CA1188219A - Method of treatment of rheumatoid arthritis - Google Patents
Method of treatment of rheumatoid arthritisInfo
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- CA1188219A CA1188219A CA000395752A CA395752A CA1188219A CA 1188219 A CA1188219 A CA 1188219A CA 000395752 A CA000395752 A CA 000395752A CA 395752 A CA395752 A CA 395752A CA 1188219 A CA1188219 A CA 1188219A
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- cysteine
- copper
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- hydroxyethyl
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Abstract
Rheumatoid arthritis is treated with substituted cysteine compounds having a lower toxicity-to-effectiveness ratio than penicillamine. Such compounds are specific alpha-substituted cysteines, beta-monosubstituted cysteines, beta-di-substituted cysteines other than penicillamine, N-acetyl penicillamine and the N-acetyl derivatives of the alpha and beta-substituted com-pounds mentioned above.
Any of the compounds may be used synergistically in combination with suitable copper compounds or with suitable gold compounds in the treatment of arthritis.
The same compounds are effective in the treatment of cystinuria and heavy metal poisoning. The same compounds as well as penicillamine are effective in combination with copper in the treatment of heavy metal poisoning.
Any of the compounds may be used synergistically in combination with suitable copper compounds or with suitable gold compounds in the treatment of arthritis.
The same compounds are effective in the treatment of cystinuria and heavy metal poisoning. The same compounds as well as penicillamine are effective in combination with copper in the treatment of heavy metal poisoning.
Description
_ _ _ ~ _ _ r __ . _ _ _ _ _ _ . _ . __ _ _ _ _ . _ _ _ _ . . _ .
BACKGROUND OF THE INVE~rION
.
Rheuma~oid arthritis, commonly re~erred to as RA, is the second most crippling disease in man, ranking i~mediately '' behind cardiovascular defects. Until recently no effective treat-ment for RA has been known. A number Df drugs which are moder-ately effective in the treatment of this disease have been found, e~amples being D-penicillamine which is ~, ~ dimethylcysteine and certain compounds of gold, such as gold sodium thiomalate, auro-thioglucose and sources o~ auric or aurous ion.
Of these compounds, the most promising is the recently discovered penicillamine, a natural metabolite of penicillin.
Unfortunately, not all patients respond to this medication; also, o it carries with it considerable toxicity so that it can, in fact, be lethal. Another difficulty is that penicillamine is slow-acting so that generally it requires 8 to 12 weeks before it can be determined whether the patient is responding and whether the dosage needs adjusting. D-penicillamine usually produces a decrease in the titer of rheumatoid factor, an index of its specific therapeutic efficacy for this human disease. There are no genuine animalmDdels of rheumatoid arthritis.
At the present time, most rheumatologists treat moder-ately severe RA that has not responded to salicylates with either a gold compound or D-penicillamine. Penicillamine is also used initially in some patients with severe RA, and those in whom rheumatoid lung disease, vasculitis, amyloidosis, Felty's syndrome or rheumatoid nodulosis complicate the clinical pictureO
Publications on the use of D-penicillamLne make it clear that the dosage employed in the past for treatment of RA
1 ~ 8~1~
has frequently been ~oo high; it is now generally agreed that a dosage of 1.5 g/day is the maximum required. It still has not been determined how long D-penicillamine therapy in RA should be continued, some rheumatologists taking the position that the drug should be continued indefinitely if it is well tolerated while others attempt to reduce the daily maintenance dose gradually in order to determine the minimum quantity of drug necessary for sustaining remission of the disease.
As is clear from the above, D-penicillamine, while for some RA patients the drug of choice at the present time, presents major difficulties, both with respect to toxicity and to the method of use. It is also frustrating that the mechanism by which the compound acts therapeutically is not understood, this ; lack of understanding having made it difficult to use this com-pound as a base from which to explore in the search for compounds having a higher therapeutic effi~acy~ this efficacy being defined as the ratio of the dose causing toxicosis to that required for therapeutic effectiveness. One clue is at hand, namely, that the efficacy of the compound D-penicillamine is linked to the presence of a sulfhydryl group in the molecule. The naturally occurring amino acid cysteine itself also has a sulfhydryl group in the molecule but is ineffective in the treatment of RA, because it dimerizes to form cystine in vivo, and is metabolized by amino acid oxidases and cysteine desulfhydrase to a much greater degree than penicillamine. The dimer, cystine, e~ecreted in the urine `( in excessive amounts in a hereditary disorder, cystinuria, forms kidney stones in quantity such that they may be lethal, since the dimer is relatively insoluble while cysteine itself is quite soluble. Further, it is evident that the equilihrium between the monomer and the dimer is far over on the side of the dimer, since, otherwise, in patients with cystinuria~dissociation ~f cystine to the soluble monomer would prevent the formation of cystine stones.
D-penicillamine proved to be effective in the treatment of cystin-uria because the asymmetrical dimer that is formed -- a combin-ation of one molecule of cysteine and one molecule of D-penicil-lamine -- poss~sa relatively high solubility so th2t it is readily excreted from the body.
While D-penicillamine has been more widely used than ! either the L-isomer or the racemic mixture, it is recognized that any of the three forms may have unique value in specific instances , so that the term "penicillamine" as u~ed herein wi~l be taken to include both isomers and the racemic mixture.
As aforenoted, the mechanism by which penicillamine causes remission of RA is unknown. Just as unknown is the cause of RA itself. However, one reason why penicillamine was invest-igated was the fact that penicillin which is ge~allywRll ~1~ by the body,ismetab~iæd inp~ to penicillamine so that it is apparent that the body can tolerate penicillamine also even if in smaller quantity. I have found that certain closely related com-pound which are not natural meta ites Of penicillir are a~
` ! 1~8 ~19 least as effective as penicillamine for the treatment of RA as well as of cystinuria and hea~y-metal poisoning.
SUMMARY OF THE INVENTION
Cysteine derivatives useful in the treatment of RA and having lower toxicity and greater therapeutic effect than penicil-lamine are alpha-substituted cysteines, beta-monosubsti~uted cysteines, beta-disubstituted cysteines other than penicillamine, alpha-substituted cysteines which are either mono- or di-sub-stituted in the beta position, and N-acetyl deri~ati~es of each o of the above which are hereinafter more fully set forth.
The spesific sulfhydryl compounds useful in the treat-ment in RA are members of the following 5 groups:
1. Cysteine derivatives in which one of the beta hydrogens is replaced by Cl, CH3, C2H5, CH20H or CH2CH20H,
BACKGROUND OF THE INVE~rION
.
Rheuma~oid arthritis, commonly re~erred to as RA, is the second most crippling disease in man, ranking i~mediately '' behind cardiovascular defects. Until recently no effective treat-ment for RA has been known. A number Df drugs which are moder-ately effective in the treatment of this disease have been found, e~amples being D-penicillamine which is ~, ~ dimethylcysteine and certain compounds of gold, such as gold sodium thiomalate, auro-thioglucose and sources o~ auric or aurous ion.
Of these compounds, the most promising is the recently discovered penicillamine, a natural metabolite of penicillin.
Unfortunately, not all patients respond to this medication; also, o it carries with it considerable toxicity so that it can, in fact, be lethal. Another difficulty is that penicillamine is slow-acting so that generally it requires 8 to 12 weeks before it can be determined whether the patient is responding and whether the dosage needs adjusting. D-penicillamine usually produces a decrease in the titer of rheumatoid factor, an index of its specific therapeutic efficacy for this human disease. There are no genuine animalmDdels of rheumatoid arthritis.
At the present time, most rheumatologists treat moder-ately severe RA that has not responded to salicylates with either a gold compound or D-penicillamine. Penicillamine is also used initially in some patients with severe RA, and those in whom rheumatoid lung disease, vasculitis, amyloidosis, Felty's syndrome or rheumatoid nodulosis complicate the clinical pictureO
Publications on the use of D-penicillamLne make it clear that the dosage employed in the past for treatment of RA
1 ~ 8~1~
has frequently been ~oo high; it is now generally agreed that a dosage of 1.5 g/day is the maximum required. It still has not been determined how long D-penicillamine therapy in RA should be continued, some rheumatologists taking the position that the drug should be continued indefinitely if it is well tolerated while others attempt to reduce the daily maintenance dose gradually in order to determine the minimum quantity of drug necessary for sustaining remission of the disease.
As is clear from the above, D-penicillamine, while for some RA patients the drug of choice at the present time, presents major difficulties, both with respect to toxicity and to the method of use. It is also frustrating that the mechanism by which the compound acts therapeutically is not understood, this ; lack of understanding having made it difficult to use this com-pound as a base from which to explore in the search for compounds having a higher therapeutic effi~acy~ this efficacy being defined as the ratio of the dose causing toxicosis to that required for therapeutic effectiveness. One clue is at hand, namely, that the efficacy of the compound D-penicillamine is linked to the presence of a sulfhydryl group in the molecule. The naturally occurring amino acid cysteine itself also has a sulfhydryl group in the molecule but is ineffective in the treatment of RA, because it dimerizes to form cystine in vivo, and is metabolized by amino acid oxidases and cysteine desulfhydrase to a much greater degree than penicillamine. The dimer, cystine, e~ecreted in the urine `( in excessive amounts in a hereditary disorder, cystinuria, forms kidney stones in quantity such that they may be lethal, since the dimer is relatively insoluble while cysteine itself is quite soluble. Further, it is evident that the equilihrium between the monomer and the dimer is far over on the side of the dimer, since, otherwise, in patients with cystinuria~dissociation ~f cystine to the soluble monomer would prevent the formation of cystine stones.
D-penicillamine proved to be effective in the treatment of cystin-uria because the asymmetrical dimer that is formed -- a combin-ation of one molecule of cysteine and one molecule of D-penicil-lamine -- poss~sa relatively high solubility so th2t it is readily excreted from the body.
While D-penicillamine has been more widely used than ! either the L-isomer or the racemic mixture, it is recognized that any of the three forms may have unique value in specific instances , so that the term "penicillamine" as u~ed herein wi~l be taken to include both isomers and the racemic mixture.
As aforenoted, the mechanism by which penicillamine causes remission of RA is unknown. Just as unknown is the cause of RA itself. However, one reason why penicillamine was invest-igated was the fact that penicillin which is ge~allywRll ~1~ by the body,ismetab~iæd inp~ to penicillamine so that it is apparent that the body can tolerate penicillamine also even if in smaller quantity. I have found that certain closely related com-pound which are not natural meta ites Of penicillir are a~
` ! 1~8 ~19 least as effective as penicillamine for the treatment of RA as well as of cystinuria and hea~y-metal poisoning.
SUMMARY OF THE INVENTION
Cysteine derivatives useful in the treatment of RA and having lower toxicity and greater therapeutic effect than penicil-lamine are alpha-substituted cysteines, beta-monosubsti~uted cysteines, beta-disubstituted cysteines other than penicillamine, alpha-substituted cysteines which are either mono- or di-sub-stituted in the beta position, and N-acetyl deri~ati~es of each o of the above which are hereinafter more fully set forth.
