US 20070259939Al
(19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0259939 A1 Stebbing (43) Pub. Date: NOV. 8, 2007
(54)
USING NALTREXONE AS A MULTI-PURPOSE HEALTH SUPPLEMENT TO IMPROVE THE HUMAN CONDITION AND PREVENTING MULTIPLE DISEASES AND INFIRMITIES BY STIMULATING IMMUNE SYSTEM VITALITY AND ROBUSTNESS Publication Classi?cation
(51)
(2006.01)
(52)
(75) Inventor:
(57)
ABSTRACT
Norfolk, NE (U S)
Correspondence Address:
BANNER & WITCOFF, LTD. TEN SOUTH WACKER DRIVE, SUITE 3000 CHICAGO, IL 60606
(73) Assignee:
11/550,742
Oct. 18, 2006
feelings of Well-being produced by naltrexone may also have far-reaching eifects, as suggested by studies shoWing
that people With positive attitudes recover more quickly from serious illnesses, for example. In another aspect of the invention, naltrexone may be used to prevent substance addiction before it ever starts, by blocking the internal positive response that normally results from the use of chemical substances.
US 2007/0259939 A1
Nov. 8, 2007
USING NALTREXONE AS A MULTI-PURPOSE HEALTH SUPPLEMENT TO IMPROVE THE HUMAN CONDITION AND PREVENTING MULTIPLE DISEASES AND INFIRMITIES BY STIMULATING IMMUNE SYSTEM VITALITY AND ROBUSTNESS CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to US. Provisional Application No. 60/797,587 ?led May 4, 2006.
FIELD OF THE INVENTION
dose levels. The FDA approved dosage siZe for treatment of alcohol dependency is a 50 mg tablet, once daily. While taking naltrexone at this dosage level, it is suggested that a counselor should be involved for support and advice and supervision. It also can be given in a sloW release form by injection or surgical implant if the patient is incapable or cannot be depended upon to take the medicine regularly.
SUMMARY OF THE INVENTION
[0006]
[0002]
contrast, embodiments of this invention provide naltrexone as a preventative medicine taken daily, usually in the late evening for greater ef?cacy. It is taken like a vitamin supplement and may prevent many of the diseases that tend
to be susceptible to a strong immune system.
[0007]
[0003] Traditional medicine has long been focused on the cure of a?lictions after they are recognized by the onset of symptoms. Aspects of this invention are dedicated to the proposition that it is better to prevent diseases then to cure
them after they have become established. There are numer ous health supplements and vitamins available noW that are
use of loW dose naltrexone may also reduce the need for pain
relief medications as Well as counter tendencies toWard
experiencing undesirable moods, such as excessive depres sion or anger. Increased feelings of Well-being may also
just for the maintenance and/ or enhancement of good health and vitality. More and more people are desirous of holding onto vigor and vitality as they age, such as baby boomers. Many people are determined to maintain their health and vitality for as long as it is possible to do so, and in?rmity is
often not accepted as inevitable. [0004] Naltrexone has been used in loW dose form since at least the mid 1980s to cure or stabiliZe a groWing list of ailments. It is used for the treatment of a number of serious diseases, such as some cancers, HIV, AIDS and multiple sclerosis. Studies have shoWn naltrexone to have a positive effect in as many as 65% of cancer patients, for example
[0008] In aspects of the invention, naltrexone may be used to prevent substance addiction before it ever starts, by taking it daily. This could result in great personal and ?nancial savings by reducing the occurrence of addiction and thus the need for rehabilitation programs. Unlike existing medica
tions such as Antabuse, a drug that Will induce nausea or
even unconsciousness if it is taken folloWed by alcohol consumption, naltrexone is more effective When taken prior
to drinking alcohol because it reduces or removes the desire to drink.
stopping the spread of tumors, as Well as causing remission in 30% of the patients. LoW dose naltrexone functions by blocking opioid, or endorphin, receptors in various types of
[0009]
endorphin level may also dull or kill pain, and often results in a feeling of Well-being because endorphins are natural mood elevating chemicals in the brain. In contrast, stress
may cause a marked reduction in endorphins, Which often
approximately 0.5 and 5 milligrams of naltrexone, and preferably betWeen 1.75 and 4.5 milligrams of naltrexone. An aspect of the invention provides administration of the daily dose of naltrexone in the late evening hours, such as
betWeen 6:00 pm and 2:00 am, so as to block the opioid
does not correct itself naturally, thus resulting in loWered immune defenses susceptible to a variety of illnesses, such
as autoimmune diseases or cancer. Cancer has occasionally
been observed in patients after about tWo to six years folloWing a period of extreme stress. [0005] With respect to the treatment of alcohol addiction, naltrexone may be effective because it eliminates the neural
immune system by causing an increase in endorphin and enkephalin production. In fact, tests have shoWn that taking
US 2007/0259939 A1
Nov. 8, 2007
diluted in liquid, as long as it is present in a readily bioavailable form. [0010] An embodiment of the invention is a method to stimulate the immune system of a patient prior to the onset of an illness via a daily dose of naltrexone that is generally in the range of 0.5 to 5 milligrams per dose, and again
behaviors, such as alcoholism, opiate, narcotic and tobacco addiction. With respect to the treatment of alcohol addiction,
naltrexone may be effective because it eliminates the neural
positive reinforcement normally experienced in the brain by blocking the receptors that provide the stimulatory effect felt
from alcohol. As a result of the lack of positive reinforce
ment, there is no internal incentive to drink alcohol. In a
tion of immune system function With marked improvement in disease ?ghting capability. In an aspect of the invention, the administration of a daily dose of naltrexone, for example
in the late evening, may prevent the onset of an illness in a
increase in endorphins resulting from the blockage of endor phin receptors by the naltrexone causes the immune system
to become more effective at ?ghting infection during its early stages. The use of naltrexone as taught here may
many forms of cancer, AIDS, HIV, multiple sclerosis, ALS, AlZheimers Disease, chronic fatigue syndrome, emphy sema, Parkinsons Disease, primary lateral sclerosis, psoria sis, rheumatoid arthritis, sarcoidosis and systemic lupus. For
example, cancer cells are routinely produced in the body, but a healthy immune system generally kills them as they occur. In fact, endorphins added to groWing human cancerous
tissue in a laboratory Petri dish have been observed to kill
the cancerous tissue. In contrast to Waiting for a disease to
Without alcohol, starting for example at about 6:00 pm. Three doses, for a total of 4.5 mg naltrexone, may be taken,
for example tWo or three doses together or single doses over a period of time, such as one per hour, as provides the most effective result for the individual. [0014] It is knoWn that it is very important to have a
surgery or chemotherapy, the disease may be prevented. Additionally, if an illness does become established, the daily naltrexone therapy may reduce or eliminate the need for
various medications to overcome the illness because of the
naturally or naltrexone induced, the increased levels of endorphins result in a better mood and an improved, enhanced and more robust immune system function, Which equates to an improved prognosis due to a greater ability of
the immune system to overcome and defeat a disease. If a
endorphin level may dull or kill pain, as endorphin levels naturally increase When injury occurs. Because naltrexone stimulates an endorphin increase, naltrexone therapy may reduce aches and pains. [0012] The employment of a daily loW dose of naltrexone
may prevent one or more psychological problems in a
of these different combinations constitute various alternative aspects of the present invention. The embodiments
resulting increase of endorphins, Which are natural mood elevating chemicals in the brain. An increased level of endorphins may preclude or prevent the onset of some mental depression or anger, for example, because endor phins are natural anti-depressives and mood enhancers. As a result of the absence of depression and improved mood and
include alternative embodiments to the extent permitted by the prior art. For example, endorphins may be administered
directly Without the use of naltrexone such as in those cases
US 2007/0259939 A1
Nov. 8, 2007
following claims.
What is claimed is:
1. A method to increase endorphin levels in a human or
animal patient comprising a daily administration of a dose of betWeen about 0.5 mg and about 5 mg naltrexone. 2. The method according to claim 1 Wherein the naltrex one is administered to the patient during an evening hour. 3. The method according to claim 2 Wherein the evening hour is betWeen approximately 6:00 pm and approximately
2:00 am.
11. The method according to claim 9 Wherein the chemi cal substance is an opiate. 12. The method according to claim 9 Wherein the chemi cal substance is alcohol. 13. The method according to claim 9 Wherein the chemi cal substance is nicotine. 14. A method to reduce physical pain in a human or animal patient comprising a daily administration of a dose of betWeen about 0.5 mg and about 5 mg naltrexone. 15. The method of claim 14 Wherein the naltrexone is
administered to the patient during an evening hour. 16. The method of claim 15 Wherein the evening hour is betWeen approximately 6:00 pm and approximately 2:00
am.
4. A method to stimulate the immune system of a human or animal patient prior to the onset of an illness comprising a daily administration of a dose of naltrexone. 5. The method according to claim 4 Wherein the dose of naltrexone is betWeen about 0.5 mg and about 5 mg. 6. The method according to claim 4 Wherein the naltrex one is administered to the patient during an evening hour. 7. The method according to claim 6 Wherein the evening
10. The method according to claim 8 Wherein the dose of naltrexone is betWeen about 0.5 mg and about 5 mg.
US006288074B1
US 6,288,074 B1
Sep. 11, 2001
(76)
(*)
Inventor:
Notice:
(57)
ABSTRACT
malignant lymphoma, chronic lymphocytic leukemia, Hodgkins lymphoma, and non-Hodgkins lymphoma, is
treated in human patients by the administration by a phar
macologically effective mode or route of an essentially pure
NOV. 15 1999
( )
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- '
56 ( )
signi?cant and most preferably substantially exclusive. Nal trexone is suitable for oral administration and is preferred.
* cited by examiner
6 Claims, N0 Drawings
US 6,288,074 B1
1
METHOD OF TREATING LYMPHOPROLIFERATIVE SYNDROME
CROSS-REFERENCE TO PROVISIONAL APPLICATION
2
patents despite the totally different nature of the earlier
diseases Which did not involve any malignant behavior. It is not possible to provide any coherent rationale for the therapeutic effectiveness of an essentially pure opiate recep
This application is a complete application of my provi sional application Ser. No. 60/108,828, ?led Nov. 17, 1998.
