[go: up one dir, main page]

EP0068314A1 - Treatment of arthritic complaints - Google Patents

Treatment of arthritic complaints Download PDF

Info

Publication number
EP0068314A1
EP0068314A1 EP82105285A EP82105285A EP0068314A1 EP 0068314 A1 EP0068314 A1 EP 0068314A1 EP 82105285 A EP82105285 A EP 82105285A EP 82105285 A EP82105285 A EP 82105285A EP 0068314 A1 EP0068314 A1 EP 0068314A1
Authority
EP
European Patent Office
Prior art keywords
desferrioxamine
treatment
diseases involving
joint inflammation
pharmaceutical preparation
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.)
Withdrawn
Application number
EP82105285A
Other languages
German (de)
French (fr)
Inventor
David Russell Dr. Blake
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Original Assignee
Ciba Geigy AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Ciba Geigy AG filed Critical Ciba Geigy AG
Publication of EP0068314A1 publication Critical patent/EP0068314A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to the treatment of arthritic and like complaints.
  • rheumatoid arthritis is a chronic form of arthritis where many joints are affected and the inflammation is often such that gross deformity and immobility of the joint may result.
  • Rheumatoid arthritis has, in the past, been treated, for example, with cortisone or with non-steroidal anti-inflammatory drugs.
  • Cortisone is effective in combating inflammation but also carries with its use a high risk of dangerous side effects.
  • Treatment with non-steroidal anti-inflammatory drugs (NSAID's) has often been found not to be as effective as desired to reduce inflammation.
  • the most popular NSAID is aspirin which has to be used in very high doses e.g. 16-18 tablets per day.
  • Desferrioxamine is an iron-chelating agent which has long been used in the treatment of iron poisoning and which has also been used extensively in the examination of iron metabolism in many diseases including rheumatoid arthritis. We are not aware, however, that the use of desferrioxamine to reduce the inflammation in the treatment of rheumatoid arthritis has ever been disclosed.
  • the present invention provides a method of treatment of rheumatoid arthritic and like diseases involving joint inflammation, which comprises administering desferrioxamine in a therapeutically effective dosage over a prolonged period.
  • the method of the invention may be applied to the treatment of non-specific monoarthritis and any other instances of joint inflammation caused by free iron catalysis.
  • the method of the invention may also be applied to any other complaint which is induced by the occurrence of free iron, for example certain instances of myocardial infarction as recently suggested.
  • the amount of desferrioxamine administered is suitably a therapeutically effective amount in the range of from 1 to 10 g per day, for example 1 to 5 g per day, suitably 2 to 3 g per day.
  • the present invention also provides a pharmaceutical preparation suitable for intra-articular administration which comprises desferrioxamine in admixture or conjunction with a pharmaceutically suitable carrier.
  • the present invention further provides a pharmaceutical preparation in the form of a pack which contains a support member together with a plurality of dosage forms comprising desferrioxamine, preferably enough for 3 weeks' supply.
  • the amount of desferrioxamine present in each dosage form in a pack of the invention is in the range of from 1 to 10 g, e.g. in the range of from 1 to 5 g, conveniently 2 to 3 g.
  • the amount of desferrioxamine may be different in each dosage form, for example a pack may comprise a set of dosage forms one containing 1 g of desferrioxamine, another 2 g of desferrioxamine and so on to 5 g, 7 g or 10 g of desferrioxamine.
  • the desferrioxamine is suitably present in lyophilised powder form as desferrioxamine mesylate but may be in a liposome formulation.
  • Desferrioxamine may be administered by any one of several routes.
  • Administration intravenously, intraperitoneally, subcutaneously, intra-muscularly or intra- articularly by infusion solution are all suitable routes, intra-articular and subcutaneous infusion being preferred.
  • Administration by infusion solution may be by continuous pump administration or administration in divided doses, i.e. twice or three times daily, daily, weekly or monthly.
  • the active substance may be present in the infusion solution prior to the start of the administration or may be injected in as a "bolus" concentrate.
  • Other routes of administration possible are via the skin or by the use of a liposome formulation.
  • Administration via the skin may be by the transdermal "delivery system" (Alza Corporation) where medication externally applied by means of a special applicator reaches the affected joint by absorption through the skin.
  • Direct topical administration may occur from once to four times daily by means of an ointment or cream containing desferrioxamine.
  • Preparations containing desferrioxamine may in addition contain the usual carriers, excipients and auxiliaries.
  • pH-regulating substances e.g. sodium phosphate and substances imparting isotonicity to the solutions, e.g. sodium chloride, may be present.
  • the period of administration of desferrioxamine will vary depending on the severity of the disease, but is usually at least 5 days. In chronic cases the administration may occur initially over a period of 3 weeks to a month with the treatment being repeated at 3, 6 or 12 month intervals or sooner if chronic inflammation occurs or recurs. In instances of subcutaneous administration by infusion solution, it has been found satisfactory for the initial 3 week treatment to consist of continuous administration over several hours daily for 5 consecutive days, followed by no administration for 2 days and then repeat treatment for the following 5 days and so on.
  • the above methods of administration are acceptable methods for introducing desferrioxamine into the body but cannot ensure that all of the active substance reaches the site of the free iron and ferritin stores in the reticuloendothelial stores. Also the most useful preparations, the infusion solutions, have to be made up shortly before use from lyophilised desferrioxamine powder because aqueous desferrioxamine solution is unstable over periods of longer than a week.
  • the present invention also provides a method for the treatment of rheumatoid arthritis, wherein a pharmaceutical preparation comprising desferrioxamine as a liposome formulation is administered to the patient orally or parenterally.
  • Liposomes are lipoid vesicles of varying sizes which encapsulate an active ingredient.
  • the lipoid walls may comprise one or more lipid bi-layers. Suitable lipids are phospholipids; they may be used in pure form or in combination with other suitable substances.
  • Desferrioxamine in aqueous solution may be incorporated into liposomes which have an avidity for the reticuloendothelial cells without apparent loss of stability.
  • each liposome formulation may contain in the range of 0.1 to 12.5 mg of desferrioxamine.
  • Desferrioxamine has been found to give a significant reduction in joint inflammation in patients suffering from rheumatoid arthritis without any apparent side- effects. It has also been found to give such results when used in conjunction with non-steroidal anti-inflammatory drugs without any apparent undesirable interactions. Desferrioxamine may thus be used as a replacement for or as a supplement to the non-steroidal anti-inflammatory drugs already used.
  • the solvent used for the lipoid mixture was chloroform.
  • the size of the liposomes was varied in certain cases from multilamellar liposomes to unilamellar liposomes by ultrasonication.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Dispersion Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Rheumatoid arthritic and like diseases involving joint inflammation are treated by administering desferrioxamine in a therapeutically effective dosage over a prolonged period.

