WO2003006032A1 - Pharmaceutical preparations for treatment or prophylaxis of arthritis urica - Google Patents
Pharmaceutical preparations for treatment or prophylaxis of arthritis urica Download PDFInfo
- Publication number
- WO2003006032A1 WO2003006032A1 PCT/DK2002/000464 DK0200464W WO03006032A1 WO 2003006032 A1 WO2003006032 A1 WO 2003006032A1 DK 0200464 W DK0200464 W DK 0200464W WO 03006032 A1 WO03006032 A1 WO 03006032A1
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- molybdenum
- treatment
- prophylaxis
- arthritis urica
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/28—Mercury; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
Definitions
- the present invention is related to treatment and prophylaxis of arthritis urica in mammals, including human beings .
- Arthritis urica is a disorder of the purine metabolism in which inflammatory changes in joints are first of an acute type, but later becomes chronic. It is a characteristic feature that it is provoked by crystals of urate, conglomerates comprising such as well as precursors therefore.
- Arthritis urica affects approximately 0.2% of the adult population. The prevalence is nearly 10 times higher in men than in women. The most characteristic symptoms are recurrent painful inflammatory attacks involving a single joint and more permanent pains, often from several joints, which develop slowly after the debut of the first attack.
- the first attack most often affects a big toe and is then termed podagra.
- the disease has heriditable aspects and is often accompanied by an excess of uric acid in the blood.
- a concentration of urate in blood serum of more than 0.45 mmol/1 is regarded as hyperuricemia .
- Hyperuricemia is regarded as a condition for the occurence of arthritis urica but the majority of persons having hyperuricemia do not develop arthritis urica.
- Hyperuricemia may be due to an increased rate of synthesis of the purine precursors of the uric acid or to decreased elimination of uric acid by the kidneys, or to both.
- the medical treatment of arthritis urica has concentrated on alleviation of the acute attacks by administration of colchicine or a non-steroid anti- inflammatoric drug (NSAID) and a prophylactic or long-term treatment in which these drugs may also be used, and in which it is usual also to include a treatment of the hyperuricemia .
- the usual drugs are allopurinol, which reduces the production of uric acid, and probenecid, which increases the excretion of uric acid by the kindneys .
- colchicine in the dosage required for efficient treatment i.e. up to 6 mg per day, causes dyspepsia or diarrhoea in nearly half of the patients.
- the non-steroid anti-inflammatoric drugs must be administered at large dosages to be efficient. As it is well-known, also this type of drugs causes dyspepsia and may cause or aggreviate peptic ulcer. Allopurinol presents several adverse effects of which some are quite severe. Thus, besides dyspepsia, exanthema, and infections of the liver and bone marrow, it may cause severe vasculities having a substantial mortality. Probenecid has no effect if the function of the kidneys is reduced. This drug increases the risk of urolithiasis and also for this drug the side-effects comprise dyspepsia and exanthema.
- Molybdenum is an element which has been subjected to only moderate research within the pharmaceutical area. It is regarded as one of the essential trace elements and the recommended daily consumption for adults is 150-500 ⁇ g .
- molybdenum is mainly provided by milk and cereal products.
- This element forms part of a number of metallo- enzy es, such as aldehyde oxidates, and it has been established that lack of a co-factor necessary for the introduction of molybdenum in the metallo-enzymes causes neuro-logical affections and mental retarding.
- Molybdenum compounds are used as components in some vitamin and mineral tablets marketed as dietary supplement .
- molybdenum influences enzymatic processes partici- pating in metabolism of proteins involving formation of uric acid, a certain influence of molybdenum on arthritis urica were to be expected. However, since the influence of molybdenum on the total purine formation and metabolism processes is very complex, the net effect of an administration of molybdenum compounds to patients suffering from arthritis urica could not be foreseen.
- the present invention comprises use of a molybdenum-containing species for the manufacture of a pharmaceutical preparation for treatment or prophylaxis of arthritis urica.
