Methods and compositions for treating allergic disorders and other disorders using metabolic derivatives of astemizole

Methods and compositions are disclosed utilizing metabolic derivatives of astemizole for the treatment of allergic disorders while avoiding the concomitant liability of adverse effects associated with the astemizole. The metabolic derivatives of astemizole are also useful for the treatment of retinopathy and other small vessel disorders associated with diabetes mellitus and such other conditions as may be related to the antihistamine activity of astemizole. For example, the metabolic derivatives of astemizole are useful for the treatment of asthma, motion sickness, and vertigo, without the concomitant liability of adverse effects associated with astemizole. Furthermore, the metabolic derivatives of astemizole, in combination with non-steroidal anti-inflammatory agents or other non-narcotic analgesics, or in combination with a decongestant, cough suppressant/antitussive or expectorant, are useful for the treatment of cough, cold, cold-like, and/or flu symptoms and the discomfort, headache, pain, fever, and general malaise associated therewith, without the concomitant liability of adverse effects associated with astemizole.

1. BACKGROUND OF THE INVENTION 
This invention relates to novel pharmaceutical compositions containing 
desmethylastemizole, 6-hydroxydesmethylastemizole and norastemizole. These 
compositions possess potent antihistaminic activity and are useful in 
treating allergic rhinitis, asthma and other allergic disorders while 
avoiding adverse effects associated with the administration of other 
antihistamines, such as astemizole, including but not limited to cardiac 
arrhythmias, drowsiness, nausea, fatigue, weakness and headache. Also, 
these compositions, in combination with non-steroidal anti-inflammatory 
agents or other non-narcotic analgesics, are useful for the treatment of 
cough, cold, cold-like, and/or flu symptoms and the discomfort, headache, 
pain, fever, and general malaise associated therewith. The aforementioned 
combinations may optionally include one or more other active components 
including a decongestant, cough suppressant/antitussive, or expectorant. 
Additionally, these novel pharmaceutical compositions containing 
desmethylastemizole, 6-hydroxydesmethylastemizole 
hydroxydesmethylastemizole and norastemizole are useful in treating motion 
sickness, vertigo, diabetic retinopathy, small vessel complications due to 
diabetes and such other conditions as may be related to the activity of 
these derivatives as antagonists of the H-1 histamine receptor while 
avoiding the adverse effects associated with the administration of other 
antihistamines, such as astemizole. 
Also disclosed are methods for treating the above-described conditions in a 
human while avoiding the adverse effects that are associated with the 
administration of other antihistamines, such as astemizole, by 
administering the aforementioned pharmaceutical compositions containing 
desmethylastemizole, 6-hydroxydesmethylastemizole and norastemizole to 
said human. 
The active compounds of these compositions and methods are metabolic 
derivatives of astemizole. Chemically, these derivatives are 
desmethylastemizole, 6-hydroxydesmethylastemizole and norastemizole. These 
compounds are described in Kamei et al., Arzneimittel-Forschung/Drug 
Research, 41: 932-36 (1991). 
Astemizole is an antagonist of the H-1 histamine receptor protein. 
Histamine receptor proteins occur in two well-identified forms in tissues, 
of which H-1 and H-2 receptors are two. The H-1 receptors are those that 
mediate the response antagonized by conventional antihistamines. H-1 
receptors are present, for example, in the ileum, the skin, and the 
bronchial smooth muscle of man and other mammals. Astemizole antagonizes 
the effect of histamine in the guinea pig isolated ileum, suppresses 
histamine-induced whealing in the skin of guinea pigs, and protects 
against histamine induced bronchoconstriction in the guinea pig. 
Through H-2 receptor-mediated responses, histamine stimulates gastric acid 
secretion in mammals and the chronotropic effect in isolated mammalian 
atria. Astemizole has no effect on histamine-induced gastric acid 
secretion, nor does it alter the chronotropic effect of histamine on 
atria. Thus, astemizole has no apparent effect on the H-2 histamine 
receptor. 
Astemizole is well absorbed but is extensively metabolized. See Uchiyama et 
al., Pharmacometrics, 40: 77-93 (1990). Three main metabolites have been 
identified, and all of the metabolites are reported to have antihistaminic 
activity. See Kamei et al., Arzneimittel-Forschung/Drug Research, 41: 
932-36 (1991). 