The spesific sulfhydryl compounds useful in the treat-ment in RA are members of the following 5 groups:
1. Cysteine derivatives in which one of the beta hydrogens is replaced by Cl, CH3, C2H5, CH20H or CH2CH20H,
2. Cysteine derivatives in which both of the beta hydrogens are replaced by one of the following pairs of sub-stituents:
chloro, chloro, methyl, chloro, ethyl, chloro, . methyl, ethyl, ethyl, ethyl, hydroxymethyl, hydroxymethyl, hydroxyethyl, hydroxyethyl, hydroxymethyl, hydroxyethyl, methyl, hydroxymethyl, methyl, hydroxyethyl, ethyl, hydroxymethyl, ethyl, hydroxyethyl, chloro, hydroxymethyl, and chloro, hydroxyethyl;
chloro, chloro, methyl, chloro, ethyl, chloro, . methyl, ethyl, ethyl, ethyl, hydroxymethyl, hydroxymethyl, hydroxyethyl, hydroxyethyl, hydroxymethyl, hydroxyethyl, methyl, hydroxymethyl, methyl, hydroxyethyl, ethyl, hydroxymethyl, ethyl, hydroxyethyl, chloro, hydroxymethyl, and chloro, hydroxyethyl;
3. Cysteine derivatives in which the alpha hydrogen is replaced by Cl, CH3, C2H59 CH2OH or CH2CH20H;
4. Cysteine derivatives in which the alpha hydrogen and one or both of the beta hydrogens are each replaced by Cl, CH3, C2H5, CH2OH or C ~CH20H in any of the possible combinations;
and
and
5. The N-acetyl derivatives of any of the compounds in the groups 1 to 4.
The preferred compounds, on the basis of the therapeutic 0 efficacy, are ~ methylcysteine,oC-methylcysteine andGC-methyl, ~-methylcysteine. Cysteine and derivatives thereof will herein-after be referred to generally as sulfhydryls or sulfhydryl com-pounds.
A fur~her discovery which I have made is that the efficacy of all of the aboYe compounds is increased i~ the treat-ment of RA when combined or complexed with copper or gold and in the treatment of heavy metal poisoning when combined or com-plexed with copper. Still further, the effectiveness of penicil-lamine is increased in the treatment of RA when used in combinatior with or complexed with copper or gold and in heavy metal poisoning when combined with or complexed with copper. Penicillamine, ~-methyl cysteine and cysteine itself are preferred sulfhydryls for use in combination with or complexed with copper. The gold compound used is preferably water-soluble, examples being chlor-auric acid, gold sodium thiomalate and aurothioglucose.
The medication, where a sulfhydryl is used alone is administered initially to a 1501b patient suffering from RA in a 1, 8;~L9 single dose of 100 mg amounting to 1.5 mg/day per kilogram of the patlent's weight and is increased by 25 mg/day at 2-3 week intervals up to 500 mg/day and then by 50 mg/day at 8-12 week intervals to a maximum of 1500 mg/day or until RA symptoms are alleviated. The dose is administered in capsule or tablet form or as a suitably formulated solution subcutaneously, intramus-cularly or intravenously. ~f the medication is well tolerated the ra-te of increase at the end o~ each interval can be S0 mg/day.
Where any of the above sulfhydryls or penicillamine is administered with gold either in combination or complexed therewith for treatment of RA, the initial daily dosage in 2 doses per day is such that the gold content thereof is 10 mg.
The form of the dose is as a solid in a capsule or tablet form or as a suitably formulated solution for injection as above.
The dosage is increased as needed by 10 mg/day (of gold) at intervals of 2-4 weeks to 100 mg/day and then by increments of 20 mg/day at intervals of 8-12 weeks to a maximum of 200 mg/day.
Preferably, the sulfhydryl content of the combinations with gold is at least equal to that of the gold by weight and may be up to 4 times the weight of the gold.
Where any of the above sulfhydryls or penicillamine is administered with copper either in combination or complexed therewith for treatment of RA the initial daily dosage is preferably 25 mg/day of the combination in 1 or 2 doses/day, the copper content of the dosage being about 7.5 mg with the remainder a sulfhydryl, the preferred sulfhydryl being penicillamine. The dosage is increased in increments of 25 mg/day at intervals of 2-3 weeks until a dosage of 150 mg/day is reached after which the dosage is increased at intervals of 8-12 weeks in increments of 50 mg/day to a maximum of 400 mg/day.
It will be noted that the dosage of penicillamine when used in combination with either copper or gold is much smaller than when administered without these metals.
A method of treating cystinuria is to administer an effective amount of any of the types of sulfhydryl compounds in the above 5 groups, ~ monomethylcysteine being preferred because of its relatively low toxicity and the solubility of the mixed dimer with cysteine. The initial dosage is 100 mg/day and can be increased by steps of 100 mg/day at intervals o 2 weeks to a maximum of 1.50 gJday. ~he dosage may be administered orally as a solid in capsule or tablet form or a solution or by injection when suitably formulated for injection as above and should be administered 1 or 2 times per day.
A method of removing heavy metals such as mercury, lead, cadmium, bismuth, vanadium and plutonium from the body is to admin-ister either orally or by injection a sulfhydryl from one of the above 5 groups either as such or combined with copper. The com-bination of penicillamine with copper is particularly effective. Acomplex of copper with a sulfhydryl is denoted as RSCu where RSH
is a sulfhydryl of one of the above groups, penicillamine or cysteine; cysteine, ~ monomethylcysteine and penicillamine are the preferred sulfhydryl compounds for use with copper. The methoc of using such RSCu compounds is restricted to removal of those ~ ~ 8~
heavy metals having a high enough association constant with the sulfhydryls to displace copper from the complex and having the capacity to form a soluble compound with the sulfhydryl. The method is particularly effective for removal of mercury, an exceed _ ingly toxic element. The initial dosage of the complex of a sulf-hydryl with copper is 200 mg repeated at 8-hour intervals~ as capsules or tablets or by injec~ion as a suitably formulated solution. The dosage is increased by steps of 200 to 400 mg and depending on the amount of mercury ingested /the response of the o patient, the maximum daily dosage being 2.00 g. The preferred combinations are copper penicillamine, copper cysteine and copper ~-methyl cysteine.
Where the cystinuria patient is to be treated with a sulfhydryl, any of the sulfhydryls in the above 5 groups may be administered as a capsule or tablet or as a suitably form-ulated solution by injectiDn, the preferred compounds being cX~-methyl cysteine and ~ methyl cysteine. The initial dosage is 1.00 g~day this being administered in 3 divided doses, the dosage being increased daily in steps of 0.5 g/day until a ma~imum of 3.00 g/day is reached.
Accordingly~ an object of the present invention is a method of treating rheumatoid arthritis with selected cysteine derivatives.
A ~urther object of the present invention is a method of treatirg rheumatoid arthritis with combinations of cysteiDe, _9_ .11~
and selected cysteine derivatives, including penicillamine with ¦gold compounds and with copper compounds.
¦ Still another object of the present invention is a metho ¦of eliminating from the body heavy metals present in excess quan-¦tity by administration of speci~ic sulfhydryls, either as such or complexed with copper. Still further, penicillamine complexed with copper can be used for this purpose.
A significant object of the present invention is a method of treating cystinuria by administration of specific o cysteine derivatives other than penicillamine.
Yet another obiect of the present invention are composi-tions of selected sulfhydryl compounds with copper or with gold, such compositions being effective for treatment of RA and composi-tions of selected sulfhydryls wiLh copper,such compositions being effective in the treatment of heavy metal poisoning.
An important object of the present invention is a method of minimizing side effects of the chemotherapy of rheumatoid toxic arthritis and cystinuria and elimination of/metals from the body.
Still other objects and advantages of the invention will in part be obvious and will in part be apparent from the specifi-cation.
The invention accordingly comprises the several steps and the relation of one or more of such steps with respect to each f the others, and the composition possessine the features, pro-8'~19 perties, and the relation of constituents, which are exempliied in the following detailed disclosure, and the scope of the inven-tion will be indicated in the claims.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
D-penicillamine, which is moderately effective in the treatment of rheumatoid arthritis~ is a metabolite of penicillin;
it can also be prepared synthetically. Prior to its use for the ~reatment of RA, it was found effective in Wilson's disease, in cystinuria and in the removal of toxic metals such as lead from o the body. It has long been approved by the Food & Drug Admin-istration as safe and effective for Wilson's disease and cystin-uria. In Wilson's disease3 ingested copper is not properly execreted. Apparently, in the removal of copper by treatment with penicillamine, chelates are formed with involvement of the SH group /the amino group attached to the alpha carbon. Cystin-uria is a disorder in which the amount of cystine in the urine exceedsthe solubility of this amino acid, with the result that ultimately fatal stones form in the kidney. Penicillamine forms an asymmetrical disulfide with cysteine of which one-half is the penicillamine molecule and the other half is the cysteine mole-cule. Although its use in the treatment of rheumatoid arthritis ¦ has recently been approved by the Food & Drug Administration, it has not as yet been approved for treatment of lead or mercury poisoning largely because of its toxicity which includes allergic reactions and direct toxicity to skin, kidneys, lung, bone marrow,l and neuromuscular system.
.
Penicillamine differs from the natural amino acid cystein only in that the two ~-hydrogen atoms are replaced by methyl groups. It is almost certain that it is the presence of these two methyl groups which keeps the molecule from forming penicillamine disulfide to the extent that cysteine dimexizes to cystine, so that an appreciable fraction of penicillamine -- in contrast to cysteine -- circulates in the body with a free SH group. As aforenoted, an asymmetrical disulfide is formed with cysteine. Moreover, it seems probable that the effect of penicillamine on rheumatoid arthritis is also related to the free SH group.
A further point with respect to the biochemistry of penicillamine is that sulfhydryl amino acids are metabolized by desulfhydrases and by amino oxidases. Tests have shown that these enzymes react only very slowly with the penicillamine isomers. However~ cysteine is very rapidly attacked by both enzymes which also accounts for the low concentration of cysteine in the blood and for its lack of effectiveness in the removal of toxic metals from the blood.
Since there are two asymmetric carbon atoms in the ~-methyl-substituted cysteine, there are four diastereoisomers.
The rate of attack on each of the isomers by D-amino aeid oxidase and L-amino oxidase has been measured and, interest-ingly, the rate of at-tack is not nearly so high as the rate of attack on cysteine itself. Accordingly, it can be seen that substitution of from l to 3 of the hydrogen atoms on the alpha and beta carbons of cysteine with substituents of small size offers the possibility of modifying the rate of attack by amino aeid oxidases and eysteine desulfhydrases, as well as 8;~1"3 the solubility, the toxicity and the effect of the compound on RA. A further enhancement of the therapeutic efficacy of appropriately chosen substituents is afEorded by replacement of one of the hydrogens on the amino group with an acetyl group.
A first group of compounds useful in the treatment of RA consists of those cysteine derivatives in ~-hich one of the beta hydrogens is replaced by a chlorine atom or a methyl, ethyl, hydroxymethyl or hydroxyethyl group. A second group of cysteine derivatives useful in the treatment of R~ is that consisting of the beta-disubstituted cysteines in which the substituents consist of one of the following pairs:
chloro, chloro, methyl, chloro, ethyl, chloro, methyl, ethyl, ethyl, ethyl, hydroxymethyl, hydroxymethyl, hydroxyethyl, hydroxyethyl, hydroxymethyl, hydroxyethyl, methyl, hydroxymethyl, methyl, hydroxyethyl, ethyl, hydroxymethyl, ethyl, hydroxyethyl, chloro, hydroxymethyl, and chloro hydroxyethyl.
