo group for all five
composite symptoms: sneezing, runny nose, nasal congestion, nasal itch and eye itch.
In terms of safety, the active study medication was well tolerated.
As per the laboratory results, a significant average increase of more than 250 percent in
post-treatment blood serum cobalamin (cyanocobalamin, methylcobalamin and
adenosylcobalamin) levels was reported in the cyanocobalamin-treated subject groups
compared with essentially no increase in placebo-treated subjects.
The following types of headaches were self-diagnosed and documented by subjects in
the study: tension headache, headache, migraine, increased frequency of headaches,
worsening sinus migraine headache, increased headache, headache worsening,
worsening of migraine, sinus headache, severe sinus headache, and sinus pressure
headache.
The following types of body pains and myasthenia were self-diagnosed and
documented by subjects in the study: ear pain, earache, sore throat, sore muscles, leg
cramps, myalgia, back pain, sprained ankle, ache, toothache, hip pain, finger pain, knee
pain, pulled back muscle, shoulder pain, pulled hamstring, neck pain, femur pain, gum
pain, sore muscle, toenail pain, sore foot, and pulled neck muscle.
Of the 294 documented reports of some type of headache and of body pain, the study
yielded the following surprising and unexpected frequencies demonstrating positive
results: 137 reports in the active group compared to 157 reports in the placebo group.
The severities of those headaches and body pains were rated in the following surprising
and unexpected intensities: “Mild” 63 reports (or 46.0%) in the active group versus 71
reports (or 45.2%) in the placebo group; “Moderate” 68 reports (or 49.6%) in the active
group versus 68 reports (or 43.3%) in the placebo group; and “Severe” 6 reports (or
4.4%) in the active group versus 18 reports (or 11.5%) in the placebo group.
EXAMPLE 3
The current invention was successfully tested in humans with a history of headache
and/or body pains in a variety of formulas. These formulas comprised dissolving
medications containing combinations of cyanocobalamin, methylcobalamin,
adenosylcobalamin, magnesium, coenzyme Q10, L-carnitine, and riboflavin.
Formula 1 was a dissolving medication with 3.3 mg of cyanocobalamin.
Formula 2 was a dissolving medication with 6.6 mg of cyanocobalamin.
Formula 3 was a dissolving medication with 3.3 mg of methylcobalamin.
Formula 4 was a dissolving medication with 3.3 mg of adenosylcobalamin.
Formula 5 was a dissolving medication with 2.2 mg of cyanocobalamin, 2.2 mg of
methylcobalamin, and 2.2 mg of adenosylcobalamin.
Formula 6 was a dissolving medication with 3.3 mg of adenosylcobalamin.
Formula 7 was a dissolving medication with 5.6 mg of cyanocobalamin, 0.5 mg of
methylcobalamin, and 0.5 mg of adenosylcobalamin.
Formula 8 was a dissolving medication with 1.1 mg of cyanocobalamin, 1.1 mg of
methylcobalamin, and 1.1 mg of adenosylcobalamin.
Formula 9 was a dissolving medication with 2.2 mg of cyanocobalamin, 2.2 mg of
methylcobalamin, 2.2 mg of adenosylcobalamin, 15 mg of coenzyme Q10, and 2.1 mg
of riboflavin.
Formula 10 was a dissolving medication with 1.1 mg of cyanocobalamin, 1.1 mg of
methylcobalamin, 1.1 mg of adenosylcobalamin, 18 mg of coenzyme Q10, and 2.1 mg
of riboflavin.
Formula 11 was a dissolving medication with 1.1 mg of cyanocobalamin, 1.1 mg of
methylcobalamin, 1.1 mg of adenosylcobalamin, 5 mg magnesium, 9 mg of coenzyme
Q10, 5 mg L-carnitine, and 2.1 mg of riboflavin.
Formula 12 was a dissolving medication with 5.6 mg of cyanocobalamin, 0.5 mg of
methylcobalamin, 0.5 mg of adenosylcobalamin, 15 mg of coenzyme Q10, and 1 mg of
riboflavin.
Formula 13 was a dissolving medication with 5.6 mg of cyanocobalamin, 0.5 mg of
methylcobalamin, 0.5 mg of adenosylcobalamin, 5 mg magnesium, 10 mg of coenzyme
Q10, and 2.1 mg of riboflavin.
