Date: Mon, 11 Oct 1999 11:12:20 EDT
To: Multiple recipients of list <>
Subject: II:  Patent: Use of ibogaine for treating neuropathic pain

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Ibogaine is a drug found in the roots of Tabernanthe iboga, a shrub from
Gabon, in equatorial west central Africa. Ibogaine has been known since
the 1800's as an agent which at low doses has psychostimulant
properties, and at high doses can induce a hallucinatory (oneirophrenic)
state. For this reason it has been used in the Gabonese society for
initiation ceremonial rites.
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
addictive drugs. Discovery of this property of ibogaine led to the
issuance of a number of U.S. patents to Howard S. Lotsof, including U.S.
Pat. No. 4,499,096 (issued in 1985, concerning heroin addiction), U.S.
Pat. No. 4,587,243 (issued in 1986, concerning cocaine and amphetamine
abuse), U.S. Pat. No. 4,857,523 (issued in 1989, concerning alcohol
abuse), U.S. Pat. No. 5,026,697 (issued in 1991, concerning tobacco and
nicotine), and U.S. Pat. No. 5,152,994 (issued in 1992, concerning
people suffering from multiple drug dependencies).
Lotsof's assertions regarding the usefulness of ibogaine in reducing
various types of drug dependencies are consistent with evidence
generated in several studies on laboratory animals. For example, in
rats, ibogaine reduces morphine self-administration and ameliorates
symptoms associated with morphine withdrawal and decreases preference
for cocaine consumption; see, e.g., Glick et al 1991, Glick et al 1992,
Sershen et al 1992, Cappendijk and Dzoljic 1993, and Sershen et al 1994
(full citations to articles are provided below).
Additional information on various cellular mechanisms involved in
ibogaine's activity are provided in Deecher et al 1992, Sershen et al
1992, Glick et al 1993, and Popik et al 1994. For example, it appears
that ibogaine inhibits binding to a dopamine transporter site (Sershen
et al 1992), to a kappa opioid receptor site (Deecher et al 1992), to a
voltage-dependent sodium channel site (Deecher et al 1992), and to an
NMDA glutamate receptor ion channel site (Popik et al 1994). It is not
clear what functional significance these findings may have, because the
studies were conducted using receptor binding assays, and a serious
limitation of such assays is that they shed no light on whether an agent
acts as an agonist or antagonist, or, indeed, whether its binding ac
tivity might produce a mixture of agonist and antagonist effects which
cancel out to yield no net effect on receptor function.
The recent report by Popik et al (1994) that ibogaine inhibits binding
to an NMDA receptor ion channel site is of special interest in relation
to the potential of ibogaine for counteracting drug dependencies.
Although the evidence from the Popik et al receptor binding study does
not clarify what type of action it may have at the NMDA subtype of
glutamate receptor, it has been reported recently that agents which are
known antagonists of NMDA receptors can prevent the development of
tolerance to opiate analgesics (see Marek et al 1991; Trujillo and Akil
1991; Ben-Eliyahu et al 1992; Tal and Bennett 1993), to benzodiazepine
anxiolytics such as diazepam (sold under the trade name VALIUM; Turski
et al, PCT patent application WO 94/01094), to cocaine (Pudiak and Boza
rth 1993), and to alcohol (Wu et al 1993). Accordingly, it was
postulated in Popik et al 1994 that the action of ibogaine in blocking
drug tolerance, craving, and dependence may signify that it acts as an
antagonist at NMDA receptors.
The Applicant has conducted recent experiments using functional bioassay
techniques demonstrating unequivocally that ibogaine does act as an
antagonist at NMDA receptors, and that it also acts as an antagonist at
sigma receptors. Both of these discoveries are important aspects of this
invention, and have not been previously reported.
In addition, the present invention pertains, not to blocking drug
addiction mechanisms, but to an entirely separate and distinct use for
ibogaine, which involves the reduction or prevention of brain damage
caused by ischemia (inadequate blood flow to the brain, as occurs during
stroke, cardiac arrest, and trauma), hypoxia (inadequate oxygen supply
to the brain, as occurs during suffocation, drowning, carbon monoxide
poisoning, etc.), and certain other types of crises or conditions. These
crises or conditions generate a process in the central nervous system
(CNS) known as "excitotoxicity". Since this subject is complex,
additional information is provided below on excitotoxicity, on the role
of glutamate as an essential neurotransmitter under healthy conditions a
nd as a deadly neurotoxin under certain abnormal conditions, and on the
roles of NMDA receptors and NMDA antagonist drugs under such conditions.
This is a brief overview; additional information on these topics is
provided in numerous articles and books, including Choi 1988 and Olney
1989 (review articles) and in the multi-volume treatise on the central
nervous system edited by Adelman (either the 1987 or the 1995 edition).
Additional newly-developed information on the neuronal circuitry
described herein is provided in a co-pending U.S. patent application,
Ser. No. 08/381,334, co-invented by the same Applicant herein, entitled