U.S. patent application number 12/350901 was filed with the patent office on 2009-07-09 for pharmaceutical compositions and methods utilizing a d-amino acid.
This patent application is currently assigned to Amino Acids Solutions Inc.. Invention is credited to Daniel Javitt.
Application Number | 20090176715 12/350901 |
Document ID | / |
Family ID | 40521899 |
Filed Date | 2009-07-09 |
United States Patent
Application |
20090176715 |
Kind Code |
A1 |
Javitt; Daniel |
July 9, 2009 |
Pharmaceutical Compositions and Methods Utilizing a D-Amino
Acid
Abstract
The present invention provides a pharmaceutical composition for
oral administration comprising a D-amino acid combined with an
antioxidant selected from the group consisting of vitamin E,
vitamin C, a glutathione or a precursor thereof.
Inventors: |
Javitt; Daniel; (Bardonia,
NY) |
Correspondence
Address: |
TOWNSEND AND TOWNSEND AND CREW, LLP
TWO EMBARCADERO CENTER, EIGHTH FLOOR
SAN FRANCISCO
CA
94111-3834
US
|
Assignee: |
Amino Acids Solutions Inc.
Bardonia
NY
|
Family ID: |
40521899 |
Appl. No.: |
12/350901 |
Filed: |
January 8, 2009 |
Current U.S.
Class: |
514/17.3 ;
514/3.8; 514/458; 514/474; 514/6.8 |
Current CPC
Class: |
A61K 31/145 20130101;
A61K 31/133 20130101; A61K 31/355 20130101; A61P 25/14 20180101;
A61K 31/198 20130101; A61K 31/375 20130101; A61P 25/24 20180101;
A61P 25/18 20180101; A61P 25/16 20180101; A61P 25/28 20180101; A61P
25/00 20180101; A61K 31/198 20130101; A61K 2300/00 20130101; A61K
31/355 20130101; A61K 2300/00 20130101; A61K 31/375 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
514/18 ; 514/458;
514/474 |
International
Class: |
A61K 31/355 20060101
A61K031/355; A61K 31/375 20060101 A61K031/375; A61K 38/06 20060101
A61K038/06; A61P 25/00 20060101 A61P025/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 9, 2008 |
IL |
188,681 |
Claims
1. A pharmaceutical composition for oral administration comprising
a D-amino acid combined with an antioxidant selected from the group
consisting of vitamin E, vitamin C, a glutathione or a precursor
thereof.
2. A pharmaceutical composition according to claim 1 in which the
D-amino acid is selected from the group consisting of D-serine,
D-alanine, D-cysteine, D-homocysteine, or D-threonine
3. A pharmaceutical composition according to claim 1 wherein the
antioxidant is glutathione or a precursor thereof.
4. A pharmaceutical composition according to claim 3 wherein the
glutathione precursor is selected from the group consisting of
L-cysteine or N-acetyl-L-cysteine and racemic versions or
combinations thereof
5. A pharmaceutical composition according to claim 1 wherein the
antioxidant is vitamin E.
6. A pharmaceutical composition according to claim 1 wherein the
antioxidant is vitamin C.
7. A pharmaceutical composition according to of claim 1 where the
D-amino acid and antioxidant are present in molar ratios of between
1:10 and 10:1.
8. A method for treating a neuropsychiatric disorder characterized
by attenuated NMDA neurotransmission comprising administering the
pharmaceutical composition of claim 1
9. The method of claim 8, wherein the neuropsychiatric disorder is
schizophrenia, schizophreniform disorder, psychosis NOS, or
prodromal schizophrenia
10. The method of claim 8, wherein the neuropsychiatric disorder is
Alzheimer's disease.
11. The method of claim 8, wherein the neuropsychiatric disorder is
autism.
12. The method of claim 8, wherein the neuropsychiatric disorder is
depression.
13. The method of claim 8 wherein the neuropsychiatric disorder is
benign forgetfulness.
14. The method of claim 8, wherein the neuropsychiatric disorder is
a childhood learning disorder.
15. The method of claim 8, wherein the neuropsychiatric disorder is
attention deficit disorder.
16. The method of claim 8, wherein the neuropsychiatric disorder is
close head injury.
