CA1211375A - Azauridine pyridoxine composition - Google Patents
Azauridine pyridoxine compositionInfo
- Publication number
- CA1211375A CA1211375A CA000426311A CA426311A CA1211375A CA 1211375 A CA1211375 A CA 1211375A CA 000426311 A CA000426311 A CA 000426311A CA 426311 A CA426311 A CA 426311A CA 1211375 A CA1211375 A CA 1211375A
- Authority
- CA
- Canada
- Prior art keywords
- azauridine
- pyridoxine
- compound
- phosphate
- mole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Abstract
ABSTRACT OF THE DISCLOSURE
A chemical system is disclosed for the treatment of diseases responsive to azauridine compounds. The chemical system comprises the chemical combination of an azauridine compound selected from the group of azauridine and esters of azauridine and a pyridoxine compound provided in an amount of at least about 0.0005 mole, preferably at least about 0.001 mole, and more preferably at least about 0.025 mole of pyridoxine compound per mole of azauridine compound admi-nistered. Pyridoxine compounds include pyridoxine, pyri-doxal phosphate, pyridoxamine, pyridoxamine phosphate, pyridoxal and pyridoxine phosphate.
A chemical system is disclosed for the treatment of diseases responsive to azauridine compounds. The chemical system comprises the chemical combination of an azauridine compound selected from the group of azauridine and esters of azauridine and a pyridoxine compound provided in an amount of at least about 0.0005 mole, preferably at least about 0.001 mole, and more preferably at least about 0.025 mole of pyridoxine compound per mole of azauridine compound admi-nistered. Pyridoxine compounds include pyridoxine, pyri-doxal phosphate, pyridoxamine, pyridoxamine phosphate, pyridoxal and pyridoxine phosphate.
Description
37~
This invention relates to a chemical system f~r the treatment of diseases responsive to the administration of a azauridine compound.
6-Azauridine and 6-Azauridine triacetate, (i.e. 2',3', 5'-triacetate-6-azauridine) commonly termed azaribine, have been established as active in the treatment of psoriasis, mycosis fungoides, polycy~_emia vera and trophoblastic malignancies. Azaribine have been withdrawn from the market because of the occurrence of thromboembolic episodes re-ported in patients with severe psoriasis treated with thisdrug.
Azaribine is deacetylated metabolically, eithex during or after its absorption from the intestine to form free azauridine. Some o the free azauridine formed undergoes intercellular phosphorylation to yield 6-azauridine 5'-monophosphate, which ~unctions as an inhibitor of orotidine-5'-monophosphate ~OMP) decarboxylase, the rate-limiting ~nzyme in the de novo biosynthesis of uridine 5'-monophos-phate (UMP).
Another biochemical ef~ect is an intPrference with the metabolism of certain amino acids which result in biochemi-cal changes resembling thos~ observed in inborn hyper-~
-alaninemia, homocystinemia `and hyperhistidinemia. The mechanism postulated has been inhibition of pyridoxal phos~
phate-dependant enzymes. The correlation or the correction has heretofore not been established~
:~Z~3~5 The invention provides a chemical system for the treat-ment, in mammals, of diseases such as psoriasis, mycosis fungo.ides, polycythemia vera and trophoblastic malignancies.
The chemical system comprises administra~ion of an azauridine compound selected from azauridine and esters of azauridine which can be cleaved by the mammal to release free azauridine, such as mono-, di-, and triesters, in- r cluding the acetates, stearates, palmitates, propionates, phosphates and the like. The chemical system further com-prises a pyridoxine compound selected from the group con-sisting o pyridoxine, pyr.idoxal phosphate, pyridoxamine, pyridoxamine phosphate/ pyridoxal, pyridoxine phosphate and mix~ures thereof, provided in a mole ratio of the pyridoxine compound to the azauridine compound of at least about 1:2000, preferably at least about 1:1000, and more preferably at least about 1:40. Lower ratios may be used.
A method for treating mammals for such a disease com-prises administration of the chemical system to the mammal in a dosage sufficient to treat the disease~ The chemical system effectively-prevents the formation of side-effects attributed to the azauridine compound.
There is further provided a method for the prevention or xeduction of detrimental side effects caused by low serum pyridoxal phosphate levels cxeated by administration of azauridine or an azauridine ester to mammals. The method comprises the additional administration of a pyridoxine compound selected from pyridoxine, pyridoxal phosphate, pyridoxamine, pyridoxamine phosphate, pyridoxal, pyr.idoxine phosphate and mixture thereof in an amount sufficient to 3~ supply at least about 0.0005 mole, preferably at least about 0.001 mole and more preferably at least about 0.025 mole of the pyridoxine compound per mole of the administered azau-ridine compound. The pyridoxine compound is preferably administered within twenty-four hours of the administration of the azauridine compound and may be adm.inistered in a combined form with the azauridine compound or independently.
