The treatment of mammals with addition products of a carbonyl group containing compound with bisulfites to improve a mammal (including man) suffering from hypertension is described.

BACKGROUND OF THE INVENTION 
Jose Antonio Arias Alvarez has previously discovered that inorganic salts 
of sulfurous acid (especially sodium bisulfite) are antihypertensive 
agents. See U.S. application, Ser. No. 75,423, filed Sept. 14, 1979, now 
U.S. Pat. No. 4,327,083 issued Apr. 27, 1982. 
Sodium bisulfite (usually shown by formula to be NaHSO.sub.3) has 
heretofore been used for many commercial purposes, such as a preservative 
for prevention of the deterioration of liquid systems, such as food stuffs 
and of pharmaceutical solids, and has also been used medically both 
externally, such as for treatment of parasitic skin diseases, and 
internally such as for a gastrointestinal antiseptic. So far as now known, 
sodium bisulfite has never previously been used by man for the treatment 
of hypertension. 
The solid sodium bisulfite of commerce reportedly consists chiefly of 
sodium metabisulfite, Na.sub.2 S.sub.2 O.sub.5, and sodium bisulfite, and, 
for purposes of this invention, such is believed to possess the same 
properties as (and to be equivalent to) sodium bisulfite when dissolved in 
aqueous solution. 
BRIEF SUMMARY OF THE INVENTION 
There has now been discovered a class of active organic agents, the members 
of which when introduced by ingestion, injection, absorption, or otherwise 
into a mammal (including man), produce avoidance, amelioration and/or 
improvement of a hypertensive condition in mammals and man when used in an 
antihypertensively effective amount as taught herein. 
The active antihypertensive agents of the present invention are salts of 
carbonyl sulfur dioxide adducts which display anticoagulant and 
antithrombotic activity. Presently preferred agents are representable by 
the formula: 
##STR1## 
where: 
R is a radical selected from the group consisting of hydrogen and 
hydroxymethyl, 
R.sup.1 is a radical selected from the group consisting of hydrogen, 
straight chain alkyl radicals each containing a total of 2, 3, 4, or 5 
hydroxylated carbon atoms, and a residue from a polysaccharide capable of 
reducing Fehling's solution, 
X is selected from the group consisting of alkali metals and ammonium. 
One presently preferred compound of formula (1) is sodium formaldehyde 
bisulfite. Sodium is presently preferred as X. 
The term "monosaccharide" as used herein has reference to an organic 
compound which is an hydroxyaldehyde or an hydroxyketone which contains an 
hydroxyl group on a carbon adjacent to a carbonyl group. The term 
"polysaccharide" as used herein has reference to a saccharide which 
contains more than one monosaccharide in its structure. Polysaccharides 
and monsaccharides useful in this invention are each capable of reducing 
Fehling's solution. For present purposes, a one gram quantity of a 
saccharide is dissolved or dispersed in 25 grams of distilled water, and 5 
milliliters of Fehling's solution is added thereto. If there is a 
precipitate of cuprous oxide formed upon standing or upon warming to 
50.degree. C. then the saccharide is usable in the practice of this 
invention as a starting material. 
A presently preferred class of starting materials comprises 
monosaccharides, each having a carbonyl group, which are selected from the 
group consisting of aldoses and ketoses wherein each ketose has its 
carbonyl group in the 2-position. More preferred such monsaccharides each 
contain five or six carbon atoms per molecule. Presently preferred aldoses 
are selected from the group consisting of glucose, mannose, ribose, 
xylose, arabinose, galactose, and the like. 
Another preferred class of starting materials comprises polysaccharides, 
such as a dextrin prepared by acid treatment of starch, maltose, 
cellobiose, lactose, melibiose, manninotriose, and the like. 
In one aspect, the present invention is directed to the use of certain 
organic carbonyl-type bisulfite compounds as antihypertensive agents in 
human medicine. 
In another aspect, the present invention is directed to a method for 
control of, and/or prevention of, hypertension in man by oral ingestion 
and/or injection of a pharmacologically effective amount of saccharide 
bisulfites and/or compound(s) within the scope of the active agents of 
this invention. 
In another aspect, the present invention leads to symptomatic and objective 
improvement in a cardiovascular disease condition, such as hypertension in 
man. By the term "symptomatic improvement", as used herein, reference is 
had to an improvement in a patient's subjective symptoms as reported by 
that patient. By the term "objective improvement", as used herein, 
reference is had to a measurable and objective change in the patient's 
condition (e.g. blood pressure), from an initial (at the start of 
treatment) to a subsequent (during or after treatment) condition. 
Naturally, an active antihypertensive agent of this invention is used, if 
at all in a mammal, at a pharmaceutically effective dose rate, that is, at 
a dose rate which is below the level of toxicity or of production of 
undesired side effects. Because of biological complexities, the complete 
biological effects of the active agents of this invention are not now 
known. 
