New Ibogaine patent
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Wed Oct 18 10:45:04 EDT 2006
Ibogaine for Hep C, yet another Howard patent ;)
Agent: Hogan & Hartson LLPIPGroup, Columbia Square - Washington, DC, US
Inventor: Howard S. Lotsof
Class: 514214030 (USPTO), (Intl Class)
CROSS REFERENCE TO RELATED APPLICATIONS
 This application claims priority under 35 U.S.C. .sctn. 119(e)
to U.S. Patent Application Ser. No. 60/668,574 filed Apr. 6, 2005 and
to U.S. Patent Application Ser. No. 60/720,467 filed Sep. 27, 2005,
both of which are incorporated herein in their entirety.
STATEMENT REGARDING SPONSORED RESEARCH OR DEVELOPMENT
 "Not Applicable."
REFERENCE TO SEQUENCE LISTING
 "Not Applicable."
BACKGROUND OF THE INVENTION
 1. Field of the Invention
 The present invention relates to compositions for the treatment
of Hepatitis. More specifically, the present invention is directed to a
composition including ibogaine and/or noribogaine, and methods of using
the same. Still more specifically, the present invention is directed to
a composition and the use of a composition comprising one or more of
ibogaine, its active salts and principal metabolite noribogaine to
treat somatic complaints, elevated liver enzymes and viral load in
patients with susceptible hepatitis C.
 2. Description of Related Art
 Hepatitis C is a member of the group of viruses known as
Flaviviridae. The virus was isolated from a blood-borne non-A, non-B
viral hepatitis genome and is identified as nonA, nonB. The virus
duplicates by RNA replication and is prone to mutation. Approximately
1.8 percent of the population test positive for viral hepatitis C(HCV)
antibodies. Chronic HCV affects three to four million individuals in
the United States and occurs in greater than 80 percent of the
individuals infected with acute HCV. A minority of patients,
approximately 15 percent, may clear the virus naturally. The infection,
however, is lifelong in the majority of infected individuals and may be
life threatening to them.
 The virus is principally transferred through blood, though other
vectors cannot be ruled out. Subsets of the population including
intravenous drug users and intravenous drug users in recovery may have
chronic HCV infection rates of 70 to 90 percent. Chronic HCV may
progress rapidly or slowly and there is significant diversity of
progression. Symptoms for chronic HCV tend to be nonspecific including
fatigue, high ALT and AST levels, muscle and joint pain and
right-upper-quadrant discomfort or tenderness of the liver. HCV
infection is a major risk factor for cirrhosis and liver cancer. An
estimated 8,000 to 10,000 fatalities a year are caused by hepatitis C
in the United States.
 The principal conventional therapy for the treatment of chronic
HCV is a therapy of interferon or pegylated interferon in combination
with riboviron (as set forth in U.S. Pat. Nos. 6,172,046 and
6,824,768). This therapy leaves much to be desired. Dose regimens,
depending on genotype, are 24 or 48 weeks and may be required to be
extended or repeated if not efficacious in obtaining a sustained
virologic response (SVR) that is the desired outcome for this
combination therapy. This therapy, depending on the form and dose of
interferon, the genotype of HCV and other factors, demonstrates
efficacy of 2 percent to 75 percent. Relapse, depending on study, dose,
genotype and other factors, may be as high as 48 percent in subjects
who demonstrated a SVR at the completion of combination therapy.
Adverse events and side effects, including possible fatal adverse
events due to interferon riboviron combination therapy are significant.
