IL29319A - Composition containing pyridine derivatives for the reduction of corticosteroid side effects - Google Patents

Description

29319/2 m ' nsiar Composition containing pyridine derivatives for the reduction of corticosteroid side effects.

Uniined, Inc This invention relates to the prevention of corticosteroid side effects which would normally occur by the administration of corticosteroids (e.g. gluco-corticoids) for various conditions for which the same have been found to be useful, the prevent on of the side effects which normally occur being accomplished by administering with, just prior to or just after the administration of the corticosteroid of an effective amount of a beta- (2- or 4-pyridyl-alkyl) amine or a similarly acting substance. It has been found that for reasons which are not yet fully explained but for which I have some theoretical explanations, that substances like beta- (2- or 4-pyridyl-alkyl) amines permit the corticosteroid to act in its normal manner for alleviation of the condition for which the same is administered, but prevent the occurrence of side effects which normally accompany the administration of the corticosteroids.

The use of corticosteroids for many conditions such as acute inflammatory and allergic diseases of the eye, skin and mucosa, rheumatoid arthritis, bronchial asthma, ulcerative colitis, and other conditions too numerous to mention, has be-come increasingly more important in recent years. The major limitations as to the use of such corticosteroids, e.g. hydrocortisone, for such purposes has been the high incidence of untoward side effects which accompany such administration. In fact the use of corticosteroids to an even greater extent than has been presently possible has been limited mainly by these undesired side effects. Attempts have been made to reduce the side effects of the corticosteroids by making various steroid w w e hese tero d deriv tives have molecule, such activity on a biological unit per biological unit basis, remains essentially parallel in side effects. It can generally be stated that no. satisfactory means have yet been achieved for reducing the undesired side effects of the corticosteroids.

Among the side effects which occur upon administration of corticosteroids are iatrogenic (or physician induced) Cushing's disease, sodium retention and potassium excretion with edema, hypertension, hyperglycemia, glycosuria, etc. In many cases the side effects of the administration of the corticosteroids are so great that continued use thereof becomes impossible despite the need for the corticosteroid desired effect. Thus, it is often necessary to give doses below the desired dose and likewise it is often necessary to discontinue treatment with the corticosteroid when continued treatment would be desirable except for the undesired side effects which take place .

Generally speaking in accordance with the invention a method is provided of preventing the side effects of a corticosteroid which would otherwise occur upon administration of the same by administering to the subject which is to receive the corticosteroid either at the time of administration of the corticosteroid or shortly before or shortly after such administration an agent which I have found has the effect of permitting the corticosteroid to act in its desired manner while at the same time preventing the undesired side effects which would otherwise occur upon simple administration of the corticosteroid.

It s cc d im r b ect of the rese t administration of corticosteroids while achieving the desired main effect thereof .

It is yet another obj ect of the present invention to provide compositions including a corticosteroid which by itself would cause undesirable s ide effects , and also including an agent which prevents the undesired side effects of corticosteroid from occurring .

It is yet a further obj ect of the present invention to provide superior compositions for the treatment of conditions which are treated by corticosteroids , these compos itions being superior because they can be given in larger doses and over longer periods of time without undesired side effects occurring.

Other objects and advantages of the present invention will be apparent from a further reading of the specification and of the appended claims .

With the above and other obj ects in view, the present invention mainly comprises a method of administering corticosteroids while preventing the occurrence of undesired s ide effects from such administration, by administering simultaneously with , j ust prior to or shortly after the administration of the corticosteroid at least one member selected from the group consisting of beta- (2 -pyr idyl-alky 1) -amines , beta- (4-pyridyl- cjfclobutaner-alkyl) -amines , 1- (2 ' -pyridyl) - 2 , 3-cis or trans dicarboxylic cyclobutane-acid =o¾*e-leJ-«*feanee , 1- (4 ' -pyridyl) y2 , 3-cis or trans dicarboxylic acid -oyei©fe»¾-aftes, alpha-picolinic acid d -loweralkyl-amides , and non-toxic acid addition salts of any of them.

This invention is ap licable to all corticosteroids merit of anti-inflammatory and other conditions. Among these steroids, which are mentioned for exemplatory purposes only, are cortisone (including derivatives thereof such as cortisone phosphate, etc.) , hydrocortisone (and derivatives thereof such as the 21-sodium succinate, etc.), prednisone, dexamethasone, ACTH, corticosterone, 11-dehydrocorticosterone, 11-desoxy-corticosterone, aldosterone, etc. These corticosteroids are administered for many purposes such as the treatment of Addison's disease, hypopituitarism, adrenal hyperphasia, col-lagen diseases such as rheumatoid arthritis, rheumatic fever and rheumatic carditis, diseases of allergy such as bronchial asthma, allergic vasomotor rhinitis, inflammatory diseases of the eye, pulmonary fibrosis , sarcoidosis , diseases of the skin, acute gouty arthritis, etc.