~2~1L3~
In ac~ordance with the present invention, there is provided a chemical system useful in treating mar~als with azauridine-treatable diseases, i.e., diseases 5 responsive to the administration of an azauridine compound.
Aæauridine treatable diseases which may be mentioned include psoriasis, mycosis fungoides, polycythemia vera and trophoblastic malignancies.
The chemical system comprises at least one azauridine compound selected from the group of azauridine and esters of azauridine in comb;nation with a pyridoxine compound selected from the group consisting of pyridoxine, pyridoxal phosphate, pyridoxamine r pyridoxamine phosphate, pyridoxal, pyridoxine phosphate, and mixtures thereof. The presently preferred azauridine compound is azaribine. The presently preferred pyridoxine compound is pyridoxine.
As used herein, ~'azauridine" means 6~azauridine;
"esters of azauridine" means those esters of azauridine that may be cleaved by the mammal in vivo to provide zo circulating free azauridine; and "azar`ibinel' means 6-azauridine triacetate, or 2',3',5'-triacetyl-6-azauridine.
The amourlt of the pyridoxine compound is sufficient to prevent significant reduct;on in serum pyridoxal phosphate levels due to administration of the azauridine compound and is sufficient to provide at least about 0.0005 mole, preferably at least about Q.001 mole, and more preferably at least about 0.025 mole of the pyridoxine compound per mole of the azauridine compound in the chemical system The preferred mole ratio of the pyridoxine compound to the azauridine compound is at least about 1:2000, preferably at least about l:lOQ0, and more preferably at least abo~t 1:40.
~Z~L3~
1 Treatment of azauridine-treatable disease in mammals comprises the administration of the chemical system in an amount sufficient to effect a reduction of or prevention of the disease, namely it reduces or prevents the e~fects or symptoms of said disease and/or reduces or prevents the growth or spread of the disease-causing agent.
Chemical systems comprising free azauridine and a pyridoxine compound are only administered parenterally.
If administered orally, intestinal bacteria partially metabolize azauridine into 6-azauracil which is toxic.
~hemical systems comprising an ~ster of azauridine, such as azaribine, and a pyridoxine compound may be administered orally. The esters of azauridine are cleaved in vivo to generate circulating free azauridine. For example, azaribine is deacetylated as it passes through the intestinal wall to form the active, free azauridine.
When the chemical system is administered parenterally, e.g. intravenous injection, it is in a liquid form~ e.~.
a saline solution. In addition to azauridine and the pyridoxine compound, the liquid may contain other compatible compounds such as identifying or coloring compounds and the like.
When administered orally, the chemical system comprising an ester of azaur~dlne and a pyridoxine compound may be in the orm of a pill or capsule, a powder, or a liquid. Suitable compatible compounds~ such as coloring compounds and the like may be included.
To be effective in the treatment of such diseases, azauridine compounds are administered in a quantity sufficient to provide from about 1 gram to about 10 grams, and preferably about 3 grams~ of free azauridine per square meter of body surface area per day, generally in two or more equal doses. For example, azaribine would ~2~7S
1 be administered in a dosage of about 1~5 grams to about 15 grams per square meter of body surface area per day.
The chemical system provides a means for preventing or reducing detrimental side effects created by administration of azauridine compounds to mammals~ It has now been found that administered azauridine compounds causes, in mammalsj a significant decrease in the levels of pyridoxal phosphate in the serum as early as five hours a~ter the initiation of dosage. Hypera~ino aciduria induced by azauridine compounds has now been attributed to depletion of otherwise available pyridoxal phosphate coenzyme.
The mechanism by which azauridine compounds interfere with pyridoxal phosphate is not understood. While not ~eing bound by theory, it is believed that catabolites of the azauridine compound may be responsible for this effect. Since most of the drug and its metabolites are excreted in the urine within six hours after administration, the initial dramatic decrease in the levels of pyridoxal phosphate in the serum possibly could be explained by its binding to a rapidly-formed metabolite.