 Side effects and medication warnings consist of neuropsychiatric
events that may include suicide, depression, return to drug abuse,
psychosis, hallucinations, bipolar disorders and mania. Other side
effects may be bone marrow toxicity including cytopenias, thyroid
disorders, hyperglycemia, diabetes; cardiovascular disorders including
hypotension, arrhythmia, tachycardia, cardiomyopathy, angina pectoris
and myocardial infarction. Additionally, the following signs and/or
conditions may be caused or aggravated by interferon riboviron
combination therapy: Respiratory failure or collapse including death,
fatal and nonfatal ulcerative hemorrhagic/ischemic colitis, abdominal
pain, bloody diarrhea, fatal and nonfatal pancreatitis, rheumatoid
arthritis, systemic lupus, loss of vision, retinopathy, and retinal
hemorrhages. Anaphylaxis may occur and interferon riboviron combination
therapy should be considered as a mutagen effecting DNA and as a
 Interferon riboviron combination therapy is also dangerous to
pregnant women directly and indirectly when used as a therapy in the
significant other of a pregnant woman or a woman who may become
pregnant. This therapy is anticipated to be an abortifacient.
 Ibogaine, ibogamine and tabernanthine are among at least 12
alkaloids found in the Tabernanthe iboga plant of Gabon, West Africa.
The Gabonese, as well as Africans in other countries on that continent,
have used the iboga alkaloids in the Bwiti religion and Mbiri medical
societies principally during the last century or two by European
 Isolation and identification of ibogaine was accomplished by
Dybowski and Landrin (Compt. rend. ac. sc. 133:748, 1901).
 Dr. Robert Goutarel considered by two generations of French
chemists to be the "father of ibogaine research" in collaboration with
Maurice-Marie Janot filed U.S. Pat. No. 2,813,873 (Nov. 19, 1957)
entitled Derivatives of the ibogaine alkaloids. A review of the field
followed. Goutarel R, Gollnhofer O & Sillans R, Pharmacodynamics And
Therapeutic Applications of Iboga and Ibogaine. (Psychedelic Monographs
& Essays, 6:71-111, 1993).
 The structure of ibogaine was investigated by Dickel et al
(J.A.C.S. 80:123, 1958). The first total synthesis was cited by Buchi
et al. (J.A.C.S. 88, 3099, 1966).
 Jurg Schneider and Marie McArthur published Potentiation Action
Of Ibogaine On Morphine Analgesia (Experiential 12:323-24, 1956)
demonstrating a direct effect of ibogaine on opioids. Cerebral
Pharmacokinetics Of Tremor-Producing Harmala And Iboga Alkaloids
(Zetler et al., Pharmacology 7(4):237-248, 1972) identified noribogaine
as well as, reporting on its tremorgenic effects.
 Ibogaine's interaction with Substance P and Substance P's
effects on the perception of pain have also been considered.
 Ibogaine has also been used as an adjunctive agent in
psychotherapy and psychoanalysis, and more recently has been described
as an agent that may be able to suppress symptoms of dependence or
withdrawal from drugs having dependence liability. Discovery of this
property of ibogaine led to the issuance of a number of U.S. patents to
Howard S. Lotsof, including patents for ibogaine to treat narcotic
dependency (U.S. Pat. No. 4,449,096), cocaine and amphetamine abuse
(U.S. Pat. No. 4,587,243), alcohol dependency (U.S. Pat. No.
4,857,523), nicotine dependence (U.S. Pat. No. 5,026,697), poly-drug
dependence (U.S. Pat. No. 5,152,994) and U.S. Pat. No. 5,591,738 for
the treatment of chemical dependence with combinations of iboga and
betacarboline alkaloids. These patents initiated two decades of intense
 Following the disclosures in HS Lotsof's U.S. patents cited
earlier, the first publication of clinical reports of the efficacy of
ibogaine in treating chemical dependence was by B. Sisko of the
International Coalition for Addict Self-Help. Sisko B. (Interrupting
Drug Dependency With Ibogaine: A Summary of Four Case Histories. MAPS
Bull. (4)2:15-23, 1993). The work of Sheppard followed in which the
author published case reports and research of The International
Coalition for Addict Self-Help (ICASH), Dutch Addict Self-Help (DASH)
and the Amsterdam Squatters movement. Sheppard SG. (A preliminary
investigation of ibogaine: case reports and recommendations for further
study. J Subst Abuse Treat. (4):379-85, 1994).
