Abstract:
A method and composition for the treatment of hormone allergy is disclosed. The method relates to using progesterone dilutions, or any other steroid hormone, to treat the systemic symptoms of hormone allergy, including pain. The composition of the hormone dilutions ranges from 10 −1  to 10 −5 . The hormone dilution may be administered sublingually, or, in the alternative, an intradermal route of administration may be chosen. Hormone dilutions may be administered at daily intervals or on any other treatment schedule as required to alleviate a patient&#39;s symptoms.

Description:
RELATED APPLICATION  
       [0001]     This application claims the benefit, under 35 U.S.C. § 119(e), of previously filed provisional application Methods And Compositions For The Treatment Of Allergy Using Dilute Hormone Solutions, Ser. No. 60/332,475, filed Nov. 16, 2001. 
     
    
     TECHNICAL FIELD  
       [0002]     The present invention relates in general to the treatment of pain and other hormone-allergy-related symptoms and in specific to the use of a dilute hormone solution for the treatment of pain and hormone-allergy symptoms.  
       BACKGROUND OF THE INVENTION  
       [0003]     Hormone allergy has been previously described in the medical literature as premenstrual asthma. Skobeloff E. M., Spivey W. H., Silverman R. A., Ekin B. A., Harchelroad F. P., Alessi T. V.: The effect of the menstrual cycle on asthma presentations in the emergency department.  Arch Intern Med  1996; 156: 1837-40. Claude F.: Asthma et menstruation.  Presse Med  1938; 46: 755-759; Eliasson O., Scherzer H., DeGraff A. C.: Morbidity in asthma in relation to the menstrual cycle.  J Allergy Clin Immunol  1986: 77: 87-94; Chandler M. H., Schuldheisz S., Phillips B., Muse K. N.: Pre-menstrual asthma: the effect of estrogen on symptoms, pulmonary function, and beta 2-receptors.  Pharmacology  1997; 17(2): 224-234.  
         [0004]     Premenstrual asthma is a condition where premenstrual fluctuations in hormones such as estrogen and progesterone cause the exacerbation of clinical symptoms. Exacerbations of symptoms appear to occur during the premenstrual period when progesterone levels are high. Several references have been made to a possible reaction to hormones. The first report of hormonal influence on asthma symptoms appeared in a case report by Frank from 1931. Frank, R T: The hormonal causes of pre-menstrual tension.  Arch Neurol Psychiatry  1931; 26: 1053-57. Severe aggravation of asthma symptoms in one patient were clearly linked to oral contraceptives. Derimov, G S, Oppenheimer J: Exacerbation of premenstrual asthma caused by an oral contraceptive.  Ann Allergy Asthma Immunol  1998; 81: 243-46.  
         [0005]     Skobeloff et. al reported a four-fold increase in the presentation of asthmatic women to the emergency department during the perimenstrual interval (days 26 to 04 of the menstrual cycle). When Skobeloff&#39;s data is superimposed over the hormone levels during the menstrual cycle, it shows that the peak emergency room visits occurred during the premenstrual period when the progesterone is highest relative to estrogen ( FIG. 1 ).  
         [0006]     There has been little investigation, however, into the systemic manifestations or treatment of hormone allergy, or the effect of hormones on organ systems other than the female reproductive tract. While there is documentation in the literature supporting the influence of hormones on premenstrual asthma, applicant knows of no established mode of action.  
       SUMMARY OF THE INVENTION  
       [0007]     In accordance with teachings of the present invention, a method and composition for treatment of hormone allergy using steroid hormone dilutions, specifically progesterone, estrogen and testosterone is provided.  
         [0008]     Observations that lead to and are a part of the present invention, suggest the possibility of an allergic reaction to the steroid hormone progesterone as a possible cause of clinical symptoms or premenstrual asthma and other disorders.  
         [0009]     One aspect of the present invention includes a previously unrecognized treatment for asthma, headache, sinus congestion, muscular pain, and bone and joint pain that involves desensitizing a body&#39;s response to its own innate hormones. The treatment may be applied to any mammal including humans. In an exemplary embodiment, the mammal is female.  
         [0010]     While hormones may fluctuate throughout the menstrual cycle, treatment is not limited to any specific point in the menstrual cycle. In an exemplary embodiment, however, dilute solutions of progesterone are administered sublingually, every day or every other day, as needed, until there is an alleviation of a patient&#39;s clinical symptoms. These dilute formulations are very similar to the type of dilutions that an allergist typically uses when treating allergic symptoms from external substances, or allergens, which are foreign to the body. However, in treating a patient with hormone allergy, instead of desensitizing the patient to a foreign substance, the patient is desensitized to his or her own innate hormone(s).  
         [0011]     Existing clinical treatments do not generally use sublingual administration of dilute hormone solutions to treat allergy symptoms. In addition, many of the symptoms that can be treated with hormone dilutions are not recognized as conventional allergy symptoms, such as bone and joint pain, muscular pain, and headache. Other symptoms which respond to treatment with hormone dilutions are recognized as classic allergy symptoms such as sinus congestion, ear and throat pain, eye and skin irritation.  