On the basis of its antihistaminic activity, researchers evaluated the 
pharmacological effects of astemizole in man. Clinical trials of efficacy 
indicated that astemizole is an effective H-1 antagonist. See Howarth, 
Clin. Exp. Allerqy, 20 (Suppl. 2): 31-41 (1990). 
Weintraub et al., Hosp. Formul., 22: 918-27 (1987) describes clinical 
efficacy of astemizole in the treatment of both seasonal and perennial 
allergies. It has also been suggested that astemizole would be useful for 
the treatment of asthma. 
Astemizole may also be useful for the treatment of motion sickness and 
vertigo. Some antihistamines have been found to be effective for the 
prophylaxis and treatment of motion sickness. See Wood, Drugs, 17: 471-479 
(1979). Some antihistamines have also proven useful for treating 
vestibular disturbances, such as Meniere's disease, and in other types of 
vertigo. See Cohen et al., Archives of Neurology, 27: 129-135 (1972). 
In addition, astemizole may be useful in the treatment of diabetic 
retinopathy and other small vessel disorders associated with diabetes 
mellitus. In tests on rats with streptozocin-induced diabetes, treatment 
by antihistamines prevented the activation of retinal histamine receptors 
which have been implicated in the development of diabetic retinopathy. The 
use of antihistamines to treat retinopathy and small vessel disorders 
associated with diabetes mellitus is disclosed in U.S. Pat. No. 5,019,591. 
It has also been suggested that astemizole, in combination with 
non-steroidal anti-inflammatory agents or other non-narcotic analgesics, 
would be useful for the treatment of cough, cold, cold-like and/or flu 
symptoms and the discomfort, pain, headache, fever, and general malaise 
associated therewith. These compositions for the treatment of the 
above-described symptoms may optionally include one or more other active 
components including a decongestant (such as pseudoephedrine), a cough 
suppressant/antitussive (such as dextromethorphan) or an expectorant (such 
as guaifenesin). 
Many antihistamines cause somewhat similar adverse effects. These adverse 
effects include but are not limited to sedation, gastrointestinal 
distress, dry mouth, and constipation or diarrhea. Astemizole has been 
found to cause relatively less sedation as compared with other 
antihistamines. See Weintraub et al., Hosp. Formul., 22: 918-27 (1987). 
However, the administration of astemizole to a human has been found to 
cause other adverse effects. These adverse effects include but are not 
limited to cardiac arrhythmias, including ventricular tachyarrhythmias, 
torsades de pointes, and ventricular fibrillation. See Knowles, Canadian 
Journal Hosp. Pharm., 45: 33,37 (1992); Craft, British Medical Journal, 
292: 660 (1986); Simons et al., Lancet, 2: 624 (1988); and Unknown, Side 
Effects of Drugs Annual, 12: 142 and 14: 135. An additional unwanted side 
effect of astemizole is appetite stimulation and weight gain in patients 
taking the drug for various indications. See Krstenansky et al., Drug 
Intell. Clin. Pharm., 21: 947-53 (1987). 
Thus, it would be particularly desirable to find a compound with the 
advantages of astemizole which would not have the aforementioned 
disadvantages. 
2. SUMMARY OF THE INVENTION 
It has now been discovered that desmethylastemizole, 
6-hydroxydesmethylastemizole and norastemizole (hereinafter metabolic 
derivatives of astemizole) are effective antihistamines which avoid 
adverse effects which are associated with the administration of 
astemizole, including but not limited to cardiac arrhythmias, cardiac 
conduction disturbances, appetite stimulation, weight gain, sedation, 
gastrointestinal distress, dry mouth, and constipation or diarrhea. It has 
also been discovered that these pharmaceutical compositions containing 
metabolic derivatives of astemizole are useful in treating allergic 
disorders and such other conditions as may be related to the composition's 
activity as an antihistamine, including but not limited to allergic 
rhinitis, solar urticaria, and symptomatic dermographism, while avoiding 
the above-described adverse effects associated with the administration of 
astemizole. The present invention also includes methods for treating the 
above-described conditions in a human while avoiding the adverse effects 
that are associated with astemizole, by administering the metabolic 
derivatives to said human. 
Furthermore, it has now also been discovered that the metabolic derivatives 
of astemizole are useful in treating asthma while avoiding the adverse 
effects associated with administration of astemizole. As stated above, 
examples of such side effects are appetite stimulation, weight gain, 
cardiac arrhythmias and cardiac conduction disturbances. Also, these 
metabolic derivatives are useful for the treatment of motion sickness and 
vertigo, while avoiding the adverse effects associated with administration 
of astemizole. In addition, the metabolic derivatives of astemizole are 
useful in treating such disorders as retinopathy and small vessel 
disorders associated with diabetes mellitus while avoiding the adverse 
effects associated with administration of astemizole. 
It has also been discovered that the metabolic derivatives of astemizole, 
in combination with non-steroidal anti-inflammatory agents or other 
non-narcotic analgesics, are useful for the treatment of cough, cold, 
cold-like and/or flu symptoms and the discomfort, pain, headache, fever, 
and general malaise associated therewith. The use of pharmaceutical 
compositions of the invention, containing the metabolic derivatives of 
astemizole, and non-narcotic analgesics or non-steroidal anti-inflammatory 
agents such as aspirin, acetaminophen or ibuprofen, may optionally include 
one or more other active components including a decongestant (such as 
pseudoephedrine), a cough suppressant/antitussive (such as 
dextromethorphan) or an expectorant (such as guaifenesin).

3. DETAILED DESCRIPTION OF THE INVENTION 
The present invention encompasses a method of treating a human afflicted by 
or susceptible to an allergic disorder while avoiding the concomitant 
liability of adverse effects associated with the administration of 
astemizole, which comprises administering to said human afflicted by or 
susceptible to an allergic disorder an amount of one or more compounds 
selected from a class of metabolic derivatives of astemizole, or a 
pharmaceutically acceptable salt thereof, said amount being sufficient to 
treat said allergic disorder, but insufficient to cause the adverse 
effects associated with astemizole. Suitable metabolic derivatives are 
compounds selected from the group consisting of desmethylastemizole, 
6-hydroxydesmethylastemizole and norastemizole, and the like. 
The present invention also encompasses a composition adapted for the 
treatment of a human having an allergic disorder which comprises an amount 
of a metabolic derivative of astemizole, or a pharmaceutically acceptable 
salt thereof, said amount being sufficient to alleviate said allergic 
disorder but insufficient to cause the adverse effects associated with 
astemizole. 
The present invention further encompasses a method of treating asthma in a 
human, while avoiding the concomitant liability of adverse effects 
associated with the administration of astemizole, which comprises 
administering to said human afflicted by asthma an amount of a metabolic 
derivative of astemizole or a pharmaceutically acceptable salt thereof, 
said amount being sufficient to alleviate said asthma but insufficient to 
cause the adverse effects associated with astemizole. Suitable metabolic 
derivatives of astemizole are compounds selected from the group consisting 
of desmethylastemizole, 6-hydroxydesmethylastemizole and norastemizole, 
and the like. 
In addition, the present invention encompasses compositions adapted for the 
treatment of a human having asthma which comprises an amount of a 
metabolic derivative of astemizole, or a pharmaceutically acceptable salt 
thereof, said amount being sufficient to alleviate said asthma but 
insufficient to cause the adverse effects associated with astemizole. 
A further aspect of the present invention includes a method of treating 
motion sickness or vertigo in a human, while avoiding the concomitant 
liability of adverse effects associated with the administration of 
astemizole, which comprises administering to said human afflicted by 
motion sickness or vertigo an amount of a metabolic derivative of 
astemizole, or a pharmaceutically acceptable salt thereof, said amount 
being sufficient to alleviate said motion sickness or vertigo but 
insufficient to cause the adverse effects associated with astemizole. 
Suitable metabolic derivatives of astemizole are compounds selected from 
the group consisting of desmethylastemizole, 6-hydroxydesmethylastemizole 
and norastemizole, and the like. 
Furthermore, the present invention includes compositions for treating 
motion sickness or vertigo in a human which comprises an amount of a 
metabolic derivative of astemizole, or a pharmaceutically acceptable salt 
thereof, said amount being sufficient to alleviate said motion sickness or 
vertigo but insufficient to cause the adverse effects associated with 
astemizole. 