A third group of compounds useful in the treatment of RA is the alpha-substituted cysteines, where the single substituent is a chlorine atom or a methyl, ethyl, hydroxy-methyl or hydroxyethyl group.
A fourth group of cysteine derivatives useful in thetreatment of RA is that in which the alpha carbon ls substituted ~ ~ 8~ 9 as in the third group and the beta carbon is substituted as in either the first group or the second group. In other words, the alpha carbon is substituted and the beta carbon is either mono-or di-substituted.
A fifth group of cysteine derivatives particularly use-ful in the treatment of RA is obtained by forming the N-acetyl derivatives of any of the compounds in the irst four groups.
Methods of synthesis of all of the compounds listed in the above five groups are well known to those skilled in the art.
lo The compounds are stable and can be dried for administration in a capsule or as a tablet. They can also be formulated for admin-istration subcutaneously, intramuscularly or intravenously.
The side effects attendant upon the use of the above compounds can be minimized through the use of two or more of the above compounds in rombination, each compound being used in a dosage smaller than would be the case were it used alone.
Accordingly, combinations of compounds in any of the above five gxoups may be used in the treatment of RA as well as combinations of said compounds with penicillamine.
In the Examples which follow, the dosages cited are appropriate for an individual weighing 68 kg (150 lb~. Where the patien~s weight differs substantially from this figure, the dosage~
should be adjusted appropriately. Moreover, all dosages, including periodic increases, must be subject to the clinician's judgement with respect to the entire patient's situation so that even the dosages to be presented as maxima can under appropriate circum-stances be exceeded 1 ~8 and signs The symp~oms/of RA are well known, these being pain in the joints, swelling ~f the j~ints, redness and heat in the ~oints and loss of mobility. During treatment with sulfhydryl compounds, the patient is monitored to determine the clinical response as assessed by symptomatic change and by objective change. The objective change is noted in the mobility, redness 3 swelling and heat of ~he joints. The objective assessment of the state of the patient's rheumatoid activity is further evaluated by measurement of the concentration of the rheumatoid factor in the blood, by o the white blood count and the differential count, by the erythro-cyte sedimentation rate~ and by measurement of the fluorescent anti-nuclear antibody. In addition, the progression of the arthri tis -- or its remission -- may on occasion be estimated by suitabl~
x-ray studies. Here again, the frequency of the tests and the variety thereof are a matter for the clinician's judgment.
Possible toxic effects to be noted include early rash, fever, leukopenia and thrombocytopenia, all of the foregoing usually occurring as allergic manifestations in the first two to four weeks of treatment. Late toxicity is manifested most importantly as suppressiOn of bone marrow, or by toxic effects to the kidneys, lungs or skin.
With respect to the examples of treatment for various conditions as presented herein, the examples are not to be con-sidered as presenting fixed and unalterable dosage schedules.
Actually, treatment schedule must beestablished by the physician on the basis of all relevant clinical inrormation.
il -15-8~ ~
Treatment of a patient suffering from RA with sulfhydryl is illustrated in the following examples.
Example 1 A patient showing the symptoms of rheumatoid arthritis is treated with ~ methyl-cysteine in a capsule containing the powdered solids. The initial dosage islO0 mg/day in a single dose. This amounts to 1.5 mg/kg/day 9 the patient weighing approximately 68 kg. The lo patient's condition is monitored with respect to the aforenoted objective changes and labor-tory tests.
At the end of two weeks, the degree of remission being considered minor~ the dosage is increased by 25 mg/day, the dosage increase being repeat~d at 2 week intervals in steps of 25 mg/day up to 500 mg/d~y, after which the . dosage is increased in steps of 50 mg/day at intervals of 8 weeks to a maximum of 1000 mg/day to provide for further remission , the patient's condition being monitored before each increase in dosage both for degree of improvement and side effects.
Example 2 To a patient suffering with RA is ad-ministered each day a tablet including25 mg ~ 8~ 1~
o~ ~-methyl cysteine and 25 mg ofc~-chloro, ~-hydroxyethyl cysteine, the patient weighing 68 kg. The dosage is continued for 3 weeks, at which time, the degree of remission and side effects, on examination of the pa~ient being minimal, the dosage of each compound is increased by 25-mg/day to induce further remission. The proce-dure is repeated, the increases being made at inter~s of 3 weeks and in steps of 50mg/day lo until a maximum of 400 mg/day is reached after which the increases are made at intervals Df 12 weeks and in increments oflO0 mg/day to achieve ~urther remission until a maximum of 1200 mg/day is reached, the patient being moni-tored before each increase in the dosage for ~he degree of remission and for tolerance of the medication.
In general in the treatment of RAw~ as~gle sulfhydryl ox$~und as disclosed herein, the initial dosage is 100 mg/day (for a 68 kg patient), increased at intervals of 2-3 weeks, depending on the response and tolerance of the patient, by steps of 50 mg/da~ .
until a dosage of 500 mg/day is reached, a~ter which the incre ments are at ~ mg/day at 8-1~ week intervals until a dosage of 1500 mg/day is reached.
In all of the examples given herein the dosages are for a 68 kg indi dual, the quantititas for patients ~f different .~ c~
weight being adjusted so that the dosage is proportional to the weight. It should also be noted that where tablets or capsules or solutiGns are to be administered~ fillers, solubilizing agents and buffers well known to those in the art may be present, al-though not specifically mentioned herein. Furthermore, where gold or copper compounds are to be combined with sulfhydryl com-pounds, the metal compounds must be pharmaceutically acceptable.
As aforenoted, gold compounds have been found to be effective in the treatment o~ RA, examples of such gold compounds being gold sodium thiomalate, aurothioglucose and ionic gold.
Colloidal gold can also be used. Combinations of gold from the above sources with sulfhydryls as listed above present advantages with respect to effectiveness in the treatment of RA and decrease in toxicity. The combination with penicillamine is particularly noteworthy~ a principal advantage provided by this combination being the enhanced therapeutic efficacy in comparison with either of the components when used alone. Evidence is available that the greater efficacy stems from the formation o a complex between the gold atom and penicillamine. It appears likely that the com-bination of a sulfhydryl with gold is a complex or chelate, but the present invention is not to be considered as dependent on the formation of a complex or chelate. The same comment applies to the complexes of copper with sulfhydryls to be described below.
The gold complexes are readily made by combining a weak solution of chlorauric acid with the selected su~fhydryl. These comments apply to a ~ o:E the atorenoted substituted cystelDes as well as I
.
~ 18- 1 11~ 8~ ~
to penicillamine and to cysteine itself. The diminished incidence of toxicity from the combination of gold with penicillamine in comparison ~o gold alone, is consistent with the fact that peni-cillamine is effective in the treatment of gold toxicosis in man.
In establ~ hing the dosage for treatment of RA with a combination of gold and a sulfhydryl compound, it is necessary to take into account the gold content of the dose. A suitable initial daily dosage is 10 mg (0.15 mg/kg) of gold itself and the method of establishing the compositi~n of the medication is lo illustrated in the following examples.
Example 3 The rheumatoid arthritis patient is to be treated with a combination of penicillamine and gold, the latter being in the form of gold sodium thiomalate monohydrate. Capsules are prepared, each capsule containing 9 9 mg of the gold compound and lO mg of penicillamine, the patient being administered two capsules per day for an initial period of 3 weeks with monitoring at weekly intervals of the patientls conditicn and for retention of gold.
The degree of remission being insuf-ficient, the dosage is increased by two capsules per day at intervals of 3 weeks until a dosage 100 mg/day of gold is reached after ~hi h -19- :
the dosage is increased by 4 capsules/day at intervals of 10 weeks un~il a maximum dosage of 200 mg/day of gold is reached to provide further remission~ the patient's condition being monitored with respect to the same observations as described in connection with treatment with a sulfhydryl alone as well as with respect to retention of the gold and its known toxic effects, particularly on skin, bone o marrow and kidneys.
Example 4 A solu~ion containing 10.4 mg of anhy-drous chlorauric acid and 20 mg ofcC-methyl cysteine per ml is dried to a powder and made up into cap-sules each containing either 5.0 mg of gold or 20 mg of gold in combination with the sulfhydryl compound. Treatment of an RA patient is started with administration of 2 of the 5 mg capsules/day, one in the morning and one in the evening and continued for 3 weeks at which time the patient is monitored both clinically and objectively to determine the degree of remission. The degree being inadequate, the dosage is increased in steps of 10 mg of gold per day at intervals o 4 weeks ~ntil a dosage of 100 mg of gold/day is reached after which the dosage is increased at intervals of 11 weeks 8~9 by increments of 20 mg/day until a dosage of 200 mg/day of gold is reached in order to provide further remission.
More generally, the dosage of gold in any suitable gold compound is increased initially at two to four week intervals in increments of lO mg/day to a maximum of lO0 mg/day as indicated by assessment of the patient's rheumatoid activity. After the dosage has reached lO0 mg/day, should further increase in dosage appear to be necessary, the dosage is increased by 20 mg/day a~ eight to twelve week intervals until a maximum dosage of 200 mg/day is reached. Assessmen-t of the patient's condition is based on the same indications as described in the case of treatment with sulfhydryls alone.
Where the gold compound and the sulfhydryl are administered in combination but not necessarily as a complex or chelate a preferred mixt~lre as the initial dose consists of 5 mg of the sulfhydryl and a quantity of gold compound such that it contains 5 mg of gold, but the weight of sulfhydryl may be up to twice that of the gold. The mixture is taken twice daily. As aforenoted, gold sodium thiomalate, gold thioglucose and ionic gold are suitable sources of gold.
Then, as the treatment proceeds, the quantities of the mixture are increased by the amounts of gold as given for the gold chelate and at the same intervals. Either or both of the gold compound and the sulfhydryl may be administered in capsule or tablet form or by injection, either indepen-~ 9 dently or together. In general, where the two materials are com-bined in solution a complex of the gold with the sulfhydryl will form.
The course of the treatment may be monitored as des-cribed above. In addition, the 24-hour urinary output of gold may be detenmined. This measurement will assess the net effect of gastrointestinal absorption (in the case of oral administratior of the drug~ and on the metabolism or retention of the metal or cornpound in the body.
Copper is also effective in the treatment of RA when used in combination with any of theaforenoted sulfhydryls, inclu-ding penicillamine, the combination with penicillamine being pre-I ferred. As is the case with gold, the copper may be provided in the form of a complex with said sulfhydryls. Copper may also be provided as a separate compound in a mixture with any of the sulfhydryls. Cupric ion reacts fairly rapi~ly with sulfhydryls such as penicillamine to form a complex which in ~ueous solution is red-vioLet in color, the wave length of the absorption maximum being at 520 nanometers. The gram-atomic extinction coefficient at the maximum is 947. It is believed that at least a part of the copper is univalent in the complex.
P. Birker and H. Freeman have shown t~at when Cl- is present, soluble copper compounds react with penicillamine (Pen) to produce the anion [Cu8C ~6Penl2Cl]5, the cation being Na+ or K+
jdepending on the salt in the solution. The moiety indicated as Pen is doubly charged negatively.