Formula 14 was a dissolving medication with 5.6 mg of cyanocobalamin, 0.5 mg of
methylcobalamin, 0.5 mg of adenosylcobalamin, 10 mg of coenzyme Q10, and 1 mg of
riboflavin.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Headaches, such as tension headache and sinus headache, are painful and can rob
individuals of quality of life. Headache symptoms include a pounding headache,
nausea, vomiting, and light sensitivity. Body soreness is a pain in the body.
Conventional headache and body pain remedies include various types of pain relievers,
pain killers, and analgesics, including COX-1, COX-2, opioids, and NSAIDs; none are
without side-effects, including drug addiction, liver damage and cardiovascular events;
and none get to the truly underlying causes of pain and neurological health, as does the
current invention.
The International Classification of Headache Disorders (ICHD) is a classification of
headaches published by the International Headache Society. The current patent applies
to primary headaches which the ICHD-2 classification defines as migraines, tension-
type headaches, cluster headache and other trigeminal autonomic cephalalgias
stabbing headaches, headaches due to cough, exertion and sexual activity (coital
cephalalgia), continuous headache on one side of the head (hemicrania continua),
paroxysmal hemicrania, daily-persistent headaches along with the hypnic headache and
thunderclap headaches.
Vitamin B12 or simply B12 are unspecific terms often used casually for a variety of
cobalamins, including cyanocobalamin, methylcobalamin, and adenosylcobalamin.
All other headache remedies with adequate research proving their efficacy have safety
profiles that contrast sharply with cyanocobalamin, methylcobalamin, and
adenosylcobalamin which are considered by the nutritionists and the FDA to have
excellent safety profiles, they are so safe and vital to health, that - like exceedingly few
other products - they are recommended to women who are pregnant and lactating! The
metal cobalt plays a central role in these molecules with its unique electrochemical
bounding abilities. These molecules are the only molecules in the human body to utilise
these special properties of cobalt, are difficult to absorb from food, and cannot be
manufactured by the body.
Cyanocobalamin (also known as CNCbl, or 5,6-dimethylbenzimidazolyl cyanocobamide)
has the molecular formula C63H88CoN14O14P. Cyanocobalamin is a manufactured
commercial form of a cobalamin, and not native to the human body. Once inside the
body cyanocobalamin is converted to methylcobalamin and adenosylcobalamin, but not
to hydroxocobalamin.
Methylcobalamin (also known as mecobalamin, or MeCbl) has the molecular formula
C63H91CoN13O14P and is notable as a rare example of an enzyme that contains
metal-alkyl bonds. Methylation is the donation of a methyl group to a substrate, and
methylcobalamin can function as the donor molecule. Proper DNA replication and cell
division require methylation. For this reason, and others, the current invention includes
cyanocobalamin and methylcobalamin.
Adenosylcobalamin (also known as cobamamide, AdCbl, or dibencozide) comprises
more than 70 percent of the cobalamins in the brain. Adenosylcobalamin functions in
reactions in which hydrogen groups and organic groups exchange places.
Adenosylcobalamin is the major form in cellular tissues, especially energy-hungry
muscles, where it is retained in the mitochondria. Adenosylcobalamin is the coenzyme
for the mitochondrial enzyme methylmalonyl CoA mutase. Problems with
methylmalonyl CoA mutase can lead to methylmalonic aciduria and dysfunction of the
mitochondria. In one preferred embodiment of the current invention,
adenosylcobalamin is included to prevent dysfunction of the mitochondria in the brain.
The mitochondrion (plural mitochondria) is the “cell’s powerhouse”. Most of the
organism’s stored energy is converted into a usable chemical energy known as
adenosine triphosphate (ATP) in the mitochondria. The citric acid cycle or Krebs cycle
generates GTP which becomes ATP. Problems with the mitochondria can cause them
to die. Problems with the mitochondria, which are also involved in cell signaling, cell
death, and cell differentiation, can disrupt the functioning of the cell, tissue and organ in
which they survive. It is an organelle with its own strand of DNA, distinct from DNA in
the nucleus. Mitochondria are found inside most animal cells. Populations of
mitochondria per cell range from one to thousands. Mitochondria living in our cells may
be hitch-hiking, symbiotic descendants of bacteria that provided some benefits to us,
indeed mitochondrial DNA resembles bacterial DNA. We certainly provided a safe living
cell as home with all the warmth and nutrients to these bacteria. When one realizes that
the basic chemical structure of cobalamins can only be synthesised by bacteria, it is not
hard to see a critical connection and history between mitochondria and cobalamins.
