Treatment of mammalian physiological reaction of IgE antibodies present in said mammal upon contact with the corresponding antigen

Abstract

A method is disclosed for blocking or reducing physiological reaction in a mammal to the interaction of IgE antibodies present in said mammal upon contact with the corresponding antigen, by the administration to said mammal of a therapeutically effective amount of a neurotoxin (CnT) derived from Clostridia sp.

Claims

1. A method of blocking or reducing the symptoms of allergic rhinitis in a mammal including sneezing, itching or nasal congestion, the method comprising administering to the mammal a therapeutically effective amount of a botulinum neurotoxin, wherein the botulinum neurotoxin is administered directly to a postganglionic parasympathetic neuron of the mammal to block and reduce the symptoms of the allergic rhinitis.

2. The method of claim 1, wherein the postganglionic parasympathetic neuron is a sphenopalatine ganglion.

3. The method of claim 1, wherein the botulinum neurotoxin is administered by injection.

4. The method of claim 1, wherein the botulinum neurotoxin is administered topically.

5. The method of claim 1, wherein the botulinum neurotoxin is administered by inhalation.

6. The method of claim 1, wherein the botulinum neurotoxin is administered using a topical biodegradable depot comprising the botulinum toxin.

7. The method of claim 1, wherein the botulinum neurotoxin is selected from the group consisting of botulinum neurotoxin serotypes A, B, C1, D, E, F or G.

8. The method of claim 1, wherein the botulinum neurotoxin is botulinum neurotoxin serotype A.

9. The method of claim 8, wherein the therapeutically effective amount is at least 10 units of botulinum neurotoxin serotype A.

10. The method of claim 8, wherein the therapeutically effective amount is at least 20 units of botulinum neurotoxin serotype A.

11. A method of blocking or reducing allergic rhinitis in a mammal, the method comprising administering to a sphenopalatine ganglia of the mammal at least 10 units of a botulinum neurotoxin serotype A to treat the allergic rhinitis.

12. The method of claim 11, wherein the botulinum neurotoxin is administered by injection.

13. The method of claim 11, wherein the botulinum neurotoxin is administered topically.

14. The method of claim 11, wherein the botulinum neurotoxin is administered by inhalation.

15. The method of claim 11, wherein the botulinum neurotoxin is delivered to the nasal mucosa of the mammal.

16. The method of claim 11, wherein the botulinum neurotoxin is administered by injection into the pterygopalatine space through the palate.

17. The method of claim 11, wherein the botulinum neurotoxin is administered to pass through the sphenopalatine canal into the area of the sphenopalatine ganglia.

Description

EXAMPLES

Example 1. Seasonal Allergic Rhinitis

(1) 1a) A 30-year-old male has seasonal allergic rhinitis. In May, prior to pollen formation, 30 units of BoNT were topically applied in each nostril. Specifically, the nasal cavity is sprayed with a solution of 1% lidocaine and % neosynephrine to anesthetize and decongest the nasal mucosa, respectively. Then 1 cc of normal saline containing 30 units of BoNT is sprayed into each nasal cavity. This method of delivery, although commonly used for application of nasal medication, is inherently inefficient as a significant percentage of a sprayed medication will exit the posterior nasal cavity and be exhaled or swallowed.

(2) 1b) In another embodiment, the patient is treated by placing 13 cm.sup.2 cotton pledgets impregnated with 20 units of BoNT onto the medial surface of the turbinates and left for one hour, then removed by the physician. This delivery method is more efficient then a spray, however a significant percentage of the BoNT will not diffuse from the pledgets to the mucosa.

(3) 1c) Alternatively, the patient has topical anesthesia applied only to a localized area, preferably the anterior end of the inferior turbinate. Then, patient has a 1 cm.sup.2 cotton pledget impregnated with 10 units of BoNT placed onto the mucosa of the anterior turbinate for one hour and then removed. Within the nasal cavity a mucociliary blanket transports fluids and particles posteriorly, thereby distributing the BoNT. This is an example of applying a BoNT to a localized region of the nasal cavity and using the normal physiology of the nasal cavity for distribution. The routes of mucociliary clearance of the nose and sinus cavities are known so that other variations of this method are apparent to those skilled in the art.

(4) 1d) In another embodiment, using a topical biodegradable depot to deliver BoNT over an extended time period to nasal mucosa is used for treating the patient. Various biodegradable compounds are known in the art that vary in consistency and rate of dissolution.

(5) An example is oxidized cellulose (marketed as Surgicel. by Johnson & Johnson, New Brunswick, N.J.). The oxidized cellulose can be manufactured with BoNT as an integral component, or the BoNT can be added to the oxidized cellulose before its clinical use. Surgicel is available in the form of a thin flexible sheet that is often cut to fit the area of the body to which it will be applied. For intranasal use the size may vary from a few square millimeters to a 4 by 8 cm.sup.2 sheet that could contact the entire exposed mucosa of the nasal cavity. BoNT can be added to the Surgicel as a lyophilized powder or after reconstitution into solution. If added as a powder it can homogeneously applied onto one side of the Surgicel and the material can be folded. The material is then moistened with normal saline to bind the material together and immobilize the BoNT prior to clinical use. In contrast the BoNT can first be constituted into solution and then absorbed into the material.