Il . ., Where sulfhydryls are to be administered in combination with copper for treatment of RA, the dosage for the first 2 to 4 weeks should be such that the initial dose of the complex will contain 5 mg of copper. Then should larger doses appear to be necessary, the increments in dosage at 2 to 4 week intervals will be equal to the initial dosage until the dose is six times the initial dosage after which the increments will be twice the initial dosage at intervals of eight to twelve weeks. The maximum copper dosage should rarely reach or exceed 100 mg/day. Where the complex of copper with a specific sulfhydryl has low solubility as is the case with copper cysteine, it must be administered orally.
Where the sulfhydryl (with or without copper or gold) ~is sufficiently soluble, it can be administered parenterally or orally as a solution for any of the conditions discussed herein~ In general the weight ratio of the sulfhydryl to copper will be about 2 to 3.
Where either gold or copper is to be administered for the treatment of RA, the combination of the metal with the sulfhydryl may be in the form of a complex as described in the case of copper-penicillamine, or as a mixture of water-soluble metal compound and sulfhydryl or both. In general, it is desirable that, in the preparation of a complex, an excess of at least 30 molar percent of the sulfhydryl be present since oxidation of part of the sulfhydryl may take place in forming the complex. Moreover, should the tolerance of the patient for the metal be lower than for the sulfhydryl, then a combination of the metal chelate with an even greater excess of the sulfhydryl should be administered according to the judyment of the clinician.
Where a sulfhydryl is to be administered in combina-tion with a copper or gold compound, said compound is preferably water-soluble as well as pharmaceutically acceptable. However, a water-insoluble metal compound may be rendered soluble by complexing or chelation with the sulfhydryl and thereby be made effective in the trea-tment of RA as well as in the treatment of heavy metal poisoning. Moreover, different complexes (or chelates) may be used with each other, such combinations offering the possibility of a higher therapeutic efficacy.
Combination of soluble cupric or cuprous sal~s with sulfhydryls, and more specifically, with cysteine, beta-mono-methylcysteine and penicillamine are of particular value in the treatment of RA. The synergism of D-penicillamine with copper salts in this regard is detailed in the following:
P.E. Lipsky and Morris Ziff. The Effect of D-Penicillamine on Mitogen-Induced Human Lymphocyte Proliferation: Synergistic Inhibi-tion by D-Penicillamine and Copper Salts. Journ.
of Irnmunology, 120: 1006-1013, March 1978.
In general, it is preferable that the sulfhydryl be present in substantial stoichiometric excess over the copper salts the ratio of sulfhydryl to copper in mols, being at least lo 3 and up to about 5, the excess sulfhydryl serving to maintain part of the copper in the cuprous state.
8~ ~
The following example illustrates treatment of RA with a combination of copper and penicillamine.
Example 5 In preparation for treatment of a patient suffering with rheumatoid arthritis a complex of copper with a sulfhydryl is synthesized as follows:
Cupric acetate is dissolved in water to prepare a solution having a con-centration of 10 mg Cu++/ml. D-penicillamine is dissolved in .05 molar sodium acetate buffer, pH 5.6,containing 2% sodium chlor;de to give a concentration of 10 mg penicillamine/
ml. The copper solution is added to the penicillamine solution in a ratio of 16 ml of copper solution to 50 ml of penicillamine solution. The ratio of penicillamine to copper in moles is 1.3. The solution immedi-ately takes on a red-violet color indicating the formation of the complex. The solution is dried to yield a powder and formed into . tablets each containing 10 mg of the combin-ation.
The initial daily dosage of the cop ~ r-penicillamine combination is 2 mg I
;
i; -25-'' ' '~
in two tablets, one taken in the morning and the other in the evening. This dosage corres-ponds to 5 mg of copper and 15 mg of penicil-lamine. The assessment of the clinical re-sponse of the patient and the detection of any toxic effect are carried/in the same manner as in patients with RA treated with sulfhydryls alone or with sulfhydryls in com~ination with gold~ Also,the dosage of the componds is moni-lo tored by a determination of the 24-hour urinary output of copper to assess the net effect of gastrointestinal absorption and of the metabolism or retention of the copper or copper compo~nd in the body.
I T~e degree of remission being inade-; quate, the dcsage is increased by steps of 20 mg/day taken at three week intervals until a dose of 200 mg/day is reached after which the increases are 40 mg/day at intervals of 10 weeks in order to achieve further remission until a maximum of 600 mg/day is reached.
It is significant that the quantity of penicillamine administered with copper is far smaller than when penicillamine I is administered without copper. The mol ratio of penicillamine to copper preferably lies in the range from 1.3 (as above) to 5, although higher rat:ios may also be useful depending on the re-sponse of the patient.
1~ 8~1~
Copper-sulfhydryl combinations can also be effective when administered as solutions as illustrated by the following example.
Example 6 For treatment of an P~ patient cupric acetate is dissolved in water to prepare a solution having a concentration of 5 mg Cu~t/ml.
One ml of this copper acetate solution is added with stirring to 4 oz of beef bouillon. To this is added 125 mg of solid penicillamine, as powder; the mixture is stirred until the penicillamine dissolves and is administeréd . for two weeks.
orally once per day, on an empty stomach/ On the last day the patient is examined for clinical changes, specifically with respect to mobility pain, swelling, redness and heat of the joints.
Also7 the erythrocyte sedimentation rate and concentration of rheumatoid factor in the blood are noted. The results indicating remission to a minor degree, the daily dosage is increased to 8, 1~ and then 16 ounces of the solution at one week intervals by administering the 4 ounce quantity of solution, twice, three times and four times daily. Also, the patient is examined as abov~ ~n the last day of eaFh - 2 ~
. ., interval. The degree of remission being insuf ficient after 4 weeks of treatment, a broth having twice the aforenoted concentrations of copper and penicillamine is prepared and the daily dosage is increased by 4 ounces of the concentrated broth at 4 week intervals to achieve further remission, the patient again being moni-tored on the last day of each interval as afore-noted. The increases are continued until the o daily dosage reaches 40 ounces, this dosage corresponding to a daily intake of 100 mg of copper and 2.5 grams of penicillamine.
As aforenoted, penicillamine is effective in the treat-ment of cystinuria due to the fact that it forms a mixed disulfide with cysteine,said~ de having a higher solubility than cystine However, cysteine derivatives other than penicillamine offer the advantages of higher solubility and different or milder side effects. Accordingly, specific sulfhydryls other than penicilla-mine also have value in the treatment of cystinuria.
The preferred dosage range for treatment of cystinuria with a sulfhydryl from the aforenoted 5 groups is from about 0.5 to 2.0 grams per day. Treatment starts with administration of 0.5 grams/day, the dosage being increased by about 0.25 grams/day at intervals of one week. The increase is continued until there is no further formation of stones or until maximum ~osage of 2.0 g/day is reached, the condition of the patient being monitored radiologically and for cysteine in the urine.
The treatment of cystinuria with sulfhydryl is related to the fact that the rate of dissolution of stones depends upon the solubility nf the mixed dimer. I~ere a combinaticn of sulf-hydryls is administered, then two or more mixed dimers with cysteine will be formed so that the rate of dissolution of the stones will not be limited by the solubility of a single mixed dimer such as the mixed dimer of cysteine with penicillamine.
The sulfhydryl compounds useful in the treatment o~
cystinuria are those listed in the aforenoted five groups. Com-binations of the members of these groups with each other and with penicillamine are also useful. Particularly useful~ due to lo solubility characteristics and structural similarity to cysteine are theo~-meth~l and ~methyl cysteines as illustrated in the following Example.
Example 7 A cystinuria patient is trea~ed with capsules each containing 50 mg ofoC-methyl cysteine and 50 mg of ~ methyl cysteine, a dose of one capsule being administered twice daily.
The extent of remission being minor9 the dosage i5 increased at intervals of 4 weeks by two cap-sules/day to provide further remission, the patient being monitored at the end of each interval for the quantity of cysteine as the mLxed dimer in the urine.
The daily dosage is increased until Q osage of 2 g/day is reached and then increased 1~ 9 by 4 capsules/day at intervals of 4 weeks until a ma~imt~ dosage of 3.0 g/day is reached. The treatment is continued until chemical and radio-logical examination indicate that existing cystine stones are dissolving and no new stones are forming.
The sulfhydryl compo~nds in the aforenoted 5 groups are effective in removing heavy metals, and particularly mercury and lead from those suffering from heavy metal poisoning. Those heavy metal ions having a high association constant with said .
lo sulfhydryls and forming a soluble complex or chelate therewith can be removed from the body by administration of specific sul-hydryls Heavy metals which can be eliminated in this way, in addition to mercury and lead are, for example, cadmium, bismuth, : vanadium and plutoniumO The progress of the treatment is moni-~ored by frequent examination of the urine for the metal in question The procedure is illustrated in the following example Example 8 A patient suffering from acute mercury poisoning is treated with ~ methyl cysteine in tablet form, the patient being given 0.25 g both morning and evening on the first day. The patient is monitored for mercury in the urine and toxic effects. The dosage is increased daily by 0 5g/
da urtil a maximum of 4.0 g/day is reached, t e Il . `
~ 9 patient being monitored daily for mercury in the urine and for the severity of side effects as described in connection with treatment of RA with sulfhydryls.
In the treatment of acute mercury poisoning the dosage is increased rapidly since life is threatened and toxic effects of long-term treatment with the sulfhydryl are of relatively little importance. Also, the treatment with sulfhydryl may be supplemented with hemodialysis since loss of kidney function o within 24 to 36 hours is likely to occur.
Copper sulfhydryl complexes are also effectiYe for the removal of several heavy metals though not of lead. For the cop-per sulfhydryl to be effective in removal of a heavy metal from the body, it is necessary that the heavy metal have an association constant for the sulfhydryl which is great enough to displace copper from the complex. In addition the heavy metal-sulfhydryl compound must be soluble in plasma. Mercuric ion, for instance reacts readily with copper penicillamine to displace the copper therefrom forming a soluble, colorless compound which can be excreted. Similarly, any other heavy metal ion which can displace the copper from the sulfhydryl complex to form a water-soluble product can be removed in the same way.
I It is significant that copper cysteine which stabilizes I the sulfhydryl in the form of a monomer is the safest medication I i for the purpose since it consists of cysteine which is a naturall~
ll .
~ 8 8~ ~
occurring amino acid and copper, a naturally occurring element that is essential to life. Copper penicillamine is also of importance as a therapeutic compound since it it known that the body can tolerate the material in quantities great enough to be effective.
The dosage of the copper sulfhydryl to be used in the treatment of heavy metal poisoning is such as to correspond to a copper content of 2 to 15 mg of copper ranging from the minimal dietary intake of copper per day to about three times the maximal o die~ary intake per day. The daily dose is preferably administered in 2 to 3 portions. The patient is monitored with particular attention to the content of both copper and heavy metal in the urine. The actual dosage will be selected by the clinician on the basis of the patient's tolerance for the copper sulfhydryl combination, which may be a complex or a mixture. The mol ratio of the sulfhydryl ts copper preferably lies 6etween 1 and 5.
A point to be noted is that the molecular weigh~s o the various sulfhydryls under consideration lie fairly close together. AccordLngly, although the dosage in the treatment of RA, cystinuria and heavy metal poisoning may be adjusted in pro-portion to the molecular weight of the compound being adminis tered in general, such adjustment is usually unnecessary, the response of the patient to the medication being the critical factor. However, where the sul~hydryl is trisubstituted, adjust-ment of the dosage in accordance with the molecular weight of he sulihydryl is appropriate. Thus, methyl-cysteine has a 1l, ~1882~9 molecular weight of 135.2 whereas ~-chloro, ~-chloro, ~ hyclroxy-ethyl cysteine has a molecular weight of 234Ø This point is illustrated in the next example.