- pharmaceutical preparation should be construed in its broadest sense as comprising not only all conventional solid, liquid or onctious pharmaceutical formulations but also compositions to be marketed as diet supplements or so-called functional -food products and food additives.
- the term is also intended as comprising implants in which molybdenum or molybdenum compounds are present in a slowly dissolving state for extended release.
- said molybdenum containing species is a molybdenum compound soluble in water to obtain a high and predictable bioavailability.
- Preferred water-soluble molybdenum compounds are salts in which the molybdenum is in oxidation step 6.
- alkaline metal molybdates which are stable and soluble in water.
- ammonium molybdate is very soluble in water.
- the pharmaceutical preparation produced is for oral adminis- tration, such as tablets, capsules, and pills, possibly for prolonged or delayed release of the active ingredient.
- Said formulations may also be effervescent to be easily dissolved or dispersed in water before administra- tion.
- granules are suitable.
- such preparations may contain one or more further active components or minerals, such as copper and iron, to compensate for possible increased excretion of such substances due to the molybdenum administration.
- Suitable formulations comprise sterile liquids for parenteral administration, such as injection liquids and infusion liquids, suppositories for rectal application and agents for transdermal application.
- a pharmaceutical preparation for oral administration is prepared as a unit dosage preparation containing a molybdenum compound in an amount corresponding to 10-500 ⁇ g molybdenum per unit. More preferably, such unit dosage preparations each contains a molybdenum compound in an amount corresponding to 20-200 ⁇ g molybdenum.
- the invention also comprises a pharmaceutical preparation for treatment or prophylaxis of arthritis urica, wherein an active component is a molybdenum species.
- said preparation is a unit dosage for oral administration containing a molybdenum compound in an amount corresponding to 10-500 ⁇ g molybdenum per unit.
- the invention comprises a therapeutical method of treating and/or preventing arthritis urica in which molybdenum is administered to a mammal suffering from this disease.
- the invention is further elucidated by means of the below report of trials.
- the table also comprises information whether the symptoms were mainly inflammatory attacks or permanent pain.
- Pre. Med is listed which prior prescribed medicine the patients received before start of the trial. The patients were instructed to continue taking this medicine until their condition were improved to such an extent that they felt they had no need for it any longer.
- the patients were instructed to take a number of drops of an aqueous solution of sodium molybdate corresponding to 75 ⁇ g molybdenum 3 times daily. Since some of the patients were in a state of malnutrition, they were also instructed to take a conventional vitamin/mineral tablet.
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- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
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- Physical Education & Sports Medicine (AREA)
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- General Chemical & Material Sciences (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Molybdenum, preferably as a molybdenum compound soluble in water, is used for the manufacture of a pharmaceutical preparation for treatment or prophylaxis of arthritis urica.
Description
Title: Pharmaceutical preparations for treatment or prophylaxis of arthritis urica.
Field of the invention The present invention is related to treatment and prophylaxis of arthritis urica in mammals, including human beings .
Arthritis urica, normally termed gout, is a disorder of the purine metabolism in which inflammatory changes in joints are first of an acute type, but later becomes chronic. It is a characteristic feature that it is provoked by crystals of urate, conglomerates comprising such as well as precursors therefore.
In connection with the present invention, it is important to distinguish this disease from other arthropathies, especially rheumatoid arthritis. Thus, a certain confusion often comes up, partly due to the fact that in some languages the same term is used for these two etiologically completely different diseases. Therefore, it is emphasized that the disease dealt with in the present specification and claims is proper arthritis urica provoked by a deposition of crystals of urate or uric acid in and around the joints and/or by precursors for urate or uric acid and/or by conglomerates comprising such.
Background of the invention
Arthritis urica affects approximately 0.2% of the adult population. The prevalence is nearly 10 times higher in men than in women. The most characteristic symptoms are recurrent painful inflammatory attacks involving a single joint and more permanent pains, often from several joints, which develop slowly after the debut of the first attack.
