AU762102B2

AU762102B2 - Method for the treatment of asthma

Info

Publication number: AU762102B2
Application number: AU36449/99A
Authority: AU
Inventors: Thomas Dosumu-Johnson
Original assignee: Individual
Current assignee: Individual
Priority date: 1998-04-16
Filing date: 1999-04-15
Publication date: 2003-06-19
Anticipated expiration: 2019-04-15
Also published as: AU3644999A; MXPA00010103A; JP2002511401A; WO1999052508A1; EP1071405A1; CA2328344A1

Description

WO 99/52508 PCT/US99/08226 Description Method for the Treatment of Asthma Technical Field The present invention relates to the treatment of symptoms of inflammatory responses and, more specifically, to the inflammatory responses attendant to asthma.

Background of the Invention An allergic reaction is any abnormal or altered reaction to an antigen or allergen. Typically, such a reaction is characterized by hypersensitivity of the body to specific substances, whether protein, lipid or carbohydrate in nature. Among allergic diseases, asthma is one of the most significant.

Asthma is a chronic condition that affects 14 to 15 million persons in the United States and is the most frequent cause for hospitalizations among children as well as adults. Asthma related morbidity and mortality rates have been increasing for more than a decade in the U.S. Hospital admissions and visits to doctors' offices have also increased for acute episodes of this condition. Current medical practice accepts asthma in afflicted individuals to be an unavoidable, incurable illness. While suppression of symptoms is usually achieved to a degree sufficient to avoid death, urgent medical visits, disturbed sleep and days lost from work are typically unavoidable.

There are wide variations in the prevalence of asthma among different countries, but the epidemiological evidence suggests that most variations are due to environmental factors and not genetic factors. Particularly, allergen exposure, diet, indoor and outdoor air pollution, along with genetic factors, gender and parental history of allergic disease all contribute to cause asthma. The risk of getting the disease increases with exposure to air pollutants.

The disease is generally associated with dyspnea, wheezing and cough, as well as reversible airway obstruction and airway hyper reactivity to nonspecific stimuli.

These responses have been observed in two phases, early and late (Lemanske, Jr., R.F.

and M.A. Kaliner, In: Allergy. Principles and Practice Ed.) pp. 224-246 (1988).

WO 99/52508 PCT/US99/08226 -2- See also Kaliner, Hosp. Prac. 22:73 (1987); Larsen, G. Hosp. Prac. 23:113 (1987)).

Inhalation of allergens by sensitized subjects typically results in an early phase response characterized by bronchoconstriction within 10 minutes of inhalation, reaching a maximum within one to two hours. In some subjects, the airway narrowing reoccurs after three to four hours a late phase response) reaching a maximum during the next few hours (O'Byrne, et al. Am. Rev. Respir. Dis. 136:740 (1987)). This late phase reaction is thought to be due to the cellular phase of inflammation (Hargreave, et al., Eur. J. Respir. Dis. 69 (Suppl. 147):16 (1986); O'Byrne, P.M. Chest 90:575 (1986); Dolovich, J. et al., J. Allergy Clin. Immunol.

83(suppl.):521 (1987)).

The current classification of asthma lists four types: Mild intermittent asthma, mild persistent asthma, moderate persistent asthma, and severe persistent asthma.

Inhaled beta-2 agonists are used for treatment of mild intermittent asthma. For the remaining types, inhaled corticosteroids along with inhaled beta-2 agonists are the treatments of choice. The underlying pathophysiology results from the release of potent leukotrienes acting as inflammatory mediators which cause broncho constriction and increased vascular permeability and mucus production. These inhaled corticosteroids are currently the anti-inflammatory medication of choice. Less effective are chromolyn and nedocromil, which inhibit release of histamine from the mast cells.

There are many concerns over the long-term side effects of corticosteroids; many cases of asthma are in fact refractory to this treatment. Asthmatics are frequently required to take many combinations of these potent drugs to receive only slight temporary relief.

Thus the agents currently available to the physician have a number of problems associated with their use including toxicity, low activity, adverse effects on the cardiovascular system and fluid retention or edema.