Description

  • The present invention relates to the treatment of arthritic and like complaints.
  • The term "arthritic" is used medically to describe the occurrence of inflammation of a joint. Arthritis exists in many forms; rheumatoid arthritis is a chronic form of arthritis where many joints are affected and the inflammation is often such that gross deformity and immobility of the joint may result. Rheumatoid arthritis has, in the past, been treated, for example, with cortisone or with non-steroidal anti-inflammatory drugs. Cortisone is effective in combating inflammation but also carries with its use a high risk of dangerous side effects. Treatment with non-steroidal anti-inflammatory drugs (NSAID's) has often been found not to be as effective as desired to reduce inflammation. The most popular NSAID is aspirin which has to be used in very high doses e.g. 16-18 tablets per day.
  • It has been previously found that in cases of rheumatoid arthritis there is a low blood plasma iron level but a high amount of iron in the synovial membrane which is stored as ferritin in synovial reticuloendothelial cells.
  • It has been found that the inflammation of joints mainly in rheumatoid arthritis is exacerbated by the production of free oxygen radicals generated in the presence of catalytic free iron, as opposed to ferritin.
  • Desferrioxamine is an iron-chelating agent which has long been used in the treatment of iron poisoning and which has also been used extensively in the examination of iron metabolism in many diseases including rheumatoid arthritis. We are not aware, however, that the use of desferrioxamine to reduce the inflammation in the treatment of rheumatoid arthritis has ever been disclosed.
  • We have surprisingly found that the treatment of rheumatoid arthritis and like diseases by the administration of desferrioxamine over a prolonged period in a suitable dosage gives remarkable reduction in the inflammation of joints. This is all the more surprising when it is realised that small or short term administration of the compound exacerbates the inflammatory condition.
  • Without wishing to be bound by any theory as to the mechanism of action of desferrioxamine within the body, it is thought that the excess iron stored as ferritin in the reticuloendothelial cells and the free iron in the synovial fluid exist in an equilibrium such that any chelation of the free iron on a short term basis disturbs the iron balance and causes the production of large amounts of free iron from the stored ferritin possibly even overcompensating for the loss of the free iron; the free iron then causes exacerbation of the joint inflammation as indicated above, and it is perhaps for this reason that where desferrioxamine has been used hitherto in studies of iron metabolism the indications have been that it would not be useful for the treatment of rheumatoid arthritis. Prolonged treatment with desferrioxamine is thought, however, to gradually "mop up" the free iron produced and to reduce the amount of free iron available for catalysis giving rise to a reduction in inflammation.
  • Accordingly, the present invention provides a method of treatment of rheumatoid arthritic and like diseases involving joint inflammation, which comprises administering desferrioxamine in a therapeutically effective dosage over a prolonged period.
  • The method of the invention may be applied to the treatment of non-specific monoarthritis and any other instances of joint inflammation caused by free iron catalysis. The method of the invention may also be applied to any other complaint which is induced by the occurrence of free iron, for example certain instances of myocardial infarction as recently suggested.
  • The amount of desferrioxamine administered is suitably a therapeutically effective amount in the range of from 1 to 10 g per day, for example 1 to 5 g per day, suitably 2 to 3 g per day.
  • The present invention also provides a pharmaceutical preparation suitable for intra-articular administration which comprises desferrioxamine in admixture or conjunction with a pharmaceutically suitable carrier.
  • The present invention further provides a pharmaceutical preparation in the form of a pack which contains a support member together with a plurality of dosage forms comprising desferrioxamine, preferably enough for 3 weeks' supply.
  • Suitably the amount of desferrioxamine present in each dosage form in a pack of the invention is in the range of from 1 to 10 g, e.g. in the range of from 1 to 5 g, conveniently 2 to 3 g. The amount of desferrioxamine may be different in each dosage form, for example a pack may comprise a set of dosage forms one containing 1 g of desferrioxamine, another 2 g of desferrioxamine and so on to 5 g, 7 g or 10 g of desferrioxamine. The desferrioxamine is suitably present in lyophilised powder form as desferrioxamine mesylate but may be in a liposome formulation.
  • Desferrioxamine may be administered by any one of several routes. Administration intravenously, intraperitoneally, subcutaneously, intra-muscularly or intra- articularly by infusion solution are all suitable routes, intra-articular and subcutaneous infusion being preferred. Administration by infusion solution may be by continuous pump administration or administration in divided doses, i.e. twice or three times daily, daily, weekly or monthly. The active substance may be present in the infusion solution prior to the start of the administration or may be injected in as a "bolus" concentrate. Other routes of administration possible are via the skin or by the use of a liposome formulation.