17. The method of claim 8, wherein the neuropsychiatric disorder is
a movement disorder.
18. The method of claim 17 where the movement disorder is
Parkinsons disease, Huntingtons chorea, Wilsons disease, Tourette's
disease, tic disorders, or obsessive-compulsive disorder.
19. A method for treating a neuropsychiatric disorder characterized
by attenuated NMDA neurotransmission in a patient, the method
comprising administering to a patient diagnosed as suffering from
the neuropsychiatric disorder an oral pharmaceutical composition
comprising a therapeutically effective amount of a D-amino acid
combined with a an anti-oxidant selected from the group consisting
of vitamin E, vitamin C, a glutathione or a precursor thereof
Description
[0001] The present invention relates to a pharmaceutical
composition for treating a neuropsychiatric disorder and to methods
utilizing the same.
BACKGROUND OF THE INVENTION
[0002] D-serine is a naturally occurring amino acid and one of a
class of amino acids that is known to be useful for treatment of
neuropsychiatric disorder but which may cause nephrotoxicity when
administered to rodents. In the brain, D-serine serves as a
modulator of N-methyl-D-aspartate (NMDA)-type glutamate receptors.
Deficiencies of D-serine or of NMDA neurotransmission may
contribute to the pathophysiology of multiple neuropsychiatric
disorders including schizophrenia, Alzheimers disease, attention
deficit hyperactivity disorder, autism, depression, and movement
disorders (Javitt 2000; Tsai 2001). It has been proposed therefore
that oral administration of D-serine at doses of 1 mg-100 g may
serve as a novel treatment for these disorders. Clinical use of
D-serine and of similar D-amino acids is potentially limited by
concerns regarding renal toxicity, which has been observed in
rodent species, especially in the rat. Thus, compounds are needed
that prevent nephrotoxicity when given orally along with
D-serine.
[0003] The ability of D-serine to induce renal injury in rats is
reviewed by (Kaltenbach et al 1979). D-serine induced
nephrotoxicity has been demonstrated since at least 1942, when it
was noted an injurious action of DL-serine administered by stomach
tube in rats maintained on a synthetic deficient in protrain and in
B vitamins. Subsequent studies demonstrated that administration of
100 mg DL-serine induced acute renal necrosis at the junction of
the renal cortex and medulla which was observed when serine was
added to either stock diet or diet deficient in B vitamins. Lesions
were consistently produced reliable with doses as small as 5 mg
D-serine per 100 g. Despite intensive investigation, the mechanism
by which orally administered D-serine induces nephrotoxicity
remains an area of active research.
[0004] Nephrotoxicity induced by D-serine and other related amino
acids is characterized by corticomedullary pathology, such as
necrosis of the straight segment of the proximal tubule in the rat
kidney following oral or intravenous administration. Severity of
nephrotoxicity can be monitored by assessment of serum levels of
creatanine and BUN (Orozco-Ibarra et al 2007). Similar
nephrotoxicity can be induced by compounds structurally related to
D-serine, including D-2,3-aminopropionic acid (DAPA) (Kaltenbach et
al 1979).
[0005] Wachstein et al. investigated the ability of various
compounds to reverse the effects of orally administered DL-serine
(100 mg) as discussed by Kaltenbach et al., (Kaltenbach et al
1982). In all cases, test compounds were administered either
subcutaneously or intramuscularly. These studies showed that
nephrotoxic effects of DL-serine could be blocked by either
DL-methionine or glutathione (GSH) when co-injected with D-serine
in rats protects against the nephrotoxicity. Other compounds
showing partial or full prevention of toxicity included glycine,
DL-threonine, glycolic acid and sodium lactate. Several other
compounds, however, were relativley ineffective including
L-cysteine, sodium thioglycollate, 2,3 dithiopropanol (BAL),
DL-alpha-alanine, L-histidine, L-arginine, DL-valine, butyric acid,
D-glucose, sodium chloride, and sodium acetate. It was hypothesized
that beneficial effects of these compounds were due to suppression
of tubular reabsorption of the D-isomer.