(6) As an example a 26 cm.sup.2 piece of oxidized cellulose is saturated with 1 cc of normal saline containing a total of 10 units of BoNT. Using a nasal speculum the nostril is dilated and the nasal cavity is visualized and the saturated cellulose place therein. The cellulose will gradually dissolve over hours while releasing a small continual dose of BoNT directly onto the nasal mucosa.

(7) Alternatively the patient is administered 0.5 cc. of normal saline containing 5 units of BoNT is applied to the oxidized cellulose which is grasped with bayonet forceps and placed flat onto the medial surface of the anterior end of the inferior turbinate of each nasal cavity. As disclosed above the mucociliary action of the nasal mucosa transports liquids and particles from the anterior to posterior nasal cavity.

(8) 1e) In another embodiment the patient is injected with BoNT solution directly into the nasal mucosa. After anesthetizing and decongesting the mucosa, 5 units of BoNT in 1 cc of saline are injected beneath the mucosa throughout the length of the inferior turbinate with a 25 gauge spinal needle coupled to a 1 cc syringe.

(9) 1f) Alternatively the patient can be treated with TeNT.

(10) Compositions of TeNT for intranasal administration, can range in dose from 0.1 to 1000 units in 0.1 cc to 10 cc of solution. One preferable composition is 10 units of TeNT in 1 cc of normal saline.

(11) As an example the same patient is treated by spraying each nostril with 1 cc of normal saline solution containing 10 units of TeNT.

(12) Alternatively, if only decongestion is desired 10 units of TeNT can be topically applied.

(13) In another embodiment, 1 unit of recombinant DNA coding for TeNT is pressure injected across the nasal mucosa to transfect mucosal cells. These cells then express the TeNT for months.

Example 2. Perennial Allergic Rhinitis

(14) 2a) Direct injection of the sphenopalatine ganglia.

(15) A 40-year-old female has chronic nasal congestion due to perennial rhinitis. Skin testing demonstrates that she is allergic to numerous environmental antigens and intranasal examination shows enlarged turbinate mucosa and nasal polyps. Testing of nasal secretions shows eosinophilia. An injection of 20 units of BoNT in a 1 cc solution of normal saline is made through the sphenopalatine canal into the area of the sphenopalatine ganglia.

(16) In another embodiment, 100 units of BoNT embedded in 0.1 micron biodegradable pellets suspended in solution is injected into the mucosa of each turbinate to slowly release its contents over 6 months.

(17) Alternatively a biodegradable carrier containing 5 units of BoNT is placed intranasally in the most superior and posterior aspect of the lateral nasal wall. This permits the BoNT to diffuse across the nasal wall to the underlying sphenopalatine ganglia.

Example 3. Serous Otitis Media

(18) A 3-year old male has a history of serous otitis media. Under general anesthesia a myringotomy is made into the tympanic membranes and 2 units of BoNT in 0.5 cc of normal saline is injected.

Example 4. Sinusitis

(19) A fifty-year-old male has a history of allergic rhinitis and recurrent sinusitis. Ten units of BoNT are injected through the palate into the pterygopalatine space to block the sphenopalatine ganglion.

Example 5. Allergic Dermatitis

(20) A seventy-year-old male has severe allergic dermatitis of the forearm skin. Each forearm is injected with 10 injections of 0.3 units BoNT in 0.1 cc of normal saline. Each injection is made intradermally at 3 cm intervals.

Example 6. Allergic Asthma

(21) A 13-year-old boy has severe allergic asthma. He is treated by bimonthly inhalation therapy of an aerosilized solution of 5 units of botulinum toxin in 5 cc of normal saline.

(22) Alternatively the same botulinum solution can be injected directly into the trachea and bronchi. After injecting local anesthesia into the skin overlying the cricothyroid membrane a needle is passed directly through the skin and cricothyroid membrane and the BoNT solution is sprayed into the trachea. The solution drips down to reach the bronchial mucosa where it is topically absorbed.

Example 7. Allergic Rhinitis

(23) A 40-year old male has allergic rhinitis and an associated reflex chronic cough. Application of CnT to the nasal cavity as described above or alternatively injected or aerosilized topical application of BoNT to the lungs is used to treat the cough.

Example 8. Food Allergies

(24) A 10-year-old boy with food allergies manifested by bloating and diarrhea is treated with a rectal suppository containing 50 units of BoNT. The suppository is composed of biocompatible material designed to be solid at room temperature but to dissolve at body temperature. Sufficient materials for the composition are cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and fatty esters of polyethylene glycol.

Example 9. Infectious Rhinitis

(25) Chronic allergic exposure causes the nervous system to become hyper responsive to non-allergic stimulation such as that caused by viral infections.

(26) A patient with rhinitis is given 10 units of BoNT and 5 units of TeNT prior to spring.