No complete, long-lasting remissions of asthma have been described in response to any existing therapeutic strategies. For example, systemically administered glucocorticosteroids are potent anti-asthmatics; however, the symptoms of the disease are only temporarily suppressed and this is at a cost of well-known side effects, WO 99/52508 PCT/US99/08226 -3including osteoporosis, weight-gain, hypertension, and diabetes (Barnes, New Eng. J. Med. 321:1517 (1989)). Inhaled steroid therapy also has complications (See Toogood, J. Allergy Clin. Immunol. 83 (suppl.):528 (1987)). Low-dose methotrexate has been offered as a substitute to steroids, particularly for patients for whom the side-effects of steroids are the most devastating. (Mullarkey, New Eng. J. Med. 318:603 (1988)). However, methotrexate, while frequently substituting for toxic doses of corticosteroids, has significant inherent toxicity. Furthermore, it does not eliminate the need for periodic corticosteroids.

There is a great need for new approaches to treatment of allergic diseases such as asthma. Specifically, there is a need for therapy that produces long-lasting antiinflammatory effect without harm to the patient.

In addition, it would be desirable to provide effective agents which are safe and relatively inexpensive as well as being easy to administer.

Accordingly, there is a substantial need for an effective, safe, relatively inexpensive, and easy to administer treatment for persistent and chronic asthma.

Disclosure of the Invention The present invention provides a method for the remediation of the inflammatory response symptoms of asthma which comprises administering a composition comprising an effective amount of at least one compound selected from the group consisting of esters of myristic acid and esters of myristoleic acid to a patient in need of such remediation.

WO 99/52508 PCT/US99/08226 -4- Detailed Description of the Invention The present invention provides a method for the remediation of the inflammatory response symptoms of asthma which comprises administering a composition comprising an effective amount of at least one compound selected from the group consisting of esters of myristic acid and esters of myristoleic acid to a patient in need of such remediation.

The medicament of the present invention will comprise at least one ester of myristic or myristoleic acid. Typically, such esters will be alkyl esters, such as methyl (CI) ethyl (C 2 propyl (C 3 or isopropyl (C 3 esters, and the like. Presently preferred esters of the invention will include even longer chain alkyls, such as cetyl

(C

5 s) esters of myristic acid or myristoleic acid.

As noted previously, the underlying pathophysiology of asthma results from the release of potent leukotrienes, which act as inflammatory mediators to cause bronchoconstriction, increased vascular permeability and mucus production. In the 1930's, a substance found to be involved in anaphylaxis and asthma was identified and named slow-reacting substance of anaphylaxis (SRS-A). It was not until the 1980's that SRS-A was purified and found to be composed of leukotrienes, which are inflammatory mediators that were presumed to be released from leukocytes when they were identified in the late 1970's. In fact, SRS-A is made up of three types of leukotrienes, LTC 4, LTD4, and LTE 4 which are collectively known as the cysteinyl or sulfidopeptide leukotrienes because each contains a thioether-linked peptide.

Like prostaglandins and thromboxanes, the leukotrienes are products of intracellular arachidonic acid metabolism, but the metabolic pathways are not the same.

The cyclooxygenase pathway, which produces the prostaglandins and thromboxanes, uses arachidonic acid either as free lipid or released from membrane phospholipid by phopholipase A 2 Leukotrienes are produced by the lipoxygenase pathway, and here arachidonic acid is utilized from phopholipid pools.

The lipoxygenase pathway also involves an enzyme-activating protein that has no counterpart in the cyclooxygenase pathway. During the early development of antileukotrienes, researchers observed that their first experimental drug inhibited WO 99/52508 PCT/US99/08226 leukotriene synthesis without affecting arachidonic acid release or activity. Binding studies carried out with radiolabeled drug disclosed a membrane protein that was necessary for leukotriene synthesis. The protein was named activating protein (FLAP), and its function may be to anchor the enzyme to the plasma membrane, where arachidonic acid is released.

Leukotrienes B 4 and C 4 are the secreted products of the lipoxygenase pathway.

They are produced mainly by mast cells and eosinophils, but they can also be released by other inflammatory cells such as basophils and macrophages. Both can exert proinflammatory effects, but LTC 4 is also converted extracellularly to LTD 4 a more potent inflammatory mediator. LTD 4 is further converted to LTE 4 which has a lesser effect and which is the form in which leukotrienes are excreted. Urinary LTE 4 is widely used as a marker of leukotriene synthesis. The leukotrienes are also found in plasma, bronchoalveolar lavage fluid, and nasal fluid, but they may be hard to detect, because only small amounts are synthesized and released.

Leukotriene binding sites, which are presumed to be receptors, have been found in epithelial and endothelial cells, smooth muscle cells, and nerve cells. Besides the lung, airways, and skin, binding sites exist in myocardium and gastric mucosa, so leukotrienes may act to depress myocardial contractility and gastric acid secretion.