It has now been found that reduction or prevention of detrimental side effects c\aused by low serum pyrîdoxal phosphate levels created by the administration of azauridine compounds to mammals, can be achieved by the administration o a pyridoxine ~ompound selected rom the group consisting of pyridoxine, pyridoxal phosphate, pyridoxamine, pyridoxamine phosphate pyridoxal, pyridoxine phosphate and mixture thereof in an amount to provide at least about 0.0005 mole, preferably at least about 0.001 mole, and preferably at least about 00025 mole per mole of the administered azauridine compoundO
1 There is no specific upper limit to the amount of pyridoxine compound that may be administered. This is because an excess of pyridoxine compounds does not detrimentally affect mammals. However, the amount of pyridoxine compound that is administered typically need not exceed about O.S moles for every mole of azauridine compound adrninistered. This amount provides an excess of pyridoxine compound needed to replenish the amount of pyridoxal phosphate typically depleted by the 1~ administration of an azauridine compound. In fact, in most applications, the amount of pyridoxine compound that is administered need not exceed about G.25 mole per mole of administered azauridine compound.
For examplel administration of azaribine in an amount 1~ of about 5 grams per square meter of body surface-area per day would typically require the administration of from about 0.5 mg to about 500 mg, prefera~ly from about 1 mg to about 250 mg, and more preferably from about 25 mg to about 250 mg of pyridoxine per day. If pyridoxal phosphate were administered rather than pyridoxine, from about 0.75 mg to about 750 mg, preferably from about 1.5 mg to about 375 mg and more preferably from about 38 mg to ahout 375 mg of the pyridoxal phosphate wo~uld be administered daily.
Administration of the pyridoxine compound may precede,
This invention relates to a chemical system f~r the treatment of diseases responsive to the administration of a azauridine compound.
6-Azauridine and 6-Azauridine triacetate, (i.e. 2',3', 5'-triacetate-6-azauridine) commonly termed azaribine, have been established as active in the treatment of psoriasis, mycosis fungoides, polycy~_emia vera and trophoblastic malignancies. Azaribine have been withdrawn from the market because of the occurrence of thromboembolic episodes re-ported in patients with severe psoriasis treated with thisdrug.
Azaribine is deacetylated metabolically, eithex during or after its absorption from the intestine to form free azauridine. Some o the free azauridine formed undergoes intercellular phosphorylation to yield 6-azauridine 5'-monophosphate, which ~unctions as an inhibitor of orotidine-5'-monophosphate ~OMP) decarboxylase, the rate-limiting ~nzyme in the de novo biosynthesis of uridine 5'-monophos-phate (UMP).
Another biochemical ef~ect is an intPrference with the metabolism of certain amino acids which result in biochemi-cal changes resembling thos~ observed in inborn hyper-~
-alaninemia, homocystinemia `and hyperhistidinemia. The mechanism postulated has been inhibition of pyridoxal phos~
phate-dependant enzymes. The correlation or the correction has heretofore not been established~
:~Z~3~5 The invention provides a chemical system for the treat-ment, in mammals, of diseases such as psoriasis, mycosis fungo.ides, polycythemia vera and trophoblastic malignancies.
The chemical system comprises administra~ion of an azauridine compound selected from azauridine and esters of azauridine which can be cleaved by the mammal to release free azauridine, such as mono-, di-, and triesters, in- r cluding the acetates, stearates, palmitates, propionates, phosphates and the like. The chemical system further com-prises a pyridoxine compound selected from the group con-sisting o pyridoxine, pyr.idoxal phosphate, pyridoxamine, pyridoxamine phosphate/ pyridoxal, pyridoxine phosphate and mix~ures thereof, provided in a mole ratio of the pyridoxine compound to the azauridine compound of at least about 1:2000, preferably at least about 1:1000, and more preferably at least about 1:40. Lower ratios may be used.
A method for treating mammals for such a disease com-prises administration of the chemical system to the mammal in a dosage sufficient to treat the disease~ The chemical system effectively-prevents the formation of side-effects attributed to the azauridine compound.
There is further provided a method for the prevention or xeduction of detrimental side effects caused by low serum pyridoxal phosphate levels cxeated by administration of azauridine or an azauridine ester to mammals. The method comprises the additional administration of a pyridoxine compound selected from pyridoxine, pyridoxal phosphate, pyridoxamine, pyridoxamine phosphate, pyridoxal, pyr.idoxine phosphate and mixture thereof in an amount sufficient to 3~ supply at least about 0.0005 mole, preferably at least about 0.001 mole and more preferably at least about 0.025 mole of the pyridoxine compound per mole of the administered azau-ridine compound. The pyridoxine compound is preferably administered within twenty-four hours of the administration of the azauridine compound and may be adm.inistered in a combined form with the azauridine compound or independently.
