Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-12-05
2002-03-26
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S570000, C514S289000
Reexamination Certificate
active
06362226
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a method for treating autism in patients. More particularly, the present invention relates to a method for modulating in vivo levels of glutamine, glycine or both glutamine or glycine in the treatment of autism.
TABLE OF ABBREVIATIONS
AICA
5-amino-4-imidazolecarboxamide
BID
twice a day
CSF
cerebrospinal fluid
DM
dextromethorphan
EAA
excitatory amino acid
g
gram(s)
GABA
gamma-aminobutyric acid
Gln
glutamine
Glu
glutamate
Gly
glycine
kg
kilogram(s)
mg
milligram(s)
&mgr;mol/L
micromole per liter
NMDA
N-methyl-D-aspartate
PA
phenylacetate
PB
phenylbutyrate
PCP
phencyclidine
po
by mouth
SB
sodium benzoate
wk(s)
week(s)
BACKGROUND OF THE INVENTION
Autism is a developmental disorder characterized by social relating and communicating impairments along with restricted, repetitive or stereotypical behavior and onset by three years of age. A genetic basis for the disorder is suggested by observations such as developmental anomalies in autistic patients, increased incidence of autism in siblings of autistic patients, and a tendency for both of a set of monozygotic twins to be either autistic or not autistic (also called “concordance” for a disorder). However, in 75-80% of autistic individuals, no underlying cause is found for the autism. Previous studies have implicated abnormalities involving neurotransmitters including serotonin, norepinephrine, and histamine in some cases of autism.
U.S. Pat. No. 4,994,467 issued Feb. 19, 1991 to Zimmerman discloses a method for treating autism in children by administration of therapeutically effective amounts of a N-methyl-D-aspartate (NMDA) receptor antagonist selected from the group consisting of ketamine and dextromethorphan.
U.S. Pat. No. 5,008,251 issued Apr. 16, 1991 to Gruber (assignee—Regents of the University of California) discloses methods for treatment of autism comprising administration of the compounds including the purine nucleoside 5-amino-4-imidazolecarboxamide riboside (AlCA riboside), AlCA ribotide, ribavirin, and ribavirin monophosphate.
U.S. Pat. No. 5,866,585 issued Feb. 2, 1999 to Fogel (assignee—Synchroneuron) discloses a method for treating tardive dyskinesia using the NMDA receptor antagonists dextromethorphan and memantine.
U.S. Pat. No. 5,506,231 issued Apr. 9, 1996 to Lipton (assignee—The Children's Medical Center Corporation) discloses the treatment of damage to the central nervous system in a patient resulting from infection with HIV with an NMDA receptor antagonist, such as dextromethorphan.
U.S. Pat. No. 5,605,911 issued Feb. 25, 1997 to Olney et al., (assignee—Washington University) discloses methods of treating or preventing central nervous system effects resulting from NMDA receptor hypofunction, including schizophrenia. The methods comprise administration to a patient in need thereof of an NMDA antagonist along with an alpha-2 adrenergic receptor agonist; or alternatively, the administration of an alpha-2 adrenergic receptor agonist drug alone.
U.S. Pat. No. 5,576,323 issued Nov. 19, 1996 to Heinz et al. (assignee—Eli Lilly and Company) discloses compounds that affect excitatory amino acid receptors, including the NMDA receptor, and that may be useful in the treatment of neurological disorders.
Despite the disclosure of the foregoing U.S. patents, there remains significant room for improvement in the treatment of autism, particularly in children. A treatment approach that is based on observed biochemical abnormalities in autistic patients would be desirable in view of the potential applicability of such an approach to the 75 to 80% of autistic individuals having primary autism in which no underlying cause is found. Such an approach is not currently available in the art.
SUMMARY OF THE INVENTION
A method of treating autism in a patient is disclosed. The method comprises administering to the patient an effective amount of a glutamine level reducing agent, a glycine level reducing agent or combinations of these with or without a modulator of the Gly NMDA receptor.