High-affinity binding sites for LTD 4 have been found in human lung, and LTE 4 also binds to these sites, but with lesser affinity.

LTB

4 is a strong chemoattractant for neutrophils and eosinophils but has not been shown to have the same effects as the cysteinyl leukotrienes in asthma. Research into LTB 4 receptor antagonists has been done mainly in conditions such as psoriasis and ulcerative colitis, not in asthma.

Even when they were collectively known as SRS-A, the leukotrienes were understood to be involved in asthma. As research progressed, leukotrienes were found to be involved in bronchospasm and most of the inflammatory processes in asthma. In fact, their effects on the bronchial tree are much more intense and potent than those of previously studied mediators such as histamine.

WO 99/52508 PCT/US99/08226 -6- In the early response phase of asthma, LTC 4 and LTD 4 are 1000 times more potent than histamine. LTD 4 is the strongest bronchoconstrictor. The onset of action of LTC 4 is slower than for LTD 4 and LTE 4 whereas LTE 4 has the longest duration of action. The extent of mast cell contribution to the late-phase response is controversial, but leukotrienes are present in brochoalveloar lavage fluid in both the early and late phase responses. Leukotrienes in the late phase may be produced by eosinophils and macrophages.

The leukotrienes are also more potent than histamine, platelet-activating factor, or prostaglandins in inducing the other features of inflammation, namely increased vascular permeability and mucus production. Discovering the potency of the inflammatory effects of the leukotrienes led to research on ways to inhibit their production or block their effects. With formulation of the earliest antileukotriene agents, the major contribution of leukotrienes to asthmatic inflammation was confirmed.

Although not intending to be bound by any theory, it is believed that the present compositions serve to remedy the inflammatory response by one or more of a series of mechanisms involving the reduction of the leukotriene mediators. For example, it is believed that increased consumption of fatty acids, of which the present compositions form a part, results in inhibition of prostaglandin E2 synthesis, an alternative to leukotriene mediation of the inflammatory response. In addition, it is believed that the esters of myristic acid and myristoleic acid inhibit the synthesis of LTC4 and, to a lesser extent, the synthesis of LTD4. It has been postulated that changes in diet, namely a reduction in the consumption of saturated fat, have contributed to an increase in the prevalence of asthma, eczema and allergic rhinitis in developed countries (Black, P.N. and S. Sharpe, Eur. Respir. J. 10(1):6-12 (1997).

WO 99/52508 PCT/US99/08226 -7- The medicament of the present invention will comprise at least one ester of myristic acid (tetradecanoic acid):

CH

3

(CH

2 1

COOH

or myristoleic acid (cis 9 tetradecanoic acid):

CH

3

(CH

2 3 CH= CH(CH) 7

COOH

There are numerous sources known for obtaining myristic acid and myristoleic acid, including both natural and synthetic means. For example, it has long been known that both myristic and myristoleic acid can be obtained for botanic sources, such as plants of the genus Myristicaceae (including Nutmeg), and palm seeds, as well as animal sources, such as milk and sperm whale oil. In fact, it has been found to be one of the major components of the total fatty acid content of most animal and vegetable fats.

One particularly desirable natural source of the subject compounds is a botanical source such as the plant Pycnanthus angolensis. This plant, endemic to old and new world rainforests, has been found to contains both acids in substantial amounts, and has been used by rainforest inhabitants as a source of oil and food. As such, the compounds of the present invention should be regarded as safe, and can therefore even be considered as food. Such compounds are also available commercially, whether derived from natural sources or prepared synthetically. One convenient commercial source for myristic or myristoleic acid is Sigma Chemical Co., St. Louis, MO.

Likewise, there are well known methods of obtaining esters of myristic or myristoleic acid; such esters can be conveniently prepared by methods known in the art. For example, the present cetyl esters can be prepared by a method described in U.S. Patent No. 4,113,441 issued on September 12, 1978. However, as the method described therein employs benzene, the residual of which can be problematic with a composition intended for use as a medicament, particularly for one intended for oral administration, it was considered desirable to modify the procedure described therein to WO 99/52508 PCT/US99/08226 -8eliminate the reliance on benzene. In this modification, approximately equimolar amounts of cetyl alcohol (CH 3

(CH

2 )sOH) and either myristic or myristoleic acid are combined with an amount ofp-toluenesulfonic acid of up to approximately 15% of the total, to serve as a catalyst. After heating in reflux conditions for approximately four hours, the material can be washed with 10% sodium hydroxide, and the non-aqueous fraction can be extracted, recovered, dried and evaporated in vacuo. This fraction will be found to consist of virtually entirely cetyl ester of myristic acid

CH

3 (CH2) 2

COO(CH

2 )isCH 3 or of myristoleic acid

CH

3

(CH

2 3 CH= CH(CH) 7 COO(CH)1sCH 3 depending upon the starting materials employed.