 In none of the studies reviewed is the effect of iboga alkaloids
including ibogaine, its nontoxic salts and/or its principal metabolite
noribogaine considered in the treatment of hepatitis C and hepatitis
 Based on a review of interferon, riboviron combination therapy
it is apparent there is still a need for a less harmful and less toxic
therapeutic composition that is useful in the treatment of hepatitis C
and hepatitis C-related complications.
SUMMARY OF THE INVENTION
 In accordance with the present invention it has been
surprisingly discovered that iboga alkaloids are effective in treating
hepatitis C symptoms, including liver swelling, increased ALT, AST and
GGT levels and to reduce HCV RNA viral counts.
 The present invention thus provides methods of treating somatic
complaints, reducing liver enzyme values and reducing viral load of
susceptible hepatitis C in animals by administering to a subject a
therapeutically effective dose of iboga alkaloids comprising one or
more of ibogaine, ibogamine, tabernanthine, their nontoxic salts and/or
the converted principal metabolite noribogaine in a dose and time
sufficient to accomplish those effects.
 The present invention further provides for the administration of
effective doses of the prodrug ibogaine, converted to noribogaine and
producing plasma levels of ibogaine and/or noribogaine sufficient to
reduce somatic complaints, liver enzyme levels and viral RNA in
 The present invention also provides effective doses and dose
regimens of the prodrug ibogaine, its salts and therapeutic
 The present invention further provides for the administration of
effective doses and dose regimens to be provided in single or multiple
doses on a single day or over a period of days in therapeutically
effective doses between 0.1 mg/kg and 25 mg/kg of the prodrug ibogaine,
converted to noribogaine and producing plasma levels of ibogaine and/or
noribogaine sufficient to reduce somatic complaints, liver enzyme
levels and viral RNA in patients having chronic hepatitis C.
 Additional advantages and novel features of this invention shall
be set forth in part in the description that follows, and in part will
become apparent to those skilled in the art upon examination of the
following specification or may be learned by the practice of the
invention. The advantages of the invention may be realized and attained
by means of the instrumentalities, combinations, compositions, and
methods particularly pointed out herein.
DETAILED DESCRIPTION OF THE INVENTION
 The present invention discloses compositions and methods of
treating hepatitis C and hepatitis C-related complications. In general,
the compositions of this invention comprise iboga alkaloids comprising
one or more of ibogaine, ibogamine, tabernanthine, their nontoxic salts
and/or the converted principal metabolite noribogaine in a therapeutic
 While not wishing to be bound by any theory, it is believed that
the agents in the compositions are less harmful and less toxic than
present anti-hepatitis C therapies.
 Methods of using the composition of the present invention and
administering to the host a therapeutically effective amount of a
composition of this invention are further disclosed. The present
invention further provides a method of treating somatic complaints,
reducing liver enzyme values and reducing viral load of susceptible
hepatitis C, comprising administering to a host a therapeutically
effective amount of a composition of this invention.
 Another aspect of the present invention is the shortness of the
treatment period, as compared to existing therapies, in that the
present treatment period may be a single day or a period of
approximately two weeks.
 The basis of the present invention is the finding that certain
plants contain iboga alkaloids that assist in the treatment of
hepatitis C and hepatitis C-related complications. This offers the
advantage of allowing therapeutically effective doses of natural agents
to be used as compared to the dose of synthetic substances that would
be required in order to achieve the same or similar therapeutic effect.
Until this invention, it was not known that natural agents extracted
from the Tabernanthe iboga plant of Gabon, West Africa, could be
combined into one single formulation that would possess the ability to
treat hepatitis C and hepatitis C-related complications.
 Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention pertains. Although
any methods and materials similar or equivalent to those described
herein can be used in the practice of the present invention, the
preferred methods and materials are described.
 The effective amount or effective dose is an amount of the
composition to be administered to the host that treats hepatitis C and
hepatitis C-related complications. Suitable doses of a composition can
be determined readily by various methods known to one skilled in the
art, including generating an empirical dose-response curve, and other
methods used in the pharmaceutical sciences.
