Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Secretin or gastrin; related peptides
Reexamination Certificate
2001-08-14
2003-12-09
Weber, Jon P. (Department: 1651)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Secretin or gastrin; related peptides
C424S198100, C514S012200
Reexamination Certificate
active
06660831
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention generally relates to methods for aiding in the diagnosis of dysautonomic disorders and dysautonomic conditions and methods for treating individuals diagnosed as having a dysautonomic disorder or a dysautonomic condition. More particularly, the invention relates to a diagnosis method comprising analyzing a stool sample of an individual for the presence of a biological marker (or marker compound) that provides an indication of whether the invidual has, or can develop, a dysuatonic disorder or dysautonomic condition, as well as a therapuetic method for treating a dysautonomic disorder or dysautonomic condition by administration of, e.g., secretin, neuropeptides, peptides and/or digestive enzymes.
BACKGROUND
Familial Dysautonomia (FD), which is also known as Riley-day syndrome, is an autosomal recessive sensory neuropathy that affects approximately 1 in 4,000 individuals of Ashkenazi Jewish descent. This disorder is marked by a reduction of unmyelinated and small myelinated fibers as well as a reduction of dopamine-beta-hyrozylase in the bood. FD decreases both the sympathetic neurons and the peripheral small fibers that modulate temperature regulation. It is thought to arise from both the failure of intrauterine development of neurons and their postnatal development. Symptomotology of FD includes, e.g., renal disease, corneal ulcerations, mental retardation, loss of pain and vibratory senses, in coordination of movements, diarrhea, esophageal reflux, secretory diarrhea, gastrointestinal paresis, hypotension, facial abnormalities, altered dentition, increased salivary secretion, abnormalities of the sweat glands, bowel distension, fecal impaction, prolonged QT intervals (>440), risk of sudden death, and orthostatic syncope. Further features include decreased pain sensation, decreased temperature regulation, difficulty feeding, lack of overflow tears while crying, recurrent pneumonias, scoliosis or hyperkyhsis, increased sweating and skin blotching, decreased stature, as well as other conditions associated with autonomic dysfunction.
Currently the underlying biochemical and genetic defects which cause the FD disorder are unknown. The gene which causes this disorder has been mapped to chromosome 9, the q31-33 region. Presently, there is no prenatal screening test for this condition, and there is no early detection of the condition other than the presence of symptomotology.
There are a plethora of dysautonmic disorders or disorders in which symptomologies of autonomic dysfunction are manifest. For instance, Parkinson's disease is marked by mild to severe autonomic dysfunction including changes in gait, tremor, discoordination, increased salivary flow, and overall loss of autonomic function. Additionally, changes in executive function are typically noted in a Parkinson's patient, often times allowing the patient to appear as having Alzheimer'disease and resulting in misdiagnosis. Executive function disorders are also found in autistic children.
It is known that Parkinson's disease is caused by a deficient state of levo-dopamine in the brain. More specifically, levo-dopa induced dyskinesis in Parkinson's patients is thought to be a result of denervation of the substantia nigra. To this date, medical science has not found a substrate that would allow an injectable form of 1-dopa to reach the brain and successfully cross the blood brain barrier. The current dopamine replacement therapy is aimed at either direct replacement or mimicking the action at the dopamine receptor sites in the brain. SinemetTM and Sinemet CR TM are the two major drugs suited to that end. While the levodopa therapy can create some benficial changs initially, those changes generally wane over time, and produce other problems such as severe sleep disturbance, dyskinesias, and constant nausea. Medical approaches to Parkinson's disease include surgical destruction of the tissue of the brain and the insertion of microelectrodes (deep brain electrical stimulation) to effected portions of the brain. The insertion of electrodes has the advantage of being reversible. These interventions, however, are generally transient and neither produce a permanent change in the Parkinsonsian state nor reverse the effects of the disease.
Parkinson's is widespread throughout the Western hemisphere and was first reported by physician James Parkinson in 1817. Parkison's disease is first detected as a tremor in a limb, and ultimately progresses to include 3 manifestatons: (i) rigidity, which is characterized by “cog-wheel” like movement and “lead-pipe” rigidity; (ii) bradykinesia or slowness in movement, and (iii) postural instability associated with a stooped stance and an impaired gait. These altered movements are features of the motor dysfunction, but in addition there can also be a mental impairment in as many as 40% of all Parkinson's patients.
Some authors suggest that Parkinson's disease is a multifactor neurodegenerative disorder, which evolves due to excesive oxidation. The substantia nigra is susceptible to oxidative damage, which supports this theory of the formation of Parkinson's disease. Abnormalities of the oxidative phosphorlation impair the mitochondria of the substantia nigra, and intensify free radical generation.
While the dyskinesias and loss of executive functioning of the brain receive the most significant mention with respect to Parkinson's, other manifestations exist that are associated with autonomic dysfunction, which are often poorly understood. Some of these manifestations include, e.g., esophageal reflux, diarrhea, and other gastrointestinal dysfunction. In addition, excessive sweating, sleep disturbances and still other symptoms of Parkinson's disease are very similar to those found in Familial Dysautonomia.
Guillaine-Barre Syndrome (GBS) is characterized as an acute autoimmune polyradiculopathy. It generally manifests as a flaccid paresis coupled with areflexia, sensory loss and disturbance, as well as an elevated cerebrospnal fluid protein level. There are multiple variations of GBS, each of which displays a specific subgrouping of symptoms, including those of the Miler Fisher Syndrome group. GBS seen primarily in the United States constitutes a subtype best characterized as a demyelinating type. In the past, GBS was thought to be caused by numerous factors such as the presence of an antecedent viral infection. The most recent hypothesis points to the presence of an antecedent infection of Campylobacter jejuni gastroenteritis. It is further postulated that the presence of this infection produces inflammation of the brain and nervous system and gastrointestinal tract.
Further, a correlation between ketoacidosis and GBS was recently discovered, whereby a patient with diarrhea and fever in a comatose state had a serum blood glucose level of 672 mg/dl, with the presence of urinary ketone bodies. This pancreatic role in the potential formation of GBS (as well as other dysautonomic conditions) is of note and is addressed by the present invention.
Furthermore, tumors of differing types can also produce dysautonomic symptomotology. For example, pheochromocytoma is a well-encapsulated, lobular, vascular tumor, which can occur anywhere in the body. It is made up of chromaffin tissue of the adrenal medulla, or sympathetic paraganglia. Hypertension is the most apparent symptom, reflecting the increased secretion of epinephrine and norepinephrine, and may be either persistent or intermittent. Attacks may occur anywhere from every few months to several times daily, and typically last less than five minutes. Physical and emotional stresses can initiate an attack. During severe attacks, patients may experience headache, sweating, apprehension, palpation, tremor, pallor or flushing of the face, nausea and vomiting, pain in the chest and abdomen, and paresthesias of the extremities, weight loss, and orthostatic hypotension. Inflammation is a hallmark of this condition. Interestingly, these symptoms are co
DeRosa, Esq. Frank V.
F. Chau & Associates LLP
Patten Patricia A
Weber Jon P.
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