Example 9 A patient suffering from mercury poison-ing is initially treated with 3 tablets/day of the reaction product of9C-chloro, ~ chloro, ~hydroxyethyl cysteine (I) with copper acetate in 3 divided doses, each tablet containing 23 mg o of copper and 177 mg of I. The total daily dos-age of copper amounts to 69 mg. The mol ratio o~ the sulfhydryl to cuprous ion is 2Ø The . urine is examined daily for copper and mercury.
Since mercury poisoning is a life-threatening condition the dosage is increased each day by 1 tablet/day, monitoring the toler-ance of the patient for the combination until a maximum of lO tablets/day (230 mg of Cu~day) is reached, copper and mercury in the urine being monitored every day and the treatment being continued until the mercury content of the urine becomes negligible.
IfOC-methyl cysteine had been used instead of the tri-substituted cysteine then the comparable quantity ofoC-methyl ~ ~ 8~ ~
cys~eine in the tablet would have been 9.25 mg rather than 16 mg, thus illustrating compensation for the molecular weight of the subs~ituted sulfhydryl.
In general, and especially when more than one dose is to be glven per day, administration as a solid (in capsule or tablet form) is preferred to injection. However, intravenous injection is preferred where it is desired to maintain a high and essentially constant level of medication even at lengthy interval. For this purpose a solution of copper-penicillamine o is particularly suitable because of the high aqueous solubility of the combination.
It will thus been seen that the objects s-et forth abcve among those made apparent from the preceding descrip~ion, are efficiently attained and, since certain changes may be made in carrying out the above method without departing rom the nature and scope of the invention, it is intended that all matter con-tained in the above description shall be interpreted as illustra-tive and not in a limitin g sence.
It is also to be understood that the following claims are intended to cover all of the generic and specific features of the invention herein described, and all statements of the scope of the invention, which, as a matter of language, might be said t~ ~11 therebetween.
11l 3~
The preferred compounds, on the basis of the therapeutic 0 efficacy, are ~ methylcysteine,oC-methylcysteine andGC-methyl, ~-methylcysteine. Cysteine and derivatives thereof will herein-after be referred to generally as sulfhydryls or sulfhydryl com-pounds.
A fur~her discovery which I have made is that the efficacy of all of the aboYe compounds is increased i~ the treat-ment of RA when combined or complexed with copper or gold and in the treatment of heavy metal poisoning when combined or com-plexed with copper. Still further, the effectiveness of penicil-lamine is increased in the treatment of RA when used in combinatior with or complexed with copper or gold and in heavy metal poisoning when combined with or complexed with copper. Penicillamine, ~-methyl cysteine and cysteine itself are preferred sulfhydryls for use in combination with or complexed with copper. The gold compound used is preferably water-soluble, examples being chlor-auric acid, gold sodium thiomalate and aurothioglucose.
The medication, where a sulfhydryl is used alone is administered initially to a 1501b patient suffering from RA in a 1, 8;~L9 single dose of 100 mg amounting to 1.5 mg/day per kilogram of the patlent's weight and is increased by 25 mg/day at 2-3 week intervals up to 500 mg/day and then by 50 mg/day at 8-12 week intervals to a maximum of 1500 mg/day or until RA symptoms are alleviated. The dose is administered in capsule or tablet form or as a suitably formulated solution subcutaneously, intramus-cularly or intravenously. ~f the medication is well tolerated the ra-te of increase at the end o~ each interval can be S0 mg/day.
Where any of the above sulfhydryls or penicillamine is administered with gold either in combination or complexed therewith for treatment of RA, the initial daily dosage in 2 doses per day is such that the gold content thereof is 10 mg.
The form of the dose is as a solid in a capsule or tablet form or as a suitably formulated solution for injection as above.
The dosage is increased as needed by 10 mg/day (of gold) at intervals of 2-4 weeks to 100 mg/day and then by increments of 20 mg/day at intervals of 8-12 weeks to a maximum of 200 mg/day.
Preferably, the sulfhydryl content of the combinations with gold is at least equal to that of the gold by weight and may be up to 4 times the weight of the gold.
Where any of the above sulfhydryls or penicillamine is administered with copper either in combination or complexed therewith for treatment of RA the initial daily dosage is preferably 25 mg/day of the combination in 1 or 2 doses/day, the copper content of the dosage being about 7.5 mg with the remainder a sulfhydryl, the preferred sulfhydryl being penicillamine. The dosage is increased in increments of 25 mg/day at intervals of 2-3 weeks until a dosage of 150 mg/day is reached after which the dosage is increased at intervals of 8-12 weeks in increments of 50 mg/day to a maximum of 400 mg/day.
It will be noted that the dosage of penicillamine when used in combination with either copper or gold is much smaller than when administered without these metals.
A method of treating cystinuria is to administer an effective amount of any of the types of sulfhydryl compounds in the above 5 groups, ~ monomethylcysteine being preferred because of its relatively low toxicity and the solubility of the mixed dimer with cysteine. The initial dosage is 100 mg/day and can be increased by steps of 100 mg/day at intervals o 2 weeks to a maximum of 1.50 gJday. ~he dosage may be administered orally as a solid in capsule or tablet form or a solution or by injection when suitably formulated for injection as above and should be administered 1 or 2 times per day.
A method of removing heavy metals such as mercury, lead, cadmium, bismuth, vanadium and plutonium from the body is to admin-ister either orally or by injection a sulfhydryl from one of the above 5 groups either as such or combined with copper. The com-bination of penicillamine with copper is particularly effective. Acomplex of copper with a sulfhydryl is denoted as RSCu where RSH
is a sulfhydryl of one of the above groups, penicillamine or cysteine; cysteine, ~ monomethylcysteine and penicillamine are the preferred sulfhydryl compounds for use with copper. The methoc of using such RSCu compounds is restricted to removal of those ~ ~ 8~
heavy metals having a high enough association constant with the sulfhydryls to displace copper from the complex and having the capacity to form a soluble compound with the sulfhydryl. The method is particularly effective for removal of mercury, an exceed _ ingly toxic element. The initial dosage of the complex of a sulf-hydryl with copper is 200 mg repeated at 8-hour intervals~ as capsules or tablets or by injec~ion as a suitably formulated solution. The dosage is increased by steps of 200 to 400 mg and depending on the amount of mercury ingested /the response of the o patient, the maximum daily dosage being 2.00 g. The preferred combinations are copper penicillamine, copper cysteine and copper ~-methyl cysteine.
Where the cystinuria patient is to be treated with a sulfhydryl, any of the sulfhydryls in the above 5 groups may be administered as a capsule or tablet or as a suitably form-ulated solution by injectiDn, the preferred compounds being cX~-methyl cysteine and ~ methyl cysteine. The initial dosage is 1.00 g~day this being administered in 3 divided doses, the dosage being increased daily in steps of 0.5 g/day until a ma~imum of 3.00 g/day is reached.
Accordingly~ an object of the present invention is a method of treating rheumatoid arthritis with selected cysteine derivatives.
A ~urther object of the present invention is a method of treatirg rheumatoid arthritis with combinations of cysteiDe, _9_ .11~
and selected cysteine derivatives, including penicillamine with ¦gold compounds and with copper compounds.
¦ Still another object of the present invention is a metho ¦of eliminating from the body heavy metals present in excess quan-¦tity by administration of speci~ic sulfhydryls, either as such or complexed with copper. Still further, penicillamine complexed with copper can be used for this purpose.
A significant object of the present invention is a method of treating cystinuria by administration of specific o cysteine derivatives other than penicillamine.
Yet another obiect of the present invention are composi-tions of selected sulfhydryl compounds with copper or with gold, such compositions being effective for treatment of RA and composi-tions of selected sulfhydryls wiLh copper,such compositions being effective in the treatment of heavy metal poisoning.
An important object of the present invention is a method of minimizing side effects of the chemotherapy of rheumatoid toxic arthritis and cystinuria and elimination of/metals from the body.
Still other objects and advantages of the invention will in part be obvious and will in part be apparent from the specifi-cation.
The invention accordingly comprises the several steps and the relation of one or more of such steps with respect to each f the others, and the composition possessine the features, pro-8'~19 perties, and the relation of constituents, which are exempliied in the following detailed disclosure, and the scope of the inven-tion will be indicated in the claims.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
D-penicillamine, which is moderately effective in the treatment of rheumatoid arthritis~ is a metabolite of penicillin;
it can also be prepared synthetically. Prior to its use for the ~reatment of RA, it was found effective in Wilson's disease, in cystinuria and in the removal of toxic metals such as lead from o the body. It has long been approved by the Food & Drug Admin-istration as safe and effective for Wilson's disease and cystin-uria. In Wilson's disease3 ingested copper is not properly execreted. Apparently, in the removal of copper by treatment with penicillamine, chelates are formed with involvement of the SH group /the amino group attached to the alpha carbon. Cystin-uria is a disorder in which the amount of cystine in the urine exceedsthe solubility of this amino acid, with the result that ultimately fatal stones form in the kidney. Penicillamine forms an asymmetrical disulfide with cysteine of which one-half is the penicillamine molecule and the other half is the cysteine mole-cule. Although its use in the treatment of rheumatoid arthritis ¦ has recently been approved by the Food & Drug Administration, it has not as yet been approved for treatment of lead or mercury poisoning largely because of its toxicity which includes allergic reactions and direct toxicity to skin, kidneys, lung, bone marrow,l and neuromuscular system.
.
Penicillamine differs from the natural amino acid cystein only in that the two ~-hydrogen atoms are replaced by methyl groups. It is almost certain that it is the presence of these two methyl groups which keeps the molecule from forming penicillamine disulfide to the extent that cysteine dimexizes to cystine, so that an appreciable fraction of penicillamine -- in contrast to cysteine -- circulates in the body with a free SH group. As aforenoted, an asymmetrical disulfide is formed with cysteine. Moreover, it seems probable that the effect of penicillamine on rheumatoid arthritis is also related to the free SH group.
A further point with respect to the biochemistry of penicillamine is that sulfhydryl amino acids are metabolized by desulfhydrases and by amino oxidases. Tests have shown that these enzymes react only very slowly with the penicillamine isomers. However~ cysteine is very rapidly attacked by both enzymes which also accounts for the low concentration of cysteine in the blood and for its lack of effectiveness in the removal of toxic metals from the blood.
Since there are two asymmetric carbon atoms in the ~-methyl-substituted cysteine, there are four diastereoisomers.
The rate of attack on each of the isomers by D-amino aeid oxidase and L-amino oxidase has been measured and, interest-ingly, the rate of at-tack is not nearly so high as the rate of attack on cysteine itself. Accordingly, it can be seen that substitution of from l to 3 of the hydrogen atoms on the alpha and beta carbons of cysteine with substituents of small size offers the possibility of modifying the rate of attack by amino aeid oxidases and eysteine desulfhydrases, as well as 8;~1"3 the solubility, the toxicity and the effect of the compound on RA. A further enhancement of the therapeutic efficacy of appropriately chosen substituents is afEorded by replacement of one of the hydrogens on the amino group with an acetyl group.
