Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-12
2002-04-02
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06365593
ABSTRACT:
TECHNICAL FIELD
This invention relates to the diagnosis and treatment of autistic disorder.
BACKGROUND
Autistic disorder or autism is a severely debilitating developmental disorder characterized by a profound deficiency in verbal communication and normal socialization. Autism is typically diagnosed in children between the ages of two or three and six with a diagnosis usually being made based on behavioral symptoms using the guidelines in the Diagnostic and Statistical Manual of Mental Disorders (DSM)(American Psychiatric Association, Washington, D.C., pages 66-71, 1994). The fourth edition of these guidelines, DSM-IV, identifies autistic disorder as one of five separate disorders under the general category of Pervasive Developmental Disorders.
A child is diagnosed as having autistic disorder if the child fits into all of categories A, B, and C as follows (APA, 1994, p. 70-71):
A. A total of six (or more) items from (1), (2), and (3), with at least two from (1), and one each from (2) and (3):
(1) qualitative impairment in social interaction, as manifested by at least two of the following: (a) marked impairment in the use of multiple nonverbal behaviors such as eye-to-eye gaze, facial expression, body postures, and gestures to regulate social interaction; (b) failure to develop peer relationships appropriate to developmental level; (c) a lack of spontaneous seeking to share enjoyment, interests, or achievements with other people (e.g., by a lack of showing, bringing, or pointing out objects of interest); and (d) lack of social or emotional reciprocity.
(2) qualitative impairments in communication as manifested by at least one of the following: (a) delay in, or total lack of, the development of spoken language (not accompanied by an attempt to compensate through alternative modes of communication such as gesture or mime); (b) in individuals with adequate speech, marked impairment in the ability to initiate or sustain a conversation with others; (c) stereotyped and repetitive use of language or idiosyncratic language; and (d) lack of varied, spontaneous make-believe play or social imitative play appropriate to developmental level.
(3) restricted repetitive and stereotyped patterns of behavior, interests, and activities, as manifested by at least one of the following: (a) encompassing preoccupation with one or more stereotyped and restricted patterns of interest that is abnormal either in intensity or focus; (b) apparently inflexible adherence to specific, nonfunctional routines or rituals; (c) stereotyped and repetitive motor mannerisms (e.g., hand or finger flapping or twisting, or complex whole-body movements); and (d) persistent preoccupation with parts of objects.
B. Delays or abnormal functioning in at least one of the following areas, with onset prior to age 3 years:
(1) social interaction,
(2) language as used in social communication, or
(3) symbolic or imaginative play.
C. The disturbance is not better accounted for by Rett's Disorder or Childhood Disintegrative Disorder.
Although useful, diagnoses based on behavioral symptoms are necessarily subjective.
Once a patient is properly diagnosed, he or she can be treated using any of a variety of different treatments for autism that are currently available. Many of the treatments, however, address the symptoms of the disease, rather than the causes. For example, therapies ranging from psychoanalysis to psychopharmacology have been employed in the treatment of autism. Although some clinical symptoms may be lessened by these treatments, modest improvement, at best, has been demonstrated in a minor fraction of the cases. On the other hand, some therapies provide significant improvement in certain autistic individuals. For example, one recently discovered therapy for autism is the use of secretin as described in WO/US 98/52593, WO/US 99/13061, U.S. Pat. No. 6,020,310, and U.S. Pat. No. 6,197,746. Absent therapy, only a small percentage of autistic persons become able to function as self-sufficient adults.
SUMMARY
The invention is based on the discovery that the levels of one or more methylxanthines, such as 7-methylxanthine, in the urine of children diagnosed with autistic disorder are significantly decreased compared to the levels in normal children. In addition, the levels of xanthines are increased in children with autistic disorder.
In particular, 7-methylxanthine (7-MX) is present in a certain range in the urine of normal children, and the level of this metabolite is significantly decreased in individuals diagnosed with autistic disorder of the same age group. Consequently, the presence in the urine of levels of this metabolite below a certain range is diagnostic of autistic disorder. On the other hand, levels of xanthines are increased in autistic children, and thus, an increased level of a xanthine in an unknown urine sample indicates the likelihood of autistic disorder.
Based on these findings, the invention features a method of diagnosing an individual for an autistic disorder by obtaining a sample of urine from the individual; measuring a level of a methylxanthine (MX) in the urine sample; and comparing the level to a normal control or to a threshold level; wherein a level below the normal control or below a threshold level of about 5.3 micrograms of methylxanthine/ml of urine indicates a possibility of autistic disorder. In this method, an MX level below about 3.4 micrograms of methylxanthine/ml of urine indicates a strong likelihood that the individual has an autistic disorder, and an MX level above about 5.3 micrograms of methylxanthine/ml of urine indicates a strong likelihood that the individual does not have an autistic disorder.
In this method, the normal control can be from an individual or group of individuals who are the same age as the individual being diagnosed, and who do not have any diagnosed symptoms of autistic disorder.
In another aspect, the invention features a method of treating an individual exhibiting one or more symptoms of autistic disorder by administering to the individual an amount of a methylxanthine composition effective to inhibit one or more of the symptoms. In some embodiments, an effective amount of the methylxanthine composition can provide a urine concentration of at least about 5.0 micrograms of methylxanthine/ml of urine. The methylxanthine composition can comprise 7-methylxanthine, a dimethylxanthine, e.g., 1,3 or 3,7 dimethylxanthine, or a trimethylxanthine, such as 1,3,7-trimethylxanthine. The composition can also include one or more of caffeine, theobromine, and theophylline. The methylxanthine can be administered in a variety of ways, e.g., orally or intravenously. The composition can be administered at least once per day or at least once per week, depending, inter alia, on the individual being treated and the severity of symptoms.
In yet another aspect, the invention features another method of diagnosing an individual for an autistic disorder by obtaining a sample of urine from the individual; measuring a level of a xanthine in the urine sample; and comparing the level to a normal control; wherein a level above the normal control indicates a likelihood that the individual has an autistic disorder. In this method, the level of xanthine in the individual who is diagnosed as having symptoms of autistic disorder scan be two or three times the level of the normal control.
A methylxanthine composition is either purified methylxanthine, a compound or product that contains methylxanthine, a compound that increases the level of methylxanthine in the patient, or a compound or molecule that mimics the biological function of methylxanthine. Such a compound can be a methylxanthine precursor or prodrug, which is processed, e.g., metabolized, degraded, or cleaved, in the body to form methylxanthine. Examples include caffeine (1,3,7-trimethylxanthine), theobromine (3,7-dimethylxanthine), and theophylline (1,3-dimethylxanthine). Such a compound can also be a methylxanthine derivative, which includes methylxanthines, and other molecules or compounds bound (e.g., covalently or non-covalently
Rusche James R.
Zhang Jundong
Fish & Richardson P.C.
Repligen Corporation
LandOfFree
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