SPECIFICATION
10
pholiferative syndrome. Indeed, any therapeutic activity of these antagonists for the lymphoproliferative syndrome
Would appear from general principles of immune action to be highly unlikely if not entirely out of the question. It is generally believed that the immunocompetent action of lymphocytes arises out of some surface structural feature, usually called receptor, that is capable in some Way of
erative syndrome and is concerned speci?cally With treat ment of this syndrome, including by such diseases as malig
nant lymphoma, chronic lymphocytic leukemia, Hodgkins lymphoma, and non-Hodgkins lymphoma, by administra
tion of an essentially pure opiate receptor antagonist such as
Naltrexone and Naloxone at a loW level dosage.
BACKGROUND
15
recognizing, perhaps by capture, some structural feature of an invading foreign antigen. This recognition mechanism, Whatever its nature, initiates the production of antibodies effective against the particular antigen. Even assuming that lymphocytes have receptors for opiates, it is quite puZZling that blocking of these receptors by an opiate
antagonist Would in some Way interfere With Whatever is the causative factor or factors in lymphatic cancers. If an occurrence of the lymphoproliferative syndrome could be traced strongly to viral or bacterial action and if such action is assumed to involve receptor sites on
The use of an essentially pure opiate receptor antagonist in the treatment of several diseases has already been dis
closed in patents in Which I am named as an inventor. In US.
20
Pat. No. 4,888,346, issued Dec. 19, 1989, the treatment Was
30
the lymphoproliferative syndrome and this theory thus could hardly apply to all of the diseases of this syndrome.
In any case, While such an association might explain hoW administration of an opiate receptor antagonist could reduce the likelihood of the original initiation of the malignancy, it Would not explain hoW such administration could provide a therapeutic action after the malignancy has progressed to the
point of treatment. It is true for lymphatic cancers as for all cancers that at the time diagnosis is possible, the cancer is
332; among others, that opiate receptor antagonists. exem pli?ed by Naltrexone and Naloxone, When administered to a variety of living organisms, including tissue and cells, can
exert either a groWth accelerating or a groWth inhibiting
effect dependent upon the length of time the opiate receptor sites of the organism are completely and continuously blocked or occupied by the antagonist. Speci?cally, a groWth
accelerating or promoting action occurs With blockage for a period of at least 12 hours per day, as can be achieved With a dosage of at least about 10 mg. and preferably about 20 mg. per day, Whereas a groWth inhibiting action occurs With
to about 0.1 mg. per day. The groWth accelerating embodiment is said to be effec tive to proliferation, migration, and differentiation of cer
65
tain speci?c cells or tissue, including organ tissues, neural tissue, bone marroW, red blood cells, lymphocytes, liver cells, etc. (See patent, col. 9, lines 1525 This disclosure,
hoWever, is silent as to Whether these any of these same
US 6,288,074 B1
3
cells or tissues can be subject to the growth inhibiting
4
nism by Which the body attacks and controls cancers gen erally. It is the lymphocytes, or their derivatives, Which recogniZe the foreign antigenic nature of cancer cells or of
antibodies associated thereWith and attack the cancer cells.
embodiment, the focus of the inhibiting embodiment dis closure paralleling the above excerpt being on Weight loss of the organism as a Whole. (See col. 9, lines 3245 and col. 10,
lines 4559.)
In addition, the groWth inhibiting aspect is described as
related to the prevention, treatment and control of cancer
The route set forth by McLaughlin et al. for controlling cancer by their treatment, as quoted above, does not make
sense When it is the lymphocytes themselves that are malig
(see col. 10, line 60col. 11, line 47), the essential disclo
sure in this connection being as folloWs; The action of the compounds of the invention can be employed to terminate
10
the rapid groWth patterns of cancer and related abnormali ties. It should be understood, that a regime of the present
compounds cannot dissipate or reduce a tumor mass or other
proliferation of normal lymphocytes essential to effective functioning of the immune system? Further, if the object of
the treatment is, as stated, to reduce the extent of the cancer
metastasiZed groWth. These compounds can only terminate the groWth of the abnormal cells and inhibit the continued
to a degree Within the capacity of the immune system (lymphocytes) to control, hoW does an active normal
opportunity to rid the body of the cancerous groWth Whether benign or malignant. This aspect of the invention is particu
The diseases usually identi?ed Within the lymphoprolif erative syndrome have been previously identi?ed and their
symptoms and other characteristics can be found in abbre viated form in any medical encyclopedia, such as Miller
concerned With cancer. Neuroblastoma is a rather rare and 30 roliferative syndrome but if other diseases should be char
column, and is essentially limited to young children up to about 10 years of age. Evidence has been reported that neuroblastoma is peculiarly susceptible to natural immuno
too Would respond to the present therapy and should be deemed Within the scope of the invention. Similarly, While Naltrexone and Waloxone are presently
35
biological resistance. According to IMMUNOBIOLOGY FOR THE CLINICIAN by Barber, Copyright 1977, John Wiley & Sons, the lymphocytes of disease-free mothers of young neuroblastoma patients have the capacity to kill
neuroblastoma cells extracted from their diseased children
but had no effect on normal tissue cells or tumor cells of
40
the patients. (Cf p. 69). The same text states (at p. 102) that incidence of neuroblastoma nodules found by autopsy is
4050 times greater than the overall incidence of clini
45
739, the relevant portions of Which, in particular col. 5, line 17col. 6, line 25, are incorporated by reference. Similarly, While the dosage levels have been brie?y
speci?ed above, more complete information as to dosage level Which is applicable to the present invention, is given in the same -739 US. patent, especially col. 6, line 59col. 7,
line 17, Which is incorporated by reference. In as much as Naltrexone is available in a form suitable for oral adminis tration and is recogniZed to be effective When so
While there is a tendency among the general public (and even the often equally uninformed media) to generaliZe
administered, it is preferred that the Naltrexone be utiliZed as the opiate antagonist and be administered orally, but
Where effective other administration routes are, in principle, not precluded and can be employed. Naloxone, on the other hand, has not generally proven to be effective When admin istered orally; it is available in a form suitable for injection
60
and is better administered by injection, It is also preferred that administration take place in the evening hours, and particularly at bedtime, since the action
of the antagonist appears to develop more strongly When the patient is sleeping and at rest.
EXAMPLES
Example 1
A37 year old female patient had been diagnosed 31/2 years earlier as having non-Hodgkins lymphoma and had been
component, if not the keystone, of the bodys immune system Which is an important, if not the principal, mecha
US 6,288,074 B1
5
successfully treated into remission With chemotherapy by an
oncologist in a different state. With this treatment, the
6
levels and his Weight loss regained, At this point, he Was
reevaluated by his oncologist and Was told he Was in remission. His Naltrexone therapy has continued for a total of about 3 years and he has remained free of all symptoms.
Example 3
10
AWoman Was examined and found to have three golf-ball siZe nodes in her groin Which on biopsy Were positive for
therapy. Six months after this recurrence began, her Weight loss had reached 20 pounds, she had enlarged lymph nodes in her axilla and groin, an enlarged spleen, an elevated White blood cells count With a number of atypical lymphocytes, and Was naturally quite frightened at her condition.
She Was started on Naltrexone at 3 mg. by mouth every
12 Weeks her groin nodes disappeared. She continued on this Naltrexone treatment and remained free of nodes until her death four years later from arteriosclerotic heart disease
(ASHD).
What is claimed is:
night at bedtime. After 3 Weeks, her fever began to subside and after 3 months, all of her symptoms had cleared Without
treatment other than the Naltrexone. After about 4 months of
Naltrexone treatment, she Was examined by her original oncologist and her related lab Work repeated, Which shoWed that her X-ray and blood abnormalities had cleared. She had regained her lost Weight, Was free of all other symptoms and
Was adjudged to be in full remission. The loW dose Naltr
exone treatment has been continued and after about one year,
consisting essentially of an essentially pure opiate receptor antagonist having a selectively higher blocking action against Mu opiate receptors than against Delta receptors, the
amount of said dose being selected to produce therapeutic
Example 2
A 38 year old man had been diagnosed by an oncologist as having Hodgkins disease based on symptoms of enlarged cancerous lymph nodes in the paravertebral areas of his chest and abdomen, an enlarged spleen, poor appetite, a
about 10 mg per day. 2. The method of claim 1 Wherein said lymphoprolifera tive syndrome is selected from the group consisting of
lymphoma, chronic lymphocytic leukemia, Hodgkins lym phoma and non-Hodgkins lymphoma.
35
20-pound Weight loss, malaise and fever. After receiving radiation and chemotherapy, these symptoms cleared, his
Weight loss Was re-gained and he Was declared to be in remission. After about four years, his symptoms recurred
3. The method of claim 1 Wherein said antagonist is administered at bedtime of the patient. 4. A method of treating a human patient suffering from
45
to exert a substantially higher opiate blocking action against Mu receptors than against Delta receptors. 5. The method of claim 4, Wherein said opiate receptor
antagonist is either naltrexone or naloxone. 6. The method of claim 4 Wherein said lymphoprolifera
chemotherapy and folloWing a neW examination con?rming the diagnosis of Hodgkins lymphoma, he Was started on Naltrexone at 3 mg. by mouth every night at bedtime. After four months of taking Naltrexone at this dosage, his enlarged nodes and spleen shrank to normal siZe as revealed by X-ray ?lm and Ct scans, his energy and appetite returned to normal
lymphoma, chronic lymphocytic leukemia, Hodgkins lym phoma and non-Hodgkins lymphoma.
* * * * *
US008067430B1
US 8,067,430 B1
Nov. 29, 2011
Schmidt, William K. Alvimopan (ADL 8-2698) is a Novel Periph eral Opioid Antagonist. The American Journal of Surgery. 2001. vol. 182, Suppl to Nov. 2001). pp. 27S-38S.*
Suzuki et al, Methadone induces CCR5 and promotes AIDS virus infection, FEBS Letters, 519 , 2002, pp. 173-177.* Medicinenet (De?nition of HTLV-III, retrieved from the internet on
(75) Inventors: Kenneth E. Ugen, Tampa, FL (US); Steven Specter, Tampa, FL (US); Susan B. Nyland, Hershey, PA (US); Chuanhai
asp?articleke}P38558.*
Schafer et al. Drug Discovery Today 2008, 13 (21/22), 9l3-9l6.* Horig et al. Journal of Translational Medicine 2004, 2(44).* Ando et al.(Remington: The science and practice of pharmacy, 20th
(Us)
(*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35
(60)
Activity of Antiretroviral Drugs in CD4+ Lymphocyte Cultures. Drug and Alcohol Dependence. vol. 64. pp. 257-263.