The specific amount of the corticosteroid which is administered depends on the specific corticosteroid and on the condition for which it is administered. The present invention is applicable to any effective amount. Thus, for example, in the case of cortisone the dosage may be 2.5 to 100 mg orally, 5 to 300 mg i.m., up to 100 mg i.v., and 0.5 - 2.5% suspension or ointment for topical administration. In the case of administration to cattle for ketosis the amount may be 1.0 - 1.5 g i.m., and to dogs for arthritis the amount may be 25 - 75 mg orally. In the case of hydrocortisone the dosage is generally about 2/3 of that of the dosage of cortisone. In the case of prednisone the oral dose is about 20 to 60 mg per day as a suppressive dose, which is gradually decre sed until o timum maintenance dose is determined. In the potent as prednisolone and 20 to 35 times as potent as hydrocortisone, the dose is about 0.5 to 1.5 mg orally and about a 0.1% lotion for topical administration. As indicated above, the present invention is applicable to the use of any effective dose of any of these and other corticosteroids .

In accordance with the present invention an agent is administered, of the type mentioned above, and of which more specific examples will be given below, either simultaneously with the corticosteroid, shortly prior thereto or shortly after administration of the corticosteroid, which agent has, for some as yet unexplained reason, the ability of preventing manifestation of the undesired side effects of the corticosteroid without interfering with the main action thereof. An effective amount of the agent is administered, the specific effective amount varying somewhat depending upon the particular agent, and the administration thereof is preferably oral.

The most preferred compounds for preventing the undesired side effects of the corticosteroids are the beta- (2-pyridyl-alkyl) -amines , beta- (4-pyridyl-alkyl) -amines and the non-toxic acid addition salts thereof. The most preferred of these compounds are those wherein the alkyl is a lower alkyl such as methyl and/or ethyl, e.g. beta- (2-pyridyl) -ethylmethyl amine, beta- (4-pyridyl) -ethylmethyl amine, 1- (2-pyridyl) -2-methylamine propane, and their non-toxic acid addition salts thereof such as the hydrochloride, tartrate, fumarate, gluconate, etc.

The beta- (2- or 4-pyridylalkyl) -amines are prefer administered 3 - 4 times a day. These compounds may be administered either orally or by injection.

Other pyridylalkyl amines and pyridylalkyl amine acid addition salts include 2- (2 ' - (N,N-dietl\ejylamino) ethyl) pyridine monofumarate ; 2- (2 ' -NL^-ethylaraino) ethyl) pyridine monofumarate ; 2- (21 - (amino) ethyl) pyridine monofumarate ; 4- (2 '- (amino) ethyl) pyridine monofurmarate 4- (2 ' - (methylamino) ethyl) pyridine monofumarate ; beta- (2-pyridyl) -ethyldiethyl-amine hydrochloride; 1- (1-pyridyl) -2-methylaminopropane hydrochloride; and beta- (2-pyridyl) -ethylamine hydrochloride.

Among the pyridyl dicarboxylic acid cyclobutanes cyclobutane-may be mentioned 1- (21 -pyridyl) -/2 , 3-trans dicarboxylic acid cyclobutaner- •eye-lobu ane ; 1- (4 ' -pyridyl) -fl , 3-trans dicarboxylic acid -eye-lo*- -bwfeafte-; 1- (2 ' -pyridyl icarboxylic acid -eye-3x¾rrtane; cyclobutane - and 1- (4 ' -pyridyl) -†l , 3-cis dicarboxylic acid -eyeioi-H*fcet«e-.

Among the alpha-picolinic acid di-loweralkyl amides may be mentioned alpha-picolinic acid diethylamide; alpha- picolinic acid dimethylamide ; and of course the acid addition salts thereof such as the hydrochloride, sulfate, etc. The amount of these compounds which is generally used, is between about 0.1 - 1 mg administered three times a day.

While this invention is not meant to be limited to any specific theory as to how or why the undesired side effects of the corticosteroids are prevented in accordance with this invention, the following theory is given in the hope that it will help others in further research in this field.

It is believed that the corticosteroids function by passive attachment to microvascular smooth muscle cells Histamine is normally found in small amounts within the smooth muscle cells. However, the rate of histamine production is increased by stressful stimuli of either a local or systemic nature. A localized activation of histamine synthesis, resulting from local tissue irritation, mediates the early phases of inflammation. A general increase in histamine synthesis occurs when a stress, e.g. extensive injury, causes release of the constrictor substances adrenaline and noradrenaline .