  • Administration via the skin may be by the transdermal "delivery system" (Alza Corporation) where medication externally applied by means of a special applicator reaches the affected joint by absorption through the skin. Direct topical administration may occur from once to four times daily by means of an ointment or cream containing desferrioxamine.
  • Preparations containing desferrioxamine may in addition contain the usual carriers, excipients and auxiliaries. In infusion solutions, for example, pH-regulating substances, e.g. sodium phosphate and substances imparting isotonicity to the solutions, e.g. sodium chloride, may be present.
  • The period of administration of desferrioxamine will vary depending on the severity of the disease, but is usually at least 5 days. In chronic cases the administration may occur initially over a period of 3 weeks to a month with the treatment being repeated at 3, 6 or 12 month intervals or sooner if chronic inflammation occurs or recurs. In instances of subcutaneous administration by infusion solution, it has been found satisfactory for the initial 3 week treatment to consist of continuous administration over several hours daily for 5 consecutive days, followed by no administration for 2 days and then repeat treatment for the following 5 days and so on.
  • The above methods of administration are acceptable methods for introducing desferrioxamine into the body but cannot ensure that all of the active substance reaches the site of the free iron and ferritin stores in the reticuloendothelial stores. Also the most useful preparations, the infusion solutions, have to be made up shortly before use from lyophilised desferrioxamine powder because aqueous desferrioxamine solution is unstable over periods of longer than a week.
  • The present invention also provides a method for the treatment of rheumatoid arthritis, wherein a pharmaceutical preparation comprising desferrioxamine as a liposome formulation is administered to the patient orally or parenterally. Liposomes are lipoid vesicles of varying sizes which encapsulate an active ingredient. The lipoid walls may comprise one or more lipid bi-layers. Suitable lipids are phospholipids; they may be used in pure form or in combination with other suitable substances. Desferrioxamine in aqueous solution may be incorporated into liposomes which have an avidity for the reticuloendothelial cells without apparent loss of stability. With such a formulation the desferrioxamine may "home in" on the reticuloendothelial cells and it is believed that such formulations will enable smaller amounts of desferrioxamine to be administered for the same anti-inflammatory effect because the active substance is retained in the liposomes until the site of action is reached. Liposomes may be administered by enteral or parenteral means, preferably by intra-articular injection or by oral administration. Suitably each liposome formulation may contain in the range of 0.1 to 12.5 mg of desferrioxamine.
  • Administration of desferrioxamine when entrapped in red cell ghosts is also possible to counter inflammation.
  • Desferrioxamine has been found to give a significant reduction in joint inflammation in patients suffering from rheumatoid arthritis without any apparent side- effects. It has also been found to give such results when used in conjunction with non-steroidal anti-inflammatory drugs without any apparent undesirable interactions. Desferrioxamine may thus be used as a replacement for or as a supplement to the non-steroidal anti-inflammatory drugs already used.
  • The following Examples illustrate the invention.
    • Desferrioxamine Preparations
    • I. Infusion Solutions
      • a) The contents of an ampoule containing 500 mg of lyophilised desferrioxamine (commercially available under the trade name Desferal in the form of lyophilised desferrioxamine mesylate) were completely dissolved in 2-3 ml of Water for Injection BP and then made up to the required amount with a suitable infusion solution. An infusion solution containing 1 g of desferrioxamine was similarly prepared using 2 ampoules as above. Also solutions containing 2 g (using 4 ampoules), 3 g (using 6 ampoules), 5 g (using 10 ampoules), 7 g (using 14 ampoules) and 10 g (using 20 ampoules) of desferrioxamine. Suitable infusion solutions are normal saline, dextrose, dextrose saline, blood and Ringers Lactate solution.
      • b) 1 g of desferrioxamine was dissolved in 10 ml of Water for Injection BP to give a 10 % solution of desferrioxamine. Sufficient sodium chloride to render the solution isotonic was added. Such a solution may be diluted with suitable infusion solutions (as mentioned above) or may be used as a concentrated or "bolus" solution.
    • II. Ointment An ointment containing 5 % by weight of desferrioxamine based on 0.4 % of cetyl alcohol, 4.6 % of wool fat, 65 % of white soft paraffin and 30 % of liquid paraffin, was prepared by known procedure comprising heating the cetyl alcohol, wool fat, white soft paraffin and liquid paraffin together and incorporating the desferrioxamine.
    • III. Liposomes The liposomes were prepared with a mixture of dipalmitoyl phosphatidylcholine, cholesterol and stearylamine, in a molar ratio of 3.6 : 2.3 : 1 respectively, dissolved in chloroform. This mixture was dried in a round bottom flask in a rotary evaporator. The flask was placed in a 37°C water bath and 1 ml of a 10-12 % aqueous solution of desferrioxamine mesylate was slowly added to the flask with immediate and constant stirring with a magnetic stirrer. The resultant suspension of liposomes containing desferrioxamine was centrifuged at 2000 rpm for 5 minutes. The supernatant was carefully pipetted off and the liposome pellet was suspended in normal saline. The centrifugation and resuspension procedure was repeated five times to ensure the complete removal of nonencapsulated desferrioxamine solution. For injection, the liposomes are to be resuspended in saline.