Consistent with the idea that certain types of headache are a result of insufficient
energy production by the mitochondria are reports of headache remedies that lessen
the brain’s demand for energy including relaxation techniques, meditation, and calming
affirmations while hypnotised. Also consistent are reports that providing more oxygen to
an individual can ameliorate headaches, such treatments include repeated deep
breathing and hyperbaric oxygen. Other consistent findings are that regular exercise
can both prevent headaches and that exercise can increase the number of mitochondria
in the brain. Conversely, strenuous physical activity by people who are not accustomed
to it can reduce oxygen concentrations in the brain and have been reported to trigger a
benign exertion headache. Likewise carbon monoxide (which binds up hemoglobin)
and tobacco smoke can reduce oxygen and are associated with headache. Brain scans
called fMRI detect where there is increased blood flow in the brain, which is a surrogate
indicator for where there is increased brain activity. Such fMRI scans show that three of
the highest energy demanding functional areas of our brains are those areas which
process vision, smell and hearing. Accordingly the mitochondrial dysfunction theory of
headache is consistent with the hypersensitivity of headache sufferers to bright lights,
bad smells, and loud noises. Indeed, visual disturbances known as aura can occur an
hour or so prior to the onset of a headache.
The brain's electrical activity correlates to changes in cerebral blood flow and cerebral
metabolic rate of oxygen. Rises in cerebral metabolic rate of oxygen are controlled by
the ATP turnover, which depends on the energy used for the Na, K-ATPase to re-
establish ionic gradients, while cerebral blood flow responses are controlled by
mechanisms that depend on Ca(2+) rises in neurons. (Lauritzen M, Neuroimage, 2012
Aug 15;62(62(2):1040-50.) Caffeine acts as a stimulant because it constricts the brain’s
blood vessels and many analgesics contain caffeine to fight headaches, especially
vascular headaches including migraines. Other products, such as adenosine, have the
opposite effect because they dilate blood vessels in the brain and the increased blood
flow can lead to a headache. Vasodilation may be part of a headache, yet it is not
required for migraine symptoms to manifest. Vasodilation and the brief vasoconstriction
that generally precedes it are not the root causes of vascular headaches, as once
believed.
The current invention teaches away from the prior art in its findings. The seemingly
contradictory idea that headaches are caused by insufficient metabolism of oxygen in
the mitochondria, and that increasing blood flow is also a cause of headaches can be
reconciled as follows: Blood vessels over essentially all of the brain are normally
constricted in a resting, non-headache state, and it is only at the local functional area(s)
in the brain where current neurological processing is taking place that momentary
vasodilation of the blood vessels (i.e. increases in local cerebral blood flow) occur.
(This increased local blood flow can be seen in fMRI images that detect the iron in
hemoglobin being fed to the high activity locations.) This local spike in cerebral blood
flow delivers a quick, just-in-time oxygen supply to permit a local increase in the
cerebral metabolic rate of oxygen. Ameliorating headaches by restricting blood flow all
over the brain (increasing mean arterial pressure) is analogous to keeping all the fire
hydrants in a city sealed shut except that one hydrant in front of a burning building
where opening just that one hydrant provides sufficient pressure to blast the water out.
Hours or days prior to the onset (aura) of a migraine attack, a headache sufferer often
experiences a set of symptoms known as prodrome consistent with the current
invention’s teachings of mitochondrial dysfunction or underperformance in the brain and
muscles. Prodrome’s symptoms include mood changes, muscle stiffness, yawning
(which is a call for more oxygen), fatigue and food (nutrition) cravings.
The current inventor contends that the root cause of many headaches and body pains is
inadequate energy (ATP) production in the mitochondria needed to fuel the energy-
hungry brain and muscle cells (and not the inflammatory response as per conventional
wisdom), and that surprisingly the current invention can provide the micronutrients
needed as raw materials to permit the optional functioning of mitochondria.
