Title:  Allergy treatment method using a rapid immunotherapy protocol

United States Patent:  6,488,937

Issued:  December 3, 2002

Inventors:  Smits; William (6409 Post Rd., Fort Wayne, IN 46814)

Appl. No.:  644719

Filed:  August 23, 2000

A method of treating a patient sensitive to an allergen includes a desensitizing rapid immunotherapy protocol of administering to the patient a series of gradually increasing doses of a composition comprising the allergen at intervals of about 15 minutes for a duration of less than about 120 minutes, and preferably less than about 90 minutes. A pretreatment protocol administers to the patient a therapeutically effective amount of at least one composition that is effective in reducing a sensitivity of the patient to an asthma associated allergenic reaction.

DETAILED DESCRIPTION OF THE INVENTION

A treatment method has been developed that is ordered towards providing therapeutic assistance to patients suffering from acute or immediate hypersensitivity to various allergens. By way of background, immediate hypersensitivity (or anaphylactic response) is a form of allergic reaction which develops very quickly, i.e., within seconds or minutes of exposure of the patient to the causative allergen. As used herein, and conventionally understood, the term "allergen" relates to a specific subclass of antigen which can trigger immediate hypersensitivity, which is mediated by IgE antibodies made by B lymphocytes.

In non-allergic patients, there is no IgE antibody of clinical relevance; however, in a person suffering with allergic diseases, IgE antibody mediates immediate hypersensitivity by sensitizing mast cells that are abundant in the skin, lymphoid organs, membranes of the eye, nose and mouth, and the respiratory tree and intestines. Mast cells have surface receptors for IgE, and the IgE antibodies in allergy-suffering patients become bound to them. When the bound IgE is subsequently contacted by the appropriate allergen, the mast cell is caused to degranulate and to release various substances called bioactive mediators, such as histamine, into the surrounding tissue.

It is the biologic activity of the substances that is responsible for the clinical symptoms typical of immediate hypersensitivity, namely, contraction of smooth muscle in the airways or the intestines, the dilation of small blood vessels and the increase in their permeability to water and plasma proteins, the secretion of thick sticky mucus, and, in the skin, redness, swelling and the stimulation of nerve endings that results in itching or pain.

According to the present invention, a treatment method is provided that encompasses a form of treatment conventionally known in various equivalent alternative forms as rapid desensitization, rapid allergen immunotherapy, rapid allergen vaccination, and rapid or rush immunotherapy. In broad terms, this procedure aims to advance an allergic patient to an immunizing or maintenance dose of extract (i.e., allergen) by administering a series of injections (or via another suitable carrier) of increasing doses of the allergen at frequent intervals. If successful, the patient will exhibit an improved resistance to the allergen, possibly even presenting a total non-reactivity to any subsequent allergen exposure. Conventional rush or rapid desensitization procedures typically take place over a period of one to two days and up to several days and weeks.

According to the present invention, an accelerated rapid immunotherapy protocol has been provided that administers the gradually increasing doses of allergen over a period of less than a few hours and yet achieves a rate of systemic reaction during or following treatment that is dramatically less than that demonstrated by conventional allergen immunotherapies which take much longer.

In accordance with one embodiment of the present invention, a method of treating a patient sensitive to an allergen includes a protocol of administering to the patient a therapeutically effective amount of a composition comprising the allergen over a duration of less than about 120 minutes, and, more preferably, less than about 90 minutes. The protocol is performed according to a rapid immunotherapy protocol in which progressively increasing doses of the allergen are administered at selected intervals, such as 10 to 20 minutes. The protocol is developed with a view towards enabling the patient to reach and/or advance to a maintenance dose within the allocated time frame.

In a preferred form, the treatment protocol employs a dilution level for each allergen dosage that is within the range from between about 1:150,000 to about 1:50,000 to between about 1:1500 to about 1:500. In a more preferred form, the allergen doses are administered at about 15 minute intervals according to the following dosage schedule:

Optional dosages of between about 1:150 to 1:50 may be administered at 90 minutes and 105 minutes.

It should be understood that the manner of delivering the allergen dosages may encompass any suitable route (e.g., oral or injection) and employ any pharmaceutically acceptable carrier as well understood by those skilled in the art. Additionally, the times and dosage levels indicated above should be understood as forming guidelines that the skilled artisan may use to make adjustments thereto within the scope of the present invention. Other aspects of performing the rapid immunotherapy procedure are well within the routine understanding and practice of those skilled in the art. The ratios, volumes, and selected allergen may be changed by the skilled artisan.

An examination and evaluation study was performed which conducted two separate half-day schedules for desensitizing and observing 311 patients according to the present invention. All patients exhibited positive percutaneous skin tests to perennial and seasonal inhalant allergens. The targeted final dose ranged from about 0.1 cc to about 0.5 cc of about a 1:1000 dilution of aqueous and glycerinated extracts manufactured by ALK and Greer Laboratories. Most patients were then continued onto higher doses by resuming a conventional immunotherapy schedule. Patients ranged from 11/2 to 68 years of age. Diagnoses included allergic rhinitis (92%), asthma (51%), and chronic sinusitis (63%). Most patients also had associated headaches.