  • Other liposome preparations were prepared by similar known methods using the lipoid mixtures given below. The abbreviations noted designate the following compounds:
    • CH = cholesterol
    • DP = dicetyl phosphate
    • DMPC = dimyristoyl phosphatidylcholine
    • DOPC = dioleoyl phosphatidylcholine
    • DPPC = dipalmitoyl phosphatidylcholine
    • PA = phosphatidic acid
    • PC = egg phosphatidylcholine
    • PCA = egg phosphatidic acid
    • PS = phosphatidylserine
    • SA = stearylamine
  • Unless specifically stated, the solvent used for the lipoid mixture was chloroform.
    • 1. 6 mg DPPC and 3 mg PCA in 1.25 ml chloroform.
    • 2. 22.5 mg PC and CH in 10-15 ml chloroform
    • 3. PC and PA in a molar ratio of 7 : 1
    • 4. PC, CH and PA in a molar ratio of 7 : 2 : 1
    • 5. PC, CH and SA in a molar ratio of 7 : 2 : 1
    • 6. PC, CH and DP in a molar ratio of 7 : 2 : 1
    • 7. PC, CH and PA in a molar ratio of 7 : 5 : 1
    • 8. PC, CH and SA in a molar ratio of 7 : 5 : 1
    • 9. DOPC, CH and PA in a molar ratio of 7 : 5 : 1
    • 10. DMPC, CH and PA in a molar ratio of 7 : 5 : 1
    • 11. PC and CH in a molar ratio of 8 : 2
    • 12. PC and CH in a molar ratio of 9 : 2
    • 13. DPPC, CH and PA in a molar ratio of 7 : 2 : 1
    • 14. PC, CH and PS in a molar ratio of 7 : 2 : 1
  • The size of the liposomes was varied in certain cases from multilamellar liposomes to unilamellar liposomes by ultrasonication.
    • Animal Tests
  • Inflammation of joints was induced by various recognised methods as indicated below and the effects of administered desferrioxamine were studied.
    • I. Induction by ureates Crystal ureate was used to induce footpad swelling in rats. 1 mg, 10 mg, 30 mg and 60 mg doses of desferrioxamine per kg were administered, each to different rats, and the footpad swelling was measured after 2 and 24 hours. The rats which had received the 1mg/kg and 10 mg/kg doses exhibited significantly increased swelling of the affected footpad whilst the higher doses showed a marked anti-inflammatory effect with reduced swelling.
    • II. Induction by carrageenan Carrageenan was used to induce footpad swelling in rats. Two doses of desferrioxamine were studied: 1 mg/kg and 60 mg/kg. The 1 kg/kg dose exhibited no effect on the footpad swelling whilst the 60 mg/kg dose significantly reduced the footpad swelling.
    • III. Induction by Bovine Gamma Globulin (BGG) The Glynn-Dumonde model of adjuvant arthritis was followed which involves the injection of BGG in Freunds complete adjuvant to instigate inflammation followed by a second injection of BGG after 10 days to maintain the induced swelling. 50 mg/kg of desferrioxamine were administered to one group of rats at the time of the second injection and the same amount was administered to a second group of rats on days 7 to 14. The dose on day 10 exacerbated the arthritis whilst that on days 7 to 14 exhibited a reduction in the inflammation of the adjuvant arthritis each compared to a control group of rats to which no desferrioxamine was administered.
    • IV. Induction by mycobacteria Adjuvant arthritis was induced by mycobacteria. 30 mg/kg of desferrioxamine were administered to a first group of rats on each of the first 5 consecutive days after induction. A reduction in the primary lesions over a group of control rats was noted. 30 mg/kg of desferrioxamine were administered to a second set of rats.on each of the 15th to 19th days after induction and note was taken of the effect on secondary lesions. The second set of rats had reduced secondary lesions over the control rats and also over the first set of rats which now exhibited worse secondary lesions than the control rats.
    Tests on Humans
    • 1. One patient with non-specific monoarthritis of the knee received 5 daily injections of desferrioxamine intra-articularly after synovial fluid aspiration. Doses of desferrioxamine were increased daily until on days 4 and 5 the patient received 1 g of desferrioxamine (injected over 1 hr). The total dose of desferrioxamine injected was 3.5 g. Results
      • a) No local or systemic side effects were observed.
      • b) There was a noticeable reduction of the swelling of the knee which continued for 3 months after the injection (longer relief than had previously been experienced).
      • c) Synovial fluid showed reduction of catalytic iron and thiobarbituric acid reactivity.
      • d) Synovial fluid ferritin levels were reduced, but no changes were found in the serum.
      • e) In 3 hours after injection there was marked leucocytosis in the synovial fluid.
    • 2. Nine patients with active rheumatoid arthritis received 1 g of desferrioxamine daily for 3 weeks (treatment on 5 days a week only) by subcutaneous infusion over 7 to 8 hours. All patients were admitted to the hospital for the time of the trial. Treatment with non-steroidal anti-inflammatory drugs was continued throughout the trial. The following clinical and laboratory parameters were evaluated at weeks 1 and 3:
      • Ritchie index, morning stiffness, grip strength, VAS pain scores, FBC, ESR, rheumatoid factor, immunoglobulins, iron, thiobarbituric acid reactivity.
    Results
  • No changes in the laboratory parameters were found; however, thiobarbituric acid reactivity was reduced in some patients studied. Clinical indices of disease activity showed improvement at week 3 (8 patients out of 9) despite,after 1 week of treatment,8 out of 9 patients having experienced flare-up of their arthritis and 1 patient having developed vasculitis (this cleared after the 3 weeks of treatment).
  • No side effects were reported.