A non-obvious mechanism of action disclosed in the current invention is that increased
mitochondrial concentrations of adenosylcobalamin (and also coenzyme Q10,
magnesium, L-carnitine, and riboflavin) prevent or lessen the severity of a cellular
energy crisis in which mitochondrial function declines. Such a decline can be due to
alternating inner membrane potential, imbalanced trans-membrane ion-transport, and
an overproduction of free radicals. (Zhuo ML, Huang Y, Liu DP, Liang CC (April 2005).
"KATP channel: relation with cell metabolism and role in the cardiovascular system". Int.
J. Biochem. Cell Biol. 37 (4): 751–64.) In such a situation, mitochondrial K(ATP)
channels open and close to regulate both internal Ca2+ concentration and the degree of
membrane swelling. This helps restore proper membrane potential, allowing further H+
outflow, which continues to provide the proton gradient necessary for mitochondrial ATP
synthesis. Without aid from the potassium channels, the depletion of high energy
phosphate would outpace the rate at which ATP could be created against an
unfavorable electrochemical gradient. (Xu M, Wang Y, Ayub A, Ashraf M (September
2001). "Mitochondrial K(ATP) channel activation reduces anoxic injury by restoring
mitochondrial membrane potential". Am. J. Physiol. Heart Circ. Physiol. 281 (3): H1295–
303.)
An ATP-sensitive potassium channel is a type of potassium channel that is gated by
ATP. Simply stated, levels of ATP influence constriction and dilation of blood vessels
which have receptors for ATP known as P2x-R. Many vascular headaches, including
migraine, begin with a brief vasoconstriction immediately followed by vasodilation,
resulting in a throbbing headache. The current invention therefore surprisingly prevents
headaches by providing the micronutrients needed for the mitochondria to function
properly.
Any shortage or deficiency of adenosylcobalamin and/or the other micronutrients
disclosed in the current invention will impair or inhibit mitochondrial functioning.
Additionally, increasing amounts of adenosylcobalamin and/or the other micronutrients
disclosed herein will accelerate the chemical reactions in the mitochondria, thereby
permitting the mitochondria to metabolise more chemical energy over a given period of
time.
One example of the utility of the current invention is its amelioration of mitochondrial
dysfunction in the hypothalamus, a hormone secreting region of the brain which is
associated with cluster headaches.
One especially preferred embodiment of the current invention is a once-daily dissolving
that is placed on the tongue and swallowed, and contains combinations of
cyanocobalamin, methylcobalamin, and adenosylcobalamin in amounts that are
effective in defending the individual against headache and body pain; and the current
invention also includes one or more of the following substances or metabolites and salts
thereof: magnesium, coenzyme Q10, L-carnitine, and riboflavin.
Magnesium ions are important to the production of nucleic acid, DNA, and RNA, and the
catalytic action of many enzymes. Of special relevance to the current invention is the
magnesium-dependant enzymes associated with the conversion of adenosine
triphosphate (ATP) into adenosine diphosphate (ADP) in the mitochondria.
Phosporylation is an important process that occurs in the mitochondria. For this reason,
one particularly preferred embodiment of the current invention includes elemental
magnesium, magnesium oxide, magnesium gluconate, magnesium citrate, magnesium
oxide, magnesium orotate, magnesium malate, and combinations thereof in the
formulation in amounts ranging from about 10 mg to about 500 mg per portion.
Proper functioning of the mitochondria requires coenzyme Q10 (CoQ10), also known as
ubiquinone or 1benzoquinone. In one preferred embodiment, coenzyme Q10 is
included in the formulation in amounts ranging from about 10 mg to about 500 mg per
portion.
Riboflavin (vitamin B2) has an important function in energy metabolism. Flavin
mononucleotide (FMN) and flavin adenine dinucleotide (FAD) function as coenzymes
for a wide variety of oxidative enzymes and remain bound to the enzymes during the
oxidation-reduction reactions. Reduction of isoalloxazine ring (FAD, FMN oxidised
form) yields the reduced forms of the flavoproteins (FMNH2 and FADH2). For this
reason, one particularly preferred embodiment of the current invention includes
riboflavin in the formulation in amounts ranging from about 0.1 mg to about 300 mg per
portion.