~2~1L3~
In ac~ordance with the present invention, there is provided a chemical system useful in treating mar~als with azauridine-treatable diseases, i.e., diseases 5 responsive to the administration of an azauridine compound.
Aæauridine treatable diseases which may be mentioned include psoriasis, mycosis fungoides, polycythemia vera and trophoblastic malignancies.
The chemical system comprises at least one azauridine compound selected from the group of azauridine and esters of azauridine in comb;nation with a pyridoxine compound selected from the group consisting of pyridoxine, pyridoxal phosphate, pyridoxamine r pyridoxamine phosphate, pyridoxal, pyridoxine phosphate, and mixtures thereof. The presently preferred azauridine compound is azaribine. The presently preferred pyridoxine compound is pyridoxine.
As used herein, ~'azauridine" means 6~azauridine;
"esters of azauridine" means those esters of azauridine that may be cleaved by the mammal in vivo to provide zo circulating free azauridine; and "azar`ibinel' means 6-azauridine triacetate, or 2',3',5'-triacetyl-6-azauridine.
The amourlt of the pyridoxine compound is sufficient to prevent significant reduct;on in serum pyridoxal phosphate levels due to administration of the azauridine compound and is sufficient to provide at least about 0.0005 mole, preferably at least about Q.001 mole, and more preferably at least about 0.025 mole of the pyridoxine compound per mole of the azauridine compound in the chemical system The preferred mole ratio of the pyridoxine compound to the azauridine compound is at least about 1:2000, preferably at least about l:lOQ0, and more preferably at least abo~t 1:40.
~Z~L3~
1 Treatment of azauridine-treatable disease in mammals comprises the administration of the chemical system in an amount sufficient to effect a reduction of or prevention of the disease, namely it reduces or prevents the e~fects or symptoms of said disease and/or reduces or prevents the growth or spread of the disease-causing agent.
Chemical systems comprising free azauridine and a pyridoxine compound are only administered parenterally.
If administered orally, intestinal bacteria partially metabolize azauridine into 6-azauracil which is toxic.
~hemical systems comprising an ~ster of azauridine, such as azaribine, and a pyridoxine compound may be administered orally. The esters of azauridine are cleaved in vivo to generate circulating free azauridine. For example, azaribine is deacetylated as it passes through the intestinal wall to form the active, free azauridine.
When the chemical system is administered parenterally, e.g. intravenous injection, it is in a liquid form~ e.~.
a saline solution. In addition to azauridine and the pyridoxine compound, the liquid may contain other compatible compounds such as identifying or coloring compounds and the like.
When administered orally, the chemical system comprising an ester of azaur~dlne and a pyridoxine compound may be in the orm of a pill or capsule, a powder, or a liquid. Suitable compatible compounds~ such as coloring compounds and the like may be included.
To be effective in the treatment of such diseases, azauridine compounds are administered in a quantity sufficient to provide from about 1 gram to about 10 grams, and preferably about 3 grams~ of free azauridine per square meter of body surface area per day, generally in two or more equal doses. For example, azaribine would ~2~7S
1 be administered in a dosage of about 1~5 grams to about 15 grams per square meter of body surface area per day.
The chemical system provides a means for preventing or reducing detrimental side effects created by administration of azauridine compounds to mammals~ It has now been found that administered azauridine compounds causes, in mammalsj a significant decrease in the levels of pyridoxal phosphate in the serum as early as five hours a~ter the initiation of dosage. Hypera~ino aciduria induced by azauridine compounds has now been attributed to depletion of otherwise available pyridoxal phosphate coenzyme.
The mechanism by which azauridine compounds interfere with pyridoxal phosphate is not understood. While not ~eing bound by theory, it is believed that catabolites of the azauridine compound may be responsible for this effect. Since most of the drug and its metabolites are excreted in the urine within six hours after administration, the initial dramatic decrease in the levels of pyridoxal phosphate in the serum possibly could be explained by its binding to a rapidly-formed metabolite.
