Methods and compositions for the treatment of symptoms of Williams Syndrome

Abstract

A therapeutic composition for the treatment of the symptoms of Williams Syndrome and the method for preparing the therapeutic agents is disclosed. The therapeutic composition is a stable pharmaceutical composition comprising one or more digestive and/or pancreatic enzymes. The therapeutic composition may be manufactured by a variety of encapsulation technologies. Delivery of the therapeutic composition may be made orally, through injection, by adherence of a medicated patch or other method. Further, a method of using fecal chymotrypsin level as a biomarker for the presence of Williams Syndrome, or the likelihood of an individual to develop Williams Syndrome is disclosed.

Claims

1. A method for treating Williams Syndrome in a patient diagnosed with Williams Syndrome who has been determined to have a fecal chymotrypsin (FCT) level of 8.4 U/gram or less, comprising administering to the patient an effective amount of a pharmaceutical composition comprising digestive enzymes; wherein said digestive enzymes comprise a protease, a lipase, and an amylase; wherein the effective amount of the pharmaceutical composition comprises at least 5,000 U.S.P. Units of protease and no more than 10,000 U.S.P. Units of lipase per kilogram weight of the patient, per day; and wherein Williams Syndrome is treated.

2. The method of claim 1, wherein the pharmaceutical composition further comprises one or more enzymes selected from the group consisting of a hydrolase, a cellulase, a sucrase, and a maltase.

3. The method of claim 1, wherein the digestive enzymes comprise pancreatic enzymes.

4. The method of claim 1, wherein the pharmaceutical composition comprises a mixture of proteases comprising chymotrypsin and trypsin.

5. The method of claim 1, wherein the digestive enzymes are derived from an animal source, a microbial source, a plant source, are synthetically prepared, or a combination thereof.

6. The method of claim 5, wherein the digestive enzymes are derived from the animal source, and wherein the animal source is a pig.

7. The method of claim 1, wherein the pharmaceutical composition comprises at least one amylase, a mixture of proteases comprising chymotrypsin and trypsin, at least one lipase, and papain.

8. The method of claim 1, wherein the pharmaceutical composition comprises the amylase in an amount of from about 10,000 to about 60,000 U.S.P. units/dose.

9. The method of claim 1, wherein the pharmaceutical composition comprises at least one protease and at least one lipase; and wherein a ratio of total protease to total lipase in United States Pharmacopeia (U.S.P.) units ranges from about 1:1 to about 20:1.

10. The method of claim 9, wherein the ratio of total protease to total lipase ranges from about 4:1 to about 10:1.

11. The method of claim 1, wherein the one or more symptoms of Williams Syndrome are selected from the group consisting of abdominal pain, concentration, sensorineural hearing loss, severe weakness in visiospatial construction, a phobia, and a combination thereof.

12. The method of claim 1, wherein the pharmaceutical composition is a dosage formulation selected from the group consisting of a pill, a tablet, a capsule, a microcapsule, a mini-capsule, a time released capsule, a mini-tab, a sprinkle, and a combination thereof.

13. The method of claim 1, wherein the pharmaceutical composition comprises the protease in an amount of from about 10,000 to about 70,000 U.S.P. units/dose.

14. The method of claim 1, wherein the effective amount of the pharmaceutical composition comprises at least 5,000 U.S.P. Units of protease and no more than 7,500 U.S.P. Units of lipase per kilogram weight of the patient, per day.

15. The method of claim 14, wherein one or more symptoms of Williams Syndrome are selected from the group consisting of abdominal pain, concentration, sensorineural hearing loss, severe weakness in visiospatial construction, a phobia, and a combination thereof.

Description

DETAILED DESCRIPTION

(1) The present disclosure provides pharmaceutical compositions and methods for treating symptoms associated with WS, Pervasive Development Disorders, and Dysautonomias. The pharmaceutical compositions described herein include one or more digestive enzymes, which are postulated by the present inventor to assist in proper digest protein and thus to ameliorate the gastrointestinal dysfunction that is associated with the described disorders.

(2) In certain embodiments, the pharmaceutical compositions can include one or more digestive enzymes, wherein the one or more digestive enzymes comprise at least one lipase and at least one protease, and wherein the ratio of total proteases to total lipases (in USP units) ranges from about 1:1 to about 20:1. In some cases, the ratio of total proteases to total lipases ranges from about 4:1 to about 10:1.

(3) In some cases, a pharmaceutical composition for use herein comprises at least one amylase, at least one protease, and at least one lipase. In certain embodiments, the pharmaceutical composition includes multiple proteases, including, without limitation, chymotrypsin and trypsin. In certain embodiments, the composition can further include one or more hydrolases, papain, bromelain, papaya, celluloses, pancreatin, sucrases, and maltases.

(4) The one or more enzymes can be independently derived from animal, plant, microbial, or synthetic sources. In some embodiments, one or more of the one or more enzymes are derived from pig, e.g., pig pancreas.

(5) One exemplary formulation for the treatment of the symptoms of Williams Syndrome is as follows:

(6) Amylase 10,000-60,000 U.S.P

(7) Protease 10,000-70,000 U.S.P

(8) Lipase 4,000-30,000 U.S.P

(9) Chymotrypsin 2-5 mg

(10) Trypsin 60-100 mg

(11) Papain 3,000-10,000 USP units/mg

(12) Papaya 30-60 mg

(13) Additional formulations comprising one or more digestive enzymes may be advantageous including formulations in which the ratio of total proteases to total lipases (in USP units) is from about 1:1 to about 20:1. In some embodiments, the ratio of total proteases to total lipases is from about 4:1 to about 10:1. Such formulations are useful for treating symptoms of WS as well as dysautonomias (e.g., familial dysautonomia, Parkinson's, Guillaine-Barre Syndrome, Aromatic-L-amino acid decarboxylase deficiency, tetrahydrobiopterin deficiency, familial paranganglioma syndrome; multiple system atrophy, dysautonomic symptoms associated with tumors such as pheochromocytoma, chemodectoma, and neuroblastoma; neurally mediated syncope, and SIDS) and pervasive development disorders such as autism, ADHD, ADD, and Asperger's.