A first group of compounds useful in the treatment of RA consists of those cysteine derivatives in ~-hich one of the beta hydrogens is replaced by a chlorine atom or a methyl, ethyl, hydroxymethyl or hydroxyethyl group. A second group of cysteine derivatives useful in the treatment of R~ is that consisting of the beta-disubstituted cysteines in which the substituents consist of one of the following pairs:
chloro, chloro, methyl, chloro, ethyl, chloro, methyl, ethyl, ethyl, ethyl, hydroxymethyl, hydroxymethyl, hydroxyethyl, hydroxyethyl, hydroxymethyl, hydroxyethyl, methyl, hydroxymethyl, methyl, hydroxyethyl, ethyl, hydroxymethyl, ethyl, hydroxyethyl, chloro, hydroxymethyl, and chloro hydroxyethyl.
A third group of compounds useful in the treatment of RA is the alpha-substituted cysteines, where the single substituent is a chlorine atom or a methyl, ethyl, hydroxy-methyl or hydroxyethyl group.
A fourth group of cysteine derivatives useful in thetreatment of RA is that in which the alpha carbon ls substituted ~ ~ 8~ 9 as in the third group and the beta carbon is substituted as in either the first group or the second group. In other words, the alpha carbon is substituted and the beta carbon is either mono-or di-substituted.
A fifth group of cysteine derivatives particularly use-ful in the treatment of RA is obtained by forming the N-acetyl derivatives of any of the compounds in the irst four groups.
Methods of synthesis of all of the compounds listed in the above five groups are well known to those skilled in the art.
lo The compounds are stable and can be dried for administration in a capsule or as a tablet. They can also be formulated for admin-istration subcutaneously, intramuscularly or intravenously.
The side effects attendant upon the use of the above compounds can be minimized through the use of two or more of the above compounds in rombination, each compound being used in a dosage smaller than would be the case were it used alone.
Accordingly, combinations of compounds in any of the above five gxoups may be used in the treatment of RA as well as combinations of said compounds with penicillamine.
In the Examples which follow, the dosages cited are appropriate for an individual weighing 68 kg (150 lb~. Where the patien~s weight differs substantially from this figure, the dosage~
should be adjusted appropriately. Moreover, all dosages, including periodic increases, must be subject to the clinician's judgement with respect to the entire patient's situation so that even the dosages to be presented as maxima can under appropriate circum-stances be exceeded 1 ~8 and signs The symp~oms/of RA are well known, these being pain in the joints, swelling ~f the j~ints, redness and heat in the ~oints and loss of mobility. During treatment with sulfhydryl compounds, the patient is monitored to determine the clinical response as assessed by symptomatic change and by objective change. The objective change is noted in the mobility, redness 3 swelling and heat of ~he joints. The objective assessment of the state of the patient's rheumatoid activity is further evaluated by measurement of the concentration of the rheumatoid factor in the blood, by o the white blood count and the differential count, by the erythro-cyte sedimentation rate~ and by measurement of the fluorescent anti-nuclear antibody. In addition, the progression of the arthri tis -- or its remission -- may on occasion be estimated by suitabl~
x-ray studies. Here again, the frequency of the tests and the variety thereof are a matter for the clinician's judgment.
Possible toxic effects to be noted include early rash, fever, leukopenia and thrombocytopenia, all of the foregoing usually occurring as allergic manifestations in the first two to four weeks of treatment. Late toxicity is manifested most importantly as suppressiOn of bone marrow, or by toxic effects to the kidneys, lungs or skin.
With respect to the examples of treatment for various conditions as presented herein, the examples are not to be con-sidered as presenting fixed and unalterable dosage schedules.
Actually, treatment schedule must beestablished by the physician on the basis of all relevant clinical inrormation.
il -15-8~ ~
Treatment of a patient suffering from RA with sulfhydryl is illustrated in the following examples.
Example 1 A patient showing the symptoms of rheumatoid arthritis is treated with ~ methyl-cysteine in a capsule containing the powdered solids. The initial dosage islO0 mg/day in a single dose. This amounts to 1.5 mg/kg/day 9 the patient weighing approximately 68 kg. The lo patient's condition is monitored with respect to the aforenoted objective changes and labor-tory tests.
At the end of two weeks, the degree of remission being considered minor~ the dosage is increased by 25 mg/day, the dosage increase being repeat~d at 2 week intervals in steps of 25 mg/day up to 500 mg/d~y, after which the . dosage is increased in steps of 50 mg/day at intervals of 8 weeks to a maximum of 1000 mg/day to provide for further remission , the patient's condition being monitored before each increase in dosage both for degree of improvement and side effects.
Example 2 To a patient suffering with RA is ad-ministered each day a tablet including25 mg ~ 8~ 1~
o~ ~-methyl cysteine and 25 mg ofc~-chloro, ~-hydroxyethyl cysteine, the patient weighing 68 kg. The dosage is continued for 3 weeks, at which time, the degree of remission and side effects, on examination of the pa~ient being minimal, the dosage of each compound is increased by 25-mg/day to induce further remission. The proce-dure is repeated, the increases being made at inter~s of 3 weeks and in steps of 50mg/day lo until a maximum of 400 mg/day is reached after which the increases are made at intervals Df 12 weeks and in increments oflO0 mg/day to achieve ~urther remission until a maximum of 1200 mg/day is reached, the patient being moni-tored before each increase in the dosage for ~he degree of remission and for tolerance of the medication.
In general in the treatment of RAw~ as~gle sulfhydryl ox$~und as disclosed herein, the initial dosage is 100 mg/day (for a 68 kg patient), increased at intervals of 2-3 weeks, depending on the response and tolerance of the patient, by steps of 50 mg/da~ .
until a dosage of 500 mg/day is reached, a~ter which the incre ments are at ~ mg/day at 8-1~ week intervals until a dosage of 1500 mg/day is reached.
In all of the examples given herein the dosages are for a 68 kg indi dual, the quantititas for patients ~f different .~ c~
weight being adjusted so that the dosage is proportional to the weight. It should also be noted that where tablets or capsules or solutiGns are to be administered~ fillers, solubilizing agents and buffers well known to those in the art may be present, al-though not specifically mentioned herein. Furthermore, where gold or copper compounds are to be combined with sulfhydryl com-pounds, the metal compounds must be pharmaceutically acceptable.
As aforenoted, gold compounds have been found to be effective in the treatment o~ RA, examples of such gold compounds being gold sodium thiomalate, aurothioglucose and ionic gold.
Colloidal gold can also be used. Combinations of gold from the above sources with sulfhydryls as listed above present advantages with respect to effectiveness in the treatment of RA and decrease in toxicity. The combination with penicillamine is particularly noteworthy~ a principal advantage provided by this combination being the enhanced therapeutic efficacy in comparison with either of the components when used alone. Evidence is available that the greater efficacy stems from the formation o a complex between the gold atom and penicillamine. It appears likely that the com-bination of a sulfhydryl with gold is a complex or chelate, but the present invention is not to be considered as dependent on the formation of a complex or chelate. The same comment applies to the complexes of copper with sulfhydryls to be described below.
The gold complexes are readily made by combining a weak solution of chlorauric acid with the selected su~fhydryl. These comments apply to a ~ o:E the atorenoted substituted cystelDes as well as I
.
~ 18- 1 11~ 8~ ~
to penicillamine and to cysteine itself. The diminished incidence of toxicity from the combination of gold with penicillamine in comparison ~o gold alone, is consistent with the fact that peni-cillamine is effective in the treatment of gold toxicosis in man.
In establ~ hing the dosage for treatment of RA with a combination of gold and a sulfhydryl compound, it is necessary to take into account the gold content of the dose. A suitable initial daily dosage is 10 mg (0.15 mg/kg) of gold itself and the method of establishing the compositi~n of the medication is lo illustrated in the following examples.
Example 3 The rheumatoid arthritis patient is to be treated with a combination of penicillamine and gold, the latter being in the form of gold sodium thiomalate monohydrate. Capsules are prepared, each capsule containing 9 9 mg of the gold compound and lO mg of penicillamine, the patient being administered two capsules per day for an initial period of 3 weeks with monitoring at weekly intervals of the patientls conditicn and for retention of gold.
The degree of remission being insuf-ficient, the dosage is increased by two capsules per day at intervals of 3 weeks until a dosage 100 mg/day of gold is reached after ~hi h -19- :
the dosage is increased by 4 capsules/day at intervals of 10 weeks un~il a maximum dosage of 200 mg/day of gold is reached to provide further remission~ the patient's condition being monitored with respect to the same observations as described in connection with treatment with a sulfhydryl alone as well as with respect to retention of the gold and its known toxic effects, particularly on skin, bone o marrow and kidneys.
Example 4 A solu~ion containing 10.4 mg of anhy-drous chlorauric acid and 20 mg ofcC-methyl cysteine per ml is dried to a powder and made up into cap-sules each containing either 5.0 mg of gold or 20 mg of gold in combination with the sulfhydryl compound. Treatment of an RA patient is started with administration of 2 of the 5 mg capsules/day, one in the morning and one in the evening and continued for 3 weeks at which time the patient is monitored both clinically and objectively to determine the degree of remission. The degree being inadequate, the dosage is increased in steps of 10 mg of gold per day at intervals o 4 weeks ~ntil a dosage of 100 mg of gold/day is reached after which the dosage is increased at intervals of 11 weeks 8~9 by increments of 20 mg/day until a dosage of 200 mg/day of gold is reached in order to provide further remission.
More generally, the dosage of gold in any suitable gold compound is increased initially at two to four week intervals in increments of lO mg/day to a maximum of lO0 mg/day as indicated by assessment of the patient's rheumatoid activity. After the dosage has reached lO0 mg/day, should further increase in dosage appear to be necessary, the dosage is increased by 20 mg/day a~ eight to twelve week intervals until a maximum dosage of 200 mg/day is reached. Assessmen-t of the patient's condition is based on the same indications as described in the case of treatment with sulfhydryls alone.
Where the gold compound and the sulfhydryl are administered in combination but not necessarily as a complex or chelate a preferred mixt~lre as the initial dose consists of 5 mg of the sulfhydryl and a quantity of gold compound such that it contains 5 mg of gold, but the weight of sulfhydryl may be up to twice that of the gold. The mixture is taken twice daily. As aforenoted, gold sodium thiomalate, gold thioglucose and ionic gold are suitable sources of gold.
Then, as the treatment proceeds, the quantities of the mixture are increased by the amounts of gold as given for the gold chelate and at the same intervals. Either or both of the gold compound and the sulfhydryl may be administered in capsule or tablet form or by injection, either indepen-~ 9 dently or together. In general, where the two materials are com-bined in solution a complex of the gold with the sulfhydryl will form.
The course of the treatment may be monitored as des-cribed above. In addition, the 24-hour urinary output of gold may be detenmined. This measurement will assess the net effect of gastrointestinal absorption (in the case of oral administratior of the drug~ and on the metabolism or retention of the metal or cornpound in the body.
Copper is also effective in the treatment of RA when used in combination with any of theaforenoted sulfhydryls, inclu-ding penicillamine, the combination with penicillamine being pre-I ferred. As is the case with gold, the copper may be provided in the form of a complex with said sulfhydryls. Copper may also be provided as a separate compound in a mixture with any of the sulfhydryls. Cupric ion reacts fairly rapi~ly with sulfhydryls such as penicillamine to form a complex which in ~ueous solution is red-vioLet in color, the wave length of the absorption maximum being at 520 nanometers. The gram-atomic extinction coefficient at the maximum is 947. It is believed that at least a part of the copper is univalent in the complex.