Brown et al. 2009. Low-Dose Naltrexone for Disease Prevention
and Quality of Life. Medical Hypotheses. vol. 72. No. 3. pp. 333
337.
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(2006.01)
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(Continued)
Primary Examiner * Jeffrey S Lundgren
Assistant Examiner * Savitha Rao
4,888,346 A *
2003/0069263 A1 *
2003/0105121 A1 *
(57)
ABSTRACT
OTHER PUBLICATIONS
A method of treating HIV infection by using the novel anti HIV activity of the opioid antagonist naloxone.
2 Claims, 4 Drawing Sheets
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US 8,067,430 B1
Page 2
OTHER PUBLICATIONS
Peng et al. 2007. Pharmacological Propeities of Bivalent Ligands
pp
. 2254-2258.
* Cited by examiner
US. Patent
Sheet 1 of4
US 8,067,430 B1
F l GU R E I A- D
Effect of Naioxone Treatment of HIV-1 Infected Cells on RT Activity
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SD - standard deviation
US. Patent
Sheet 2 of4
US 8,067,430 B1
FIGURE 2A and B
Percent inhibition of Recombinant RT
' Activity as A Function of Naloxone
Treatment DOSES
101
Q 0
1|]9 10
10
10
10
1o
mU/mi = miliiunits/ml
US. Patent
Sheet 3 of4
US 8,067,430 B1
In
gp120 expression
Key:
Std = protein molecular weight standard of 98KB in size
US. Patent
Sheet 4 of4
US 8,067,430 B1
FlGURE 4
10
VC 0C "115'
US 8,067,430 B1
1
ANTI-HIV ACTIVITY OF THE OPIOID ANTAGONIST NALOXONE CROSS REFERENCE TO RELATED APPLICATIONS
2
In yet another embodiment, provided is an antiviral com
pound comprising an opioid antagonist, Wherein the opioid antagonist is naloxone hydrochloride.
BRIEF DESCRIPTION OF THE DRAWINGS
This application claims priority to US. Provisional Patent Application No. 60/481,156 of the same title and by the same inventors, ?led Jul. 29, 2003.
GOVERNMENT SUPPORT
For a fuller understanding of the nature and objects of the invention, reference should be made to the folloWing detailed description, taken in connection With the accompanying
draWings, in Which:
FIG. 1 (A-D) shoWs the results of the differential effect of
a range of molar concentrations of naloxone or AZT on
reverse transcriptase activity in HIV infected cells: FIG. 1A shoWs the RT activity in HIV-MN infected Supt 1 cells treated With different molar concentrations of naloxone.
The data demonstrate that as the treatment dose of naloxone
increases from 10-11 to 10-4 M RT activity decreases. The column in the graph labeled 0 is the control (i.e. no drug
treatment).
FIG. 1B shoWs the % decrease in RT activity for the dif ferent treatment doses compared to the RT activity in the control.
FIGS. 1C and 1D shoW results from the treatment of HIV MN infected Supt 1 cells With an identical molar dose range
25
regions, sophisticated antiretroviral therapy is not available Which often results in high and often rapid mortality.
Short of the availability of an effective vaccine it is abso
RT (that is, protein not Within the HIV viral lysate). Analo
gous to the effects on RT in HIV, naloxone demonstrated a
30
therapies. This is particularly important because of the ability of the human immunode?ciency virus (HIV), the causative
agent for AIDS, to become resistant to some effective thera
FIG. 3 shoWs the immunoblot (Western blot) results using lysates from HIV infected Supt 1 cells that had been treated
With different molar concentrations of either AZT or nalox
35
pies.
One of the problems With the generation of neW drug
therapies against HIV is the development of resistance by the virus to the therapy. Unfortunately, the development of resis
tance has become a serious problem With AZT (Zidovudine). Resistant viruses are also developing against the neWer pro
one. The expression of the essential HIV coat protein gp120 is measured by this technique. Western Blot analysis of gp 1 20 detected With a murine anti-gp 120 monoclonal antibody from
HIV-1 infected cells treated With naloxone or AZT. HIV-MN
tease inhibitor drug therapies. With the development of resis tance it is critical to continually develop neW drug therapies
against HIV. Therefore, What are needed are novel ef?cacious
40
infected Supt 1 cells treated Will different molar concentra tions of naloxone or AZT. Cells Were lysed at 3 days after infection of the cells With cell free HIV-1MN and 100 pg of
the lysate Was loaded onto SDS-PAGE, transferred onto a
SUMMARY OF INVENTION
This invention describes the discovery of novel anti-HIV activity for naloxone hydrochloride, NARCAN, Which is cur
step of administering to the patient a therapeutically effective amount of an opioid antagonist. The target virus is the human
embodiments, reference is made to the accompanying draW ings, Which form a part hereof, and Within Which are shoWn by Way of illustration speci?c embodiments by Which the invention may be practiced. It is to be understood that other embodiments may be utiliZed and structural changes may be made Without departing from the scope of the invention. Administering or Contactingias used herein refers to the
process of delivering to a cell, ex vivo, or a host, in vivo, a
naloxone hydrochloride.
Another embodiment of the present invention includes a method of modulating the expression of a coat protein of a
virus comprising the step of contacting the virus With a thera peutically effective amount of naloxone hydrochloride,
Wherein the coat protein of the virus is chosen from the group
65
therapeutic sub stance, or a combination of several therapeutic substances. The process can include any method knoWn in the art and is dependent on the type of substance or substances administered. Possible methods include, but are not limited
US 8,067,430 B1
3
organ), mucosal (i.e. intranasally), pulmonary (i.e. via inha lation), topical, via catheter (i.e. iontopheretically) or orally.
Administration is usually achieved via a pharmaceutically
4
experiment, the effects ofAZT or naloxone (at identical molar concentrations) on RT activity. Naloxones Effect on Retrovirus Binding Activity
In addition to having a direct effect on RT activity the ability of naloxone to inhibit HIV Was measured through the determination of expression of critical coat proteins of HIV
acceptable carrier.
CCR-Sias used herein refers to the protein encoded by
the gene for CCR5 Which is located on chromosome 3 in the
Example 1
Cell Infection by HIV and Sample Preparation for
Analysis
200TCID-50 per milliliter (tissue culture infectious dose)
of HIV-MN cell free virus Was used to infect 500,000/milli
ine co-receptors used by the virus to gain entry into T cells. gp41ias used herein refers to glycoprotein 41, a protein embedded in the outer envelope of HIV. gp 41 plays a key role in HIVs infection of CD4+ T cells by facilitating the fusion
of the viral and the cell membranes. Therapeutically Effective Amountias used herein is that
amount of a substance necessary to achieve a desired thera
a range of concentrations) or absence (control) of naloxone HC1/or AZT. The TCID-50 is an amount of virus Which Will infect 50% of non-infected target cells. The virus+cells+ drugs (naloxone or AZT) Were incubated at 37 degrees Cel sius in an atmosphere of 5% carbon dioxide for three days.
30
peutic result. For example, if the therapeutic result desired is the enhanced yield of stem cells, the therapeutically effective
amount is that amount that facilitates, or achieves, an increase
in the total number of stem cells in a given population. The therapeutically effective amount can be a dosage adminis
tered in at least one amount and can include an administration
35
Cells Were lysed by using a detergent 1% Triton-X100. This preparation Was froZen in liquid nitrogen and thaWed at 37 degrees Celsius for three cycles. The preparation Was vor texed vigorously for 20 seconds at the end of each cycle. Samples Were then stored at 80 degrees Celsius until analy sis. Total RNA from the samples Were prepared by using the Tri-reagent assay and aliquoted and stored at 80 degrees
HIV activity of naloxone hydrochloride (NARCAN), a nar cotic antagonist, to treat patients infected With HIV. The medical indication for this drug is the treatment and partial, or total, reversal of the effects of opioid abuse. That is, naloxone is a competitive narcotic antagonist used in the management and reversal of overdoses caused by narcotics and synthetic narcotic agents. Unlike other narcotic antagonists, Which do
mg/ml solution of polyA and incubated at room temperature overnight With rocking. The plate Was then Washed 3>< With
not completely inhibit the analgesic properties of opiates, naloxone antagoniZes all actions of morphine.
Naloxones Effect on Reverse Transcriptase Activity Many studies have dealt With the effects of opioids (mor phine and analogs) on infection of cells by pathogenic human retroviruses (HIV and another retrovirus called the human T cell leukemia virus (HTLV)). In these experiments it may be necessary to antagoniZe the effect of the opioids With an antagonist, in order to con?rm the speci?city of any effect by
50
TBS (Tris buffered saline, pH 7.8) 100 ul/Well of either lysed experimental samples (from infected drug treated cells) or RT
standards Were added to the Wells folloWed by the addition of 60 ul/Well of RT buffer. This Was folloWed by the addition of 40 ul/Well of a nucleotide mix. The reaction mixture Was then incubated at 37 degrees Celsius for 40 min. The plates Were then Washed 3>< With TBS folloWed by the addition of anti
115000 in TGSE (a 10 mM pH 7.5 Tris buffer containing 1% gelatin and 1 mM sodium EDTA) buffer at 100 OWen and
incubated for 1 hour at 37 degrees Celsius. Plates Were then
inhibitory effect by the drug on the reverse transciptase (RT) enZyme activity of the virus. RT activity is essential for rep lication of the virus and ultimately the ability of the virus to infect cells. By comparison, the established anti-HIV drug
AZT (Zidovudine) inhibits HIV through its effect on RT. Importantly; initial analysis indicates that naloxone is at least
as effective as AZT in inhibiting RT activity at similar con
60
Washed 6>< With TBS folloWed by the addition of 100 ul/Well of a soluble substrate for HRP designated TMB (tetra-methyl benZidine) in perborate buffer. Color development, due to the reaction of the substrate With the enZyme (HRP) conjugate
Was alloWed to occur at room temperature for 15 min. The
65
colorimetric reaction Was stopped by the addition of 25 ul/Well of 2 molar sulfuric acid. The color reaction in the Wells Was measured spectrophotometrically. Color development
Was proportional to the amount of RT in the Wells and quan titation Was made based upon a standard curve of using
US 8,067,430 B1
5
recombinant RT. FIG. 1 (A-D) shows the results of the dif
ferential effect of a range of molar concentrations of naloxone orAZT on reverse transcriptase activity in HIV infected cells.