In practicing the method of the present invention, the therapeutic medicament will be administered to a host in need of such treatment at a therapeutically effective dosage level. The compositions of the present invention will desirably be administered orally, in the form of capsules, tablets or suspensions, after first preparing the esters in powder form. Alternatively, the compositions can be administered topically, parenterally, or be any other means considered desirable.

The lowest effective dosage levels can be determined routinely by initiating treatment at higher dosage levels and reducing the dosage level until relieved from inflammatory reaction is no longer obtained. Generally, therapeutic dosage levels will range from about 0.01 to 100 milligrams per kilogram of host body weight. As a starting point, typically 1 gm. to 1.5 gm of the present composition is given three times a day for the first 7 to 10 days. The composition can also be administered at 2.5 to 6000 milligrams per kilogram of body weight. Response generally occurs between 7 to 10 days, a maintenance dose of approximately 500 mg to 1 gram is recommended. The WO 99/52508 PCT/US99/08226 -9amount necessary to achieve therapeutic effect for a particular individual will depend upon a number of factors such as body weight, severity of asthma and age of the individual.

It is not intended that the present invention be limited by the particular nature of the therapeutic preparation. For example, such compositions can be provided together with pharmaceutically acceptable and physiologically tolerable liquid, gel or solid carriers, diluents, adjuvents and excipients. These therapeutic preparations can be administered to mammals, both for veterinary use, such as with domestic animals, and clinical use in humans in a manner similar to other therapeutic agents. In general, the dosage required for therapeutic efficacy will vary according to the type of use and mode of administration, as well as the particularized requirements of individual hosts.

Such compositions are typically prepared for oral administration, or as sprays intra nasal aerosols) for topical use. However, they may be prepared either as liquid solutions or suspensions, or in solid forms including respirable and nonrespirable dry powders. Oral formulations for gastrointestinal absorption) usually includes such normally employed additives such as binders, fillers, carriers, preservatives, stabilizing agents, emulsifiers, buffers and excipients such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained-release formulations, or powders, and typically contain 1% to 95% of active ingredient, preferably 2% to 70%. The compositions of the present invention are also capable of being prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid prior to injection may also be prepared.

The compounds of the present invention are often mixed with diluents or excipients which are physiologically tolerable and compatible. Suitable diluents and excipients are, for example, water, saline, dextrose, glycerol, or the like, and combinations thereof. In addition, if desired, the compositions may contain minor amounts of auxiliary substances such as wedding or emulsifying agents, stabilizing or pH buffering agents.

WO 99/52508 PCT/US99/08226 Additional formulations which are suitable for other modes of administration, such as topical administration, includes salves, tinctures, creams, lotions and, in some cases, suppositories. For salves and creams, traditional binders, carriers and excipients may include, for example, polyalkylene glycols or triglycerides.

The following examples serve to illustrate certain preferred embodiments and aspects of the present invention and are not to be construed as limiting the scope thereof.

Experimental In the experimental disclosure which follows, all weights are given in grams milligrams micrograms nanograms or picograms all amounts are given in moles (mol), millimoles (mmol), micromoles (pmol), nanomoles (nmol), picomoles (pmol), or femtomoles (fmol), all concentrations are given as percent by volume proportion by volume molar millimolar micromolar (SiM), nanomolar picomolar femtomolar or normal all volumes are given in liters milliliters or microliters and linear measurements are given in millimeters or nanometers (nm) unless otherwise indicated.

The following examples demonstrate the practice of the present invention in Example 1: A 23-year old female with a history of chronic asthma had been on three to four drug therapy for the last seven to ten years. Her history included two episodes of respiratory arrest documented in medical records.

She began a course of treatment receiving 750mg of the encapsulated composition of the present invention three time a day. A dramatic decrease occurred in her symptoms after 1 week: She was able to reduce reliance on her bronchodilator; by the 2 n d week of the present therapy she used it only at bedtime. Follow up a few weeks later showed that she continued to display reduced symptoms.