It has now been found that reduction or prevention of detrimental side effects c\aused by low serum pyrîdoxal phosphate levels created by the administration of azauridine compounds to mammals, can be achieved by the administration o a pyridoxine ~ompound selected rom the group consisting of pyridoxine, pyridoxal phosphate, pyridoxamine, pyridoxamine phosphate pyridoxal, pyridoxine phosphate and mixture thereof in an amount to provide at least about 0.0005 mole, preferably at least about 0.001 mole, and preferably at least about 00025 mole per mole of the administered azauridine compoundO
1 There is no specific upper limit to the amount of pyridoxine compound that may be administered. This is because an excess of pyridoxine compounds does not detrimentally affect mammals. However, the amount of pyridoxine compound that is administered typically need not exceed about O.S moles for every mole of azauridine compound adrninistered. This amount provides an excess of pyridoxine compound needed to replenish the amount of pyridoxal phosphate typically depleted by the 1~ administration of an azauridine compound. In fact, in most applications, the amount of pyridoxine compound that is administered need not exceed about G.25 mole per mole of administered azauridine compound.
For examplel administration of azaribine in an amount 1~ of about 5 grams per square meter of body surface-area per day would typically require the administration of from about 0.5 mg to about 500 mg, prefera~ly from about 1 mg to about 250 mg, and more preferably from about 25 mg to about 250 mg of pyridoxine per day. If pyridoxal phosphate were administered rather than pyridoxine, from about 0.75 mg to about 750 mg, preferably from about 1.5 mg to about 375 mg and more preferably from about 38 mg to ahout 375 mg of the pyridoxal phosphate wo~uld be administered daily.
Administration of the pyridoxine compound may precede,
2~ be simultaneous with, or follow the administration of the azauridine compound. Administration of the pyridoxine compound within twenty-four hours of the administration of the azauridine compound will eliminate the side-effect which caused removal from the market of the azauridine compounds as a useful medicine. The pyridoxine compound may be administered in combination with the azauridine compound or independently from the azauridine compound.
Administration in combination, as for instance by a blended mixture in liquid or solid form, is preferred to
Administration in combination, as for instance by a blended mixture in liquid or solid form, is preferred to
3~
37~i 1 prevent a patient from forgetting to take the pyridoxine compound. Thus it ensures against the azauridine compound causing a deleteriously effect. "
; This invention has a striking advantage in that azauridine compounds, which have been proven useful in the treatment of certain diseases, can now be administered without a resulting reduction in the serum pyridoxal phosphate levels which results in detrimental side-effects.
lo Example 1 Six male New Zealand albino rabbits weighing from 1.9 kg to 2.6 kg were accommodated in an animal facility for two weeks. Each rabbit was housed separately in a metal cage and was kept on a standard diet of Wayne's Rabbit Ration manufactured by Allied Millst Inc. of Chicago, Illinois. Rabbits were used as experimental animals because they have been found to be predictive for the changes in the levels of amino acids caused by azauridine compounds in man.
Azaribine was administered for three days by gastric gavage in two doses daily. The doses totaled ~ gram per kilogram`body weight per day ~about lG grams per square meter of body surface area per-day), of which the first half was given six hours prior to the second half.
~lood samples were taken before treatment and six hours after the administration of each first daily portion of the azaribine on the first, second and third days. The animals were fasted for at least six hours before each blood sample was drawn. Serum samples were analyzed for pyridoxal phosphate by enzymic assay.
The average serum pyridoxal phospXate levels are tabulated in Table 1~ The student paired T-test was used for ~he statistical analysis of the changes in the concentration of pyridoxal phosphate in the serum after 3~i 1 the oral administration of azaribine, in comparison to the pretreatment values.
As established, azaribine caused a significant decrease in the levels of pyridoxal phosphate in the serum; a sharp diminution in the level of the coenzyme occurred within six hours after oral administration of the first dosage of azaribine (0.5g/kg). The levels of pyridoxal phosphate in the serum dropped from an average treatment value of 52.7 ng/ml to an average value of 31.22 ng/ml six hours after administration and continued to decline as shown in Tahle 1.
Example 2 The procedure of Example 1 was repeated to confirm the results. The average results are also shown in Table 1. The average pretreatment serum pyridoxal phosphate level was 55.0 ng/ml ! and a~ain decreased significantly as shown.
Table 1 Average Pyridoxal Phosphate Levels ~ng/ml) Pre- . .
treat-6 ~ 30 54 78 menthours ~ hours hcurs hours Example 152.7031.22 15.70 12.08 13.48 +7O55~3.85 +2.76 -~ 1 +1.49 Example 255.0040.70 17.70 15.10 - .
+7.50+14.20 ~4.0~ ~1.30 - . .