[0006] Subsequent studies demonstrated significant protective
effects of D-alanine, D-threonine, D-homoserine,
DL-alpha-methylserine, beta-hydroxy-DL-leucine, and
alpha-aminoisobutryic acid. As in Wachstein, all compounds were
administered by injection prior to D-serine administration
(Kaltenbach et al 1982). More recently, protective effects of
alpha-aminoisobutyric acid (AIB) have been confirmed. It is
hypothesized that this compound prevents uptake of D-serine into
renal tubular cells, thereby limiting its nephrotoxic effects (Krug
et al 2007)
[0007] In general, nephrotoxic effects of D-serine are considered
to result from its metabolism by D-aminoacid oxidase (DAAO), which
liberates reactive oxygen species such as peroxide (Krug et al
2007; Maekawa et al 2005; Williams and Lock 2005). This theory is
supported by the observation that D-serine is not nephrotoxic is
rats lacking-DAAO (Maekawa et al 2005), and that toxicity can be
prevented by intrarenal injection of equimolar glutathione with
D-serine (Krug et al 2007) or by intraperitoneal administration of
large doses of sodium benzoate (Williams and Lock 2005). However,
this theory is challenged by a recent study that failed to detect
increased reactive oxygen species or peroxidation markers in rat
kidney following D-serine injection. Further, several compounds
with an antioxidant effect failed to prevent D-serine
nephrotoxicity. (Orozco-Ibarra et al 2007). Therefore, not only can
it be concluded from this reference that oxidative stress alone may
be an insufficient model for nephrotoxicity, but this reference
also constitutes a clear teaching away from the discovery of the
present invention that in fact certain antioxidants when
administered together with a D-amino acid are effective for
reducing the risk of nephrotoxicity.
SUMMARY OF THE INVENTION
[0008] Thus, the present invention derives from the discovery that
orally administered precursors of glutathione (GSH), including the
compounds N-acetylcysteine and L-cysteine, prevent nephrotoxicity
induced by the amino acid D-serine. The present invention provides
a method for oral administration of D-serine or similar amino acids
that minimizes risks of nephrotoxicity. This formulation therefore
represents a significant, clinically useful improvement over use of
D-serine or other amino acids alone as medicaments for
neuropsychiatric or other medical conditions.
[0009] D-amino acids in general, and D-serine in specific are
considered appropriate therapeutics in various neuropsychiatric
conditions including schizophrenia, movement disorders, cognitive
dysfunction, memory disorders and attentional disorders. Use of
these compounds in clinical settings, however, is potentially
limited by nephrotoxicity. In animal studies, intravenous or
intraperitoneal administration of glutathione has been shown to
limit toxicity induced by D-serine. However, non-oral routes of
administration are not feasible for clinical treatment,
necessitating alternative approaches. Oral NAC administration is a
widely used treatment for hepatotoxicity, particularly following
acetominophen administration (Amirzadeh and McCotter 2002; Betten
et al 2007), and is equally effective to iv NAC in the majority of
cases (Kanter 2006). However, oral NAC or other glutathione
precursors have not been found to be effective treatments for
nephrotoxicity induced by a wide variety of agents including
contrast agents and chemotherapies. Despite intensive investigation
of treatments that might reverse D-serine nephrotoxicity, oral NAC
or other glutathione precursors have not been evaluated previously
against D-serine-induced nephrotoxicity either in humans or animal
models.
[0010] According to the present invention, there is now some
evidence suggesting that the combination of NAC and L-cysteine
(Groups B&C) are superior to either agent alone (Groups
D&E) as seen in the examples here and after. No one has
previously suggested using the presently suggested combined
treatment, and the observed synergy is an unexpected finding.
[0011] Furthermore, as far as applicant was able to determine, the
research leading to the common invention was the first study to
evaluate NAC in combination with L-cysteine. The observed efficacy
of both NAC and L-cysteine in the present examples is however
consistent with the concept that NAC functions largely by supplying
L-cysteine to the portal circulation as postulated by Dilger and
Baker 2007.
[0012] More specifically, according to the present invention, there
is now provided a pharmaceutical composition for oral
administration comprising a D-amino acid combined with an
antioxidant selected from the group consisting of vitamin E,
vitamin C, a glutathione or a precursor thereof.