         [0012]     In accordance with another aspect of the present invention, dilutions of a hormone solution, such as progesterone are used to treat hormone allergy symptoms. A hormone dilution ranging in concentration from 5 mg/ml to 0.5 μg/ml is administered sublingually. The strength of the dilution selected for treatment may be based on the severity of the patient&#39;s symptoms and prior treatment history. The amount, frequency and strength of the hormone dilution may be varied depending on severity of symptoms and on response achieved.  
         [0013]     In an alternative embodiment of the invention, the route of administration may be intradermal.  
         [0014]     In accordance with a further aspect of this invention a dilute progesterone solution (concentration 5 mg/ml to 0.5 μg/ml) or a dilute estrogen solution (concentration 5 mg/ml to 0.5 μg/ml) may be administered to treat hormone allergy symptoms in females.  
         [0015]     In accordance with another aspect of this invention a dilute testosterone solution (concentration 5 mg/ml to 0.5 μg/ml) may be used to treat allergy symptoms in males. Other steroid hormone solutions may also be used. All solutions of the present invention may be administered in a pharmaceutically-acceptable carrier.  
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0016]     A more complete and thorough understanding of the present invention and advantages thereof may be acquired by referring to the following description taken in conjunction with the accompanying drawings, in which like reference numbers indicate like features, and wherein:  
         [0017]      FIG. 1  illustrates the number of female asthmatic patient visits to an emergency department during the menstrual cycle; and  
         [0018]      FIG. 2  illustrates spirometry results of a patient before and after treatment with a dilute steroid hormone composition incorporating teachings of the present invention.  
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0019]     The present invention relates to a treatment of systemic allergic manifestations and pain caused at least in part by steroid hormones. Such manifestations have been observed and treated in female patients. For the condition of acute asthma alone, data on 83 patients treated with dilute progesterone has been collected. Measuring symptom response rate on a 10-point scale, a response rate of 93% overall was observed. The average reduction in symptom severity on the 10-point scale was 3.1 points. The present data show a 57% reduction in symptoms on average. These results are statistically significant at a level of p&lt;0.0001.  
         [0020]     A composition of the present invention may include a standard solution of aqueous progesterone, or any other indicated steroid hormone, diluted with normal saline to achieve concentrations of 5 mg/ml to 0.5 μg/ml. The strength of a dilution selected for treatment may be based on a severity of the patient&#39;s symptoms and prior treatment history. This selection methodology may be similar to that used in treatments with foreign allergens and appropriate selections for an individual patient will be apparent to one skilled in the art.  
         [0021]     Typically, 0.1 cc of a hormone dilution (0.5 mg-0.05 μg per dose) is administered sublingually every other day. The frequency of administration may be increased to every day or more often, as required, to achieve a desired treatment response. The strength of the hormone dilution selected for treatment may also be varied depending on severity of symptoms and on response achieved. Response to therapy may be measured on a 10-point scale of symptom severity as reported by a patient to a clinical provider. Additional tests for abatement of symptoms may also be used. Treatment of hormone allergy symptoms may continue for months or years as indicated by each patient&#39;s clinical condition.  
         [0022]     In an alternative embodiment of this invention, the dilution may be administered intradermally for instance, in patients who may have no response to sublingual drops or are unable to use the sublingual delivery method.  
       EXAMPLES  
     Example 1  
     Dilution Protocol  
       [0023]     Progesterone USP 50 mg/ml (Schein Laboratories, Florham, N.J.) is diluted with physiologically-compatible (normal) saline to produce the progesterone dilutions used in treatments. The initial progesterone is suspended in sesame oil. Therefore, to achieve an even suspension, the vial must be vigorously shaken at each stage of the initial preparation and before use of each vial. The first dilution is made by adding 0.5 ml of progesterone to 4.5 ml normal saline. This results in a 1:10 dilution of progesterone (progesterone 5 mg/ml) which is labeled “PROG 1.” After vigorously shaking the PROG 1 vial, 0.5 ml is withdrawn and injected into the next vial of 4.5 ml of normal saline. This results in a 1:100 dilution of Progesterone (0.5 mg/ml, “PROG 2”). To produce the next dilution, a vial of PROG 2 is immediately withdraw 0.5 ml and injected into the next vial of 4.5 ml of normal saline. This results in a 1:1000 dilution of Progesterone (50 μg/ml “PROG 3”). These steps are repeated until there are five serial dilutions labeled “PROG 1” through “PROG 5.” (See Table 1). A milligram (mg) is defined as 1/1000 or 10 −3  of a gram. A microgram (μg) is defined as 1/1,000,000 or 10 −6  of a gram.  
                                                                   TABLE 1                           Progesterone Dilutions                            Dosage               Progesterone       Used           Label   Concentration   Dilution   (.1 ml)                            PROG 1   5   mg/ml   10 −1     .5   mg           PROG 2   .5   mg/ml   10 −2     .05   mg           PROG 3   50   μg/ml   10 −3     5   μg           PROG 4   5   μg/ml   10 −4     .5   μg           PROG 5   .5   μg/ml   10 −5     .05   μg                      
 