Levocarnitine (or L-carnitine) plays an important role in energy metabolism by helping
the transport of fatty acids from the cytosol into the mitochondria. Also, it helps remove
toxic chemical byproducts from the mitochondria so they do not accumulate. In one
preferred embodiment of the current invention, L-carnitine, acetyl-L-carnitine (L-
acetylcarnitine), L-propionyl carnitine, or L-carnitine fumarate, and combinations thereof
is included in doses between 1 mg and 400 mg per portion.
One especially preferred embodiment of the current invention is a once-daily dissolving
medication that is placed on the tongue and swallowed, and contains combinations of
cyanocobalamin, methylcobalamin, adenosylcobalamin, magnesium, coenzyme Q10,
and riboflavin in amounts that are effective in defending the individual against headache
and body pain.
One particularly preferred embodiment of the current invention is a once- or twice-daily
dissolving that is placed on the tongue and swallowed. Each dosage’s approximate
contains are: 1.1 mg of cyanocobalamin, 1.1 mg of methylcobalamin, 1.1 mg of
adenosylcobalamin, 5 mg of coenzyme Q10, and 1.2 mg of riboflavin.
In one preferred embodiment, the current invention includes one or more of the
following plants or extracts thereof: feverfew (Tanacetum parthenium, Chrysanthemum
parthenium, Pyrethrum parthenium), kudzu (Pueraria lobata), capsicum (solanaceae),
butterbur (Petasites hybridus), ginger (zingiber officinale) and ginko (ginko biloba).
In the current invention, formulation of dissolving medication can employ hydrophilic
polymers that rapidly dissolve in the mouth, preferably on top of the tongue. The
cyanocobalamin, methylcobalamin, and adenosylcobalamin permeate the skin of the
mouth and, in a certain percentage, are ingested for absorption by the gut, especially
the ileum. In one preferred embodiment of the current invention, formulation of
dissolving medication involves the application of both aesthetic and performance
characteristics such as polymers, plasticisers, active pharmaceutical ingredients,
sweetening agents, saliva stimulating agents, flavoring agents, coloring agents,
stabilizing and thickening agents. In the current invention, formulation of dissolving
medication can employ polymers such as maltodextrin, microcrystalline cellulose and
piroxicam made with a hot extrusion technique. To make the medication more flexible;
plasticiser excipients such as propylene glycol, glycerol, dimethyl phthalate, diethyl
phthalate, dibutyl phthalate, triacrtin, castor oil, triethyl citrate, tributyl citrate, acetyl
citrate in the current invention. In one preferred embodiment of the current invention
Stevia (steviol glycoside) is used to sweeten the medications.
In one particularly preferred embodiment, the headache medication is delivered to the
headache sufferer in a dissolving medication placed in the mouth. The dissolving
medication is a thin film delivery technology, and is also referred to as a dissolving film
or an oral strip. The current invention defines a dissolving strip as a thin film delivery
means to administer active agent(s) via absorption in the mouth. This absorption can
be in the mouth as a whole (buccally) on top of the tongue (supralingually), or under the
tongue (sublingually) followed up by swallowing.
The skin, including the surface of the tongue, provides a physical barrier that can
interfere with the absorption of active drug ingredients. Although cyanocobalamin,
methylcobalamin, and adenosylcobalamin are known to permeate the skin in the mouth,
a penetration enhancer can increase their transdermal delivery in one preferred
embodiment. Penetration enhancers that can increase transdermal delivery and can be
used preferably in various embodiments of the current invention include but are not
limited to: dimethyl isosorbide, alpha bisobola, sulphoxides (e.g. dimethylsulphoxide),
azones (e.g. laurocapram), pyrrolidones (e.g. 2-pyrrolidone), alcohols and alkanols (e.g.
ethanol and decanol), glycols (e.g. propylene glycol), surfactants, terpenes, fatty acids,
fatty acid esters, fatty alcohols, fatty alcohol esters, biologics, enzymes, amines,
amides, complexing agents, macrocyclics, classical surfactants and the like. Gels and
creams with a Lamellar or liquid crystal structure also enhance penetration of active
ingredients.
When considering the various embodiments of the invention described herein, those
knowledgeable in the art will appreciate that these are illustrative only. Such
embodiments do not limit the scope of the invention. Those knowledgeable in the art
involved will appreciate that many variations, substitutions, equivalents, and like
modifications may be made within the scope of the present invention.