(5 hr) -- ~
1 Example 3 Two groups of six rabbits were compared. The first group was a treated group. Each animal was given two equal doses of azaribine totalling 1.0 gram per kilogram ' of body weight per day. The second group was a control group. These animals were administered water in the same volume as the azaribine ~hat was administered to the first group. Conditions were otherwise as described in Example 1. Blood samples were takPn from each animal and analyzed for pyridoxal phosphateO
The average serum pyridoxal phosphate levels before treatment and on the fourth and fifth days of the treatment are tabulated in Table 2~ As can be seen, the serum pyridoxal phosphate levels significantly decreased for the treated group, and no significant change occurred in the control group.
Table 2 Average Pyridoxal Phosphate Levels (ng/ml) Pre-treat-Fourth Day Fifth Day ment .
Group 1 (Azaribine 44.41 22.30 14.39 treated) +8.29 ~3.00 +6.48 Group 2 57.33 43.33 51.97 (~ontrols) ~ +15.62 +12.02 +9~32 _g_ LJ~
1 Example ~
Three groups of six rabbits were compared. To Group 1 (control group) water was administered. To Group 2, 1.0 gram per kilogram of body weight per day of azaribine was administered. To Group 3, 1.0 gram per kilogram of body weight per day of azaribine plus 50 milligrams per kilogram of body weight per day of pyridoxine was administered. Conditions were otherwise as described in Example 1. Blood samples were taken from each animal and analyzed for pyridoxal phosphate~
The average serum pyridoxal phosphate levels before treatment and on the fourth and fifth days of treatment for each group are tabulated in Table 3. As can be seen, serum pyridoxal phosphate levels again significantly 1~ decreased for the azaribine treated animals (Group 2).
The control gro~p ~Group 1) again showed no significant decrease in serum pyridoxal phosphate levels.
Group 3, the azaribine and pyridoxine treated animals, displayed no significant decrease in serum pyridoxal phosphate levels, Serum homocystine levels were also measured as an indication of homocystinemia. In the control group, no homocystine was found in the pretreatment samples or during the treatment. Homocystine levels ranging from 5 nmol/ml to 112 nmol/ml were found in the azaribine treated rabbits (Group 2). No serum homocystine was detected in any of the azaribine and pyridoxine treated rabbits.
.; .
- -lQ-~2 1 Table 3 Average Pyridoxal Phosphate Levels (n~/ml) Pre-treat- r ment _ Fourth Day Fifth Day Group ]57~60 54.43 56.31 ~Controls)_13.86~8.90 +13 7 03 Group 277.72 29.32 7~36 (Azaribine) _17.20 ~15.45 -~6~24 Group 356.80 72.49 56.00 ~Azaribine & +7.7~ +10.08 +12.12 Pyridoxine~
Example 5 A screening test was conducted to establish the effect of varying doses of pyridoxine. Four rabbits were each given identical amounts of azaribine, i.e., 1.0 gram per kilogram of body weight, per day, given in two equal doses.
They were respectively given dosages of pyr;doxine to levels of 0.1, 0.5, 1 and 5 milligrams per kilogram of body weight per day.
Over the period of test, no rabbit developed homo-cystinemia or a reduction in serum pyridoxal phosphate levels.
While described is the presently most readily assimulatable compounds, "azauridine compound" as used herein and in the claims is intended to cover any analog which gives rise to circulating azauridine.
.
37~i 1 prevent a patient from forgetting to take the pyridoxine compound. Thus it ensures against the azauridine compound causing a deleteriously effect. "
; This invention has a striking advantage in that azauridine compounds, which have been proven useful in the treatment of certain diseases, can now be administered without a resulting reduction in the serum pyridoxal phosphate levels which results in detrimental side-effects.
lo Example 1 Six male New Zealand albino rabbits weighing from 1.9 kg to 2.6 kg were accommodated in an animal facility for two weeks. Each rabbit was housed separately in a metal cage and was kept on a standard diet of Wayne's Rabbit Ration manufactured by Allied Millst Inc. of Chicago, Illinois. Rabbits were used as experimental animals because they have been found to be predictive for the changes in the levels of amino acids caused by azauridine compounds in man.
Azaribine was administered for three days by gastric gavage in two doses daily. The doses totaled ~ gram per kilogram`body weight per day ~about lG grams per square meter of body surface area per-day), of which the first half was given six hours prior to the second half.
~lood samples were taken before treatment and six hours after the administration of each first daily portion of the azaribine on the first, second and third days. The animals were fasted for at least six hours before each blood sample was drawn. Serum samples were analyzed for pyridoxal phosphate by enzymic assay.
The average serum pyridoxal phospXate levels are tabulated in Table 1~ The student paired T-test was used for ~he statistical analysis of the changes in the concentration of pyridoxal phosphate in the serum after 3~i 1 the oral administration of azaribine, in comparison to the pretreatment values.