The first attack most often affects a big toe and is then termed podagra.
The disease has heriditable aspects and is often accompanied by an excess of uric acid in the blood. A concentration of urate in blood serum of more than 0.45 mmol/1 is regarded as hyperuricemia .
Hyperuricemia is regarded as a condition for the occurence of arthritis urica but the majority of persons having hyperuricemia do not develop arthritis urica.
Hyperuricemia may be due to an increased rate of synthesis of the purine precursors of the uric acid or to decreased elimination of uric acid by the kidneys, or to both.
Hitherto, the medical treatment of arthritis urica has concentrated on alleviation of the acute attacks by administration of colchicine or a non-steroid anti- inflammatoric drug (NSAID) and a prophylactic or long-term treatment in which these drugs may also be used, and in which it is usual also to include a treatment of the hyperuricemia . For this last-mentioned purpose, the usual drugs are allopurinol, which reduces the production of uric acid, and probenecid, which increases the excretion of uric acid by the kindneys .
Unfortunately, these conventional treatments are not always as efficient as desired, and all the above-mentioned drugs show side-effects (ADR = adverse drug reaction) , which put severe limits to their application or, in certain circumstances, prevent such.
Thus, colchicine in the dosage required for efficient treatment, i.e. up to 6 mg per day, causes dyspepsia or diarrhoea in nearly half of the patients.
The non-steroid anti-inflammatoric drugs must be administered at large dosages to be efficient. As it is well-known, also this type of drugs causes dyspepsia and may cause or aggreviate peptic ulcer. Allopurinol presents several adverse effects of which some are quite severe. Thus, besides dyspepsia, exanthema, and infections of the liver and bone marrow, it may cause severe vasculities having a substantial mortality. Probenecid has no effect if the function of the kidneys is reduced. This drug increases the risk of
urolithiasis and also for this drug the side-effects comprise dyspepsia and exanthema.
For both these two substances used against hyperuricemia, it applies that initially the administra- tion may provoke a new acute attack of arthritis urica.
Thus, there is a need for an efficient medicine for the treatment and prophylaxis of arthritis urica, not possessing the adverse side-effects of the drugs conventionally used for this purpose. Molybdenum is an element which has been subjected to only moderate research within the pharmaceutical area. It is regarded as one of the essential trace elements and the recommended daily consumption for adults is 150-500 μg .
In a normal diet, molybdenum is mainly provided by milk and cereal products.
This element forms part of a number of metallo- enzy es, such as aldehyde oxidates, and it has been established that lack of a co-factor necessary for the introduction of molybdenum in the metallo-enzymes causes neuro-logical affections and mental retarding.
It has also been described that a high consumption of molybdenum due to copper antagonism may result in copper deficiency and a syndrom similar to arthritis urica.
Molybdenum compounds are used as components in some vitamin and mineral tablets marketed as dietary supplement .
In 2 papers by H. Krzymien, viz. "Reumatologia" . 1970/8 (3) :193-8 and "Pol Tyg Lek" . 1973 Nov 12 ; 28 (46 : 1808- 10) , attempts to use molybdenum compounds for treatment of diseases different from arthritis urica are described. Thus, administration of ammonium molybdate in an amount corresponding to 0.15 g molybdenum daily to patients suffering from rheumatoid arthritis or Sjόgreen's syndrom caused a significant improvement. However, in said 2 papers, there is no suggestion or hint to try molybdenum in the treatment or prophylaxis of arthritis urica. Since molybdenum influences enzymatic processes partici-
pating in metabolism of proteins involving formation of uric acid, a certain influence of molybdenum on arthritis urica were to be expected. However, since the influence of molybdenum on the total purine formation and metabolism processes is very complex, the net effect of an administration of molybdenum compounds to patients suffering from arthritis urica could not be foreseen.
Summary of the invention It has now surprisingly been experienced that administration of molybdenum compounds to patients suffering from arthritis urica results in a rather fast occuring improvement of the condition of such patients.