[0013] In preferred embodiments of the present invention the
D-amino acid is selected from the group consisting of D-serine,
D-alanine, D-cysteine, D-homocysteine, or D-threonine
[0014] In some preferred embodiments of the present invention the
antioxidant is glutathione or a precursor thereof.
[0015] In other preferred embodiments of the present invention the
glutathione precursor is selected from the group consisting of
L-cysteine or N-acetyl-L-cysteine and racemic versions or
combinations thereof.
[0016] In other preferred embodiments of the present invention the
antioxidant is vitamin E while in yet other preferred embodiments
the antioxidant is vitamin C.
[0017] Preferably, the D-amino acid and antioxidant are present in
molar ratios of between 1:10 and 10:1.
[0018] In another aspect of the present invention, there is
provided a method for treating a neuropsychiatric disorder
characterized by attenuated NMDA neurotransmission comprising
administering the pharmaceutical composition defined above.
[0019] In some preferred embodiments of the present invention the
neuropsychiatric disorder is schizophrenia, schizophreniform
disorder, psychosis NOS, or prodromal schizophrenia
[0020] In other preferred embodiments of the present invention the
neuropsychiatric disorder is Alzheimer's disease.
[0021] The present invention also provides a method for treating a
neuropsychiatric disorder characterized by attenuated NMDA
neurotransmission in a patient, the method comprising administering
to a patient diagnosed as suffering from the neuropsychiatric
disorder an oral pharmaceutical composition comprising a
therapeutically effective amount of a D-amino acid combined with a
an anti-oxidant selected from the group consisting of vitamin E,
vitamin C, a glutathione or a precursor thereof
[0022] Orally active compounds have been described that serve as
glutathione precursors and protect the liver. In particular,
N-acetylcysteine (NAC) is a glutathione prodrug that is currently
approved for treatment of acetaminophen-induced hepatotoxicity
(Atkuri et al 2007) and also to treat glutathione deficiency. NAC
has also been evaluated as potential treatment for nephrotoxicity
induced by a variety of agents, especially intravenous contrast
fluid (Stacul et al 2006). At present however, no oral treatments
are known that prevent oxidative damage to the kidney in response
to D-serine or other potentially nephrotoxic agents.
[0023] Although the efficacy of intravenously administered NAC
against nephrotoxicity has been shown repeatedly (Briguori et al
2007; Recio-Mayoral et al 2007), similar studies using oral NAC
have not found benefit over hydration alone for blockade of
nephrotoxicity due to intravenous contrast (Azmus et al 2005;
Goldenberg et al 2004; Lawlor et al 2007; Sandhu et al 2006;
Shalansky et al 2005). Previous studies have also not found
beneficial effects of oral NAC against experimental nephrotoxicity
induced by cisplatin in rats, although invtravenous NAC was
effective (Dickey et al 2007). Further, it has previously been
reported that kidney NAC levels are not increased following either
acute or chronic oral administration in rat, and that NAC alone may
worsen oxidative stress (Arfsten et al 2007). Other cysteine
prodrugs have also been shown to be ineffective (Li et al 2002). Of
note, however, no studies to date have investigated effects of
orally administered glutathione precursors on D-serine-induced
nephrotoxocity in vivo, or effects of N-acetylcysteine and other
glutathione precursors administered in combination.
[0024] The present invention is further distinguished from prior
treatments for D-amino acid-induced nephrotoxicity in that it
employs oral, rather than intravenous administration of
N-acetylcysteine and L-cysteine for reversal of D-serine induced
nephrotoxicity, and utilizes combinations of glutathione precursors
rather than administration of individual precursors alone. Despite
over 60 years of research in this field, no prior studies have
evaluated use of oral glutathione precursors or other anti-oxidants
such as vitamin E or vitamin C against D-amino acid induced
toxicity.
[0025] The invention is useful in that it permits administration of
oral D-amino acids to humans with reduced risk of nephrotoxicity.
D-amino acids, particularly D-serine, have proven effective for
treatment of neuropsychiatric disorders. The present invention
therefore provides an improved method for treatment of
neuropsychiatric disorders. Other features and advantages of the
invention will be apparent from the following detailed description,
and from the claims.