 The agents used in the compositions of this invention may be
provided in the form of pure substances, or as root bark of the natural
plant containing the natural agents in concentrations between about 1
to 6 percent of which approximately fifty percent is ibogaine, or as
concentrated plant extracts containing the natural agents in
concentrations between about 5 to 40 percent of which one half is
ibogaine. Doses of the root bark or total alkaloid extract would be
extrapolated to correspond to doses of purified ibogaine in keeping
with the dose recommendations and regimens for purified ibogaine and
associated alkaloids as described in the present invention. The amount
of agent contained in a composition of this invention will depend in
part on the desired results of the treatment, the stage of hepatitis C,
its associated complications, and/or the health of the patient.
 Another embodiment of the present invention includes improved
methods for using the agents. It was discovered that various methods of
administering the present invention to a host achieve therapeutically
effective results, thus allowing therapeutically effective doses of
agents to be administered to patients that suffer from various medical
conditions, for example, conditions that make oral administration and
digestion difficult. Until this invention, it was not known that the
agents of the present invention could be administered by methods that
would treat hepatitis C and hepatitis C-related complications in the
 The present invention thus provides methods of treating
hepatitis C and hepatitis C-related complications comprising
administering a composition of this invention to a host in need of
therapy. The doses, routes of administration, and carriers and/or
adjuvants used may vary based on the view of known procedures for
treatment of hepatitis C and hepatitis C-related complications or the
delivery of any manner of drug product known to those familiar with the
 One feature of the method of using the invention is that the
composition can be administered in the form of a tablet, capsule or
other pharmacologically appropriate carrier, in a parenteral solution,
in a suppository, in a rectal solution, in the form of a tea, or in the
form without plant material in a tablet, capsule, transdermal
technology or other pharmacological carrier, in a parenteral solution,
or in a suppository which contains at least one of the agents
comprising iboga alkaloids.
 The compositions of this invention may also be administered as a
solution and other oral or parenteral administration can be used. For
example, a compound with poor solubility in acidic media may show poor
or erratic bioavailability when absorbed orally. Further, intravenous
administration requires that a drug be administered in a soluble form.
Compounds that are intended for oral administration but are susceptible
to rapid degradation at low pH (i.e. gastric acids) will likely require
protection from low pH environments like the stomach. Protection can
often be afforded by administering the drug in a dosage form with an
acid-resistant coating. Thus, while it is possible to administer the
compositions of this invention alone, the compositions may also be
administered as part of a formulation. For oral administration, the
compositions of this invention can be used in the form of tablets,
capsules, granules, powders, lozenges, syrups, elixirs, solutions,
suspensions, and the like, in accordance with standard pharmaceutical
practice. A dried extract can be compounded into tablets, capsules, or
other solid-dosage form. A solubilized liquid formulation can be
combined with syrup or other agent to formulate suspensions, solutions,
elixirs, or tinctures to improve the taste, potency, or shelf life.
 For parenteral administration, which includes intramuscular,
intraperitoneal, subcutaneous and intravenous use, sterile solutions of
the agents are usually prepared, and the pH of the solutions are
suitably adjusted and buffered.
 Carriers useful in formulating the preparations are commonly
used pharmaceutically acceptable non-toxic carriers such as gelatin,
lactose sodium citrate, salts of phosphoric acid, starch, magnesium
stearate, sodium lauryl sulfate, talc, polyethylene glycol, etc. The
carrier may be used with other additives such as diluents, binders,
buffer agents, preservatives, sweetening agents, flavoring agents,
glazes, disintegrators, coating agents emulsifying agents, suspending
 The dosage regimen may be regulated according to the potency of
the individual agents utilized in the compositions of this invention,
the mode of administration, and the needs of the host depending on
factors such as the degree and severity of the disease state and age
and general condition of the host being treated. Dosing ranges from 0.1
to 25 milligrams of the composition of the present invention per
kilogram of body weight, once or multiple times daily, for one day to
four weeks or longer depending upon the severity and length of
hepatitis C infection and the response of the patient.