Claims (10)

1. Method of use of desferrioxamine in case of rheumatoic arthritic and like diseases involving joint inflammation, which comprises converting desferrioxamine with pharmaceutical auxiliaries into a pharmaceutical preparation and using such for the treatment of rheumatoid arthritic and like diseases involving joint inflammation in a therapeutically effective dosage over a prolonged period.
2. A method as claimed in claim 1 for the use of desferrioxamine in case of rheumatoid arthritic and like diseases involving joint inflammation, which comprises converting desferrioxamine with pharmaceutical auxiliaries into a pharmaceutical preparation and using such for the treatment of rheumatoid arthritic and like diseases involving joint inflammation in a dosage of 1 to 10 g per day with respect to desferrioxamine used over a prolonged period.
3. A method as claimed in claims 1 and 2, which comprises converting desferrioxamine with pharmaceutical auxiliaries into a pharmaceutical preparation and using such for the treatment of rheumatoid arthritic and like diseases involving joint inflammation in a dosage of 2 to 3 g per day with respect to desferrioxamine used over a prolonged period.
4. A method as claimed in claims 1 to 3 in which the period of use is at least 5 days.
5. A method as claimed in claims 1 to 3 in which the period of use is at least 3 weeks.
6. A method as claimed in any preceding claims 1 to 5, which comprises converting desferrioxamine with pharmaceutical auxiliaries into a pharmaceutical preparation and using such for the treatment of rheumatoid arthritic and like diseases involving joint inflammation intravenously, intraperitoneally, subcutaneously, intramuscularly, intraarticularly or transdermally.
7. A method as claimed in any preceding claims 1 to 5, which comprises converting desferrioxamine with pharmaceutical auxiliaries into a pharmaceutical preparation in the form of a liposome formulation and using such for the treatment of rheumatoid arthritic and like diseases involving joint inflammation.
8. A pharmaceutical preparation for the use of treating rheumatoid arthritic and like diseases involving joint inflammation containing desferrioxamine and pharmaceutical auxiliaries.
9. A pharmaceutical preparation for the treatment of rheumatoid arthritic and like diseases involving joint inflammation in the form of a pack which contains a support member together with a plurality of dosage form comprising desferrioxamine and pharmaceutical auxiliaries.
10. A pharmaceutical preparation as claimed in claim 9 which contains sufficient dosage forms for at least 3 weeks' supply.
EP82105285A 1981-06-19 1982-06-16 Treatment of arthritic complaints Withdrawn EP0068314A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8119006 1981-06-19
GB8119006 1981-06-19

Publications (1)

Publication Number Publication Date
EP0068314A1 true EP0068314A1 (en) 1983-01-05

Family

ID=10522661

Family Applications (1)

Application Number Title Priority Date Filing Date
EP82105285A Withdrawn EP0068314A1 (en) 1981-06-19 1982-06-16 Treatment of arthritic complaints

Country Status (8)

Country Link
US (1) US4397867A (en)
EP (1) EP0068314A1 (en)
JP (1) JPS5823619A (en)
BE (1) BE893559A (en)
IT (1) IT8248659A0 (en)
NZ (1) NZ201010A (en)
PH (1) PH18342A (en)
ZA (1) ZA824327B (en)