6
protein gp4l is measured by this molecular analysis. As
shoWn in FIG. 4, naloxone inhibits HIV at the molecular level
Speci?cally, FIG. 1A shoWs the RT activity in HIV-MN infected Supt 1 cells treated With different molar concentra
tions of naloxone. The data demonstrate that as the treatment
Example 4
dose of naloxone increases from 10'1 l to 10'4 M RT activity decreases. The column in the graph labeled 0 is the control (i.e. no drug treatment). FIG. 1B shoWs the % decrease in RT activity for the different treatment doses compared to the RT activity in the control. FIGS. 1C and 1D shoW results from the
treatment of HIV-MN infected Supt 1 cells With an identical
RT (that is, protein not Within the HIV viral lysate). Analo
gous to the effects on RT in HIV, naloxone demonstrated a direct inhibitory effect on RT. Therefore, it can be seen that
Example 3
RT-PCR (Reverse Transcriptase-Polymerase Chain Reac
tion)i(for Quantitation of Viral RNA as a Function of Treat
FIG. 3 shoWs the immunoblot (Western blot) results using lysates from HIV infected Supt 1 cells that had been treated
With different molar concentrations of either AZT or nalox
cial RT-PCR kits (Gibco/ BRL/ Life Technologies, Inc., Rock ville, Md.). The gene for the HIV gp4l transmembrane enve lope glycoprotein Was ampli?ed from the RT products through the use of the folloWing PCR cycling conditions: 94 degrees Celsius for 2 minutes folloWed by 52 degrees Celsius for 1 minutes then folloWed by 32 cycles at 94 degrees Celsius for 1 minutes, 52 degrees Celsius for 1 minutes, 72 degrees
Celsius for 15 minutes, then PCR extension Was accom
plished at 72 degrees Celsius for 10 minutes. The cycles Were then ended by incubation at 4 degrees Celsius for 16 hours. 5
ml (microliters) of PCR products Were then loaded onto a
40
include the effects of the drug on the expression of viral messenger RNA or protein necessary for infectivity at the gene and/ or protein. As for anti-HIV drugs, most recogniZed methods used are the measurement of HIV-I protein level
indicated by p24 (HIV-l core antigen) levels, RT (reverse transcriptase) activity, and immumoblot (i.e. Western)
method. The method for measurement of messenger RNA
45
level is RT-PCR (reverse transcriptase-polymerase chain reaction). Any measured changes in the parameters and meth
ods of measurement listed above can indicate an inhibitory or
control. No effect of drug treatment on expression of this enZyme Was noted indicating that the RT used in the assay condition Was not affected by the drug. That is GADPH can be considered a housekeeping gene of the T cell Which should have the same level of expression under all the drug
treatment conditions. The lack of an effect on GADPH also
55
attained and since certain changes may be made in the above construction Without departing from the scope of the inven tion, it is intended that all matters contained in the foregoing description or shoWn in the accompanying draWings shall be
interpreted as illustrative and not in a limiting sense. It is also to be understood that the folloWing claims are
65
intended to cover all of the generic and speci?c features of the invention herein described, and all statements of the scope of the invention Which, as a matter of language, might be the to fall therebetWeen. NoW that the invention has been described,
US 8,067,430 B1
SEQUENCE LISTING
cagcgatagg agctctgttc c
21
<400> SEQUENCE: 3
ggtgaaggtc ggagtcaacg ga
22
<2ll> LENGTH:
23
23
45
contacting the Virus With naloxone hydrochloride wherein the coat protein of the Virus is chosen from the group consisting
2. A method of modulating the expression of a coat protein of a human immunode?ciency Virus comprising the step of
US007879870B2
US 7,879,870 B2
Feb. 1, 2011
g;
Zoos/6261329 A1 11/2005
gages)? J
'
OTHER PUBLICATIONS
International Search Report for PCT/US2007/009228, mailed Jun. 3,
( ) Nonce'
(22) Filed:
(65)
Shows Withdrawal Drug Offers Symptom Relief to Crohns Suffer ers (May 23, 2006). LDNiLow Dose NaltreXone, www.digitalnaturopath.com (as
accessed on Apr. 17, 2007). Low Dose NaltreXone: Informal Clinical Study Report, Jul. 1, 2005, www.stronadZieci.org (as accessed on Apr. 17, 2007).
(57)
ABSTRACT
(200601)
Methods for the treatment of in?ammatory and ulcerative diseases of the bowel (e.g., Crohns disease and ulcerative colitis) with a therapeutically effective dose less than 50 mg.
of antagonists (e_g_, naltrexones nalmefene Or nalOX one) are disclosed. An embodiment of the invention includes
(58)
5,631,263 A
6,194,382 B1 6,395,705 B2
US. Patent
Feb. 1, 2011
Sheet 1 0f 10
US 7,879,870 B2
BL4WWW
M**
L DN
ohmz?nv
m 1% %
12 16
Week
FIG. 1
US. Patent
Feb. 1, 2011
Sheet 2 0f 10
US 7,879,870 B2
A Response
LDN
100 _
Z! 4-WkS p0St_LDN
80
3,:x23.1
o 4 60
0 D
16
Week
B. Remission
60
mw?mwl Q0
2 3 4 1
0
12
%/ /
16
Week
FIG. 2
US. Patent
Feb. 1, 2011
Sheet 3 0f 10
US 7,879,870 B2
III!
'
_
EZZZZ
200 -
s post-LDN
****
* * >1<
****
150 -
QISuecsBtoirDnea
%
\ ;\ e
Week
FIG. 3
US. Patent
Feb. 1, 2011
Sheet 4 0f 10
II! Baseline
_ L DN
US 7,879,870 B2
m 4 -wks
posl-LDN
Bodily Pain
Role - Physical
Energy
Physical Functioning
Social Functioning
Role - Emotional
Emotional Health
Week
FIG. 4
US. Patent
Feb. 1, 2011
Sheet 5 0f 10
US 7,879,870 B2
110
N0 DSS
105 -
100
LIJ U)
+'
95 +
I I I I I l | I I l
g
E a
1
D88: V 0
.97:
g2
g
D .97
g 0, E
100 _ . . .
D88
. . . . . .. . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . ..
Tn
In'_
E cu
a)
95 -
Q:
90 -
85
80 _
9 Saline
Day
US. Patent
40
Feb. 1, 2011
Sheet 6 0f 10
US 7,879,870 B2
1':
~k
**
u0
ST(9, MIFno:eEtaoMk:ndle)
MO
Saline
6.3
NTX
350
NTX
Saline
6.3
NTX
350
NTX
ug/kg ug/kg
No D88
ug/kg ug/kg
D88
120
100 -
1.
**
**
on O
ITSM(Wn1; oaemtEalMknre,)
(D O
NO
Saline
6.3
NTX
350
NTX
Saline
6.3
NTX
350
NTX
ug/kg ug/kg
No D88
ug/kg ug/kg
D88
FIG. 5C
US. Patent
Feb. 1, 2011
Sheet 7 0f 10
US 7,879,870 B2
N0 DSS
1.0
9 Saline
0.5
0.0 -
DSS: V
2 5.
Necropsy: 0
DSS
2.0
1.5
1.0
0.5 -
0.0
Day
FIG. 6
US. Patent
Feb. 1, 2011
Sheet 8 0f 10
US 7,879,870 B2
30
**
2 1
**
0 5
_ _ _
Ec9o=20m wE
3mm 58% H
ll
Saline 6.3
NTX
350 NTX
Saline
350
ug/kg ug/kg
N0 DSS
ug/kg ug/kg
NTX
FIG. 7A
U S. Patent
Feb. 1, 2011
Sheet 9 0110
US 7,879,870 B2
FIG. 7B
US. Patent
Feb. 1, 2011
Sheet 10 0110
US 7,879,870 B2
10
a
E 2(U
3
a 8
"E
(U
3 6*
]L
o
(D
o
(D
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n:
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60
50
40
30
20
- No D88 + Saline l:l D88 + Saline W D88 + 6.3 ug/kg NTX D88 + 350 ug/kg NTX
10*
STATS
FIG. 8
US 7,879,870 B2
1
TREATMENT OF INFLAMMATORY AND ULCERATIVE DISEASES OF THE BOWEL WITH OPIOID ANTAGONISTS CROSS REFERENCE TO RELATED APPLICATIONS
2
Treatment of Crohns disease usually includes administra
This application claims the priority of US. provisional patent application No. 60/745,119, ?led on Apr. 19, 2006, incorporated herein by reference in its entirety.
FIELD
mucosal in?ammation (anti-tumor necrosis factor, TNF). Although this speci?c immunotherapy has helped those With
Crohns disease, still about 20% do not respond to this treat ment and many cannot continue this therapy due to untoWard side effects. Additionally, treatment With the monoclonal
Example embodiments of the invention include methods for the treatment of in?ammatory and ulcerative diseases of the boWel (e.g., Crohns disease and ulcerative colitis) With
loW dose opioid antagonists (e.g., naltrexone, nalmefene or naloxone), pharmaceutical compositions for use in such methods, and methods for the manufacture of such pharma ceutical compositions.
BACKGROUND
antibody in?iximab (sold as REMICADE, a registered trademark of Centocor, Inc. of Malvern, Pa.) is expensive
With each infusion costing in excess of US$3,000. Ulcerative colitis is a form of colitis, an in?ammatory disease of the intestine, usually the colon, that includes char acteristic ulcers. Symptoms of active disease usually include
20
diarrhea mixed With blood, usually accompanied With vary ing degrees of abdominal pain, from mild discomfort to severely painful cramps. Although ulcerative colitis has no
knoWn cause, there is a presumed genetic component to sus
Which is mucosal in?ammation, and that several genetic and environmental factors are implicated in the pathogenesis of
the disease. Because of the name, IBD is often confused With irritable boWel syndrome (IBS), a troublesome but much less seri ous condition. Irritable boWel syndrome is a gastrointestinal disorder characterized by altered boWel habits and abdominal
Surgery is also used to manage complications of Crohns disease, such as ?stulae and small boWel obstructions, and for
Accordingly, a continuing need exists for effective phar macological treatments of in?ammatory boWel disease, such
as Crohns disease and ulcerative colitis.
ulceration of the boWel. No clear diagnostic markers exist and no pathognomonic abnormalities have been identi?ed for
IBS, so all de?nitions of the disease are based on the clinical
SUMMARY
50
Example embodiments of the invention include methods for the treatment of in?ammatory and ulcerative diseases of
chemotherapies for IBS include stool bulking agents, antis pasmodics, and antidiarrheal agents.