(14) Patients below the age of 18 are typically given a dosage such that the formulation would deliver at least 5,000 USP Units of protease and no more than 10,000 USP Units of lipase per kilogram weight of patient, per day. Beneficially the formulation would deliver at least 5,000 USP Units of protease and no more than 7,500 USP units of lipase per Kilogram weight of patient per day. Patients above the age of 18 are typically given no less than 5,000 USP units of protease per kilogram weight of patient per day.

(15) The dosage formulation may be administered by an oral preparation including, but not limited to, an encapsulated tablet, mini-tabs, microcapsule, mini-capsule, time released capsule, sprinkle or other methodology. In one embodiment, the oral preparation is encapsulated using lipid. Alternatively, the oral preparation may be encapsulated using enteric coating or organic polymers. A formulation may also be prepared using lipid encapsulation, direct compression, dry granulation, wet granulation, and/or a combination of these methods.

(16) Fecal chymotrypsin level is a sensitive, specific measure of proteolytic activity; see, e.g., U.S. Pat. No. 6,660,831, incorporated by reference herein. Normal levels of chymotrypsin are considered be greater than 8.4 U/gram. Decreased values (less than 4.2 U/gram) suggest diminished pancreatic output (pancreatic insufficiency), hypoacidity of the stomach or cystic fibrosis. Elevated chymotrypsin values suggest rapid transit time, or less likely, a large output of chymotrypsin from the pancreas.

(17) For the fecal chymotrypsin test, a stool sample is collected from each of the subjects. Each stool sample can be analyzed using an enzymatic photo spectrometry analysis to determine the level of fecal chymotrypsin in the stool; in some cases the assay is performed at 30 C.; see, e.g., U.S. Pat. No. 6,660,831, incorporated by reference herein. Alternatively, other methods, such as the colorimetric method, use of substrates, use of assays, and/or any other suitable method may be used to measure the fecal chymotrypsin levels. The levels of fecal chymotrypsin in the samples of the individuals having Williams Syndrome are compared to the levels of fecal chymotrypsin in individuals not diagnosed with Williams Syndrome to determine if the individuals having Williams Syndrome would benefit from the administration of digestive enzymes.

EXAMPLES

(18) In a study conducted by the inventor, four children diagnosed with Williams Syndrome were examined. Each was administered a pharmaceutical composition as described herein that included digestive enzymes comprising lipases, amylases and proteases. The subjects were given a dosage of 900-2700 mg of digestive enzymes per day. The dosages were taken 3 to 4 times a day with food.

(19) Table 1 illustrates the children's starting fecal chymotrypsin (FCT) levels, prior to administration of the pharmaceutical compositions.

(20) TABLE-US-00001 TABLE 1 SUBJECT AGE SEX FCT LEVELS 1 7 F 3.8 2 4 M 1.2 3 9 F 2 4 17 F 2.2

(21) As seen in Table 1, the fecal chymotrypsin levels of the four subjects are less than 8.4 U/gram, and in fact less than 4.2 U/gram.

(22) As previously discussed, individuals diagnosed with Williams Syndrome have certain mental strengths and weaknesses. Referring to Table 2 below, it can be seen that the subjects had difficulties in concentrating prior to the administration of any digestive enzymes. The inability to concentrate was measured on a scale of 0 to 10, with 0 being an inability to concentrate most of the time and 10 being the ability to concentrate without any trouble. The subjects were monitored at 30, 60, and 90 day intervals of treatment. Over the course of the 90 day treatment, the subjects' ability to concentrate increased.

(23) TABLE-US-00002 TABLE 2 PRE-ENZYME CONCENTRATION SUBJECT LEVEL 30 DAYS 60 DAYS 90 DAYS 1 0 5 6 8 2 2 5 5 9 3 4 5 6 10 4 3 4 9 9 10 = CAN CONCENTRATE WITHOUT ANY TROUBLE 0 = CAN NOT CONCENTRATE MOST OF THE TIME

(24) As previously discussed, individuals diagnosed with Williams Syndrome commonly experience chronic abdominal pain. Referring to Table 3 below, it can be seen that the subjects had stomach pains prior to the administration of any digestive enzymes. The pain was measured on a scale of 0 to 10, with 0 being no pain and 10 being in pain for all or most of the time. The subjects were monitored at 30, 60, and 90 day intervals of treatment. Over the course of the 90 day treatment, the subjects' pain level decreased.

(25) TABLE-US-00003 TABLE 3 PRE-ENZYME STOMACH ACHE SUBJECT LEVELS 30 DAYS 60 DAYS 90 DAYS 1 9 7 5 2 2 8 3 2 0 3 10 8 7 4 4 7 4 2 0 10 = PAIN ALL OR MOST OF THE TIME 0 = NO PAIN OR DISCOMFORT

(26) The foregoing description of the embodiments of the disclosure has been presented for the purposes of illustration and description. It is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. Many modifications and variations are possible in light of this disclosure. It is intended that the scope of the disclosure be limited not by this detailed description, but rather by the claims appended hereto.