 The present invention also provides methods of treating
hepatitis C and related complications in the significant other or
sexual partner of a pregnant female without having an observable toxic
effect on the fetus.
 A further embodiment of the present invention provides for the
treatment of hepatitis C symptoms, including liver swelling, increased
liver enzyme levels, including .gamma.-glutamyl transferase (GGT),
Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) and
Alkaline Phosphatase levels, and for the reduction in HCV RNA viral
counts. Elevated levels of GGT, ALT, AST and Alkaline Phosphatase
indicate injury or trauma to the liver. Conversely, reduced levels of
GGT, AST, ALT and Alkaline Phosphatase indicate reduced trauma or
injury of the liver.
 Another embodiment of the present invention is that it can be
effective in a chemically dependent population--a population which has
greater tendency to be susceptible to hepatitis C infection.
 Another embodiment of the present invention is that it can
concurrently treat signs and symptoms of hepatitis C infection and
chemical dependence disorders.
 The following embodiments are for illustrative purposes only and
are not intended nor should they be interpreted to limit the scope of
 A thirty-three year old male diagnosed as HCV positive and using
1/2 gram of heroin per day was administered 25 mg/kg of ibogaine HCl.
Following the administration of ibogaine, heroin use ceased along with
swelling of the liver and pain in the area of the liver.
 A twenty-six year old male testing positive for HCV and
dependent on heroin and methadone self-administered 14 mg/kg of
ibogaine HCl. AST was reduced from pretreatment level of 201 to post
treatment level of 25. ALT was reduced from pretreatment level of 410
to post treatment level of 50. GGT level was reduced from 155 to 33.
 A sixty year old male testing positive for HCV RNA genotype 1,
administered the following dose regimen of ibogaine HCl. Subject
weighed 79 kg. Doses administered were as total doses and not mg/kg.
Day 1: 10 mg ibogaine HCl. Day 2: 20 mg ibogaine HCl. Day 3: 20 mg
ibogaine HCl. Day 4: 30 mg ibogaine HCl. Day 5: 50 mg ibogaine HCl. Day
6: 75 mg ibogaine HCl. Day 8: 100 mg ibogaine HCl. Day 10: 150 mg
ibogaine HCl. Day 14: 300 mg ibogaine HCl. HCV RNA IU/mL was reduced
from 780,000 to 644,000. Pretreatment Alkaline Phosphatase was 99, AST
was 103 and ALT 195. Post treatment Alkaline Phosphatase 88, AST 89 and
ALT 127. An additional 250 mg of ibogaine HCl further reduced HCV RNA
IU/mL to 384,000. A final dose within this regimen of 250 mg ibogaine
was administered reducing the HCV RNA IU/mL to 154,000.
 A forty-two year old female weighing 160 lbs tested positive HCV
RNA genotype 3. RNA IU/mL was 12,600,000. Subject was administered a
total of 27 mg/kg of ibogaine HCl over a period of 48 hours in the
following regimen: 2 mg/kg, 2 mg/kg, 2 mg/kg, 2 mg/kg, 2 mg/kg, 2
mg/kg, 12 mg/kg, and 3 mg/kg. HCV RNA IU/mL was reduced to 50,100.
Prior to ibogaine therapy patient's urine was dark and stool light.
Post treatment color of urine and stool were normal.
 The foregoing description is considered as illustrative only of
the principles of the invention. Further, since numerous modifications
and changes will readily occur to those skilled in the art, it is not
desired to limit the invention to the exact construction and process
shown as described above. Accordingly, all suitable modifications and
equivalents may be resorted to falling within the scope of the
invention as defined by the claims that follow. The words "comprise,"
"comprising," "include," "including," and "includes" when used in this
specification and in the following claims are intended to specify the
presence of stated features, integers, components, or steps, but they
do not preclude the presence or addition of one or more other features,
integers, components, steps, or groups thereof.
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