SUMMARY OF THE INVENTION
Consistent with original study findings on almost 2,000 people, most of whom were in a
Phase III placebo-controlled clinical study, the present invention is directed to safe and
effective cyanocobalamin, methylcobalamin, and/or adenosylcobalamin containing,
orally-dissolving medications to reduce the frequency and severity of pains in the head
and body in humans and for enhancing the normal functioning of the human body by
boosting the human defense against headaches and body pains.
A non-obvious mechanism of action disclosed in the current invention is that higher
concentrations of adenosylcobalamin (and other disclosed compounds) in the
mitochondria prevent or lessen the severity of a cellular energy crisis in which
mitochondrial function declines. Mitochondria convert sugars into chemical
energy the cell can use called ATP. Levels of ATP also function to constrict and
dilate blood vessels. Many vascular headaches, including migraine, begin with a
brief narrowing of the blood vessels (vasoconstriction) followed by an opening up
blood vessels resulting in a throbbing headache. The current invention therefore
surprisingly prevents headaches by providing the micronutrients needed for the
mitochondria to function properly.
Claims (8)
1. Use of an effective amount of a compound selected from the group consisting of cyanocobalamin, methylcobalamin and adenosylcobalamin, or combinations thereof, in the manufacture of a dissolvable oral medicament for the treatment or prevention of headache in a human in need thereof.
2. The use according to claim 1, wherein said medicament is in the form of a dissolving strip, a lozenge, a spray, a tablet, a capsule, a dot, a solution, an emulsion, an encapsulated microsphere or a suspension.
3. The use according to claim 1 or claim 2, wherein said medicament is suitable for administration on top of the tongue, under the tongue and combinations thereof.
4. The use according to any one of claims 1 to 3, wherein the medicament comprises 0.05 mg to 6 mg of cyanocobalamin, and/or 0.05 mg to 6 mg methylcobalamin and/or 0.05 mg to 6 mg adenosylcobalamin, or combinations thereof.
5. The use according to any one of claims 1 to 4, wherein said medicament is to be administered repeatedly over a period of about 5 days to about 60 days.
6. The use according to any one of claims 1 to 5, wherein the medicament further comprises at least one compound selected from the group consisting of magnesium, L- carnitine, coenzyme Q10, riboflavin, caffeine, melatonin, L-arginine, feverfew, kudzu, capsicum, butterbur, ginger, ginko and combinations thereof.
7. A composition for the treatment and prevention of headache comprising about 0.05 mg to about 6 mg cyanocobalamin, about 0.05 mg to about 6 mg methylcobalamin, and/or about 0.05 mg to about 6 mg adenosylcobalamin, and further comprising about 3 mg to about 8 mg magnesium, about 0.1 mg to about 250 mg L-carnitine, about 5 mg to about 100 mg coenzyme Q10, and/or about 0.1 mg to about 25 mg riboflavin.
8. The composition of claim 7, wherein the composition is in a form selected from the group consisting of a dissolving strip, a lozenge, a spray, a tablet, a capsule, a dot, a solution, an emulsion, an encapsulated microsphere and a suspension.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US201261695540P | 2012-08-31 | 2012-08-31 |
Publications (1)
Publication Number | Publication Date |
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NZ614375A true NZ614375A (en) | 2015-03-27 |
Family
ID=49397060
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NZ614375A NZ614375A (en) | 2012-08-31 | 2013-08-16 | Cyanocobalamin, methylcobalamin, and/or adenosylcobalamin to help maintain a pain-free head and pain-free body and provide defense against headaches and body pain |
Country Status (3)
Country | Link |
---|---|
AU (1) | AU2013216665A1 (en) |
GB (1) | GB201315470D0 (en) |
NZ (1) | NZ614375A (en) |
Families Citing this family (1)
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JP2022549583A (en) * | 2019-09-25 | 2022-11-28 | ソシエテ・デ・プロデュイ・ネスレ・エス・アー | Compositions and methods using adenosylcobalamin |
-
2013
- 2013-08-16 NZ NZ614375A patent/NZ614375A/en not_active IP Right Cessation
- 2013-08-16 AU AU2013216665A patent/AU2013216665A1/en not_active Abandoned
- 2013-08-30 GB GB201315470A patent/GB201315470D0/en not_active Ceased
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GB201315470D0 (en) | 2013-10-16 |
AU2013216665A1 (en) | 2014-03-20 |
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