       Example 2  
     Treatment Protocol  
       [0024]     Before beginning treatment, all of a patient&#39;s symptoms are assessed and assigned a numerical value by the patient, based on a 10-point scale. Drops are administered to a patient in a standard sequence, starting with plain normal saline (NS) to assess the placebo effect. After plain normal saline, PROG 5 is administered, followed by PROG 3, and then PROG 1.  
         [0025]     After the drops are placed under a patient&#39;s tongue, the patient is instructed not to swallow for 5 seconds. Then the patient is asked to swallow the drops. After an additional 15 seconds, the patient is asked to note any change in any symptoms. The patient is questioned about each area of possible symptoms whether they are initially complained of or not. The question is always asked in the same manner, “Are your symptoms worse, unchanged, or better?” The question is asked in this way to always give the patient the option of selecting “worse” or “unchanged” before “better.” This is designed to minimize the power of suggestion or “placebo” effect.  
         [0026]     If all of the symptoms disappear completely after the placebo, the results are recorded and no further treatment is administered. If at any point, all the symptoms are relieved, the tests are concluded and the patient is provided with a vial with the same dilution of progesterone drops that relieved the symptoms. The patient is instructed to use the drops as often as needed. If symptom relief does not last 12-24 hours, this is an indication that the patient needs a vial one dilution stronger than what she is currently using.  
         [0027]     Patients are questioned about each of twelve standard categories of discomfort (see Table 2). If patients are only asked generally to describe their symptoms they will often omit symptoms that are not included in their chief complaint but that they are experiencing concomitantly with the chief complaint. The patient is asked to grade the symptoms on a scale of 1 to 10. “Zero” is no symptoms at all and “ten” is the most intense discomfort the patient has experienced with a symptom.  
                                           TABLE 2                           Standard Template for Recording Response to       Progesterone Dilutions            Symptom   Normal                   Location   Saline   PROG 5   PROG 3   PROG 1                    Neck       Nose       Eyes       Throat       Shortness of       Breath       Headache       Skin       Ears       Back       Hips       Lower       Extremity       Upper       Extremity       Other                  
 