In contrast, Crohns disease is an in?ammatory disease
55
the boWel (e.g., Crohns disease and ulcerative colitis) With loW dose opioid antagonists (e.g., naltrexone, nalmefene or naloxone), pharmaceutical compositions for use in such methods, and methods for the manufacture of such pharma
ceutical compositions.
In another example embodiment, the invention includes the
use of an opioid antagonist in the preparation of a loW dose pharmaceutical composition for the treatment of a boWel disease characterized by in?ammation or ulceration of the intestinal Wall. In yet another embodiment, the invention includes a method for treating a boWel disease comprising administer ing to a subject in need thereof a loW dose of an opioid antagonist effective to treat a boWel disease in the subject
include abdominal pain, diarrhea, gastrointestinal bleeding, malabsorption, and Weight loss. Although the etiology is
unknoWn, research suggests it involves a complex interplay of
60
US 7,879,870 B2
3
In still yet another embodiment, the invention includes a pharmaceutical composition for use in the treatment of a boWel disease characterized by in?ammation or ulceration of
4
preferred embodiments, taken in conjunction With the accom
antagonist.
The invention provides heretofore unknown evidence that loW dose naltrexone, an opioid antagonist, is a safe and effec
tive treatment for Crohns disease. In summary, an open
FIG. 1 illustrates mean Crohns Disease Activity Index scores associated With LDN therapy in human patients. FIG. 2 illustrates the percent of patients responding, and
labeled prospective trial of human subjects Was conducted, as described more fully herein beloW. The safety and e?icacy of loW dose naltrexone (LDN) Was tested in patients With
human patients.
FIG. 4 illustrates mean SF-36 Health Survey scoresiSEM
receiving either normal drinking Water (upper panel) or 2% DSS in drinking Water (loWer panel). FIG. 5B illustrates the total food intake per animal during the DSS/NTX experiment.
20
FIG. 5C illustrates the total Water intake per animal over the course of the study.
FIG. 6 illustrates the reduction of daily modi?ed Disease Activity Index scores in laboratory animals treated With nal
trexone.
longitudinal sections of the distal colon upon staining and evaluation. FIG. 7B illustrates representative stained sections
of distal colon. FIG. 8 illustrates the real-time RT-PCR quanti?cation of total RNA from the distal colons of control mice, mice With untreated colitis, and mice With colitis treated With naltrex
one.
DETAILED DESCRIPTION
Example embodiments of the invention include methods for the treatment of in?ammatory and ulcerative diseases of
the boWel With loW dose opioid antagonists (e.g., less than
about 5 mg naltrexone, nalmefene or naloxone per day),
40
colitis, as described more completely herein beloW. Brie?y, laboratory mice received either untreated drinking Water or Water containing 2% dextran sulfate sodium (DSS) for six days. Three days after DSS introduction, animals Were administered 0.1 mL saline (control) or naltrexone (NTX,
pharmaceutical compositions for use in such methods, and methods for the manufacture of such pharmaceutical compo
sitions. In an embodiment, the invention relates to the treatment of in?ammatory boWel disease, such as Crohns disease and ulcerative colitis. In?ammatory boWel disease (IBD) is a
45
6.3 or 350 ug/kg) daily for six days. Disease activity index
(DAI) scores Were calculated daily. Mice Were necropsied on day nine and colon in?ammation Was analyZed histologi
cally. Colonic RNA Was evaluated by microarray and real time RT-PCR. By day 4, DSS-treated animals had signi?cant
Weight loss (p:0.006) and higher DAI scores (p<0.00l) com
pared to Water controls. DSS-treated mice that received nal
50
trexone (350 ug/kg) had less Weight loss, loWer DAI scores,
and less in?ammation compared to DSS mice treated With
lagenous colitis, lymphocytic colitis, ischemic colitis, diver sion colitis, Behcets syndrome, infective colitis, and indeter
minate colitis. Crohns disease and UC differ is the location
55
and nature of the in?ammatory changes in the intestine. Crohn s may affect any part of the gastrointestinal tract, from
mouth to anus, although the terminal ileum is the area most
colitis. Expression of the transcription factors STAT3 and STAT4, doWnstream effectors of cytokine signaling, Was also up-regulated in DSS-treated mice and similarly reversed by
naltrexone. Naltrexone therefore appears to have reversed
commonly involved. Ulcerative colitis, in contrast, is gener ally restricted to the colon and the rectum. Microscopically, ulcerative colitis is restricted to the mucosa (i.e., the epithelial lining), While Crohn s disease may affect the entire thickness of the intestinal Wall. Finally, Crohns disease and ulcerative
colitis present With extra-intestinal manifestations such as
disease manifestations and histologic evidence of in?amma tion in DSS-induced colitis. Other features and advantages of the present invention Will be apparent from the folloWing more detailed description of
US 7,879,870 B2
5
mal bowel movement frequency (e.g., diarrhea), intestinal
stenosis or ?stulization, perianal discomfort or pruritis, vom
6
salt thereof (e.g., naltrexone hydrochloride, nalmefene hydrochloride, and naloxone hydrochloride).
According to an embodiment of the invention, the opioid
antagonist is administered as a loW dose. For example, the
tulae, gastrojejunocolic ?stulae, enterocutaneous ?stulae, anorectal ?stulae, enterovaginal ?stulae, enterovesical ?stu lae, and enteroenteral ?stulae. Diagnosis of in?ammatory boWel disease is generally by colonoscopy With biopsy of pathological lesions or by radiographic (e.g., X-ray) exami
nation, Which often reveals in?ammation or ulceration of the
pharmaceutical composition is administered once per day in the morning or after Waking from sleep.
Another embodiment of the invention includes a method of
portion thereof, eg the mucosa. As used herein a boWel disease may be characterized by abdominal pain or discomfort, abnormal boWel movement frequency, intestinal stenosis or ?stulization, perianal dis comfort or pruritis, or abnormal stool consistency. Further
more, a boWel disease may be characterized by in?amma tion or ulceration of the small intestine (e.g., the ileum) or
25
colon (e.g., the ileocecum). A boWel disease may also be characterized by the presence of a ?stula, eg of the gas trointestinal system. In particular, a boWel disease may include in?ammatory boWel disease (IBD), such as
Crohns disease or ulcerative colitis. A boWel disease as
30
used herein does not include irritable boWel syndrome per se. Another embodiment of the invention includes the use of
immediate release formulation comprising an opioid antago nist and an excipient, Which may be selected from, eg the group consisting of sucrose, cellulose, and combinations
boWel disease characterized by in?ammation or ulceration of the intestinal Wall or any portion thereof, eg the mucosa, the pharmaceutical comprising a loW dose of an opioid antago nist. In still another embodiment, the invention relates to a phar maceutical composition for use in the treatment of a ?stula, eg a connection from the boWel to either the skin, another
40
45
able for oral administration. For example, the liquid dosage form may comprise an opioid antagonist and a liquid carrier, Which may comprise Water. Similarly, the pharmaceutical composition may be formulated as a topical dosage form suitable for topical administration. It is especially advantageous to formulate pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. A unit dosage form refers to physi cally discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of opioid antagonist calculated to produce the desired thera peutic effect in association With the required pharmaceutical vehicle. The speci?cation of unit dosage forms may be dic tated by and directly dependent on the unique characteristics of the particular opioid antagonist and the limitations inherent
in the art of compounding such a compound for the treatment ofa boWel disease.
Opioid antagonists may be formulated for administration using physiologically acceptable carriers or excipients in a
manner fully Within the skill of the art. For example, the
55
opioid antagonists, optionally With the addition of pharma ceutically acceptable excipients, may be suspended or dis
solved in an aqueous medium, With the resulting solution or
boWel disease in said subject, Wherein said boWel disease is characterized by in?ammation or ulceration of the intestinal Wall. The amount of opioid antagonist may be from about 1.75 mg to about 4.5 mg per dose, or alternatively form about
1.75 mg to about 3 mg per dose, or in another embodiment from about 3 mg to about 4.5 mg per dose.
60
As used herein, an opioid antagonist may be selected from the group consisting of naltrexone, nalmefene, nalox
compressed into tablets. For oral therapeutic administration, the opioid antagonist may be incorporated With excipients
and used in the form of ingestible tablets, buccal tablets,
the like.
For topical administration, the opioid antagonist may be provided in the form of ointments, creams, gels, lotions,
US 7,879,870 B2
7 shampoos, powders (including spray powders), pessaries,
tampons, sprays, dips, aerosols, or drops (e.g., eye ear or nose
8
that may be cleaved to reveal an intermediate compound that
opioid antagonists may be prepared in situ during their ?nal isolation and puri?cation or by separately reacting the puri
?ed compound in its free acid or base form with a suitable
derivatiZing agent. See, eg R. B. Silverman, The Organic Chemistry of Drug Design and Drug Action, Academic Press, Chp. 8 (1992).
EXAMPLES
mulation according to methods well known in the art. Opioid antagonists are typically alkaloids that contain a
basic functional group, such as amino group, and are thus
Crohn s Disease
capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids. The term pharmaceuti
cally acceptable salts in this respect, refers to the relatively non-toxic, inorganic and organic acid addition salts of opioid antagonists. These salts may be prepared in situ during the ?nal isolation and puri?cation of the compounds, or by sepa rately reacting a puri?ed compound in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the hydrohalide (includ
20
eligible patients were both male and female, at least eighteen years of age, and with the con?rmed diagnosis of Crohns
ing hydrobromide and hydrochloride), sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stear ate, laurate, benZoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, 2-hydroxyethylsulfonate, lau
rylsulphonate salts and the like. See, eg Berge, et al., Phar maceutical Salts, .1. Pharm. Sci. 66, 1-19 (1977).