The following table illustrates the dosing schedule used in the foregoing study, using about 15 minute intervals for administering the allergen dosage.

The dosages at 90 minutes and 105 minutes are optional. It should be understood that the indicated volumetric quantities applicable to each dosage may be suitably adjusted in a known manner to facilitate or otherwise adapt the immunotherapy protocol based upon the patient reaction or condition or in response to other factors well understood by those skilled in the art. Dosage ratios may be varied within the scope of the present invention. One reason the ratios may need to be changed may be sensitivity of the patient to the allergen (e.g., 1:1,000,000,000, 1:1,000,000) to create an effective treatment for very allergic patients.

The foregoing dosage schedule would be used in conjunction with administering the allergen amount into one arm of the patient, for example. A substantially identical schedule would be used to administer another allergen amount into the other arm. Preferably, different allergen types would be used to enable rapid desensitization involving two different antigens within the same day. The two desensitization regimens may be performed concurrently with one another (as in the foregoing study) or may be conducted in serial manner with one protocol following the other, preferably within the same day.

Follow-up observations of the patients involved in the study revealed that eleven patients (3.5%) experienced a mild systemic reaction. Significantly, these documented systemic reactions occurred less frequently with the treatment protocol disclosed herein and used a lower targeted final dose than previously described in the art. All of the patients responded to subcutaneous epinephrine and/or nebulized albuterol and were deemed fit to return home. None of the patients experienced true anaphylactic shock. These clinical results confirm that maintenance immunotherapy according to the present invention can be reached quickly, safely, effectively and with improved compliance.

In accordance with another embodiment of the present invention, a pretreatment method is provided for use in combination with the treatment protocol described above. The pretreatment method is performed on the patient prior to receiving rapid immunotherapy in the manner described above.

According to one aspect of the pretreatment method, there is provided a protocol or regimen of administering to the patient prednisone (or any other suitable corticosteroid) and at least one of an H₁ histamine antagonist and an H₂ histamine antagonist. The H₁ histamine antagonist may be selected from the group comprising Claritin.TM. (Loratadine), Seldane.TM. (Terfenadine), Zyrtec.TM. (Cetirizine hydrochloride), and Allegra.TM. (Fexofenadine hydrochloride), for example, while the H₂ histamine antagonist may be selected from the group including Zantac.TM. (Ranitidine hydrochloride), Pepcid.TM. (Famotidine), and Tagamet.TM. (Cimetidine), where the associated generic drug name is indicated in parentheses. However, these individual drug types should not be considered in limitation of the present invention as it should be apparent that other suitable anti-histamine or histamine-blocking agents may be used. Additionally, any suitable manner known to those skilled in the art may be used to prepare and administer this premeditation regimen.

It was observed that the efficacy of the rapid immunotherapy protocol (as measured in part by the number and degree of systemic reactions) tended to correlate roughly with the extent of pretreatment that was directed towards reducing or eliminating a sensitivity of the patient to an asthma associated allergenic reaction, such as might occur during and/or after the immunotherapy protocol. Accordingly, the foregoing pretreatment method is enhanced by administering to the patient a therapeutically effective amount of at least one composition which is effective in reducing the sensitivity of the patient to an asthma associated allergenic reaction. For example, the patient may be administered a corticosteroid (oral or inhaled), and a leukotriene medication such as Singular.TM., Accolade.TM., Zyflo.TM., or a combination thereof. Additional asthma medications may also be used.

By controlling this vulnerability or susceptibility to an asthma-related allergenic reaction, it was found that the rate of systemic reactions was capable of being further reduced. The administration of this anti-asthma medication as part of the pretreatment protocol is preferably done in combination with the first premedication regimen discussed above. Notably, the invention does not use antacids as part of the pretreatment protocol.

In the study mentioned above, 107 patients received premedication with prednisone (60 mg daily for adults and 2 mg/kg for children) and H₁ antihistamine (Claritin.TM., Seldane.TM., Zyrtec.TM., or Allegra.TM.), for three days prior to receiving rapid desensitization. Additionally, 204 patients received a premedication regimen of prednisone in combination with both H₁ and H₂ blockade (Zantac.TM., Pepcid.TM., or Tagamet.TM.) and Singular.TM. with a dosage level of approximately 4 to 20 mg.

While this invention has been described as having a preferred methodology and design, the present invention can be further modified within the spirit and scope of this disclosure. This application is therefore intended to cover any variations, uses, or adaptations of the invention using its general principles. Further, this application is intended to cover such departures from the present disclosure as come within known or customary practice in the art to which this invention pertains and which fall within the limits of the appended claims.

Claim 1 of 36 Claims

What is claimed is:

1. A method of treating a patient sensitive to an allergen, comprising administering to said patient a therapeutically effective desensitizing amount of a composition comprising said allergen at intervals between 10 to 20 minutes over a duration of less than about 120 minutes according to a rapid immunotherapy protocol.
 

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.