         [0028]     The symptoms in Table 2 are defined as follows: “neck” refers to musculoskeletal pain in the neck, “nose” refers to blockage or stuffiness in the nose, “eyes” refers to irritation such as burning or itching, “shortness of breath” is defined as a patient&#39;s perception of the inability to take a deep breath, “headache” refers to pain in the head region, “skin” is defined as itching, burning or a rash on the skin, “ears” refers to pain or pressure in the ears, “back,” “hips,” “lower extremity” and “upper extremity” all refer to pain in those areas including arthritis-type pain or pain from chronic or acute injury.  
       Example 3  
     Treatment Response  
       [0029]     Data has been gathered on the clinical response to dilute progesterone therapy for over 300 patients. Patients presenting for treatment ranged in age from 30 to 70 years old and were predominantly female. See Table 3.  
                             TABLE 3                       Patient Demographics                                    Age Range   30-70 years           Male:Female   1:4           Progesterone Dosage   0.5 mg-.05 μg           Length of Treatment   1-90 days                      
 
         [0030]     Patients generally responded favorably in the areas of both allergy and pain symptoms. In the area of allergy symptoms, 66-87% of patients responded depending on the site of allergy symptoms. See Table 4.  
                                                           TABLE 4                           Response to Treatment - Allergy Symptoms (N = 300)                # of       %           Site   Patients   Responders   Improvement   % Responders                    Nose   109   89   63%   82%       Eyes   90   73   57%   81%       Throat   92   70   64%   76%       Ear   35   23   52%   66%       Skin   34   27   74%   79%       Asthma/SOB   142   124   67%   87%                  
 
         [0031]     In the area of pain symptoms, 72-92% of patients responded depending on site of pain symptoms. See Table 5. Over half of the total patients in both groups responded with symptom relief in excess of 60%.  
                                                           TABLE 5                           Response to Treatment - Pain Symptoms (N = 300)                No. of       Percent   Percent       Site   Patients   Responders   Improvement   Responders                    Neck   144   104   62%   72%       Headache   103   84   69%   82%       Back   57   57   72%   82%       Hips   26   24   79%   92%       Arm   61   48   76%   79%       Leg   50   40   75%   80%                  
 
         [0032]     Progesterone antibody levels (immunoglobulins-IgG and IgM) have also been measured (Immunosciences Lab, Beverly Hills, Calif.) and are higher than normal range in approximately 70% of patients before treatment.  
       Example 4  
     Improvement in Shortness of Breath  
       [0033]     Spirometry was performed on 22 patients with shortness of breath who were treated with dilute progesterone drops. All 22 had improvement in spirometry with hormonal allergy treatment. An example of the improvement is shown in  FIG. 2  which shows rate of air flow and lung volume in an individual patient pre- and post-treatment. Both the rate of air exchange ( FIG. 2A , F(L/S)=air flow in liters per second) and the lung volume ( FIG. 2B , V(L)=lung volume in liters, LLN=lower limits of normal for lung volume) of a female patient improved after dilute progesterone treatment in accordance with teachings of the present invention.  
         [0034]     Although the present invention has been described with respect to specific preferred embodiments thereof, various changes and modifications may be suggested to one skilled in the art and it is intended that the present invention encompass such changes and modifications within the scope of the appended claims.