P. Birker and H. Freeman have shown t~at when Cl- is present, soluble copper compounds react with penicillamine (Pen) to produce the anion [Cu8C ~6Penl2Cl]5, the cation being Na+ or K+
jdepending on the salt in the solution. The moiety indicated as Pen is doubly charged negatively.
Il . ., Where sulfhydryls are to be administered in combination with copper for treatment of RA, the dosage for the first 2 to 4 weeks should be such that the initial dose of the complex will contain 5 mg of copper. Then should larger doses appear to be necessary, the increments in dosage at 2 to 4 week intervals will be equal to the initial dosage until the dose is six times the initial dosage after which the increments will be twice the initial dosage at intervals of eight to twelve weeks. The maximum copper dosage should rarely reach or exceed 100 mg/day. Where the complex of copper with a specific sulfhydryl has low solubility as is the case with copper cysteine, it must be administered orally.
Where the sulfhydryl (with or without copper or gold) ~is sufficiently soluble, it can be administered parenterally or orally as a solution for any of the conditions discussed herein~ In general the weight ratio of the sulfhydryl to copper will be about 2 to 3.
Where either gold or copper is to be administered for the treatment of RA, the combination of the metal with the sulfhydryl may be in the form of a complex as described in the case of copper-penicillamine, or as a mixture of water-soluble metal compound and sulfhydryl or both. In general, it is desirable that, in the preparation of a complex, an excess of at least 30 molar percent of the sulfhydryl be present since oxidation of part of the sulfhydryl may take place in forming the complex. Moreover, should the tolerance of the patient for the metal be lower than for the sulfhydryl, then a combination of the metal chelate with an even greater excess of the sulfhydryl should be administered according to the judyment of the clinician.
Where a sulfhydryl is to be administered in combina-tion with a copper or gold compound, said compound is preferably water-soluble as well as pharmaceutically acceptable. However, a water-insoluble metal compound may be rendered soluble by complexing or chelation with the sulfhydryl and thereby be made effective in the trea-tment of RA as well as in the treatment of heavy metal poisoning. Moreover, different complexes (or chelates) may be used with each other, such combinations offering the possibility of a higher therapeutic efficacy.
Combination of soluble cupric or cuprous sal~s with sulfhydryls, and more specifically, with cysteine, beta-mono-methylcysteine and penicillamine are of particular value in the treatment of RA. The synergism of D-penicillamine with copper salts in this regard is detailed in the following:
P.E. Lipsky and Morris Ziff. The Effect of D-Penicillamine on Mitogen-Induced Human Lymphocyte Proliferation: Synergistic Inhibi-tion by D-Penicillamine and Copper Salts. Journ.
of Irnmunology, 120: 1006-1013, March 1978.
In general, it is preferable that the sulfhydryl be present in substantial stoichiometric excess over the copper salts the ratio of sulfhydryl to copper in mols, being at least lo 3 and up to about 5, the excess sulfhydryl serving to maintain part of the copper in the cuprous state.
8~ ~
The following example illustrates treatment of RA with a combination of copper and penicillamine.
Example 5 In preparation for treatment of a patient suffering with rheumatoid arthritis a complex of copper with a sulfhydryl is synthesized as follows:
Cupric acetate is dissolved in water to prepare a solution having a con-centration of 10 mg Cu++/ml. D-penicillamine is dissolved in .05 molar sodium acetate buffer, pH 5.6,containing 2% sodium chlor;de to give a concentration of 10 mg penicillamine/
ml. The copper solution is added to the penicillamine solution in a ratio of 16 ml of copper solution to 50 ml of penicillamine solution. The ratio of penicillamine to copper in moles is 1.3. The solution immedi-ately takes on a red-violet color indicating the formation of the complex. The solution is dried to yield a powder and formed into . tablets each containing 10 mg of the combin-ation.
The initial daily dosage of the cop ~ r-penicillamine combination is 2 mg I
;
i; -25-'' ' '~
in two tablets, one taken in the morning and the other in the evening. This dosage corres-ponds to 5 mg of copper and 15 mg of penicil-lamine. The assessment of the clinical re-sponse of the patient and the detection of any toxic effect are carried/in the same manner as in patients with RA treated with sulfhydryls alone or with sulfhydryls in com~ination with gold~ Also,the dosage of the componds is moni-lo tored by a determination of the 24-hour urinary output of copper to assess the net effect of gastrointestinal absorption and of the metabolism or retention of the copper or copper compo~nd in the body.
I T~e degree of remission being inade-; quate, the dcsage is increased by steps of 20 mg/day taken at three week intervals until a dose of 200 mg/day is reached after which the increases are 40 mg/day at intervals of 10 weeks in order to achieve further remission until a maximum of 600 mg/day is reached.
It is significant that the quantity of penicillamine administered with copper is far smaller than when penicillamine I is administered without copper. The mol ratio of penicillamine to copper preferably lies in the range from 1.3 (as above) to 5, although higher rat:ios may also be useful depending on the re-sponse of the patient.
1~ 8~1~
Copper-sulfhydryl combinations can also be effective when administered as solutions as illustrated by the following example.
Example 6 For treatment of an P~ patient cupric acetate is dissolved in water to prepare a solution having a concentration of 5 mg Cu~t/ml.
One ml of this copper acetate solution is added with stirring to 4 oz of beef bouillon. To this is added 125 mg of solid penicillamine, as powder; the mixture is stirred until the penicillamine dissolves and is administeréd . for two weeks.
orally once per day, on an empty stomach/ On the last day the patient is examined for clinical changes, specifically with respect to mobility pain, swelling, redness and heat of the joints.
Also7 the erythrocyte sedimentation rate and concentration of rheumatoid factor in the blood are noted. The results indicating remission to a minor degree, the daily dosage is increased to 8, 1~ and then 16 ounces of the solution at one week intervals by administering the 4 ounce quantity of solution, twice, three times and four times daily. Also, the patient is examined as abov~ ~n the last day of eaFh - 2 ~
. ., interval. The degree of remission being insuf ficient after 4 weeks of treatment, a broth having twice the aforenoted concentrations of copper and penicillamine is prepared and the daily dosage is increased by 4 ounces of the concentrated broth at 4 week intervals to achieve further remission, the patient again being moni-tored on the last day of each interval as afore-noted. The increases are continued until the o daily dosage reaches 40 ounces, this dosage corresponding to a daily intake of 100 mg of copper and 2.5 grams of penicillamine.
As aforenoted, penicillamine is effective in the treat-ment of cystinuria due to the fact that it forms a mixed disulfide with cysteine,said~ de having a higher solubility than cystine However, cysteine derivatives other than penicillamine offer the advantages of higher solubility and different or milder side effects. Accordingly, specific sulfhydryls other than penicilla-mine also have value in the treatment of cystinuria.
The preferred dosage range for treatment of cystinuria with a sulfhydryl from the aforenoted 5 groups is from about 0.5 to 2.0 grams per day. Treatment starts with administration of 0.5 grams/day, the dosage being increased by about 0.25 grams/day at intervals of one week. The increase is continued until there is no further formation of stones or until maximum ~osage of 2.0 g/day is reached, the condition of the patient being monitored radiologically and for cysteine in the urine.
The treatment of cystinuria with sulfhydryl is related to the fact that the rate of dissolution of stones depends upon the solubility nf the mixed dimer. I~ere a combinaticn of sulf-hydryls is administered, then two or more mixed dimers with cysteine will be formed so that the rate of dissolution of the stones will not be limited by the solubility of a single mixed dimer such as the mixed dimer of cysteine with penicillamine.
The sulfhydryl compounds useful in the treatment o~
cystinuria are those listed in the aforenoted five groups. Com-binations of the members of these groups with each other and with penicillamine are also useful. Particularly useful~ due to lo solubility characteristics and structural similarity to cysteine are theo~-meth~l and ~methyl cysteines as illustrated in the following Example.
Example 7 A cystinuria patient is trea~ed with capsules each containing 50 mg ofoC-methyl cysteine and 50 mg of ~ methyl cysteine, a dose of one capsule being administered twice daily.
The extent of remission being minor9 the dosage i5 increased at intervals of 4 weeks by two cap-sules/day to provide further remission, the patient being monitored at the end of each interval for the quantity of cysteine as the mLxed dimer in the urine.
The daily dosage is increased until Q osage of 2 g/day is reached and then increased 1~ 9 by 4 capsules/day at intervals of 4 weeks until a ma~imt~ dosage of 3.0 g/day is reached. The treatment is continued until chemical and radio-logical examination indicate that existing cystine stones are dissolving and no new stones are forming.
The sulfhydryl compo~nds in the aforenoted 5 groups are effective in removing heavy metals, and particularly mercury and lead from those suffering from heavy metal poisoning. Those heavy metal ions having a high association constant with said .
lo sulfhydryls and forming a soluble complex or chelate therewith can be removed from the body by administration of specific sul-hydryls Heavy metals which can be eliminated in this way, in addition to mercury and lead are, for example, cadmium, bismuth, : vanadium and plutoniumO The progress of the treatment is moni-~ored by frequent examination of the urine for the metal in question The procedure is illustrated in the following example Example 8 A patient suffering from acute mercury poisoning is treated with ~ methyl cysteine in tablet form, the patient being given 0.25 g both morning and evening on the first day. The patient is monitored for mercury in the urine and toxic effects. The dosage is increased daily by 0 5g/
da urtil a maximum of 4.0 g/day is reached, t e Il . `
~ 9 patient being monitored daily for mercury in the urine and for the severity of side effects as described in connection with treatment of RA with sulfhydryls.
In the treatment of acute mercury poisoning the dosage is increased rapidly since life is threatened and toxic effects of long-term treatment with the sulfhydryl are of relatively little importance. Also, the treatment with sulfhydryl may be supplemented with hemodialysis since loss of kidney function o within 24 to 36 hours is likely to occur.
Copper sulfhydryl complexes are also effectiYe for the removal of several heavy metals though not of lead. For the cop-per sulfhydryl to be effective in removal of a heavy metal from the body, it is necessary that the heavy metal have an association constant for the sulfhydryl which is great enough to displace copper from the complex. In addition the heavy metal-sulfhydryl compound must be soluble in plasma. Mercuric ion, for instance reacts readily with copper penicillamine to displace the copper therefrom forming a soluble, colorless compound which can be excreted. Similarly, any other heavy metal ion which can displace the copper from the sulfhydryl complex to form a water-soluble product can be removed in the same way.
I It is significant that copper cysteine which stabilizes I the sulfhydryl in the form of a monomer is the safest medication I i for the purpose since it consists of cysteine which is a naturall~
ll .
~ 8 8~ ~
occurring amino acid and copper, a naturally occurring element that is essential to life. Copper penicillamine is also of importance as a therapeutic compound since it it known that the body can tolerate the material in quantities great enough to be effective.
The dosage of the copper sulfhydryl to be used in the treatment of heavy metal poisoning is such as to correspond to a copper content of 2 to 15 mg of copper ranging from the minimal dietary intake of copper per day to about three times the maximal o die~ary intake per day. The daily dose is preferably administered in 2 to 3 portions. The patient is monitored with particular attention to the content of both copper and heavy metal in the urine. The actual dosage will be selected by the clinician on the basis of the patient's tolerance for the copper sulfhydryl combination, which may be a complex or a mixture. The mol ratio of the sulfhydryl ts copper preferably lies 6etween 1 and 5.