In other cases, an opioid antagonist may contain one or more acidic functional groups and thus be capable of forming
Patients had moderate to severely active disease as de?ned by a Crohns Disease Activity Index (CDAI score) of >220 and <450. See, Best, et al., Development of a Crohns disease
Gaslroenlerology 70, 439-44 (1976). Patients taking stable doses of aminosalicylates, immunomodulators, corticoster
30
oids, or antibiotics were permitted to enter the study, and they were continued at the same dosage throughout the trial.
pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term pharmaceutically acceptable
salts in these instances refers to the relatively non-toxic,
Women of childbearing age were permitted to enroll and, if not surgically sterile, were required to use adequate contra ception (de?ned as oral or depot contraceptive, IUD, or bar
40
subjects with an ileostomy, colostomy, ileorectal anastomo sis, or short bowel syndrome from surgery, and patients with abnormal liver function tests. Subjects taking tacrolimus, cyclosporine, mycophenolate, or in?iximab within eight
weeks of enrollment were excluded.
bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Rep resentative organic amines useful for the formation of base
TABLE 1
45
Patient Demographics
Mean age 1 SEM (years) 42.1 r 2.6
addition salts include ethylamine, diethylamine, ethylenedi amine, ethanolamine, diethanolamine, piperaZine and the like. See, Berge, Ibid. Pharmaceutically acceptable includes those compounds,
materials, compositions, or dosage forms that are, within the
scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without exces
(range)
Gender, N (% of patients)
50
(23-63)
3 (18%) 14 (82%)
72 r 4
Male Female
Mean body weight 1 SEM (kg)
(range)
Disease site
55
(53-101)
2 (12%) 10 (59%) 5 (29%)
Past resection performed, N (% of patients) 8 (47%) Prior anti-TNF-ot therapy, n (% of patients) 13 (76%) Concomitant meds for Crohns, N (% of patients)
Arninosalicylates
Immunomodulators Glucocorticoids Antibiotics
65
11 (65%)
8 (47%) 4 (24%) 1 (6%)
The study was an open-labeled pilot investigation to evalu ate safety, toxicity, and response to LDN in subjects with
US 7,879,870 B2
10
active Crohns disease. Eligibility Was assessed by telephone,
and potential candidates Were scheduled for a screening visit.
P-values for binary outcomes response and remission Were
physical examination and laboratory testing (chemistry panel, complete blood count [CBC], urinalysis, and eryth
rocyte sedimentation rate [ESR]). Patients Were dispensed a seven-day diary to record symptoms of frequency of diar
scheduled for Weeks 4, 8, 12, and 16. Naltrexone hydrochloride Was compounded into capsules containing 4.5 mg by GMP-approved standards at a phar macy. Because the dosage used in this study Was loWer than
the current FDA-approved dose of 50 mg, it is referred to as loW dose naltrexone or LDN. Quality assurance of packag
ing and purity Were con?rmed an analytical research labora tory. Patients Were treated With LDN orally each evening for three months.A monthly supply of medication Was dispensed to patients. On the ?rst visit, an additional ten-day supply of LDN Was provided in the event of an appointment delay. Subjects Were required to bring the vials to each appointment
therapy.
Referring to the draWings, FIG. 1 illustrates the mean
Crohns Disease Activity Index (CDAI) scoresiSEM, shoWn at baseline (Week 0), Weeks 4, 8, and 12 after initiation of
25
dispensed.
Routine blood Work including CBC, chemistry panel, and
ESR Were assessed monthly. In addition, urine tests and preg nancy tests Were done for monitoring and safety purposes
and 12 and 4 Weeks after discontinuation of LDN therapy (Week 16). FIG. 3 illustrates mean In?ammatory BoWel Dis
ease Questionnaire (IBDQ) scoresiSEM, shoWn at baseline (Week 0), Weeks 4, 8, and 12 after initiation of LDN therapy, and 4 Weeks after discontinuation of treatment (Week 16).
35
enkephalin levels Were determined by radioimmunoassay (RIA) at baseline and Weeks 4, 8, 12, and 16.
In order to assess the effect of LDN on disease activity,
***p<0.001, and ****p<0.0001. In FIG. 4, mean SF-36 Health Survey scoresiSEM are shoWn at baseline (Week 0), Weeks 4, 8, 12 of LDN therapy, and 4 Weeks after discontinu ation of treatment (Week 16) for each of the parameters mea
40
assess quality of life, patients completed tWo standardized quality of life surveys, the In?ammatory BoWel Disease Questionnaire (IBDQ) and SF-36 Health Survey. See, Irv
ine, et al., Quality of life: a valid and reliable measure of
sured by the SF-36 Health Survey. Signi?cant differences from baseline values included the folloWing: *p<0.05,
therapeutic e?icacy in the treatment of in?ammatory boWel disease. Canadian Crohns Relapse Prevention Trial Study
activity and in?ammatory response to LDN therapy. Mean CDAI scores (FIG. 1) at Weeks 4, 8, and 12 folloWing the
initiation of LDN therapy Were 41%, 55% and 49%, respec tively decreased from baseline. Four Weeks after discontinu ation of therapy (Week 16), the mean CDAI score Was 45%
(1992).
The safety and toxicity of LDN Were assessed by adverse
50
less than baseline and not statistically different from the mean scores measured during the therapy. FIG. 2 shoWs the per
events, laboratory parameters, and vital signs. Nonhemato logic and hematologic toxicity Were determined by the WHO criteria. See, Oken, et al., Toxicity and response criteria of the Eastern Cooperative Oncology Group, Am. J. Clin. Oncol. 5(6), 649-55 (1982).
An intent-to-treat analysis Was performed in Which the available data from all evaluable patients Were included in the
55
statistical analysis. The parameters of measurement (CDAI scores, laboratory values, and quality of life surveys) Were analyZed by a biostatistician comparing baseline values to those obtained monthly and four Weeks post-therapy. A lon gitudinal data analysis based upon the linear mixed-effects model Was applied using PROC MIXED program (available from SAS Institute Inc., Cary, NC.) The Bonferroni statis tical method Was used to adjust signi?cance Where analysis including multiple comparisons to the baseline Were made.
60
65
LDN.
US 7,879,870 B2
11
Health Survey (FIG. 4) Were administered to patients receiv ing LDN treatment. By both measures, patients experienced a signi?cant improvement in their quality of life on LDN
12
indicated that for tWo separate quality of life surveys a sig ni?cant difference from baseline occurred in those individu
als on LDN. Moreover, even one month after discontinuation
completion of treatment.
of LDN therapy, the quality of life remained better in almost all parameters measured for these patients. As of the date of application for patent hereof, a double-blinded placebo-con trolled Phase II clinical trial of human subjects has not
revealed any serious adverse events. Treatment With LDN provides advantages over other stan
dard therapy for Crohns disease. The safety pro?le of LDN appears to be excellent in this study, With infrequent and
minor side effects and no knoWn suppression of immunity or
physical function (FIG. 4E) Was 23% greater than baseline values. Social function (FIG. 4F) Was 70% greater than base line at Weeks 4, 8, and 12, but Was only statistically different at Week 8. Role-emotional (FIG. 4G) and emotional health (FIG. 4H) Were comparable to baseline values at Weeks 4, 8,
and 12 of LDN treatment. At 4 Weeks after termination of
With the neW anti-TNF-ot compounds, these drugs can also increase the risk of reactivation of tuberculosis and induce a
lupus-like reaction, serum sickness syndrome, or anaphy laxis. Some investigators have suggested that in?iximab (an
anti-TNF-ot compound) or other immunomodulators may
(i.e., 50 mg) used for alcohol and opioid abuse have been
30
reported to elevate liver transaminases. In contrast, the use of LDN herein at 4.5 mg daily did not change liver transami nases during treatment. In?iximab has become a standard medical therapy for
value of 2.6 (normal <0.8) at baseline to a value of 0.9 by the 12 Week of treatment, and this change Was statistically sig
ni?cant (p:0.03). The ESR decreased from a mean baseline value of 23310.4 mm/hr to 17.9103 mm/hr, Which Was also
35
Week 12 of LDN therapy, but this difference in plasma enkephalin levels Was not statistically signi?cant. The mo st frequently reported side effect With LDN therapy
Was sleep disturbances, and this Was noted in 7 patients; one
45
infusion generally exceeds several thousand dollars (not men tion of the time aWay from the Workplace for intravenous administration). Naltrexone is a generic medication and the cost is therefore inexpensive. Moreover, effective mesalamine (PENTASA, a trademark of Ferring B. V. of The Netherlands) therapy may require up to 8-16 tablets per
day. Another advantage of LDN is the once-a-day dosing Which may improve patient compliance.
Ulcerative Colitis
of pro-in?ammatory cytokines, Which are thought to play a central role in disease progression. Cytokines can both sup press apoptosis and drive activation of immune cells that
contributes to a chronic state of in?ammation. Treatments
US 7,879,870 B2
13
aimed at reducing this excessive in?ammatory response have
14
minimiZe the impact of variation among animals, RNA from
individual mice Was pooled Within each treatment group.
Arrays Were run in duplicate and three pairWise comparisons Were performed to identify genes for Which expression Was
lyZed at the level of Whole animal symptoms, tissue histology, and RNA pro?ling. Six to eight-Week-old male C57 black/6] mice (Charles River Laboratories, Inc., Wilmington, Mass.) Were randomly
allocated into one of tWo groups of 24 mice each. Food and
Ware (Agilent Technologies, Palo Alto, Calif.). RNA (18S and 28S bands) Was visualiZed using the Agilent
then produced from 1.0 pg of total RNA using random hex amer primers and the SuperScript III Reverse Transcription
Water Were provided ad libitum. The ?rst group (Normal) received normal drinking Water and the second group (DSS) received Water containing 2% dextran sulfate sodium having
kit (Invitrogen). The concentration and quality of resulting cDNA Was quanti?ed and analyZed using the Agilent 2100 BioanalyZer or spectroscopically With the NanoDrop
a molecular Weight of 40,000 (TdB Consultancy AB, Upp sala, SWeden) for six days folloWed by normal Water for three
additional days and necropsy on day 9 (FIG. 5A). Each mouse
Was housed in an individual cage for accurate measurement of
Samples Were standardized to 30 ng/uL and 60 ng of cDNA per sample Was then used as a template for real-time PCR
food and Water intake. Animal Weight, Water intake, and food consumption Were measured daily. Bedding Was changed and fresh stool pellets Were collected daily and analyZed for occult blood. The colitis disease activity index (DAI) Was calculated for each mouse according to the system estab
using a SYBR Green Master Mix (Qiagen, Valencia, Calif.). 18S rRNA primers (Eurogentec, San Diego, Calif.) and the
beta-actin, 6671509a; IL-5, 6754336a; IL-6, 13642311a; IL-12, 6680395a; STAT3, 13277852a; STAT4, 6755670a; Muc2, 3452503a2; TFF3, 6755773a1; Palladin, 9828173a1;
and TGF-beta BP, 7305243a1. To exclude the possibility of genomic DNA contamination, control reactions With no cDNA template Were also performed for each gene-speci?c primer set. PCR ampli?cation and analysis Were performed
30
With the Applied Biosystems Sequence Detection System 7300 using the Relative Quanti?cation (ddCt). Ampli?cation
data for the genes of interest Were normaliZed to 18S Within
35
each individual reaction. Triplicate reactions Were performed and the resultant data from multiple runs Were averaged.