As established, azaribine caused a significant decrease in the levels of pyridoxal phosphate in the serum; a sharp diminution in the level of the coenzyme occurred within six hours after oral administration of the first dosage of azaribine (0.5g/kg). The levels of pyridoxal phosphate in the serum dropped from an average treatment value of 52.7 ng/ml to an average value of 31.22 ng/ml six hours after administration and continued to decline as shown in Tahle 1.
Example 2 The procedure of Example 1 was repeated to confirm the results. The average results are also shown in Table 1. The average pretreatment serum pyridoxal phosphate level was 55.0 ng/ml ! and a~ain decreased significantly as shown.
Table 1 Average Pyridoxal Phosphate Levels ~ng/ml) Pre- . .
treat-6 ~ 30 54 78 menthours ~ hours hcurs hours Example 152.7031.22 15.70 12.08 13.48 +7O55~3.85 +2.76 -~ 1 +1.49 Example 255.0040.70 17.70 15.10 - .
+7.50+14.20 ~4.0~ ~1.30 - . .
(5 hr) -- ~
1 Example 3 Two groups of six rabbits were compared. The first group was a treated group. Each animal was given two equal doses of azaribine totalling 1.0 gram per kilogram ' of body weight per day. The second group was a control group. These animals were administered water in the same volume as the azaribine ~hat was administered to the first group. Conditions were otherwise as described in Example 1. Blood samples were takPn from each animal and analyzed for pyridoxal phosphateO
The average serum pyridoxal phosphate levels before treatment and on the fourth and fifth days of the treatment are tabulated in Table 2~ As can be seen, the serum pyridoxal phosphate levels significantly decreased for the treated group, and no significant change occurred in the control group.
Table 2 Average Pyridoxal Phosphate Levels (ng/ml) Pre-treat-Fourth Day Fifth Day ment .
Group 1 (Azaribine 44.41 22.30 14.39 treated) +8.29 ~3.00 +6.48 Group 2 57.33 43.33 51.97 (~ontrols) ~ +15.62 +12.02 +9~32 _g_ LJ~
1 Example ~
Three groups of six rabbits were compared. To Group 1 (control group) water was administered. To Group 2, 1.0 gram per kilogram of body weight per day of azaribine was administered. To Group 3, 1.0 gram per kilogram of body weight per day of azaribine plus 50 milligrams per kilogram of body weight per day of pyridoxine was administered. Conditions were otherwise as described in Example 1. Blood samples were taken from each animal and analyzed for pyridoxal phosphate~
The average serum pyridoxal phosphate levels before treatment and on the fourth and fifth days of treatment for each group are tabulated in Table 3. As can be seen, serum pyridoxal phosphate levels again significantly 1~ decreased for the azaribine treated animals (Group 2).
The control gro~p ~Group 1) again showed no significant decrease in serum pyridoxal phosphate levels.
Group 3, the azaribine and pyridoxine treated animals, displayed no significant decrease in serum pyridoxal phosphate levels, Serum homocystine levels were also measured as an indication of homocystinemia. In the control group, no homocystine was found in the pretreatment samples or during the treatment. Homocystine levels ranging from 5 nmol/ml to 112 nmol/ml were found in the azaribine treated rabbits (Group 2). No serum homocystine was detected in any of the azaribine and pyridoxine treated rabbits.
.; .
- -lQ-~2 1 Table 3 Average Pyridoxal Phosphate Levels (n~/ml) Pre-treat- r ment _ Fourth Day Fifth Day Group ]57~60 54.43 56.31 ~Controls)_13.86~8.90 +13 7 03 Group 277.72 29.32 7~36 (Azaribine) _17.20 ~15.45 -~6~24 Group 356.80 72.49 56.00 ~Azaribine & +7.7~ +10.08 +12.12 Pyridoxine~
Example 5 A screening test was conducted to establish the effect of varying doses of pyridoxine. Four rabbits were each given identical amounts of azaribine, i.e., 1.0 gram per kilogram of body weight, per day, given in two equal doses.
They were respectively given dosages of pyr;doxine to levels of 0.1, 0.5, 1 and 5 milligrams per kilogram of body weight per day.
Over the period of test, no rabbit developed homo-cystinemia or a reduction in serum pyridoxal phosphate levels.
While described is the presently most readily assimulatable compounds, "azauridine compound" as used herein and in the claims is intended to cover any analog which gives rise to circulating azauridine.
.