Thus, corticosteroid antagonism of the increased histamine effect in stress could underly the essential stress function of these hormones, the susceptibility of adrenal-deficient animals to stress, and the large variability in corticosteroid requirements. Corticosteroid antagonism of increased local histamine effects might be the underlying factor in the anti-inflammatory effect of the corticosteroid.

It v/ould therefore seem that the harmful side effects of corticosteroid therapy may arise from the tendency of those hormones to close microvascular sphincters by opposing the normal dilator action of histamine. As a result, corticosteroid dosing reduces capillary blood flow, tissues become undernourished, and widespread abnormalities in cell chemistry and function develop, the side effects of the corti-consteroid therapy being manifested as a result.

The agents which are used according to the present invention to prevent the manifestation of the corticosteroid side effects apparently counteract the tendency of the hormones occurring, while at the same time not interfering with the antiinflammatory effect of the corticosteroid. These agents according to the present invention have, in addition, low toxicity and, of considerable importance, are effective upon oral administration.

The following examples are given to further illustrate the present invention. The scope of the invention is not, however, meant to be limited to the specific details of the examples .

Example 1 A stressed adrenalectomized rat is injected with 5 mg hydrocorticose . Increased closure time of hepatic microvascular sphincters results in an abnormally rapid perfusion of those sinusoids remaining open. This process triggers metabolic activation of the overfed hepatic cells and the generalized non-specific hepatic anabolism characteristic of the corticosteroid treated animal arises.

Another stressed adrenalectomized rat is injected with the same amount of hydrocortisone plus 1 mg of beta- (2-pyridyl) methylethylamine hydrochloride (beta-histine hydrochloride in physiological salt solution. Due to the restoration of the open and closed sphincters, the degree of side effects is considerably lessened.

Example 2 Tablets are prepared by usual tabletting procedure, each tablet containing: cortisone 10 mg.

The above tablet can be administered for any purpose for which cortisone is orally administered to achieve the full effect of the cortisone with reduced danger of the undesired side effects.

Example 3 Ampoules are prepared, each containing 10 cc, and each cc consisting of 50 mg hydrocortisone and 10 mg of 1- (2-pyridyl) -2-ethylmethylamine hydrochloride, dissolved in 0.9% sodium chloride solution. The solution can be administered for all purposes for which hydrocortisone is administered, and over prolonged periods of time, without the danger of side effects which would ordinarily occur by the administration of the hydrocortisone alone.

Example 4 Tablets are prepared by the usual tabletting procedure, each tablet containing: prednisone 5 mg. beta- (2-pyridyl) -ethylamine hydrochloride 2 mg. lactose q.s. 250 mg.

The above tablet can be freely used in all conditions calling for the use of prednisone, with considerably reduced danger of the undesired side effects of the prednisone.

Example 5 A patient having an acute inflammatory condition of the mucosa is treated by daily injections If 100 mg of cortisone acetate administered intramuscularly. The patient is given 12 mg of beta- (2-pyridyl) -ethyIdiethylamine hydro taining the same. No untoward side effects of the cortisone are manifest after several weeks of such treatment.

Example 6 Ophthalmic eye drops are prepared having the fol- lowing composition per cubic centimeter: dexamethasone sodium phosphate 1 mg beta- (2-pyridyl) methylethylamine hydrochloride 2 mg sodium bisulfite (preservative) 0.32% water for injection q.s. 1 cc Example 7 An ointment preparation is made of the following composition: hydrocortisone acetate 25 mg beta- (2-pyridyl) methylethylamine hydrochloride 5 mg bland, non-irritating base of anhydrous lanoline, white petrolatum and mineral oil q.s. 1 gram The above ointment may be applied topically to the skin for control of local inflammatory conditions.

It is believed that from the foregoing adaptations and variations of the invention can be made without departing from the essential characteristics thereof. Such adaptations and variations are meant to be comprehended within the scope of the appended claims.

Claims (1)

1. Claims Composition for reducing side effects which when a corticosteroid is administered to a said composition comprising at least one member selected from group consisting of acid and ic acid addition salts thereof pins a pharmaceutically acceptable Composition according to claim 1 wherein said member is selected the group consisting of and acid addition salts Composition according to claias 1 or 2 wherein the carrier is suitable for oral according to claims wherein the is present a unit dose of about Corticosteroid composition with reduced corticosteroid side said a corticosteroid and least one selected from the group consisting of pyridyl acid acid acid and acid salts according to 5 said is selected frora the group consisting of 1 addition salts Composition according to 5 or wherein said is present in an amount of about according to any of 5 to 7 wherein composition is in for oral Composition according to any of 5 to 7 in wherein said corticosteroid and said are distributed in an injectable rence to the this day 1968 the Applicants Hess insufficientOCRQuality