Results Were calculated as meaniSEM. Statistical com
folloWing: saline (control), 6.3 ug/kg naltrexone (NTX), or 350 ug/kg NTX (Sigma Chemicals, St. Louis, Mo.). On day 9,
all animals Were necropsied and their colons resected. At necropsy, the entire colon Was excised, measured in
40
parisons Were performed betWeen NTX treatment sub -groups and their corresponding saline control, as Well as betWeen the Normal and DSS groups, comparing corresponding treat
ments. Parametric analyses Were performed (Minitab 13, State College, Pa.) using a modi?ed Bonferroni method to correct for multiple comparisons to controls. Over the nine day course of study, animals given untreated
pared to DSS+saline; hoWever, the DSS+6.3 ug/kg NTX mice only reached statistical signi?cance on day 6 (p:0.02). Among the three DSS sub-groups, no signi?cant difference in
Weight Was evident at necropsy, When the animals had been
55
severity, extent of in?ammation (mucosa, submucosa, trans mural) and crypt damage. Each of these scores Was Weighted
to re?ect the percent involvement of the overall section and the Weighted scores from each of the six ?elds Were averaged
to achieve an overall in?ammation score for each mouse.
NTX treatment, had signi?cantly decreased total food con sumption (FIGS. 5B and 5C). Total Water intake Was also reduced in DSS mice compared to mice receiving normal
Water. Among the Normal mice, a reduction in Water con
ter, Inc. of Cincinnati, Ohio) and subjected to microarray analysis using a 10K mouse microarray (MWG Biotech, High
Point, NC.) and a Packard Biosciences ScanArray 4000KL machine (Functional Genomics Core Facility of the Section of Research Resources, Penn State College of Medicine). To
65
sumption Was noted in those treated With 6.3 ug/kg NTX relative to saline (FIG. 5C). In FIGS. 5B and 5C, asterisks
indicate signi?cantly different values betWeen corresponding DSS and Normal (no DSS) treatment groups (*p<0.025; **p<0.005; n:7-8). Signi?cant differences betWeen saline
and NTX-treated mice are indicated by a T(p<0.025).
US 7,879,870 B2
15
To monitor disease progression, a disease activity index (DAI) Was assessed daily for each mouse. Modi?ed DAI scores for all Normal mice (both saline and NTX-treated) shoWed no evidence of colitis (FIG. 6, upper panel). As With
16
be up-regulated in DSS-induced colitis, Were increased in DSS+saline animals in comparison to Normal controls (FIGS. 8B and 8C). The increase in IL-6 mRNA Was 73-fold,
While the signi?cant increase in IL-l2 Was more modest
Weight loss, the DSS mice developed colitis symptoms, including hemoccult-positive stools and increased DAI scores, by day 4 Which continued to increase through day 8
(FIG. 6, loWer panel). A reduction in these DAI scores Was
evident With naltrexone treatment. On day 6, DSS+350 ug/kg NTX animals had signi?cantly loWer (55%) DAI scores than DSS+saline mice (p:0.0l5). In FIG. 6, a signi?cant differ ence betWeen DSS+350 ug/kg NTX-treated mice and the
in?ammatory cytokines IL-6 and IL-l2 mRNAs had func tional consequences, the mRNA for doWnstream signaling
intermediates Was also measured by real-time RT-PCR. Both
8).
Reduced colon length, another indicator of DSS-induced colitis, Was also evident in all DSS animals (Normal+saline: 9.321039 cm, meanzSEM; DSS+saline: 6.95:0.43;
p:0.002). DSS-mice treated With naltrexone had more nor
mal colon lengths, although they Were still shorter than in the untreated animals.
Histological in?ammation scores of the distal colon con
both STAT3 and STAT4 mRNA levels Were decreased by greater than 50% after naltrexone treatment. In fact, levels of STAT3 mRNA in the naltrexone-treated animals Were statis
?rm that DSS induced an in?ammatory state (FIG. 7A). No differences in colonic in?ammation in Normal+saline and Normal+NTX animals Were evident histologically. This indi cates that naltrexone alone did not alter the mucosal integrity of the colon. All DSS animals had increased in?ammation scores, and exhibited crypt damage and increased leukocyte in?ltration (FIG. 7B). HoWever, the DSS+NTX animals had a dose-dependent decrease in in?ammation and damage, as evidenced by loWer in?ammation scores in comparison to
animals given DSS+saline (FIG. 7A). In FIG. 7A, asterisks indicate signi?cantly different values between corresponding DSS and Normal (No DSS) treatment groups (*p<0.025;
**p<0.005; n:7-8). While this trend did not reach statistical signi?cance, the DSS+350 ug/kg NTX mice had improved crypt architecture and feWer invading leukocytes than Were observed in the DSS+saline mice (FIG. 7B). In FIG. 7B,
representative H&E sections of distal colon are shoWn. Com
35
quantity, and signi?cance is based on non-overlapping CIs. Relative RNA levels for (A) beta-actin and the cytokine IL-5; (B) cytokine IL-l2 and its doWnstream effector STAT4; and
(C) cytokine IL-6 and its downstream effector STAT3, reveal signi?cant DSS-induced elevations in pro-in?ammatory mediators, and signi?cant restoration toWard normal levels
When animals Were treated With naltrexone.
pared to the normal appearance of healthy murine colon (no DSS+saline; top), leukocyte in?ltration and an absence of
normal crypt architecture are evident in the DSS+saline mice
40
(middle). Improved architecture and less in?ammation are clearly discemable in DSS mice treated With 350 ug/kg nal trexone (bottom of FIG. 7B). Differences in distal colon gene expression betWeen Nor mal+saline, DSS+saline, and DSS+NTX mice Were initially assessed using a murine spotted oligonucleotide array. Out of
9800 genes on the arrays, 506 genes Were initially identi?ed
This study is the ?rst to report improvement of colitis in a murine model upon treatment With an opioid antagonist. Nal trexone treatment resulted in a rapid mitigation of colitis symptoms in DSS mice, While in the absence of colitis, it had no signi?cant impact. DSS Was administered for three days prior to either saline or naltrexone injections, emulating a condition of established boWel in?ammation preceding treat ment. Animals With DSS in their drinking Water exhibited
as being signi?cantly changed (p<0.05) in DSS+saline mice When compared to Normal+saline mice (data not shoWn).
Among the most differentially expressed genes Were mucin
50
Because naltrexone reduced the in?ammatory histology of DSS-induced colitis, the expression of several genes of inter est, including both cytokines and doWnstream mediators, Was examined by real-time RT-PCR. Expression of beta-actin, cytokines IL-5, IL-6, IL-l2 and transcription factors STAT3
and STAT4, Were assessedusing 18S rRNA as an endogenous control. The expression of beta-actin and IL-5 Were not sig
evidence also indicated that subsequent naltrexone treatment had a dramatic impact on these pro-in?ammatory signaling
60
65
decreases in cytokine expression also proved to be func tionalireducing the expression of the doWnstream signaling molecules, STAT3 and STAT4. By moderating the over stimulation of immune responses and restoring cytokine lev
els, naltrexone treatment alloWed a more normal mucosal structure to reappear. By this means, naltrexone treatment
ni?cantly changed by either DSS+saline or by DSS+NTX (FIG. 8A). By contrast, cytokines IL-6 and IL-l2, knoWn to
US 7,879,870 B2
17
reversed the increase in both the molecular markers of disease
18
6. The method according to claim 1, Wherein said boWel
disease is Crohns disease or ulcerative colitis.
antibodies, are designed to eliminate pro-in?ammatory cytokines, these therapies carry an increased risk of infection due to immune suppression. HumaniZed monoclonal anti
bodies also shoW diminished e?icacy over time and have
7. The method according to claim 1, Wherein said pharma ceutically acceptable salt is a hydrochloride salt thereof. 8. The method according to claim 1, Wherein said opioid antagonist is provided as a pharmaceutical composition. 9. The method according to claim 8, Wherein said pharma ceutical composition is administered once per day in the
evening or at bedtime.
10. The method according to claim 8, Wherein said phar maceutical composition is administered once per day in the
morning or after Waking from sleep. 11. The method according to claim 8, Wherein said phar
maceutical composition is formulated as a solid dosage form suitable for oral administration. 12. The method according to claim 11, Wherein said solid dosage form is an immediate release formulation comprising an opioid antagonist and an excipient.
20
compliance.
While the invention has been described With reference to
to the teachings of the invention Without departing from the essential scope thereof. Therefore, it is intended that the invention not be limited to any particular embodiments dis closed as the best mode contemplated for carrying out this invention, but that the invention Will include all embodiments falling Within the scope of the appended claims. The invention claimed is: 1. A method for treating a boWel disease comprising administering to a subject in need thereof a therapeutically effective dose less than 50 mg of an opioid antagonist effec
tive to treat a boWel disease in said subject, Wherein said boWel disease is characterized by in?ammation or ulceration
25
13. The method according to claim 12, Wherein said excipi ent is selected from the group consisting of sucrose, cellulose, and combinations thereof. 14. The method according to claim 8, Wherein said phar maceutical composition is formulated as a topical dosage form suitable for topical administration. 15. The method according to claim 8, Wherein said phar maceutical composition of a therapeutically effective dose less than 50 mg is formulated as a liquid dosage form suitable for oral administration. 16. The method according to claim 8, Wherein said liquid
30
of the intestinal Wall and Wherein the opioid antagonist is selected from the group consisting of naltrexone, nalmefene,
35
40
stool consistency.