Cited By (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0214101A2 (en) * 1985-09-03 1987-03-11 Ciba-Geigy Ag Use of iron(III) chelators of the type desferrioxamine-B and desferriferrithiocine in the treatment of malaria
EP0227593A1 (en) * 1985-11-25 1987-07-01 The Hospital For Sick Children Use of chelating agents
EP0652008A1 (en) * 1993-07-23 1995-05-10 The Minister Of National Defence Of Her Majesty's Canadian Government Liposome-encapsulated ciprofloxacin
EP0706375A1 (en) * 1993-06-14 1996-04-17 Emisphere Technologies, Inc. Proteinoid carriers
EP0726771A1 (en) * 1993-10-26 1996-08-21 Emisphere Technologies, Inc. Desferrioxamine oral delivery system
US5629020A (en) * 1994-04-22 1997-05-13 Emisphere Technologies, Inc. Modified amino acids for drug delivery
US5643957A (en) 1993-04-22 1997-07-01 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US5650386A (en) 1995-03-31 1997-07-22 Emisphere Technologies, Inc. Compositions for oral delivery of active agents
US5667806A (en) 1995-06-07 1997-09-16 Emisphere Technologies, Inc. Spray drying method and apparatus
US5709861A (en) 1993-04-22 1998-01-20 Emisphere Technologies, Inc. Compositions for the delivery of antigens
US5714167A (en) 1992-06-15 1998-02-03 Emisphere Technologies, Inc. Active agent transport systems
US5766633A (en) 1993-04-22 1998-06-16 Emisphere Technologies, Inc. Oral drug delivery compositions and methods
US5792451A (en) 1994-03-02 1998-08-11 Emisphere Technologies, Inc. Oral drug delivery compositions and methods
US5804688A (en) 1997-02-07 1998-09-08 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US5811127A (en) 1992-06-15 1998-09-22 Emisphere Technologies, Inc. Desferrioxamine oral delivery system
US5820881A (en) 1995-04-28 1998-10-13 Emisphere Technologies, Inc. Microspheres of diamide-dicarboxylic acids
US5824345A (en) 1995-06-07 1998-10-20 Emisphere Technologies, Inc. Fragrances and flavorants
US5840340A (en) 1992-06-15 1998-11-24 Emisphere Technologies, Inc. Proteinoid carriers and methods for preparation and use thereof
US5863944A (en) 1997-04-30 1999-01-26 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US5866536A (en) 1995-03-31 1999-02-02 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US5876710A (en) 1997-02-07 1999-03-02 Emisphere Technologies Inc. Compounds and compositions for delivering active agents
US5879681A (en) 1997-02-07 1999-03-09 Emisphere Technolgies Inc. Compounds and compositions for delivering active agents
US5939381A (en) 1997-02-07 1999-08-17 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US5958457A (en) 1993-04-22 1999-09-28 Emisphere Technologies, Inc. Compositions for the delivery of antigens
US5962710A (en) 1997-05-09 1999-10-05 Emisphere Technologies, Inc. Method of preparing salicyloylamino acids
US5965121A (en) 1995-03-31 1999-10-12 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US5972387A (en) 1992-12-21 1999-10-26 Emisphere Technologies, Inc. Modified hydrolyzed vegetable protein microspheres and methods for preparation and use thereof
US5976569A (en) 1994-09-29 1999-11-02 Emisphere Technologies, Inc. Diketopiperazine-based delivery systems
US5989539A (en) 1995-03-31 1999-11-23 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US5990166A (en) 1997-02-07 1999-11-23 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US6001347A (en) 1995-03-31 1999-12-14 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US6051258A (en) 1995-06-07 2000-04-18 Emisphere Technologies, Inc. Proteinoid emulsions and methods for preparation and use thereof
US6060513A (en) 1997-02-07 2000-05-09 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US6071510A (en) 1995-03-31 2000-06-06 Emisphere Technologies, Inc. Modified amino acids and compositions comprising the same for delivering active agents
US6084112A (en) 1995-09-11 2000-07-04 Emisphere Technologies, Inc. Method for preparing ω-aminoalkanoic acid derivatives from cycloalkanones