Definitions
[0026] The term amino acid as used herein refers to amino acid is a
molecule that contains both amine and carboxyl functional groups.
In biochemistry, this term refers to alpha-amino acids with the
general formula H.sub.2NCHRCOOH, where R is an organic substituent.
In the alpha amino acids, the amino and carboxylate groups are
attached to the same carbon, which is called the .alpha.-carbon.
The various alpha amino acids differ in which side chain (R group)
is attached to their alpha carbon. They can vary in size from just
a hydrogen atom in glycine, through a methyl group in alanine, to a
large heterocyclic group in tryptophan.
[0027] The term anti-oxidant as used herein refers to a molecule
capable of slowing or preventing the oxidation of other molecules.
Oxidation is a chemical reaction that transfers electrons from a
substance to an oxidizing agent. Oxidation reactions can produce
free radicals, which start chain reactions that damage cells.
Antioxidants terminate these chain reactions by removing free
radical intermediates, and inhibit other oxidation reactions by
being oxidized themselves. Examples of antioxidants include
glutathione, vitamin C, and vitamin E. The term Vitamin C refers to
L-ascorbate and related molecules. The term Vitamin E refers is the
general name for two classes of molecules (tocopherols and
tocotrienols) having vitamin E activity in nutrition
[0028] The term "neuropsychiatric disorder" as used herein refers
to a disease having a pathophysiological component of attenuated
NMDA receptor-mediated neurotransmission. Examples of such
disorders include schizophrenia, Alzheimer's disease, autism,
depression, benign forgetfulness, childhood learning disorders,
close head injury, and attention deficit disorder.
[0029] The term "schizophrenia" as used herein refers to a
psychiatric disorder that includes at least two of the following:
delusions, hallucinations, disorganized speech, grossly
disorganized or catatonic behavior, or negative symptoms. The term
"schizophreniform disorder" as used herein refers to a psychiatric
disorder that are identical to those of schizophrenia except for
two differences: the total duration of the illness (including
prodromal, active, and residual phases) is at least 1 month but
less than 6 months and impaired social or occupational functioning
during some part of the illness is not required (although it may
occur). The term "psychosis NOS" as used herein refers to a
psychiatric disorder comprising a psychosis but not meeting
criteria for either schizophrenia or schizophreniform disorder.
Patients can be diagnosed as having schizophrenia, schizophreniform
disorder or psychosis NOS using the DSM-IV criteria (APA, 1994,
Diagnostic and Statistical Manual of Mental Disorders (Fourth
Edition), Washington, D.C.). The term "prodromal schizophrenia"
refers to a condition in which symptoms of schizophrenia are
present in attenuated form, so that full criteria for a
schizophrenic disorder are not present.
[0030] The term "Alzheimer's Disease" as used herein refers to a
progressive mental deterioration manifested by memory loss,
confusion and disorientation beginning in late middle life and
typically resulting in death in five to ten years. Pathologically,
Alzheimer's Disease can be characterized by thickening,
conglutination, and distortion of the intracellular neurofibrils,
neurofibrillary tangles and senile plaques composed of granular or
filamentous argentophilic masses with an amyloid core. Methods for
diagnosing Alzheimer's Disease are known in the art. For example,
the National Institute of Neurological and Communicative Disorders
and Stroke-Alzheimer's Disease--and the Alzheimer's Disease and
Related Disorders Association (NINCDS-ADRDA) criteria can be used
to diagnose Alzheimer's Disease (McKhann et al., 1984, Neurology
34:939-944). The patient's cognitive function can be assessed by
the Alzheimer's Disease Assessment Scale-cognitive subscale
(ADAS-cog; Rosen et al., 1984, Am. J. Psychiatry
141:1356-1364).
[0031] The term "autism" as used herein refers to a state of mental
introversion characterized by morbid self-absorption, social
failure, language delay, and stereotyped behavior. Patients can be
diagnosed as suffering from autism by using the DSM-IV
criteria.
[0032] The term "depression" as used herein refers to a clinical
syndrome that includes a persistent sad mood or loss of interest in
activities, which lasts for at least two weeks in the absence of
treatment. The DSM-IV criteria can be used to diagnose patients as
suffering from depression.
