Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-11-24
2002-12-24
Carlson, Karen Cochrane (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C424S198100, C530S300000, C530S324000
Reexamination Certificate
active
06498143
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates in general to differential diagnosis and therapeutic treatment of autistic syndromes, and in particular to a new and useful method for diagnosing and treating autistic syndromes by measurement and administration of secretin.
BACKGROUND OF THE INVENTION
Autistic syndrome (or autism) is a pervasive developmental behavioral disorder of very early onset that is characterized by a fundamental lack of normal interest in other people. (Original description, Kanner L. Autistic disturbances of affective contact.
Nervous Child
1943;2:217-250.) The recent diagnostic criteria (DSM IV) for autistic disorder are shown in Table 3 below from the American Psychiatric Association
1
Epidemiologic studies suggested a prevalence rate of autistic behavior of approximately 2 to 5 cases in 10,000, however, recent surveys including the entire spectrum of the disease indicate that rates of 15 per 10,000 are a more accurate disease prevalence
2.3
. Such figures indicate that this disorder affects four hundred thousand Americans, with significant social and public health costs.
Despite the substantial body of evidence implicating neurobiological factors in the pathogenesis, precise etiologic mechanisms of autism have yet to be identified. In the absence of a clear etiology, although both behavioral and medical interventions are available to improve learning and behavior, there is no evidence of a cure for autism, nor any efficient psychopharmacological treatments for the core symptoms.
Autism is a syndrome with multiple etiologies, as is made clear both by the evidence of neurobiological research and by the catalog of disorders that are present with autistic behaviors
4
. Based on clinical observations, there are subgroups and subtypes of subjects with significantly different patterns of strengths and deficits, different patterns of comorbidity, levels of severity, and different psychological/cognitive profiles. The response to therapeutic trials also showed a wide variety of outcomes, which may support the possibility that there are multiple etiologies for autism. Although we know that genetic, infectious, metabolic, immunologic, neurophysiological, and environmental causes may lead to similar patterns of altered development with autistic behavior, the recognition of these clear neuropathological disorders does not help us to understand the basic pathogenic mechanism of autism.
There is no clear biological marker of autism to allow early diagnosis or screening of this disease even though it is generally believed that early recognition and management is crucial in the prognosis. Under these circumstances, every clinical observation is important and may lead us to a better understanding of this disorder.
While the specific neuropathological mechanism that produces autism is unknown, it is thought to be the result of a dysfunction of particular groups of neurons in the central nervous system. The primary structures implicated in the autistic disorder are the cerebellum, cerebral cortex, and medial temporal structures. One study showed a significant loss of Purkinje cells, and to lesser extent, of granular cells in the cerebellar hemispheres of six autistic subjects
5
. Studies of two patients with autism showed that the hippocampal pyramidal neurons in the CA1 and CA4 fields displayed a decrease in dendritic branching
6
. Metabolic dysfunction of cortical areas was found through measurements by Single Photon Emission Computed Tomography (SPECT)
7
. In addition, involvement of the medial temporal lobe has been implicated by autopsy studies demonstrating increased cell density, and small cell size in the hippocampus, amygdala, enthorhinal cortex and septal nuclei
8
. An additional argument for the temporal lobe involvement is the case report describing a child with a left lateral oligodendroglioma, who fulfilled the criteria of autistic behavior
9
. This case supports the hypothesis that damage to mesial-temporal structures at an early developmental period may lead to the autistic syndrome. Experimental evidence also supports this argument. A two-stage removal of the amygdalo-hippocampal complex in newborn monkeys resulted in behavioral changes (abnormalities of social interactions, absence of facial and body expressions and stereotypical behavior), resembling autism in children
10
. It is important to note that subgroups of autistic children displayed distinct patterns of brain activity in the frontal and temporal regions. Differences were more prominent in the left than the right hemisphere
11
. Four adult patients with autism had regionally decreased blood flow in the right lateral temporal, and in the right, left, and midfrontal lobes compared with controls
2
.
The neurobiological etiology of autism is supported by the observation that epilepsy is a common concomitant of autism
13
, affecting approximately one-third of adults who had childhood autism which usually had began in infancy or adolescence. In addition, different subgroups of patients have exhibited a variety of biochemical/immunological abnormalities. For example, in 20-40% of patients, whole blood serotonin levels are elevated
14
, and platelet serotonin is altered. Other observations include changes in the levels of dopamine-beta-hydroxylase (DBH) in plasma
15
, elevations in the levels of beta-endorphin, norepinephrine, arginine-vasopressin, and abnormally low levels of adrenocorticotropic hormone in 70% of autistic children
16
, however, there are no supporting data for the autoimmune mechanism and the therapeutic trials with steroid treatment are disappointing so far.
Drug trials for autism have included tests of the effects of dopamine agonists, and antagonists to dopamine, serotonin and opiates, as well as beta blockers, ACTH analogs, and oxytocin
18
. Most of these treatments were associated with some beneficial effect in small groups of patients. The broad range of biochemical abnormalities that stimulated this wide diversity of pharmacotherapeutic trials is a clear indication that we are still far from the understanding the main pathological events in the brain resulting in autistic behavior.
Two recent hypotheses of autism are the opioid- and the immune theory. The opioid theory is based on the observation that the main features of autism are similar to features of opiate addiction. The autistic-like behavior elicited by opiate administration include: reduced socialization, affective lability, repetitive stereotyped behavior, episodes of increased motor activity, diminished crying, insensitivity to pain, and poor clinging. Motivated by this similarity, clinical trials have been conducted by using an opioid antagonist, naltrexone, in autistic patients. In an open trial, 8 to 10 children were judged to show a positive response to naltrexone
19
. However, more recent double-blinded studies found that naltrexone treatment failed to produce significant changes in social behavior
20
.
Other researchers suppose that the opioids are derived from food sources. The enzymatic digest of casein and gluten contains peptides with opioid activity
21
. Fukudome and Yoshikawa isolated four opioid peptides from the digest of wheat gluten
22
. One of these peptides occurred in 15 different sites in the primary structure of glutenin, which is high molecular weight protein in wheat and considered as innocent protein in celiac disease. An additional indirect argument for the possible role of exogenous peptides was the presence of an abnormal urinary peptide pattern in patients with autism
23
. Although there is no scientific evidence that these exogenous peptides may enter the bloodstream, open clinical trials in Norway have been undertaken with the long-term elimination of gluten and casein from the diet of patients with autistic behavior and found only mild improvement
24
. As can be seen by prior research studies, while administration of opioids causes autistic behavior trials with specific and very restricted diets and opioid antagonists have not resulted in evident improvement in the behavior a
Beck Victoria
Horvath Karoly
Carlson Karen Cochrane
Fish & Richardson P.C.
Repligen Corporation
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