Thus, in one aspect, the present invention comprises use of a molybdenum-containing species for the manufacture of a pharmaceutical preparation for treatment or prophylaxis of arthritis urica.
In the present specification and the attached claims the term pharmaceutical preparation should be construed in its broadest sense as comprising not only all conventional solid, liquid or onctious pharmaceutical formulations but also compositions to be marketed as diet supplements or so-called functional -food products and food additives. The term is also intended as comprising implants in which molybdenum or molybdenum compounds are present in a slowly dissolving state for extended release.
However, in the preferred embodiment of the invention, said molybdenum containing species is a molybdenum compound soluble in water to obtain a high and predictable bioavailability.
Preferred water-soluble molybdenum compounds are salts in which the molybdenum is in oxidation step 6.
Examples of such salts are alkaline metal molybdates, which are stable and soluble in water. Also ammonium molybdate is very soluble in water.
In the preferred use according to the invention, the pharmaceutical preparation produced is for oral adminis-
tration, such as tablets, capsules, and pills, possibly for prolonged or delayed release of the active ingredient.
Said formulations may also be effervescent to be easily dissolved or dispersed in water before administra- tion. For such purpose, also granules are suitable.
Besides conventional extenders and adjuvants, such preparations may contain one or more further active components or minerals, such as copper and iron, to compensate for possible increased excretion of such substances due to the molybdenum administration.
Other suitable formulations comprise sterile liquids for parenteral administration, such as injection liquids and infusion liquids, suppositories for rectal application and agents for transdermal application. In a preferred use according to the invention, a pharmaceutical preparation for oral administration is prepared as a unit dosage preparation containing a molybdenum compound in an amount corresponding to 10-500 μg molybdenum per unit. More preferably, such unit dosage preparations each contains a molybdenum compound in an amount corresponding to 20-200 μg molybdenum.
These ranges for preferred contents of molybdenum compound in the unit dosage preparations reflect the fact that, based on the experiences hitherto, an oral daily dosage of approximately 3 x 75 μg (calculated as molybdenum) is regarded as suitable, at least in the beginning of the treatment .
The surprising, beneficial effects of treatments using this low dosage of the molybdenum appear from the trials reported below.
No animal experiments have been conducted to establish the acute toxicity of the relevant molybdenum compounds. This is because such experiments are regarded as superfluous in view of the fact that the dosage used in connection with the present invention is approximately 600 times less than the dosage used for very prolonged treatments according to the two above-cited papers by H.
Krzymien. In said papers no adverse effects are reported, at least not in the abstracts.
The scope of the present invention is in no way restricted by any theoretical explanation as to the effect obtained. However, the fact that the improvement occurs substantially earlier than when a conventional anti- hyperuremic treatment is applied, sustains the following hypothesis :
In the metabolism of proteins, the following inter- mediates are formed:
proteins -> purines -> hypoxantin -> xantin -> uric acid.
In case of molybdenum insufficiency xantin oxidase is inhibited and thus the concentration of xantin (and hypoxantin) increases. Since xantin is less soluble than uric acid, it is assumed that precipitation of xantin takes place in an area near the affected joint. When a sufficient amount of molybdenum is supplied, a sufficient xantin oxidase acitivity is rather fast reestablished resulting in conversion of xantin into the more easily dissolving uric acid which is thus excreted.
The invention also comprises a pharmaceutical preparation for treatment or prophylaxis of arthritis urica, wherein an active component is a molybdenum species.
Preferably, said preparation is a unit dosage for oral administration containing a molybdenum compound in an amount corresponding to 10-500 μg molybdenum per unit.
Furthermore, the invention comprises a therapeutical method of treating and/or preventing arthritis urica in which molybdenum is administered to a mammal suffering from this disease.
The invention is further elucidated by means of the below report of trials.
Trials
12 patients having arthritis urica diagnosed more than 1 year before, and for most of them several years before the start of the trial, participated.
As it appears from the following table, said patients were domiciled in various parts of the world, for which reason their disease were hardly caused by local deficiencies in the diet.