US6090958A (en) 1995-03-31 2000-07-18 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US6099856A (en) 1992-06-15 2000-08-08 Emisphere Technologies, Inc. Active agent transport systems
US6100285A (en) 1995-06-07 2000-08-08 Emisphere Technologies, Inc. Method of solubilizing itraconazole
US6221367B1 (en) 1992-06-15 2001-04-24 Emisphere Technologies, Inc. Active agent transport systems
US6242495B1 (en) 1997-02-07 2001-06-05 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
WO2001049266A2 (en) * 1999-12-30 2001-07-12 Gwathemy Judith K Iron chelator delivery system
US6331318B1 (en) 1994-09-30 2001-12-18 Emisphere Technologies Inc. Carbon-substituted diketopiperazine delivery systems
US6375983B1 (en) 1996-06-14 2002-04-23 Emisphere Technologies, Inc. Microencapsulated fragrances and method for preparation
US7417022B2 (en) 1996-03-29 2008-08-26 Mhr Institutional Partners Iia Lp Compounds and compositions for delivering active agents
US7553872B2 (en) 1997-02-07 2009-06-30 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE34313E (en) * 1983-09-23 1993-07-13 National Research Development Corporation Pharmaceutical compositions
US4912118A (en) * 1983-09-23 1990-03-27 National Research Development Corporation Pharmaceutical compositions
US5177068A (en) * 1984-04-19 1993-01-05 National Research Development Corporation Pharmaceutical compositions
US4863964A (en) * 1985-07-02 1989-09-05 Biomedical Frontiers, Inc. Method for the stabilization of deferoxamine to chelate free ions in physiological fluid
US5217998A (en) * 1985-07-02 1993-06-08 Biomedical Frontiers, Inc. Composition for the stabilization of deferoxamine to chelate free ions in physiological fluid
US4743587A (en) * 1985-09-10 1988-05-10 G. D. Searle & Co. Hydroxamic acid based collagenase inhibitors
US4599361A (en) * 1985-09-10 1986-07-08 G. D. Searle & Co. Hydroxamic acid based collagenase inhibitors
US4698431A (en) * 1985-11-12 1987-10-06 The United States Of America As Represented By The United States Department Of Energy Hydroxypyridonate chelating agents
US4797285A (en) * 1985-12-06 1989-01-10 Yissum Research And Development Company Of The Hebrew University Of Jerusalem Lipsome/anthraquinone drug composition and method
US5707604A (en) * 1986-11-18 1998-01-13 Access Pharmaceuticals, Inc. Vivo agents comprising metal-ion chelates with acidic saccharides and glycosaminoglycans, giving improved site-selective localization, uptake mechanism, sensitivity and kinetic-spatial profiles
US5672334A (en) * 1991-01-16 1997-09-30 Access Pharmaceuticals, Inc. Invivo agents comprising cationic metal chelators with acidic saccharides and glycosaminoglycans
US5043166A (en) * 1987-01-09 1991-08-27 Hadasit Medical Research, Inc. Liposome/anthraquinone drug composition and method
US6106866A (en) * 1995-07-31 2000-08-22 Access Pharmaceuticals, Inc. In vivo agents comprising cationic drugs, peptides and metal chelators with acidic saccharides and glycosaminoglycans, giving improved site-selective localization, uptake mechanism, sensitivity and kinetic-spatial profiles, including tumor sites
US8029795B2 (en) * 1999-12-30 2011-10-04 Gwathmey, Inc. Targeted iron chelator delivery system
US9737511B2 (en) * 2004-05-24 2017-08-22 Geoffrey C. GURTNER Method of treating or preventing pathologic effects of acute increases in hyperglycemia and/or acute increases of free fatty acid flux
US10098857B2 (en) 2008-10-10 2018-10-16 The Board Of Trustees Of The Leland Stanford Junior University Topical and transdermal delivery of HIF-1 modulators to prevent and treat chronic wounds
PL2854769T3 (en) * 2012-07-05 2023-08-07 Taiwan Liposome Company, Ltd. Methods of treating arthritis
SI3922241T1 (en) 2013-02-01 2024-03-29 Celator Pharmaceuticals, Inc. Remote loading of sparingly water-soluble drugs into liposomes
US10004759B2 (en) 2014-08-04 2018-06-26 Zoneone Pharma, Inc. Remote loading of sparingly water-soluble drugs into lipid vesicles
US11331288B2 (en) 2017-09-14 2022-05-17 The Board Of Trustees Of The Leland Stanford Junior University Conditioning irradiated tissue for increasing vascularity