Accordingly, it is an object of this invention to provide an improved method of treating autism, particularly in children.
It is another object of this invention to provide a method of treating autism that is based on observed biochemical abnormalities in autistic patients.
It is a further object of this invention to provide a method of treating autism that is based on observed elevated levels of glutamine and glycine in autistic patients.
It is still a further object of this invention to provide a method of treating autism that pertains to the modulation of glutamine and glycine levels in autistic patients.
Some of the objects of the invention having been stated hereinabove, other objects will become evident as the description proceeds, when taken in connection with the accompanying Examples as best described hereinbelow.
DETAILED DESCRIPTION OF THE INVENTION
Autism is characterized by deficits in sociability, reciprocal verbal and nonverbal communication, repetitive or stereotypical behavior, and onset by 3 years of age. Most (i.e. about 75-80%) autistic individuals have primary autism in which no underlying cause is found.
In screening a series of consecutive autistic probands, the present co-inventors detected 5/36 (14%) who had elevated plasma levels of glutamine (Gln) or glycine (Gly), or elevated levels of both Gln and Gly, on repeated studies. One patient in the screening series was diagnosed as having autism at age 2 years, 10 months. His Gln (mean 884 &mgr;mol/L—normal 370-682 &mgr;mol/L) and Gly (mean 379 &mgr;mol/L—normal 120-315 &mgr;mol/L) levels were consistently elevated above the normal range on all 5 studies done between age 4 years, 1 1 months and age 6. Urine Gln and Gly levels were 1410 &mgr;mol/g creatinine (normal 165-510 &mgr;mol/g creatinine) and 5663 &mgr;mol/g creatinine (normal 569-1395 &mgr;mol/g creatinine), respectively. His cerebrospinal fluid (CSF) Gln was 708 &mgr;mol/L (normal 356-680 &mgr;mol/L) while his CSF Gly level was normal. His electrolytes, anion gap and plasma ammonia levels were all well within the normal range and his urine organic acid profile was normal. Another patient in the series had persistent elevated Gly levels on multiple plasma amino acid profiles. These levels ranged from 324-439 &mgr;mol/L (normal for age ranges from 120-315 &mgr;mol/L).
The present invention thus pertains to the identification of elevated levels of glutamine and glycine as compared to normal levels in autistic patients, and particularly in autistic children. The present invention thus also pertains to a method of treating autism in a patient comprising administering to the patient an effective amount of a glutamine level reducing agent (e.g. phenylbutyrate or PB), a glycine level reducing agent (e.g. sodium benzoate or SB) or combinations of these agents, with or without a modulator of the Gly NMDA receptor (e.g. dextromethorphan or DM). Until the disclosure of the present invention, a role for modulation of in vivo glutamine and glycine levels in the treatment of autism has not been characterized in the art. Correspondingly, prior to the disclosure of the present invention, no motivation can be found in the art to modulate in vivo glutamine and glycine levels in the treatment of autism.
A. General Considerations
Glutamic acid is one of the 20 common amino acids used by all living cells to make protein. The ionized form of glutamic acid, glutamate, is the predominant form of this compound in neutral solutions. In mammals, glutamate serves as the predominant excitatory neurotransmitter in mammalian central nervous systems. See e.g., Olney. J. W., “Glutamate,” pp. 468-70 in
Encyclopedia of Neuroscience
, G. Adelman, ed. (Birkhauser, Boston, 1987). Glutamate (Glu) is also employed in vivo as a precursor in the production of glutamine (Gln), also one of the 20 common amino acids used by all living cells to make protein. As is well known in the art, glutamate and glutamine are structurally very similar, varying only in the presence of an amino group (Gln) instead of a carboxyl grou
McGrew Susan G.
Phillips, III John A.
Jarvis William R. A.
Jenkins & Wilson, P.A.
Vanderbilt University
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