WO 99/52508 PCT/US99/08226 -11- Example 2 A 63-year old female chronic asthmatic with a history of frequent 911 emergency calls was documented.

She began a course of treatment receiving one teaspoon (9 grams) of the pure powder version of a composition of the present invention, three times a day. One week after starting the treatment of the present invention, she reported that not only was her breathing significantly improved, but her energy level had improved significantly as well. The daily administration of her prescribed medications was reduced to an as needed basis. She was then placed on a maintenance does of one half teaspoon grams) daily.

Example 3 A young man from New Zealand whose brother had died eighteen months previously from complications of asthma, had become greatly incapacitated from his disease, believing he was literally waiting to die.

He began a course of treatment receiving 1.5 grams of the present composition per day. Three weeks later, he experienced a brief exacerbation of his symptoms, which lasted for three days. After that episode, he has resumed a more normal life, utilizing his asthma medication on an as needed basis. He has remained on a maintenance dose of the present composition.

Example 4 A 14-year old female asthmatic with frequent exacerbations of her asthma was documented as requiring nebulizations.

She began a course of treatment receiving 750mg of the present composition per day. After three days her symptoms improved significantly. She had previously missed school repeatedly due to her asthma. After receiving the present treatment, and a maintenance dose of 500mg daily, she has had no recurrence of her symptoms.

WO 99/52508 PCTIUS99/08226 -12- Example A 45-year old female from Mexico displayed chronic cough in the mornings.

She denied any history of asthma, but had noted that she coughs with exertion and any vigorous physical activity, such as brisk walking.

She began a course of treatment receiving 1 teaspoon (9 grams) of the powdered version of the present composition in the evening. The following morning she displayed no coughing spells, and after approximately one week she was free from her symptoms even when engaging in vigorous physical activity.

Example 6 An 8-year old female with history of eczema and asthma, was also documented as reactive to house dust and household cleaning chemicals.

She began a course of treatment receiving 1000mg twice a day, and obtained some observable relief of her asthma. There was only modest improvement of the eczema.

She was advised to cease the course of treatment for approximately ten days and reestablish the course of treatment at a much higher dose of 1000mg four times a day.

Experience with the composition of the treatment requires a large starting dose for individuals who respond poorly initially. This patient's asthma will be controlled during this second course of treatment, then she will receive a maintenance dose of 1000mg per day.

Example 7 A 50-year old man paralyzed from polio had a persistent non-productive cough for approximately two years. He admitted to a family history of asthma, and was believed to have asthma himself.

He began a course of treatment receiving 1 teaspoon (9 grams) of the powdered version of the present composition three times a day. In one week his symptoms cleared. He has remained on a maintenance dose of 1 teaspoon per day without recurrence of his formerly frequent coughing episodes.

WO 99/52508 PCT/US99/08226 -13- Example 8 A 19-year old male with documented recurrent episodes of emergency room visits due to of his severe symptoms.

He began a course of treatment receiving 1 teaspoon (9 grams) of the powdered version of the present composition three times a day. On the third day, the tightness in his chest cleared. In one week he was symptom free.

He continued a course of treatment receiving a maintenance dose of one teaspoon daily for three months, with occasional noncompliance. He ceased the course of treatment for two months, and his symptoms gradually returned. He has again resumed treatment and has since returned to his symptom free state.

0 15 *0 0 0* o So

OOSS

0 All patents and patent applications cited in this specification are hereby incorporated by reference as if they had been specifically and individually indicated to be incorporated by reference.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be apparent to those of ordinary skill in the art in light of the disclosure that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Where the terms "comprise", "comprises", "comprised" or "comprising" are used in this specification, they are to be interpreted as specifying the presence of the stated features, integers, steps or components referred to, but not to preclude the presence or addition of one or more other feature, integer, step, component or group thereof

Claims

1. A method for the remediation of the inflammatory response symptoms of asthma which comprises administering a composition comprising an effective amount of at least one compound selected from the group consisting of esters of myristic acid and esters of myristoleic acid to a patient in need of such remediation.

2. The method of claim 1 wherein the composition is administered orally.

3. The method of claim 1 wherein the composition further comprises a pharmaceutically acceptable carrier.

4. The method of claim 1 wherein the compound of the composition comprises an alkyl ester.

The method of claim 4 wherein the alkyl ester is cetyl myristate or cetyl myristoleate.

6. The method of claim 1 wherein the composition is administered at approximately 2.5 to approximately 6000 milligrams per kilogram of body weight.