The table also comprises information whether the symptoms were mainly inflammatory attacks or permanent pain.
Under the title, "Pre. Med." is listed which prior prescribed medicine the patients received before start of the trial. The patients were instructed to continue taking this medicine until their condition were improved to such an extent that they felt they had no need for it any longer.
The patients were instructed to take a number of drops of an aqueous solution of sodium molybdate corresponding to 75 μg molybdenum 3 times daily. Since some of the patients were in a state of malnutrition, they were also instructed to take a conventional vitamin/mineral tablet.
As it appears from the table, all 12 patients recovered to such an extent that their symptoms disap- peared, they could discontinue their previous medication and follow a normal drink and food pattern in contrast to the diet, which 9 of them previously felt necessary to avoid aggrevating their disease.
It should be observed that the improvement, as it appears, was manifest already within a couple of weeks.
The patients were instructed to continue the administration of the sodium molybdate drops after recovery. At the end of May 2001, no recrudescences were reported.
No..Ctry Age Sex Diag. Sympts . Symp . Diet Pre .Med. Treatment Improved Nil diet and yrs M/F year inflm.atta. perm. pain Yes/No begin condition no symptoms 0*
(t>
1 FR 70 1998 yes no yes Al 25.10.00 03.11.00 10.11.00 M
2 DK - M - yes no no lb 11.01.01 27.01.01 16.02.01
3 DK 57 M 1996 yes no no none 01.02.01 06.02.01 20.02.01
4 O 70 M 1995 yes yes yes Pr 11.02.01 17.02.01 16.03.01
5 US 65 M 1999 - yes yes Co, Id 22.02.01 09.03.01 30.04.01
6 GB 45 M 1990 yes yes yes In 09.03.01 25.03.01 05.05.01
7 AU 62 M 1974 yes yes yes Al, In 12.03.01 26.03.01 04.04.01
8 AU 45 M 1990 yes yes yes In 27.03.01 20.04.01 30.04.01
9 US 41 M 1994 yes yes yes Id, Co 08.04.01 19.04.01 15.05.01
10 US 56 F 1992 yes yes yes In 18.04.01 04.05.01 21.05.01
11 US 34 M 1998 yes yes yes Re, Ce 07.05.01 - 22.05.01
12 DK 53 M - yes yes - lb, Vo 01.05.01 30.05.01 ...
00
Prior Prescribed Medicine
Al Allopurinol
In Indomethacin
Pr Probecid
Co Colchicine
Id Indomethacin
Co Cortisone
Re Relefan
Ce Celebrex lb Ibuprofen
Vo Voltaren
Claims
P A T E N T C L A I M S 1. Use of a molybdenum species for the manufacture of a pharmaceutical preparation for treatment or prophylaxis of arthritis urica.
2. Use according to claim 1, wherein said species is a molybdenum compound soluble in water.
3. Use according to claim 2 , wherein said molybdenum compound is a salt, in which the molybdenum is in oxidation step 6.
4. Use according to claim 3, wherein said salt is selected from the group consisting of ammonium and alkaline metal molybdates.
5. Use according to anyone of the preceding claims, wherein the pharmaceutical preparation is for oral admin- istration.
6. Use according to claim 5, wherein the pharmaceutical preparation is a unit dosage preparation containing a molybdenum compound in an amount corresponding to 10-500 μg molybdenum per unit.
7. Use according to claim 5, wherein the unit dosage preparation contains a molybdenum compound in an amount corresponding to 20-200 μg molybdenum per unit.
8. Pharmaceutical preparation for treatment or prophylaxis of arthritis urica, c h a r a c t e r i z e d in containing a molybdenum species.
9. Pharmaceutical preparation according to claim 8, c h a r a c t e r i z e d in being a unit dosage for oral administration and containing a molybdenum compound in an amount corresponding to 20-200 μg molybdenum per unit.