[0033] The term "benign forgetfulness," as used herein, refers to a
mild tendency to be unable to retrieve or recall information that
was once registered, learned, and stored in memory (e.g., an
inability to remember where one placed one's keys or parked one's
car). Benign forgetfulness typically affects individuals after 40
years of age and can be recognized by standard assessment
instruments such as the Wechsler Memory Scale (Russell, 1975, J.
Consult Clin. Psychol. 43:800-809).
[0034] The term "childhood learning disorders" as used herein
refers to an impaired ability to learn, as experienced by certain
children. Such learning disorders can be diagnosed by using the
DSM-IV criteria.
[0035] The term "closed head injury," as used herein, refers to a
clinical condition after head injury or trauma which condition can
be characterized by cognitive and memory impairment. Such a
condition can be diagnosed as "amnestic disorder due to a general
medical condition" according to DSM-IV.
[0036] The term "attention deficit disorder," as used herein,
refers to at disorder that is most commonly exhibited by children
and which can be characterized by increased motor activity and a
decreased attention span. The DSM-IV criteria can be used to
diagnose attention deficit disorder.
[0037] The terms "D-serine" and "D-alanine" as used herein refer to
the D isomers of the amino acids serine and alanine, respectively.
As D isomers, rather than L isomers, these amino acids are not
naturally found in proteins.
[0038] The term "nephrotoxicity" or "renal toxicity" as used herein
refers to drug-induced damage to the kidney and, particularly, to
necrosis of the renal tubules. Such damage may be caused by any of
a number of nephrotoxic agents including aminoglycosides,
cis-platinum, intravenous contrast, and D-amino acids.
[0039] The term "pharmaceutical treatment" as used herein refers to
any pharmacological agent, nutritional product, micronutrient or
other such agent whether or not currently approved that is used to
alleviate symptoms of a neuropsychiatric disorder. Such treatments
may be used either in single dose or in repeated doses over days,
weeks, months, years or lifetime of an individual.
[0040] The term "glutathione" or "GSH" as used herein refers to a
tripeptide comprised of the amino acids L-cysteine, L-glutamate and
glycine. It contains an unusual peptide linkage between the amine
group of cysteine and the carboxyl group of the glutamate side
chain. It is synthesized first by combination of L-glutamate and
L-cysteine to form the compound gamma-glutamylcysteine, whereafter
glycine is added to the C-terminal of gamma-glutamylcysteine to
form the glutatione tripeptide. N-acetyl cysteine (NAC) is an
N-acetylated form of the amino acid L-cysteine that has been
approved for pharmaceutical use in the USA. The term "glutathione
precursor" refers to the amino acids or intermediates that
participate in glutathione synthesis, or compounds that readily
interconvert with such agents.
[0041] While the invention will now be described in connection with
certain preferred embodiments in the following examples so that
aspects thereof may be more fully understood and appreciated, it is
not intended to limit the invention to these particular
embodiments. On the contrary, it is intended to cover all
alternatives, modifications and equivalents as may be included
within the scope of the invention as defined by the appended
claims. Thus, the following examples which include preferred
embodiments will serve to illustrate the practice of this
invention, it being understood that the particulars shown are by
way of example and for purposes of illustrative discussion of
preferred embodiments of the present invention only and are
presented in the cause of providing what is believed to be the most
useful and readily understood description of formulation procedures
as well as of the principles and conceptual aspects of the
invention.
EXAMPLE
[0042] The example below illustrates how orally administered
glutathione precursors may be used to minimize nephrotoxic effects
of orally administered D-serine. Subjects consisted of Sprague
Dawley rats, which are known to be sensitive to nephrotoxic effects
of D-serine. Rats were divided into 5 separate groups of four male
and four female animals each. The groups received the following
treatments by oral gavage, in addition to standard diet: [0043]
Group A: D-serine alone; [0044] Group B: D-serine, L-cysteine and
N-acetylcysteine in a ratio of 4:3:1; [0045] Group C: D-serine,
L-cysteine and N-acetylcysteine in a ratio of 2:1:1; [0046] Group
D: D-serine, L-cysteine and N-acetylcysteine in a ratio of 1:0:1;
and [0047] Group E: D-serine, L-cysteine and N-acetylcysteine in a
ratio of 1:1:0.