Claims (3)
1. A chemical system for the treatment of diseases responsive to the administration of an azauridine compound in mammals, comprising an azauridine compound in combination with a pyridoxine compound selected from the group consisting of pyridoxine, pyridoxal, phosphate, pyri-doxamine, pyridoxamine phosphate, pyridoxal pyridoxine phosphate and mixtures thereof provided in a mole ratio of the pyridoxine compound to the azauridine compound of at least about 1:2000.
2. A chemical system as claimed in claim 1 wherein the mole ratio of the pyridoxine compound to the azauridine compound is at least about 1:1000.
3. A chemical system as claimed in claim 1 wherein the mole ratio of the pyridoxine compound to the azauridine compound is at least about 1:40.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US37074882A | 1982-04-22 | 1982-04-22 | |
| US370,748 | 1982-04-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1211375A true CA1211375A (en) | 1986-09-16 |
Family
ID=23460995
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000426311A Expired CA1211375A (en) | 1982-04-22 | 1983-04-20 | Azauridine pyridoxine composition |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1211375A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0495270A1 (en) * | 1987-09-23 | 1992-07-22 | William Dr. Drell | Azaribine composition |
| EP0552057A1 (en) * | 1992-01-17 | 1993-07-21 | Ur Labs, Inc. | Azauridine compounds in the treatment of rheumatoid arthritis |
-
1983
- 1983-04-20 CA CA000426311A patent/CA1211375A/en not_active Expired
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0495270A1 (en) * | 1987-09-23 | 1992-07-22 | William Dr. Drell | Azaribine composition |
| EP0552057A1 (en) * | 1992-01-17 | 1993-07-21 | Ur Labs, Inc. | Azauridine compounds in the treatment of rheumatoid arthritis |
| AU661364B2 (en) * | 1992-01-17 | 1995-07-20 | Ur Labs, Inc. | Method for administration of azauridine for the treatment of rheumatoid arthritis |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0675714B1 (en) | COMBINATION OF A CHOLESTEROL BIOSYNTHESIS INHIBITOR AND A $g(b)-LACTAM CHOLESTEROL ABSORPTION INHIBITOR | |
| Kutt et al. | Insufficient parahydroxylation as a cause of diphenylhydantoin toxicity | |
| US5626883A (en) | Ascorbic acid compositions providing enhanced human immune system activity | |
| US4815446A (en) | Process for treating metastasis of cancerous tumors | |
| EP0697862B1 (en) | Pharmaceutical compositions and methods using isobutyramide for treating betaglobin disorders | |
| EP0252227A2 (en) | Use of inositol triphosphate in the treatment of metal intoxication | |
| Bliznakov | Effect of stimulation of the host defense system by coenzyme Q10 on dibenzpyrene-induced tumors and infection with Friend leukemia virus in mice | |
| Lipschitz et al. | Some factors affecting the release of iron from reticuloendothelial cells | |
| EP0699440B1 (en) | Use of a ascorbyl tocopheryl phosphate for the manufacture of a medicament for the treatment of pancreatitis | |
| GB2223404A (en) | The treatment of abnormal levels of lipoproteins. | |
| US4778788A (en) | Agent against multiple sclerosis | |
| US5645852A (en) | Butyric ester cyto-differtiating agents | |
| CA1211375A (en) | Azauridine pyridoxine composition | |
| US6071888A (en) | Composition for treating cancer | |
| EP0488928B1 (en) | Pharmaceutical formulations containing a mixture of higher primary aliphatic alcohols in the treatment of hypercholesterolaemia and hyperlypoproteinaemia type II and stimulation of sexual behavior in animals and humans | |
| US4355027A (en) | Process and composition for treating disorders by administering piracetam and choline | |
| RICHTER et al. | Calcium appetite of parathyroidectomized rats used to bioassay substances which affect blood calcium | |
| Heinonen et al. | Plasma lidocaine levels in patients treated with potential inducers of microsomal enzymes | |
| US4626527A (en) | Process for utilizing choline to sustain muscular performance | |
| US4558050A (en) | Treatment of metabolic disorders with dichloroacetate-thiamine preparations | |
| US5447712A (en) | Method of reducing cyclophosphamide induced hemorrhagic cystitis | |
| Erf et al. | Retention of orally administered radio-phosphorus by mice. | |
| US3803319A (en) | Treating hyperlipemia with isatin | |
| US3809761A (en) | Method for reducing plasma lipid levels | |
| Simon et al. | Administration of obidoxime tablets to man: plasma levels and side reactions |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |