Compositions and methods of treatment of Ehlers-Danlos syndromes

Abstract

A method is provided for treatment of symptoms of Ehlers-Danlos Syndromes comprising administration of a composition comprising rubeola virus, histamine and collagen.

Claims

1. A method of treating symptoms of an Ehlers-Danlos Syndrome in a subject suffering therefrom comprising the step of administering to said subject an effective amount of a composition comprising rubeola virus, histamine and collagen wherein the symptom is selected from the group consisting of fatigue, range of motion and emesis.

2. The method of claim 1 wherein the Ehlers-Danlos Syndrome is selected from the group of hypermobile EDS (hEDS) and classical EDS (cEDS).

3. The method of claim 1 wherein the Ehlers-Danlos Syndrome is hypermobile EDS (hEDS).

4. The method of claim 1 wherein the composition comprises rubeola virus in a dosage of from 0.4 TCID.sub.50 to 400 TCID.sub.50.

5. The method of claim 1 wherein the composition comprises histamine in a dosage of from 0.001 mg to 0.1 mg.

6. The method of claim 1 wherein the histamine is a water soluble histamine salt.

7. The method of claim 1 wherein the histamine is histamine phosphate.

8. The method of claim 1 wherein the composition comprises collagen in a dosage of from 0.0001 mg to 0.1 mg.

9. The method of claim 1 wherein the composition further comprises Immunoglobulin.

10. The method of claim 9 wherein the composition comprises Immunoglobulin in a dosage of from 0.0001 mg to 0.3 mg.

11. The method of claim 9 in which the immunoglobulin is human immunoglobulin.

12. The method of claim 9 in which the immunoglobulin is IgG.

13. The method of claim 4 in which the composition comprises rubeola virus in a dosage of from 1 TCID.sub.50 to 10 TCID.sub.50.

14. The method of claim 5 in which the composition comprises histamine in a dosage of from 0.01 mg to 0.05 mg.

15. The method of claim 8 in which the composition comprises collagen in a dosage of from 0.001 mg to 0.01 mg.

16. The method of claim 10 in which the composition comprises immunoglobulin in a dosage of from 0.001 mg to 0.03 mg.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) The present invention is directed to treatment of symptoms of Ehlers-Danlos Syndrome. In particular the invention is directed to treatment of symptoms of one or more symptoms of Ehlers-Danlos Syndrome by the administration of compositions comprising an effective amount of a composition comprising rubeola virus, histamine and collagen,

(2) According to one aspect of the invention a composition is provided which comprises a composition comprising rubeola virus, histamine and collagen. The components can be solubilized in phenylated saline and formulated to be administered by drop (0.05 mL) sublingually at various intervals daily to treat symptoms of EDS and particularly hEDS. Nevertheless, given the heterogeneous causes of the many syndromes that fall under the Ehlers-Danlos label it is anticipated that many patients suffering from other types of EDS will respond to treatment with the compositions of the invention.

(3) According to one aspect of the invention EDS symptoms of pain, fatigue, emesis can be reduced and joint mobility (range of motion) and quality of life measures can be improved by administration of the compositions of the invention.

(4) The compositions of the invention comprise rubeola (measles) virus in a dosage of from 0.4 TCID.sub.50 to 400 TCID.sub.50, more preferably 1 TCID.sub.50 to 10 TCID.sub.50 and most preferably 4 TCID.sub.50. Rubeola virus is commercially available in vaccine form such as attenuated live virus such as Attenuvax® (Merck & Co., Whitehouse Station, N.J.) but those of skill in the art would appreciate that other forms of rubeola virus from other sources could be used in practice of the invention.

(5) The composition further comprises histamine in a dosage of from 0.001 mg to 0.1 mg, more preferably 0.01 mg to 0.05 mg and most preferably 0.008 mg. Various forms of histamine can be used in the practice of the invention such as water soluble histamine salts including histamine dihydrochloride and histamine phosphate. One particularly useful source of histamine is Hollister-Stier Allergy (Spokane Wash.) Those of skill in the art would appreciate that other forms of histamine would be useful in practice of the invention.

(6) Collagen is present in the compositions of the invention in dosages of from 0.0001 mg to 0.1 mg, more preferably 0.001 mg to 0.01 mg and most preferably 0.002 mg. Useful collagen can be denatured or undenatured and of any type derived from any animal source but a particularly preferred collagen is calf or bovine derived collagen from Sigma-Aldrich (also known as Millipore-Sigma).

(7) According to one aspect of the invention immunoglobulin can be incorporated into the compositions comprising Rubeola virus, histamine and collagen. Such compositions can comprise Immunoglobulin in dosages of from 0.0001 mg to 0.3 mg, more preferably 0.001 mg to 0.03 mg and most preferably 0.003 mg. According to one aspect of the invention the immunoglobulin is human immune globulin such as is commercially available as GamaSTAN™ (Talecris Biotherapeutics, Inc. Research Triangle Park, N.C.) which is believed to be primarily IgG but the immunological specificity of the Immunoglobulin is not thought to be relevant to its utility in the practice of the invention.

(8) A particularly preferred composition according to the invention comprises Rubeola virus at a dosage of 4 TCID.sub.50 (Attenuvax®, Merck & Co., Whitehouse Station, N.J.), 0.008 mg histamine (Hollister Stier Allergy, Spokane, Wash.), 0.002 mg calf or bovine derived collagen from Sigma-Aldrich (also known as Millipore-Sigma) and 0.003 mg Immunoglobulin (GamaSTAN™ Talecris Biotherapeutics, Inc. Research Triangle Park, N.C.) in a phenylated saline buffer.

(9) It is preferred that initial treatment will involve four doses per day but patients can titrate their therapy to fewer doses after experiencing a therapeutic effect.

(10) The compositions of the invention can be combined with pharmaceutically acceptable diluents, adjuvants and carriers as would be known to the art. It is contemplated that other suitable components could be combined with the components of the invention but none are required. The compositions can also be administered to the subjects to be treated parenterally or enterally. According to one aspect of the invention the compositions can be administered parenterally to the subjects to be treated such as by subcutaneous injection but other sublingual administration is particularly preferred.

Example 1

(11) According to this example, a woman diagnosed with hEDS was treated by sublingual administration four times daily with one drop (0.05 ml) of a composition comprising Rubeola virus at a dosage of 4 TCID.sub.50 (Attenuvax®, Merck & Co., Whitehouse Station, N.J.), 0.008 mg histamine (Hollister Stier Allergy, Spokane, Wash.), 0.002 mg bovine derived collagen from Sigma-Aldrich (also known as Millipore-Sigma) and 0.003 mg Immunoglobulin (GamaSTAN™ Talecris Biotherapeutics, Inc. Research Triangle Park, N.C.) in a phenylated saline buffer.

(12) When the subject was evaluated after ten (10) days of treatment her physician reported the following:

(13) “After only 10 days, she has had a remarkable alteration of her symptomology. Previously, she was a stay-at-home mother with a fulltime nanny, unable to care for her 3 children, couch-bound & only able to leave the house for perhaps an hour per day, only shop 1×/week after which she would be unfunctional due to fatigue & brain fog. She was consuming both LongActing Oxycontin and Oxycodone/Tylenol @ 6/day.”

(14) “Currently she has ‘more energy than in past 10 years’, is ‘chasing the kids’ around the house, was out of the house for 6 hours yesterday with no collapse afterwards. Her pain has diminished to point of reducing her pain meds from 6 Percocet/day to 2/d within a week, without any withdrawal symptoms. (She has been at this level of daily narcotics for 2 years).”

Example 2

(15) According to this example, a different female subject diagnosed with Type 3 Ehlers-Danlos Syndrome who had been suffering from the syndrome for about eight (8) years was treated by sublingual administration four times daily of one drop (0.05 ml) of a composition comprising Rubeola virus at a dosage of 4 TCID.sub.50 (Attenuvax®, Merck & Co., Whitehouse Station, N.J.), 0.008 mg histamine (Hollister Stier Allergy, Spokane, Wash.), 0.002 mg bovine derived collagen from Sigma-Aldrich (also known as Millipore-Sigma) and 0.003 mg Immunoglobulin (GamaSTAN™ Talecris Biotherapeutics, Inc. Research Triangle Park, N.C.) in a phenylated saline buffer.

(16) When the subject was evaluated after approximately 60 days of days of treatment the treating physician reported the following:

(17) “Patient reported that she had decreased her pain medication from where it was when we started. Her Fentanyl patch has decreased from 125 to 37 mg and the Gabapentin has decreased from 1200 to 300 to 600 at night. Her energy level was evidenced to be increased as the patient spontaneously lifted herself out of her wheelchair into a chair in our office. This observation of increased energy was reinforced by a report from her mother indicating that she was doing more for herself at home. Patient still reported spontaneously dislocating, and her sleep intervals have not apparently increased. Her personality was improved since last visit and she was more civil in her responses and her interactions.”