Other and further aspects, objects, purposes, advantages, aims, utilities, 
features, and the like will be apparent to those skilled in the art from a 
reading of the present specification. 
DETAILED DESCRIPTION 
More particularly, this invention concerns a process for treating a human 
to control, ameliorate, or prevent a cardiovascular disease such as 
hypertension wherein there is introduced, preferably orally, into such a 
human a pharmaceutically effective amount of an active agent of this 
invention as defined above (preferably a bisulfite). 
In one preferred mode of using this invention, an aqueous solution of from 
about 1 to 15% by weight active agent is prepared. Then such solution is 
orally consumed by a human, for example, in the form of drops, at a total 
(or accumulated) dose rate ranging from 0.2 to 20 mg per each kilogram of 
body weight per day, more preferably in the form of from two to four 
spaced doses per day, each such dose being preferably taken around meal 
time. 
Symptomatic and/or objective improvement in a patient's hypertensive 
condition even at relatively low dosage rates may occur within two weeks 
to four months of such a continuous oral usage of active agent in accord 
with these teachings of this invention. 
Such dilute active agent solutions can be used before, during, or after the 
onset of a cardiovascular disease with beneficial results. Even when used 
on patients who might be considered terminally affected by such condition, 
beneficial results are observable. 
It is believed that larger and/or smaller such doses can be used without 
departing from the spirit and scope of the present discovery. One dose 
rate, for example, which has usually been found to be effective for man 
varies from about 0.2 to 75 mgm per day per average human adult patient 
(e.g. about 70 kg) of active agent taken orally as dilute aqueous solution 
of from about 1 to 5 percent by weight in distilled water and ingested 
before, during or after each of the daily meals, such as breakfast, lunch, 
and dinner. Presently, a preferred dose rate for a patient using a 
self-administered dilute aqueous system comprises one in the range from 
about 1.0 to 20 mgm per kg of body weight per day taken in the form of at 
least two spaced oral doses (using such an aqueous solution as described 
herein). The water used in such a solution is preferably purified (e.g. 
filtered, deionized, distilled or the like). After preparation, such a 
solution is preferably stored in a closed container. 
Such an aqueous solution can be directly consumed by a patient as drops 
(e.g. from about 5 to 20 drops per meal, depending upon dose rate for an 
individual patient), or as a capsule, or the like, as desired. 
A subjective improvement in atherosclerosis may be observable by some 
patients who have been dosed as described above. It may be that use of 
this invention exerts a favorable influence on blood lipids, such as a 
fall in total cholesterol. 
One important advantage of the present invention is the circumstance that 
the indicated desirable results may be achieved with little or no apparent 
side effects surprisingly. For example, no change in a normal excretion 
rate of such metallic ions as sodium, potassium, magnesium, or calcium 
through urine appears to be associated with the use of active agents of 
this invention, contrary to normal experience with conventional diuretic 
agents which are used to lower blood pressure. 
The active agents of this invention can be administered by any convenient 
or appropriate procedure. For example, injection by intravenous, 
intraperitoneal, intramuscular or subcutaneous administration of such a 
dilute aqueous solution as described above may afford a more rapid 
reduction in blood pressure than is observable from oral administration 
for reasons which are not presently known. Suppositories containing active 
agents can be used for absorption. 
The active agents of the present invention can be formulated in any desired 
manner for administration. For example, conventional excipients, 
extenders, compounding agents and the like can be blended with powdered 
active agents and the resulting blends can be tableted, pelletized, or the 
like and then used as solid oral dosage forms. Conveniently, individual 
dosage units, in whatever form prepared or compounded, can range from 
about 50 to 500 milligrams (mg) each. 
Per diem (24 hour day) dose rates for active agents of this invention for 
mammals (including man) are believed to range from about 0.2 to 50 mg per 
kg of body weight, with doses ranging from about 1 to 20 mg per kg being 
more general, convenient and typical for practical, safe administration. 
Larger and smaller dose rates can be employed without departing from the 
spirit and scope of this invention. 
One convenient preparation technique for preparing a saccharide/bisulfite 
compound of formula (1) above is to agitate a saturated aqueous solution 
of the desired bisulfite salt with at least a stoichiometric amount of a 
carbonyl compound which corresponds to the desired carbonyl sulfur dioxide 
adduct desired. In the case of monsaccharide adducts, one or more 
equivalents of the sugar is (are) mixed with an equivalent of the 
bisulfite compound in aqueous medium to provide a solution of the 
bisulfite adduct of the sugar. Solutions containing more than about 60 
weight percent water are preferred. Other known synthetic methods may be 
used if desired in order to obtain the saccharide-bisulfite compounds as 
solids as for oral ingestion. 
Aqueous solutions represent a practical way of practicing this invention. 
The agents of this invention do not oxidize readily in air-exposed aqueous 
solutions. 
In one preferred mode of using this invention, an aqueous solution 
containing from about 1 to 10 percent by weight of an active agent of this 
invention, preferably sodium glucose bisulfite or sodium formaldehyde 
bisulfite, is used. Then, such solution is injected into, or orally 
consumed by, a patient at total (or accumulated) dose rate preferably 
ranging from about 1.0 to 50 mg per each kg of body weight per day, more 
preferably in the form of at least two spaced doses per day, and still 
more preferably in the form of at least three spaced dose per day, such a 
dose being preferably taken around meal time. Solid or encapsulated active 
agents may be orally consumed alternatively. 
One presently preferred composition for use in the practice of this 
invention is prepared by dissolving a desired quantity of an alkali metal 
bisulfite in an aqueous glucose solution, such as a standardized medical 
solution of about 5 weight percent glucose in distilled water (of the type 
used for intravenous administration to a patient). 
The active agents used in any aqueous solution can be directly used in 
accordance with the teachings of this invention, in which such a solution 
can be dispensed dropwise, or such a solution can be encapsulated, or the 
like, and used as measured dosage units, as desired. For example, an 
aqueous solution containing 5 weight percent of sodium glucose bisulfite 
or sodium formaldehyde bisulfite can be injected into a patient or it can 
be directly consumed by a patient as drops (e.g., from about 5 to 30 drops 
per meal for each of the two or three meals eaten by such patient per day, 
depending upon an individual patient's body weight, or the like).

EMBODIMENTS 
The present invention is further illustrated by reference to the following 
case histories. Those skilled in the art will appreciate that other and 
further embodiments are obvious and within the spirit and scope of this 
invention from the teachings of these present examples taken with the 
accompanying specification. 
PREATION OF ACTIVE AGENTS 
Example A 
A solution of sodium formaldehyde bisulfite is prepared by dissolving 
commercially available solid sodium formaldehyde bisulfite in distilled 
water at room temperature to form a 3 percent by weight aqueous solution. 
Example B 
Another solution of sodium formaldehyde bisulfite is prepared by dissolving 
commercially available solid sodium formaldehyde bisulfite in distilled 
water at room temperature to form a 10 percent by weight aqueous solution. 
Example C 
A capsule of sodium formaldehyde bisulfite is prepared by charging to each 
of standard gelatin capsules sufficient sodium formaldehyde bisulfite to 
make 25 mg of active agent. 
Example D 
The procedure of Example C is repeated except that 50 mg capsule of active 
agent are prepared. 
Example E 
A solution to contain 2% by weight of sodium bisulfite is prepared by 
dissolving the desired amount of bisulfite with one equivalent of glucose. 
Example F 
The procedure of Example E is repeated except that four equivalents of 
glucose are used. 
Example G 
The procedure of Example F is repeated except that the product is heated on 
a steam bath (about 90.degree. C.) for one hour. 
Example H 
The procedure of Example E is repeated except that in place of glucose, 
fructose is used. 
Example I 
The procedure of Example E is repeated except that in place of glucose 
arabinose is used. 
Examples 1 
To demonstrate effectiveness of an agent of the present invention, 
experiments were carried out with hypertensive rats. 
Rats of the SHR (spontaneous hypertensive rat) strain, weighing about 250 
g, were anesthetized with urethane (ethyl carbamate) using 1500 milligrams 
per kilogram IP. The trachea was cannulated to avoid respiratory distress 
and the body temperature maintained constant with a heated pad controlled 
from a rectal sensor. The carotid artery was cannulated with a fine nylon 
catheter connected to a Honeywell blood pressure transducer filled with 
heparinized saline. The mean and phasic blood pressures were recorded on a 
Devices F19 multi-channel recorder. Test substances were administered by 
the intraperitoneal route, unless otherwise stated. Soluble materials were 
given as aqueous solutions and insoluble materials as emulsions or 
suspensions in aqueous vehicles. The test substances were given at a 
series of increasing dose levels each subsequent dose being twice the 
previous dose. The results quoted in the Table give the lowest dose level 
firstly to cause a clear lowering of blood pressure and secondly the dose 
found to cause the death by the preparation. 
TABLE I 
______________________________________ 
Hypertensive and Toxic 
Dose Levels of Sulfite Derivatives 
Hypertensive 
Toxic Dose 
Route of Dose Level Level 
Substance Administration 
mg/kg mg/kg 
______________________________________ 
Sodium Glucose 
Sodium Bisulfite 
IP 20 Not Obtained 
______________________________________ 
Clearly the sodium glucose bisulfite lowers blood pressure.