A point to be noted is that the molecular weigh~s o the various sulfhydryls under consideration lie fairly close together. AccordLngly, although the dosage in the treatment of RA, cystinuria and heavy metal poisoning may be adjusted in pro-portion to the molecular weight of the compound being adminis tered in general, such adjustment is usually unnecessary, the response of the patient to the medication being the critical factor. However, where the sul~hydryl is trisubstituted, adjust-ment of the dosage in accordance with the molecular weight of he sulihydryl is appropriate. Thus, methyl-cysteine has a 1l, ~1882~9 molecular weight of 135.2 whereas ~-chloro, ~-chloro, ~ hyclroxy-ethyl cysteine has a molecular weight of 234Ø This point is illustrated in the next example.
Example 9 A patient suffering from mercury poison-ing is initially treated with 3 tablets/day of the reaction product of9C-chloro, ~ chloro, ~hydroxyethyl cysteine (I) with copper acetate in 3 divided doses, each tablet containing 23 mg o of copper and 177 mg of I. The total daily dos-age of copper amounts to 69 mg. The mol ratio o~ the sulfhydryl to cuprous ion is 2Ø The . urine is examined daily for copper and mercury.
Since mercury poisoning is a life-threatening condition the dosage is increased each day by 1 tablet/day, monitoring the toler-ance of the patient for the combination until a maximum of lO tablets/day (230 mg of Cu~day) is reached, copper and mercury in the urine being monitored every day and the treatment being continued until the mercury content of the urine becomes negligible.
IfOC-methyl cysteine had been used instead of the tri-substituted cysteine then the comparable quantity ofoC-methyl ~ ~ 8~ ~
cys~eine in the tablet would have been 9.25 mg rather than 16 mg, thus illustrating compensation for the molecular weight of the subs~ituted sulfhydryl.
In general, and especially when more than one dose is to be glven per day, administration as a solid (in capsule or tablet form) is preferred to injection. However, intravenous injection is preferred where it is desired to maintain a high and essentially constant level of medication even at lengthy interval. For this purpose a solution of copper-penicillamine o is particularly suitable because of the high aqueous solubility of the combination.
It will thus been seen that the objects s-et forth abcve among those made apparent from the preceding descrip~ion, are efficiently attained and, since certain changes may be made in carrying out the above method without departing rom the nature and scope of the invention, it is intended that all matter con-tained in the above description shall be interpreted as illustra-tive and not in a limitin g sence.
It is also to be understood that the following claims are intended to cover all of the generic and specific features of the invention herein described, and all statements of the scope of the invention, which, as a matter of language, might be said t~ ~11 therebetween.
11l 3~
Claims (15)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A composition effective in the treatment of rheuma-toid arthritis, comprising at least one sulhydryl compound selected from the group consisting of cysteine, beta-mono-substituted cysteine, the substituent being selected from a first subgroup consisting of chloro, methyl, ethyl, hydroxy-methyl and hydroxyethyl; beta-disubstituted cysteine, the sub-stituents being selected from a second subgroup consisting of the pairs, chloro, chloro, methyl, chloro, ethyl, chloro, methyl, ethyl, ethyl, ethyl, hydroxymethyl, hydroxymethyl, hydroxyethyl, hydroxyethyl, hydroxymethyl, hydroxyethyl, methyl, hydroxymethyl, methyl, hydroxyethyl, ethyl, hydroxymethyl, ethyl, hydroxyethyl, chloro, hydroxymethyl, and chloro, hydroxyethyl, alpha-substituted cysteine, the substituent being selected from a third subgroup identical with said first subgroup;
beta-monosubstituted, alpha-substituted cysteine, the substituents in both positions being selected from a fourth subgroup identical with the members of said first subgroup;
alpha-substituted, beta-disubstituted cysteine, the substituents being selected from a fifth subgroup consisting of the combinations of the members of said first subgroup with the members of said second subgroup; and an N-acetyl derivative of a member of said group of sulfhydryl compounds; and combinations of said compounds.
beta-monosubstituted, alpha-substituted cysteine, the substituents in both positions being selected from a fourth subgroup identical with the members of said first subgroup;
alpha-substituted, beta-disubstituted cysteine, the substituents being selected from a fifth subgroup consisting of the combinations of the members of said first subgroup with the members of said second subgroup; and an N-acetyl derivative of a member of said group of sulfhydryl compounds; and combinations of said compounds.
2. The composition of claim 1, wherein the sulfhydryl compound is in combination with a pharmaceutically acceptable compound of copper, gold and collodial gold.
3. A composition effective in the treatment of rheu-matoid arthritis, comprising at least one sulfhydryl compound selected from the groups consisting of cysteine, beta-mono-substituted cysteine, the substituent being selected from a first subgroup consisting of chloro, methyl, ethyl, hydroxy-methyl and hydroxyethyl; beta-disubstituted cysteine, the sub-stituents being selected from a second subgroup consisting of the pairs, chloro, chloro, methyl, chloro, ethyl, chloro, methyl, ethyl, ethyl, ethyl, hydroxymethyl, hydroxymethyl, hydroxyethyl, hydroxyethyl, hydroxymethyl, hydroxyethyl, methyl, hydroxymethyl, methyl, hydroxyethyl, ethyl, hydroxymethyl, ethyl, hydroxyethyl, chloro, hydroxymethyl, and chloro, hydroxyethyl, alpha-substituted cysteine, the substituent being selected from a third subgroup identical with said first subgroup;
beta-monosubstituted, alpha-substituted cysteine, the substitutents in both positions being selected from a fourth subgroup identical with the members of said first subgroup;
alpha-substituted, beta-disubstituted, cysteine, the substituents being selected from a fifth subgroup consisting of the combinations of the members of said first subgroup with the members of said second subgroup;
an N-acetyl derivative of a member of said group of sulfhydryl compounds; and combinations of said compounds;
in combination with a pharmaceutically acceptable com-pound of copper.
beta-monosubstituted, alpha-substituted cysteine, the substitutents in both positions being selected from a fourth subgroup identical with the members of said first subgroup;
alpha-substituted, beta-disubstituted, cysteine, the substituents being selected from a fifth subgroup consisting of the combinations of the members of said first subgroup with the members of said second subgroup;
an N-acetyl derivative of a member of said group of sulfhydryl compounds; and combinations of said compounds;
in combination with a pharmaceutically acceptable com-pound of copper.
4. A composition as claimed in claim 3, wherein said compound is at least partly complexed with the copper in said copper compound.
5. A composition as claimed in claim 3, wherein said composition is the reaction product of said compound of said group of said compound of copper.
6. A composition as claimed in claim 3, wherein said reaction product is a member of the group consisting of copper-cysteine, copper ? -methylcysteine, copper .beta.-methylcysteine and copper ?, .beta.-dimethylcysteine.
7. A composition effective in the treatment of rheu-matoid arthritis, comprising at least one compound selected from the group consisting of beta-monosubstituted cysteine, the substituent being selected from a first subgroup consisting of chloro, methyl, ethyl, hydroxymethyl and hydroxyethyl;
beta-disubstituted cysteine, the substitutents being selected from a second subgroup consisting of the pairs, chloro, chloro, methyl, chloro, ethyl, chloro, methyl, ethyl, ethyl, ethyl, hydroxymethyl, hydroxymethyl, hydroxyethyl, hydroxyethyl, hydroxymethyl, hydroxyethyl, methyl, hydroxymethyl, methyl, hydroxyethyl, ethyl, hydroxymethyl, ethyl, hydroxyethyl, chloro, hydroxymethyl, and chloro, hydroxyethyl, alpha-substituted cysteine, the substituent being selected from a third subgroup identical with said first subgroup;
beta-monosubstituted, alpha-substituted cysteine, the substituents in both positions being selected from a fourth subgroup identical with the members of said first subgroup;
alpha-substituted, beta-disubstituted cysteine, the substituents being selected from a fifth subgroup consisting of the combinations of the members of said first subgroup with the members of said second subgroup;
an N-acetyl derivative of a member of said group of sulfhydryl compounds; and combinations of said compounds;
and a member of a second group consisting of a pharma-ceutically acceptable compound of gold and colloidal gold.
beta-disubstituted cysteine, the substitutents being selected from a second subgroup consisting of the pairs, chloro, chloro, methyl, chloro, ethyl, chloro, methyl, ethyl, ethyl, ethyl, hydroxymethyl, hydroxymethyl, hydroxyethyl, hydroxyethyl, hydroxymethyl, hydroxyethyl, methyl, hydroxymethyl, methyl, hydroxyethyl, ethyl, hydroxymethyl, ethyl, hydroxyethyl, chloro, hydroxymethyl, and chloro, hydroxyethyl, alpha-substituted cysteine, the substituent being selected from a third subgroup identical with said first subgroup;
beta-monosubstituted, alpha-substituted cysteine, the substituents in both positions being selected from a fourth subgroup identical with the members of said first subgroup;
alpha-substituted, beta-disubstituted cysteine, the substituents being selected from a fifth subgroup consisting of the combinations of the members of said first subgroup with the members of said second subgroup;
an N-acetyl derivative of a member of said group of sulfhydryl compounds; and combinations of said compounds;
and a member of a second group consisting of a pharma-ceutically acceptable compound of gold and colloidal gold.
8. A composition as claimed in claim 7, wherein said compound is at least partly complexed with gold in said gold compound.
9. A composition as claimed in claim 8, wherein said composition is the reaction product of said compound of said group and said compound of gold.
10. A composition as claimed in claim 9, wherein said reaction product is a member of the group consisting of gold cysteine, gold ? -methylcysteine and gold ?, .beta. -dimethyl-cysteine.
11. A composition effective in the treatment of rheuma-toid arthritis comprising gold in combination with penicil-lamine.
12. A composition for the treatment of rheumatoid arthritis comprising a pharmaceutically acceptable carrier and a rheumatoid arthritis treatment effective amount of a complex of penicillamine of N-acetyl penicillamine with gold or copper.
13. A composition for the treatment of rheumatoid arthritis, comprising a pharmaceutically acceptable carrier and a rheumatoid arthritis treatment effective amount of a mixture of penicillamine or N-acetyl penicillamine with a non-toxic water soluble salt of copper, wherein the ratio of penicillamine and N-acetyl penicillamine to copper is between about 1.3-5:1.
14. A composition according to claim 12, wherein the complex is of penicillamine or N-acetyl penicillamine with copper.
15. A composition according to claim 12, wherein the complex is of penicillamine or N-acetyl penicillamine with a non-toxic water soluble salt of gold.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000395752A CA1188219A (en) | 1982-02-08 | 1982-02-08 | Method of treatment of rheumatoid arthritis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000395752A CA1188219A (en) | 1982-02-08 | 1982-02-08 | Method of treatment of rheumatoid arthritis |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1188219A true CA1188219A (en) | 1985-06-04 |
Family
ID=4121998
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000395752A Expired CA1188219A (en) | 1982-02-08 | 1982-02-08 | Method of treatment of rheumatoid arthritis |
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| Country | Link |
|---|---|
| CA (1) | CA1188219A (en) |
-
1982
- 1982-02-08 CA CA000395752A patent/CA1188219A/en not_active Expired
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