Also included in the present invention is a method of treating retinopathy 
or other small vessel diseases associated with diabetes mellitus while 
avoiding the concomitant liability of adverse effects associated with the 
administration of astemizole, which comprises administering to said human 
an amount of a metabolic derivative of astemizole, or a pharmaceutically 
acceptable salt thereof, said amount being sufficient to alleviate said 
retinopathy or other small vessel diseases associated with diabetes 
mellitus but insufficient to cause the adverse effects associated with 
astemizole. Suitable metabolic derivatives of astemizole are compounds 
selected from the group consisting of desmethylastemizole, 
6-hydroxydesmethylastemizole and norastemizole, and the like. 
Additionally, the present invention includes compositions for treating 
retinopathy or other small vessel diseases associated with diabetes 
mellitus in a human, comprising an amount of a metabolic derivative of 
astemizole, or a pharmaceutically acceptable salt thereof, said amount 
being sufficient to alleviate said retinopathy or other small vessel 
diseases associated with diabetes mellitus but insufficient to cause the 
adverse effects associated with astemizole. 
Furthermore, the present invention includes a pharmaceutical composition 
for use in the treatment of cough, cold, cold-like and/or flu symptoms and 
the discomfort, pain, fever and general malaise associated therewith, in a 
human, said composition comprising (i) a therapeutically effective amount 
of at least one metabolic derivative of astemizole, with (ii) a 
therapeutically effective amount of at least one non-steroidal 
anti-inflammatory agent or non-narcotic analgesic such as acetylsalicylic 
acid, acetaminophen, ibuprofen, ketoprofen, and naproxen, or 
pharmaceutically acceptable salts thereof. 
Additionally, the present invention includes a pharmaceutical composition 
for use in the treatment of cough, cold, cold-like and/or flu symptoms and 
the discomfort, pain, fever and general malaise associated therewith, in a 
human, said composition comprising (i) a therapeutically effective amount 
of at least one metabolic derivative of astemizole, with (ii) a 
therapeutically effective amount of a decongestant such as 
pseudoephedrine, or pharmaceutically acceptable salts thereof. 
The present invention further encompasses a method for the treatment of 
cough, cold, cold-like, and/or flu symptoms and the discomfort, pain, 
fever, and general malaise associated therewith, in a human in need of 
such treatment, by administering to said human a composition comprising 
(i) a therapeutically effective amount of at least one metabolic 
derivative of astemizole, with (ii) a therapeutically effective amount of 
at least one non-steroidal anti-inflammatory agent or non-narcotic 
analgesic such as acetylsalicylic acid, acetaminophen, ibuprofen, 
ketoprofen, and naproxen, or pharmaceutically acceptable salts thereof. 
Additionally, the present invention encompasses a method for the treatment 
of cough, cold, cold-like, and/or flu symptoms and the discomfort, pain, 
fever, and general malaise associated therewith, in a human in need of 
such is treatment comprising administering to said human a composition 
comprising (i) a therapeutically effective amount of at least one 
metabolic derivative of astemizole with (ii) a therapeutically effective 
amount of a decongestant such as pseudoephedrine, or pharmaceutically 
acceptable salts thereof. 
A further aspect of this invention includes a method of treating an 
allergic reaction in a human with a composition comprising (i) a 
therapeutically effective amount of at least one metabolic derivative of 
astemizole, with (ii) a therapeutically effective amount of at least one 
non-steroidal anti-inflammatory agent or non-narcotic analgesic such as 
acetylsalicylic acid, acetaminophen, ibuprofen, ketoprofen, and naproxen, 
or pharmaceutically acceptable salts thereof. 
Furthermore, the present invention includes a method of treating an 
allergic reaction in a human with a composition comprising (i) a 
therapeutically effective amount of at least one metabolic derivative of 
astemizole, with (ii) a therapeutically effective amount of a decongestant 
such as pseudoephedrine, or pharmaceutically acceptable salts thereof. 
Astemizole has antihistaminic activity and provides therapy and a reduction 
of symptoms for a variety of conditions and disorders related to allergic 
disorders, diabetes mellitus and other conditions; however, this drug, 
while offering the expectation of efficacy, causes adverse effects. 