Example 3

(18) According to this example, a middle aged male subject diagnosed with Type 3 Ehlers-Danlos Syndrome who had been suffering from the syndrome was treated by was treated by sublingual administration of one drop (0.05 ml) of a composition comprising Rubeola virus at a dosage of 4 TCID.sub.50 (Attenuvax®, Merck & Co., Whitehouse Station, N.J.), 0.008 mg histamine (Hollister Stier Allergy, Spokane, Wash.), 0.002 mg bovine derived collagen from Sigma-Aldrich (also known as Millipore-Sigma) and 0.003 mg Immunoglobulin (GamaSTAN™ Talecris Biotherapeutics, Inc. Research Triangle Park, N.C.) in a phenylated saline buffer. The subject reported reduced pain, reduced fatigue and improved quality of life.

Example 4

(19) According to this example a 61 year old female with joint hypermobility since childhood was treated She has not been classified as to EDS type by genetic evaluation, but would be classified as suffering from hEDS in the present vernacular. She is the owner of a small deli store where she works six days per week. At the time of initiating therapy she complained of soreness, tiredness, joint aches and pains, and difficulty making it through her long work days.

(20) The subject was treated by sublingual administration four times daily of one drop (0.05 ml) of a three component composition comprising 4 TCID.sub.50 (Attenuvax®, Merck & Co., Whitehouse Station, N.J.), 0.008 mg histamine (Hollister Stier Allergy, Spokane, and WA), 0.002 mg bovine derived collagen from Sigma-Aldrich (also known as Millipore-Sigma) in a phenylated saline buffer.

(21) After six weeks of treatment with the three component composition the subject was treated by sublingual administration four times daily of one drop (0.05 ml) of administration of a four component composition comprising Rubeola virus at a dosage of 4 TCID.sub.50 (Attenuvax®, Merck & Co., Whitehouse Station, N.J.), 0.008 mg histamine (Hollister Stier Allergy, Spokane, Wash.), 0.002 mg calf or bovine derived collagen from Sigma-Aldrich (also known as Millipore-Sigma) and 0.003 mg Immunoglobulin (GamaSTAN™ Talecris Biotherapeutics, Inc. Research Triangle Park, N.C.) in a phenylated saline buffer.

(22) The subject noted that while all the previous symptoms were still present were significantly reduced. Although she did not mention much about the state of loose joints at the first visit, at the six week mark she did say her shoulders felt better, or tighter. The subject reported reduced fatigue during the day after 10-14 days of treatment and reported that reduced pain was evident before the two week mark. No adverse effects were reported.

Example 5

(23) A 27 year old male diagnosed with hEDS (Type 3 EDS) suffered from weakness, pain, and joint dislocations and had difficulty sleeping and reported suffering from “brain fog.” The subject also reported that the symptoms of his condition made it difficult for him to maintain employment.

(24) The subject was treated by sublingual administration four times daily of one drop (0.05 ml) of a three component composition comprising Rubeola virus at a dosage of 4 TCID.sub.50 (Attenuvax®, Merck & Co., Whitehouse Station, N.J.), 0.008 mg histamine (Hollister Stier Allergy, Spokane, Wash.), and 0.002 mg bovine derived collagen from Sigma-Aldrich (also known as Millipore-Sigma) in a phenylated saline buffer.

(25) After six weeks of treatment the subject reported that he felt stronger, had considerably less joint pain, had better sleeping patterns and reduced “brain fog.” He especially noted that he could rotate his arm at the shoulder for the first time in months without pain and with an increase in range of motion without dislocation. No adverse effects were reported.

(26) After six weeks of treatment with the three component composition the subject was treated by sublingual administration four times daily of one drop (0.05 ml) of administration of a four component composition comprising dosage of 4 TCID.sub.50 (Attenuvax®, Merck & Co., Whitehouse Station, N.J.), 0.008 mg histamine (Hollister Stier Allergy, Spokane, Wash.), 0.002 mg bovine derived collagen from Sigma-Aldrich (also known as Millipore-Sigma) and 0.003 mg Immunoglobulin (GamaSTAN™ Talecris Biotherapeutics, Inc. Research Triangle Park, N.C.) in a phenylated saline buffer. Administration of the four component mixture further comprising Immunoglobulin maintained the improved symptoms but did not significantly improve them compared to when they were treated with the three component mixture.

(27) Ten additional patients suffering from forms of EDS have been treated by administration of the compositions of the invention and those subjects have reported improvements in symptoms similar to those reported above.