10. Therapeutical treatment for alleviation or prophylaxis of arthritis urica comprising administration of molybdenum to a mammal suffering from said disease.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DKPA200101107 | 2001-07-13 | ||
| DKPA200101107 | 2001-07-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2003006032A1 true WO2003006032A1 (en) | 2003-01-23 |
Family
ID=8160626
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/DK2002/000464 WO2003006032A1 (en) | 2001-07-13 | 2002-07-03 | Pharmaceutical preparations for treatment or prophylaxis of arthritis urica |
Country Status (1)
| Country | Link |
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| WO (1) | WO2003006032A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2252729A (en) * | 1991-02-13 | 1992-08-19 | Bharat Sridhar Pancham | Vitamin- and/or mineral-containing pharmaceutical composition |
| RU2156087C1 (en) * | 1999-11-25 | 2000-09-20 | Товарищество с ограниченной ответственностью Фирма "Электронная медицина" | Biologically active addition |
-
2002
- 2002-07-03 WO PCT/DK2002/000464 patent/WO2003006032A1/en not_active Application Discontinuation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2252729A (en) * | 1991-02-13 | 1992-08-19 | Bharat Sridhar Pancham | Vitamin- and/or mineral-containing pharmaceutical composition |
| RU2156087C1 (en) * | 1999-11-25 | 2000-09-20 | Товарищество с ограниченной ответственностью Фирма "Электронная медицина" | Biologically active addition |
Non-Patent Citations (11)
| Title |
|---|
| ACTA VET. SCAND., vol. 22, no. 3-4, 1981, pages 289 - 295, ISSN: 0044-605x * |
| DATABASE MEDLINE [online] 12 November 1973 (1973-11-12), KRZYTMIEN H: "[Further therapeutic attempts at using molybdenum compounds in rheumatoid atrhritis]", XP002902700, retrieved from STN accession no. 74078223 Database accession no. nlm4771857 * |
| DATABASE MEDLINE [online] 1970, KRZYMIEN H: "[Attempts at treating rheumatoid arthritis and other chronic rheumatoid diseases with molybdenum compounds]", XP002902724, retrieved from STN accession no. 71004692 Database accession no. NLM5469424 * |
| DATABASE MEDLINE [online] 1984, LENER J ET AL: "Effects of molybdenum on the organism (a review).", XP002902725, retrieved from STN accession no. 85132602 Database accession no. NLM6396329 * |
| DATABASE MEDLINE [online] 1999, BARCELOUX D G: "Molybdenum.", XP002902726, retrieved from STN accession no. 199311567 Database accession no. NLM10382558 * |
| DATABASE STN INTERNATIONAL [online] FILE CAPLUS; KARRING M ET AL: "The influence of dietary molybdenum and copper supplementation on the contents of serum uric acid and some trace elements in cocks.", XP002902698, retrieved from STN accession no. 96:161272 Database accession no. 1982:161272 * |
| DATABASE STN INTERNATIONAL [online] FILE CAPLUS; SHOLOKHOV V M ET AL: "Biologically active addition.", XP002902699, retrieved from STN accession no. 135;343656 Database accession no. 2001:851947 * |
| JOURNAL OF HYGIENE, EPIDEMIOLOGY, MICROBIOLOGY, AND IMMUNOLOGY. CZECHOSLOVAKIA 1984, vol. 28, no. 4, 1984, pages 405 - 419, ISSN: 0022-1732 * |
| JOURNAL OF TOXICOLOGY. CLINICAL TOXICOLOGY. UNITED STATES 1999, vol. 37, no. 2, 1999, pages 231 - 237, ISSN: 0731-3810 * |
| POLSKI TYGODNIK LEKARSKI (WARSAW, POLAND: 1960), vol. 28, no. 46, 12 November 1973 (1973-11-12), pages 1808 - 1810, ISSN: 0032-3756 * |
| REUMATOLOGIA. POLAND 1970, vol. 8, no. 3, 1970, pages 193 - 198, ISSN: 0034-6233 * |
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