Utilizing the metabolic derivatives of astemizole results in clearer 
dose-related definitions of efficacy, diminished adverse effects, and 
accordingly, an improved therapeutic index. It is, therefore, more 
desirable to use metabolic derivatives of astemizole than to use 
astemizole itself, and the metabolic derivatives of astemizole may be 
administered in greater doses than would be appropriate for astemizole. 
The term "adverse effects" includes, but is not limited to cardiac 
arrhythmias, cardiac conduction disturbances, appetite stimulation, weight 
gain, sedation, gastrointestinal distress, dry mouth, constipation, and 
diarrhea. The term "cardiac arrhythmias" includes, but is not limited to 
ventricular tachyarrhythmias, torsades de pointes, and ventricular 
fibrillation. 
The phrase "therapeutically effective amount" means that amount of one or 
more of the metabolic derivatives of astemizole which provides a 
therapeutic benefit in the treatment or management of allergic disorders, 
asthma, retinopathy or other small vessel disorders associated with 
diabetes mellitus, motion sickness, vertigo, or cough, cold, cold-like, 
and/or flu symptoms and the discomfort, pain, fever, and general malaise 
associated therewith. Examples of allergic disorders include, but are not 
limited to, allergic rhinitis, solar urticaria, and symptomatic 
dermographism. The symptoms associated with these allergic disorders and 
the cough, cold, cold-like, and/or flu symptoms include, but are not 
limited to, sneezing, rhinorrhea, lacrimation, and dermal irritation. The 
term "asthma" is defined as a disorder characterized by increased 
responsiveness of the trachea and bronchi to various stimuli which results 
in symptoms which include wheezing, cough, and dyspnea. The term "vertigo" 
as used herein means the dizziness associated with, but not limited to, 
motion, height, and changes in body position. The term "diabetic 
retinopathy" or "retinopathy associated with diabetes mellitus" is that 
disorder caused by increased permeability of the capillaries in the eye 
which leads to hemorrhages and edema in the eye and can lead to blindness. 
The term "small vessel disorders associated with diabetes mellitus" 
includes, but is not limited to, diabetic retinopathy and peripheral 
vascular disease. 
The magnitude of a prophylactic or therapeutic dose of the metabolic 
derivatives of astemizole in the acute or chronic management of disease 
will vary with the severity of the condition to be treated and the route 
of administration. The dose, and perhaps the dose frequency, will also 
vary according to the age, body weight, and response of the individual 
patient. In general, the total daily dose range, for the conditions 
described herein, is from about 1 mg to about 200 mg administered in 
single or divided doses orally, topically, transdermally, or locally by 
aerosol. For example, a preferred oral daily dose range should be from 
about 1 mg to about 50 mg. It is further recommended that children, 
patients aged over 65 years, and those with impaired renal or hepatic 
function initially receive low doses, and that they then be titrated based 
on individual response(s) or blood level(s). It may be necessary to use 
dosages outside these ranges in some cases as will be apparent to those 
skilled in the art. Further, it is noted that the clinician or treating 
physician will know how and when to interrupt, adjust, or terminate 
therapy in conjunction with individual patient response. 
The various terms "an amount sufficient to alleviate said allergic disorder 
but insufficient to cause said adverse effects," "an amount sufficient to 
alleviate said asthma but insufficient to cause said adverse effects," "an 
amount sufficient to alleviate said motion sickness but insufficient to 
cause said adverse effects," and "an amount sufficient to alleviate said 
retinopathy or other small vessel diseases associated with diabetes 
mellitus but insufficient to cause said adverse effects" are encompassed 
by the above-described dosage amounts and dose frequency schedule. In 
addition, the terms "a pharmaceutical composition for use in the treatment 
of cough, cold, cold-like and/or flu symptoms and the discomfort, pain, 
fever and general malaise associated therewith, in a human, said 
composition comprising (i) a therapeutically effective amount of at least 
one metabolic derivative of astemizole, with (ii) a therapeutically 
effective amount of at least one non-steroidal anti-inflammatory agent or 
non-narcotic analgesic" and "a pharmaceutical composition for use in the 
treatment of cough, cold, cold-like and/or flu symptoms and the 
discomfort, pain, fever and general malaise associated therewith, in a 
human, said composition comprising (i) a therapeutically effective amount 
of at least one metabolic derivative of astemizole, with (ii) a 
therapeutically effective amount of a decongestant" are also encompassed 
by the above-described dosage amounts and dose frequency schedule. 
Any suitable route of administration may be employed for providing the 
patient with an effective dosage of the metabolic derivatives of 
astemizole. For example, oral, rectal, parenteral, transdermal, 
subcutaneous, intramuscular, and like forms of administration may be 
employed. Dosage forms include tablets, troches, dispersions, suspensions, 
solutions, capsules, patches, and the like. 
The pharmaceutical compositions of the present invention comprise the 
metabolic derivatives of astemizole as active ingredient, or a 
pharmaceutically acceptable salt thereof, and may also contain a 
pharmaceutically acceptable carrier, and optionally, other therapeutic 
ingredients. 
The term "pharmaceutically acceptable salts" refers to salts prepared from 
pharmaceutically acceptable non-toxic acids or bases including inorganic 
acids or bases or organic acids or bases. Examples of such inorganic acids 
are hydrochloric, hydrobromic, hydroiodic, sulfuric, and phosphoric. 
Appropriate organic acids may be selected, for example, from aliphatic, 
aromatic, carboxylic and sulfonic classes of organic acids, examples of 
which are formic, acetic, propionic, succinic, glycolic, glucoronic, 
maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, 
mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, 
benzenesulfonic, stearic, sulfanilic, algenic, and galacturonic. Examples 
of such inorganic bases include metallic salts made from aluminum, 
calcium, lithium, magnesium, potassium, sodium, and zinc. Appropriate 
organic bases may be selected, for example, from 
N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, 
ethylenediamine, meglumaine (N-methylglucamine), lysine and procaine. 
The compositions of the present invention include compositions such as 
suspensions, solutions and elixirs; aerosols; or carriers such as 
starches, sugars, microcrystalline cellulose, diluents, granulating 
agents, lubricants, binders, disintegrating agents, and the like, in the 
case of oral solid preparations (such as powders, capsules, and tablets), 
with the oral solid preparations being preferred over the oral liquid 
preparations. The most preferred oral solid preparations are tablets. 
Because of their ease of administration, tablets and capsules represent the 
most advantageous oral dosage unit form, in which case solid 
pharmaceutical carriers are employed. If desired, tablets may be coated by 
standard aqueous or nonaqueous techniques. 
In addition to the common dosage forms set out above, the compounds of the 
present invention may also be administered by controlled release means 
and/or delivery devices such as those described in U.S. Pat. Nos. 
3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, the disclosures 
of which are hereby incorporated by reference. 
Pharmaceutical compositions of the present invention suitable for oral 
administration may be presented as discrete units such as capsules, 
cachets, or tablets, or aerosol sprays, each containing a predetermined 
amount of the active ingredient, as a powder or granules, or as a solution 
or a suspension in an aqueous liquid, a non-aqueous liquid, an 
oil-in-water emulsion, or a water-in-oil liquid emulsion. Such 
compositions may be prepared by any of the methods of pharmacy, but all 
methods include the step of bringing into association the active 
ingredient with the carrier which constitutes one or more necessary 
ingredients. In general, the compositions are prepared by uniformly and 
intimately admixing the active ingredient with liquid carriers or finely 
divided solid carriers or both, and then, if necessary, shaping the 
product into the desired presentation. 
For example, a tablet may be prepared by compression or molding, 
optionally, with one or more accessory ingredients. Compressed tablets may 
be prepared by compressing in a suitable machine the active ingredient in 
a free-flowing form such as powder or granules, optionally mixed with a 
binder, lubricant, inert diluent, surface active or dispersing agent. 
Molded tablets may be made by molding, in a suitable machine, a mixture of 
the powdered compound moistened with an inert liquid diluent. Desirably, 
each tablet contains from about 5 mg to about 150 mg of the active 
ingredient, and each cachet or capsule contains from about 5 mg to about 
150 mg of the active ingredient, i.e., a metabolic derivative of 
astemizole. Most preferably, the tablet, cachet or capsule contains either 
one of three dosages, 5 mg, 10 mg or 20 mg of the active ingredient. 
The invention is further defined by reference to the following examples 
describing in detail the preparation of the compounds and the compositions 
of the present invention, as well as their utility. It will be apparent to 
those skilled in the art that many modifications, both to materials and 
methods, may be practiced which are within the scope of this invention. 
4. EXAMPLES 
4.1. Example 1 
Preparation of Astemizole and Its Metabolites 
Atemizole can be synthesized by methods disclosed in U.S. Pat. No. 
4,319,559. The metabolites are prepared similarly, by reaction steps 
conventional in the art, as depicted below: 
##STR1## 
Reaction of the isothiocyanate shown with phenylenediamine gives the 
corresponding thiourea. N-Alkylation with .rho.-fluorobenzylbromide gives 
the secondary amine which, upon cyclization, yields the substituted 
benzimidazole shown. Treatment of the benzimidazole with base hydrolyzes 
the urethane moiety to give norastemizole. N-Alkylation of norastemizole 
with .rho.-methoxyphenethyl bromide yields astemizole. Astemizole can be 
converted to desmethylastemizole by demethylation using, for example, a 
Lewis acid, such as boron trifluoride, boron trichloride, aluminum 
trichloride, and the like. 
6-Hydroxydesmethylastemizole can be produced through a scheme analogous to 
that described above, using 3,4-diaminoanisole in place of 
phenylenediamine. The final deprotection step with Lewis acid can be made 
to cleave both aryl methyl ether moieties, yielding 
6-hydroxydesmethylastemizole. 
4.2. Example 2 
Activities of astemizole and its metabolites at the histamine H.sub.1 
-receptor are assessed using the [.sup.3 H]pyrilamine binding assay as 
described in Chang et al., J. Neurochem. 32: 1653-1663 (1979). Briefly, 
membranes from bovine cerebellum are incubated with [.sup.3 H]pyrilamine 
and varying concentrations of test compound. The reactions are carried out 
in 50 mM sodium phosphate buffer (pH 7.5) at 25.degree. C. for 30 minutes. 
The reaction is terminated by rapid vacuum filtration onto glass fiber 
filters. Radioactivity trapped on the filters is determined and compared 
to control values to acertain the interaction of the test compound with 
the H.sub.1 -receptor. 
4.3. Example 3 
Single ventricular myocytes are obtained from isolated cat hearts by 
conventional techniques. The rod-shaped single cells are maintained in a 
HEPES buffer and then are "patch clamped" using suction pipettes. A 
Patch-Clamp L/M-PEC 7 amplifier is used to record current tracings and the 
recording electrodes are filled with a solution of potassium aspartate. 
Voltage clamp pulses and data acquisition are controlled by a Sperry PC/IT 
Computer running P Clamp software. A minimum of 4 cells are studied at 
each test concentration of the following drugs: astemizole, astemizole 
metabolites, and quinidine (as a reference compound). 
4.4. Example 4 
______________________________________ 
Oral Formulation - Capsules: 
Quantity per capsule in mg. 
Formula A B C 
______________________________________ 
Active ingredient 
5.0 10.0 20.0 
Astemizole 
metabolite 
Starch 1500 39.0.0 
9.0 
Magnesium Stearate BP 
1.0 
1.0 
1.0 
Compression Weight 
100.0 
100.0 
100.0 
______________________________________ 
The active ingredient is sieved and blended with the excipients. The 
mixture is filled into suitably sized two-piece hard gelatin capsules 
using suitable machinery. Other doses may be prepared by altering the fill 
weight and if necessary, changing the capsule size to suit. 
4.5. Example 5 
______________________________________ 
Oral Formulation - Tablets: 
Quantity per Tablet in mg. 
Formula A B C 
______________________________________ 
Active ingredient, 
5.0 10.0 20.0 
Astemizole 
metabolite 
Lactose BP 93.53.5 
63.5 
Starch BP 30.00.0 
30.0 
Pregelatinized Maize 
15.0 
15.0 
15.0 
Starch BP 
Magnesium stearate 
1.5 
1.5 
1.5 
Compression Weight 
200.0 
200.0 
200.0 
______________________________________ 
The active ingredient is sieved through a suitable sieve and blended with 
the lactose until a uniform blend is formed. Suitable volumes of water are 
added and the powders are granulated. After drying, the granules are then 
screened and blended with the magnesium stearate. The resulting granules 
are then compressed into tablets of desired shape. Tablets of other 
strengths may be prepared by altering the ratio of active ingredient to 
the excipient(s) or the compression weight.