[0048] In addition, a control group received only standard diet.
Compounds A, B, C, D & E were administered by single oral
gavage at the doses of 50 mg/kg, 100 mg/kg, 200 mg/kg & 400
mg/kg body weight and at the dose volume of 5 ml/kg. Effects of
various doses were investigated in a sequential manner starting
with 50 mg/kg. Dose level was doubled every three days up to four
doses (50 mg, 100 mg, 200 mg & 400 mg).
[0049] During the study, no significant mortality was observed in
any group. All animals survived until study termination. Further,
all animals were free of clinical abnormalities up to the dose of
400 mg/kg.
[0050] Nephrotoxicity was assessed in two ways: first, by
creatanine levels and second by histophathology at necropsy.
[0051] Creatanine levels during D-serine treatment are shown in
Table 1. Both control and D-serine alone groups showed a
significant increase in creatanine levels during chronic treatment,
as did Groups B and C, but not groups D (D-serine+N-acetylcysteine)
and E (D-serine+L-cysteine). For all experimental groups (Groups
B-E), the degree of increase in creatanine during treatment with
combined treatment was significantly less than during treatment
with D-serine alone. Further, for both groups D and E, the degree
of increase in creatanine level was significantly less than for the
control group. The degree of creatanine increase during treatment
was small in both groups D and E and did not differ significantly
between these two treatments. These findings indicate that
L-cysteine and NAC, alone or in combination, significantly reduce
levels of creatanine increase seen with D-serine treatment
alone.
TABLE-US-00001 TABLE 1 Ratio T-test T-test D-ser:L- Pre- Post- post
vs. Group cyst:N- treatment treatment Change vs. D-ser Assignment
acetylcyst Mean stdev mean stdev mean stdev pre alone Control
Control 0.67 0.03 0.77 0.06 0.10 0.08 0.01 A D-serine 0.65 0.03
0.77 0.02 0.12 0.04 0.00 alone (1:0:0) B 4:3:1 0.65 0.03 0.74 0.03
0.10 0.03 0.00 0.0406 C 2:1:1 0.65 0.02 0.72 0.04 0.07 0.04 0.01
0.0111 D 1:0:1 0.65 0.02 0.69 0.02 0.04 0.03 0.22 0.0000 E 1:1:0
0.64 0.04 0.68 0.05 0.04 0.06 0.92 0.0003
Potential nephrotoxic effects of D-serine alone or in combination
with L-cysteine or N-acetylcysteine were also evaluated by
histopathological examination at necropsy. The kidney section in
these studies showed features of early tubular nephrosis changes,
especially involving the tubular structure of medullary and
corticomedullary junction when compared with the kidney section of
control animals, indicating early nephrotoxic changes induced by
the test compounds. The mean severity grade of tubular nephrosis
across compounds is show in Table 2, with the D-serine group
showing a mean nephrosis grade of 1.91 (mild). Both the 4:3:1
(Group B) and 2:1:1 (Group C) combinations of D-serine, L-cysteine
and N-acetylcysteine showed reduced nephrosis ratings compared to
D-serine alone, although nephrosis ratings with combined D-serine
and L-cysteine (Group D) alone or combined D-serine and
N-acetylcysteine alone (Group E) were slightly higher than those
with D-serine alone (Group A).
[0052] Taken together, these findings indicate that a 2:1:1 ratio
of D-serine:L-cysteine:N-acetylcysteine produces both decreased
rise in creatanine and also less evidence of histopathological
evidence of nephrotoxicity vs. D-serine alone, and thus represents
a preferential oral formulation. Other combinations also show
superiority in either the creatanine or hydronephrosis assay with
no significant inferiority in either assay and thus may also be
used as embodiments of this invention.
TABLE-US-00002 TABLE 2 Results of histopathological examination
Nephrosis Group Compostion and ratio level Control Vehicle Control
(Water) A D-serine alone 1.91 B D-serine + L-cysteine +
N-acetylcysteine (4:3:1) 1.00 C D-serine + L-cysteine +
N-acetylcysteine (2:1:1) 1.33 D D-serine + L-cysteine +
N-acetylcysteine (1:0:1) 2.00 E D-serine + L-cysteine +
N-acetylcysteine (1:1:0) 2.00
DETAILED DESCRIPTION
[0053] The invention describes a method for reducing risk of
nephrotoxicity during oral treatment with a D-amino acid,
comprising a composition containing a D-amino acid combined with an
orally active antioxidant. The invention also describes an improved
method for treating a patient diagnosed as suffering from a
neuropsychiatric disorder having a deficit in neurotransmission via
the NMDA receptor, for whom D-serine treatment might be desirable.
The present invention has the advantage of decreasing risk of
nephrotoxicity during treatment with D-serine or other
neuropsychiatric illness.
[0054] The treatment method of the invention entails administering
to a patient diagnosed as having a neuropsychiatric disorder an
oral pharmaceutical composition containing a therapeutically
effective amount of (i) a D-amino acid including but not limited to
D-serine, and (ii) an orally effective anti-oxidant, including but
not limited to glutathione, N-acetylcysteine, L-cysteine or
glutathione precursors. D-amino acids, glutathione and glutathione
precursors are commercially available (e.g. Sigma Chemicals, St.
Louis, Mo.)
[0055] Typically, in this invention, the antioxidant is given in
molar ratios of 10:1 to 1:10 with the D-amino acid, with preferred
embodiments having ratios of between 4:1 and 1:1. Typically, the
D-amino acid is given in doses of 1 g/d-100 g/d. A typical
implementation of this invention, therefore, would be to administer
a formulation consisting of 8 g D-serine and 2 g N-aceytlcysteine,
L-cysteine or a combination thereof in 1-3 daily divided doses. In
all of the methods of the invention, glutathione or glutathione
precursors can be combined with or replaced with the antioxidants
vitamin E or vitamin C.
[0056] In all of the methods of the invention, appropriate dosages
of D-amino acids combined with NAC, L-cysteine or other NAC
precursors can readily be determined by those of ordinary skill in
the art of medicine by monitoring the patient for signs of disease
amelioration or inhibition, and increasing or decreasing the dosage
and/or frequency of treatment as desired.
[0057] The pharmaceutical compositions can be administered to the
patient by any, or a combination, of several routes other than
intravenous or intramuscular, such as oral, trans-mucosal (e.g.,
nasal, vaginal, etc.), pulmonary, transdermal, ocular, buccal, or
sublingual. Solid compositions for oral administration can contain
suitable carriers or excipients, such as corn starch, gelatin,
lactose, acacia, sucrose, microcrystalline cellulose, kaolin,
mannitol, dicalcium phosphate, calcium carbonate, sodium chloride,
lipids, alginic acid, or ingredients for controlled slow release.
Disintegrators that can be used include, without limitation,
micro-crystalline cellulose, corn starch, sodium starch glycolate
and alginic acid. Tablet binders that may be used include, without
limitation, acacia, methylcellulose, sodium carboxymethylcellulose,
polyvinylpyrrolidone (Povidone), hydroxypropyl methylcellulose,
sucrose, starch, and ethylcellulose.
[0058] Liquid compositions for oral administration prepared in
water or other aqueous vehicles can include solutions, emulsions,
syrups, and elixirs containing, together with the active
compound(s), wetting agents, sweeteners, coloring agents, and
flavoring agents. Various liquid and powder compositions can be
prepared by conventional methods for inhalation into the lungs of
the patient to be treated.
[0059] Alternatively, the pharmaceutical composition can be
formulated as a chewing gum, lollipop, or the like.
[0060] It will be evident to those skilled in the art that the
invention is not limited to the details of the foregoing
illustrative examples and that the present invention may be
embodied in other specific forms without departing from the
essential attributes thereof, and it is therefore desired that the
present embodiments and examples be considered in all respects as
illustrative and not restrictive, reference being made to the
appended claims, rather than to the foregoing description, and all
changes which come within the meaning and range of equivalency of
the claims are therefore intended to be embraced therein.
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