Example 6

(28) According to this example, a 21 year old female subject presented with a high arched palate, joint hypermobility, joint pain/dislocations, abnormal skin with easy bruising, abnormal scars, delayed wound healing, skin stretching and striae and myopia was diagnosed with hEDS and had a Brighton score of 6/9. She also had soft/velvety skin, easy bruising, symptoms of Postural orthostatic tachycardia syndrome (POTS), and muscle pain.

(29) She was treated by sublingual administration four times daily of one drop (0.05 ml) of a three component composition comprising Rubeola virus at a dosage of 4 TCID.sub.50 (Attenuvax®, Merck & Co., Whitehouse Station, N.J.), 0.008 mg histamine (Hollister Stier Allergy, Spokane, Wash.), and 0.002 mg bovine derived collagen from Sigma-Aldrich (also known as Millipore-Sigma) in a phenylated saline buffer.

(30) The results of treatment presented in Table 1 below show improved generalized pain and improvements in the knee function. There were no changes in hypermobility, soft/velvety skin, or easy bruising but she was able to exercise for longer periods without pain and was eating a healthier diet. On one case, where she missed her dosage she passed out as a result of POTS.

(31) TABLE-US-00001 TABLE 1 SF-36 scores: initiation of therapy and most current (0 = poor; 100 = optimal) Day 1 Day 471 Difference physical functioning 40 80 40 role limitations due physical health 0 50 50 role limitations due emotional problems 33.3 0 −33.3 energy/fatigue 15 15 0 emotional well-being 36 12 −24 social functioning 37.5 25 −12.5 pain 12.5 57.5 45 general health 10 55 45

Example 7

(32) According to this example, a 17 year old female subject presented with Initial symptoms of knee and shoulder dislocations, chronic fatigue and illnesses (e.g. mononucleosis, strep throat), easy scarring and bruising, swollen glands, and memory fog. She also had a 8/9 Brighton score and a physical exam revealed chronic fatigue, general pain, purplish, velvety skin highly reactive to hot/cold. The subject also presented as being uncomfortable, and having emotional difficulties including crying, panic attacks, and depression, shaking hands, pain and tingling throughout body, joint dislocations, irritable bowel syndrome, acid reflux, nausea, fatigue, dizziness, difficulty swallowing, rashes, dry-eye syndrome and mouth ulcerations.

(33) She was treated by sublingual administration four times daily of one drop (0.05 ml) of a three component composition comprising Rubeola virus at a dosage of 4 TCID.sub.50 (Attenuvax®, Merck & Co., Whitehouse Station, N.J.), 0.008 mg histamine (Hollister Stier Allergy, Spokane, Wash.), and 0.002 mg bovine derived collagen from Sigma-Aldrich (also known as Millipore-Sigma) in a phenylated saline buffer.

(34) After two weeks of treatment the patent reported improvement in all areas saying she had more energy and reported feeling as though she has normal health and has participated in more aspects of normal living including work, socializing and exercise. The results of treatment are presented in Table 2 below.

(35) TABLE-US-00002 TABLE 2 SF-36 scores: initiation of therapy and most current (0 = poor: 100 = optimal) Day 1 Day 241 Difference physical functioning 50 75 25 role limitations due physical health 50 50 0 role limitations due emotional problems 67 100 33 energy/fatigue 15 40 25 emotional well-being 60 64 4 social functioning 50 62.5 12.5 pain 45 55 10 general health 20 35 15

Example 8

(36) According to this example, subjects diagnosed with hEDS, cEDS and other EDS variants are divided into control and treatment groups with the treatment groups treated according to a protocol in which they were treated by sublingual administration four times daily of one drop (0.05 ml) of a three component composition comprising Rubeola virus at a dosage of 4 TCID.sub.50 (Attenuvax®, Merck & Co., Whitehouse Station, N.J.), 0.008 mg histamine (Hollister Stier Allergy, Spokane, Wash.), and 0.002 mg calf or bovine derived collagen from Sigma-Aldrich (also known as Millipore-Sigma) in a phenylated saline buffer.

(37) The control and test subjects are evaluated prior to treatment for pain, fatigue, range of motion, emesis, and general quality of life such as can be measured by tools such as the Short Form Health Survey (SF36) and then periodically over a 90 day trial period and at the end of the trial period to determine the degree to which each symptom is improved.

(38) Numerous modifications and variations in the practice of the invention are expected to occur to those skilled in the art upon consideration of the presently preferred embodiments thereof. Consequently, the only limitations which should be placed upon the scope of the invention are those which appear in the appended claims.