3. The method according to claim 1, Wherein said boWel disease is further characteriZed by in?ammation or ulceration
of the small intestine or colon.
17. The method according to claim 8, Wherein said liquid carrier comprises Water. 18. The method according to claim 1, Wherein said thera peutically effective dose less than 50 mg is from about 1.75 mg to about 4.5 mg of said opioid antagonist. 19. The method according to claim 1, Wherein said thera peutically effective dose less than 50 mg is from about 1.75 mg to about 3 mg of said opioid antagonist. 20. A method of pharmaceutical treatment comprising orally administering to a human subject having Crohns dis
ease or ulcerative colitis a therapeutic pharmaceutical com
4. The method according to claim 1, Wherein said boWel disease is further characteriZed by the presence of a ?stula. 5. The method according to claim 1, Wherein said boWel
to about 4.5 mg of naltrexone, nalmefene, naloxone, or a hydrochloride salt thereof in an immediate release solid dos age formulation.
US 20070259939Al
(19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0259939 A1 Stebbing (43) Pub. Date: NOV. 8, 2007
(54)
USING NALTREXONE AS A MULTI-PURPOSE HEALTH SUPPLEMENT TO IMPROVE THE HUMAN CONDITION AND PREVENTING MULTIPLE DISEASES AND INFIRMITIES BY STIMULATING IMMUNE SYSTEM VITALITY AND ROBUSTNESS Publication Classi?cation
(51)
(2006.01)
(52)
(75) Inventor:
(57)
ABSTRACT
Norfolk, NE (U S)
Correspondence Address:
BANNER & WITCOFF, LTD. TEN SOUTH WACKER DRIVE, SUITE 3000 CHICAGO, IL 60606
(73) Assignee:
11/550,742
Oct. 18, 2006
feelings of Well-being produced by naltrexone may also have far-reaching eifects, as suggested by studies shoWing
that people With positive attitudes recover more quickly from serious illnesses, for example. In another aspect of the invention, naltrexone may be used to prevent substance addiction before it ever starts, by blocking the internal positive response that normally results from the use of chemical substances.
US 2007/0259939 A1
Nov. 8, 2007
USING NALTREXONE AS A MULTI-PURPOSE HEALTH SUPPLEMENT TO IMPROVE THE HUMAN CONDITION AND PREVENTING MULTIPLE DISEASES AND INFIRMITIES BY STIMULATING IMMUNE SYSTEM VITALITY AND ROBUSTNESS CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to US. Provisional Application No. 60/797,587 ?led May 4, 2006.
FIELD OF THE INVENTION
dose levels. The FDA approved dosage siZe for treatment of alcohol dependency is a 50 mg tablet, once daily. While taking naltrexone at this dosage level, it is suggested that a counselor should be involved for support and advice and supervision. It also can be given in a sloW release form by injection or surgical implant if the patient is incapable or cannot be depended upon to take the medicine regularly.
SUMMARY OF THE INVENTION
[0006]
[0002]
contrast, embodiments of this invention provide naltrexone as a preventative medicine taken daily, usually in the late evening for greater ef?cacy. It is taken like a vitamin supplement and may prevent many of the diseases that tend
to be susceptible to a strong immune system.
[0007]
[0003] Traditional medicine has long been focused on the cure of a?lictions after they are recognized by the onset of symptoms. Aspects of this invention are dedicated to the proposition that it is better to prevent diseases then to cure
them after they have become established. There are numer ous health supplements and vitamins available noW that are
use of loW dose naltrexone may also reduce the need for pain
relief medications as Well as counter tendencies toWard
experiencing undesirable moods, such as excessive depres sion or anger. Increased feelings of Well-being may also
just for the maintenance and/ or enhancement of good health and vitality. More and more people are desirous of holding onto vigor and vitality as they age, such as baby boomers. Many people are determined to maintain their health and vitality for as long as it is possible to do so, and in?rmity is
often not accepted as inevitable. [0004] Naltrexone has been used in loW dose form since at least the mid 1980s to cure or stabiliZe a groWing list of ailments. It is used for the treatment of a number of serious diseases, such as some cancers, HIV, AIDS and multiple sclerosis. Studies have shoWn naltrexone to have a positive effect in as many as 65% of cancer patients, for example
[0008] In aspects of the invention, naltrexone may be used to prevent substance addiction before it ever starts, by taking it daily. This could result in great personal and ?nancial savings by reducing the occurrence of addiction and thus the need for rehabilitation programs. Unlike existing medica
tions such as Antabuse, a drug that Will induce nausea or
even unconsciousness if it is taken folloWed by alcohol consumption, naltrexone is more effective When taken prior
to drinking alcohol because it reduces or removes the desire to drink.
stopping the spread of tumors, as Well as causing remission in 30% of the patients. LoW dose naltrexone functions by blocking opioid, or endorphin, receptors in various types of
[0009]
endorphin level may also dull or kill pain, and often results in a feeling of Well-being because endorphins are natural mood elevating chemicals in the brain. In contrast, stress
may cause a marked reduction in endorphins, Which often
approximately 0.5 and 5 milligrams of naltrexone, and preferably betWeen 1.75 and 4.5 milligrams of naltrexone. An aspect of the invention provides administration of the daily dose of naltrexone in the late evening hours, such as
betWeen 6:00 pm and 2:00 am, so as to block the opioid
does not correct itself naturally, thus resulting in loWered immune defenses susceptible to a variety of illnesses, such
as autoimmune diseases or cancer. Cancer has occasionally
been observed in patients after about tWo to six years folloWing a period of extreme stress. [0005] With respect to the treatment of alcohol addiction, naltrexone may be effective because it eliminates the neural
immune system by causing an increase in endorphin and enkephalin production. In fact, tests have shoWn that taking
US 2007/0259939 A1
Nov. 8, 2007
diluted in liquid, as long as it is present in a readily bioavailable form. [0010] An embodiment of the invention is a method to stimulate the immune system of a patient prior to the onset of an illness via a daily dose of naltrexone that is generally in the range of 0.5 to 5 milligrams per dose, and again
behaviors, such as alcoholism, opiate, narcotic and tobacco addiction. With respect to the treatment of alcohol addiction,
naltrexone may be effective because it eliminates the neural
positive reinforcement normally experienced in the brain by blocking the receptors that provide the stimulatory effect felt
from alcohol. As a result of the lack of positive reinforce
ment, there is no internal incentive to drink alcohol. In a
tion of immune system function With marked improvement in disease ?ghting capability. In an aspect of the invention, the administration of a daily dose of naltrexone, for example
in the late evening, may prevent the onset of an illness in a
increase in endorphins resulting from the blockage of endor phin receptors by the naltrexone causes the immune system
to become more effective at ?ghting infection during its early stages. The use of naltrexone as taught here may
many forms of cancer, AIDS, HIV, multiple sclerosis, ALS, AlZheimers Disease, chronic fatigue syndrome, emphy sema, Parkinsons Disease, primary lateral sclerosis, psoria sis, rheumatoid arthritis, sarcoidosis and systemic lupus. For
example, cancer cells are routinely produced in the body, but a healthy immune system generally kills them as they occur. In fact, endorphins added to groWing human cancerous
tissue in a laboratory Petri dish have been observed to kill
the cancerous tissue. In contrast to Waiting for a disease to
Without alcohol, starting for example at about 6:00 pm. Three doses, for a total of 4.5 mg naltrexone, may be taken,
for example tWo or three doses together or single doses over a period of time, such as one per hour, as provides the most effective result for the individual. [0014] It is knoWn that it is very important to have a
surgery or chemotherapy, the disease may be prevented. Additionally, if an illness does become established, the daily naltrexone therapy may reduce or eliminate the need for
various medications to overcome the illness because of the
naturally or naltrexone induced, the increased levels of endorphins result in a better mood and an improved, enhanced and more robust immune system function, Which equates to an improved prognosis due to a greater ability of
the immune system to overcome and defeat a disease. If a
endorphin level may dull or kill pain, as endorphin levels naturally increase When injury occurs. Because naltrexone stimulates an endorphin increase, naltrexone therapy may reduce aches and pains. [0012] The employment of a daily loW dose of naltrexone
may prevent one or more psychological problems in a
of these different combinations constitute various alternative aspects of the present invention. The embodiments
resulting increase of endorphins, Which are natural mood elevating chemicals in the brain. An increased level of endorphins may preclude or prevent the onset of some mental depression or anger, for example, because endor phins are natural anti-depressives and mood enhancers. As a result of the absence of depression and improved mood and
include alternative embodiments to the extent permitted by the prior art. For example, endorphins may be administered
directly Without the use of naltrexone such as in those cases
US 2007/0259939 A1
Nov. 8, 2007
following claims.
What is claimed is:
1. A method to increase endorphin levels in a human or
animal patient comprising a daily administration of a dose of betWeen about 0.5 mg and about 5 mg naltrexone. 2. The method according to claim 1 Wherein the naltrex one is administered to the patient during an evening hour. 3. The method according to claim 2 Wherein the evening hour is betWeen approximately 6:00 pm and approximately
2:00 am.
11. The method according to claim 9 Wherein the chemi cal substance is an opiate. 12. The method according to claim 9 Wherein the chemi cal substance is alcohol. 13. The method according to claim 9 Wherein the chemi cal substance is nicotine. 14. A method to reduce physical pain in a human or animal patient comprising a daily administration of a dose of betWeen about 0.5 mg and about 5 mg naltrexone. 15. The method of claim 14 Wherein the naltrexone is
administered to the patient during an evening hour. 16. The method of claim 15 Wherein the evening hour is betWeen approximately 6:00 pm and approximately 2:00
am.
4. A method to stimulate the immune system of a human or animal patient prior to the onset of an illness comprising a daily administration of a dose of naltrexone. 5. The method according to claim 4 Wherein the dose of naltrexone is betWeen about 0.5 mg and about 5 mg. 6. The method according to claim 4 Wherein the naltrex one is administered to the patient during an evening hour. 7. The method according to claim 6 Wherein the evening
10. The method according to claim 8 Wherein the dose of naltrexone is betWeen about 0.5 mg and about 5 mg.