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB999583A (en) * 1959-09-25 1965-07-28 Ciba Ltd Pharmaceutical preparations containing trihydroxamic acids

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB999583A (en) * 1959-09-25 1965-07-28 Ciba Ltd Pharmaceutical preparations containing trihydroxamic acids

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 88, no. 24, 12th June 1978, page 433, no. 177134q, Columbus Ohio (USA); *
CHEMICAL ABSTRACTS, vol. 92, no. 17, 28th April 1980, page 125, no. 141457r, Columbus Ohio (USA); *
CHEMICAL ABSTRACTS, vol. 95, no. 2, 13th July 1981, page 362, no. 12709n, Columbus Ohio (USA); *
CHEMICAL ABSTRACTS, vol. 95, no. 5, 3rd August 1981, page 547, no. 40507p, Columbus Ohio (USA); *

Cited By (62)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0214101A2 (en) * 1985-09-03 1987-03-11 Ciba-Geigy Ag Use of iron(III) chelators of the type desferrioxamine-B and desferriferrithiocine in the treatment of malaria
EP0214101A3 (en) * 1985-09-03 1989-05-31 Ciba-Geigy Ag Use of iron(iii) chelators of the type desferrioxamine-b and desferriferrithiocine in the treatment of malaria
EP0227593A1 (en) * 1985-11-25 1987-07-01 The Hospital For Sick Children Use of chelating agents
US6245359B1 (en) 1992-06-15 2001-06-12 Emisphere Technologies, Inc. Active agent transport systems
US5714167A (en) 1992-06-15 1998-02-03 Emisphere Technologies, Inc. Active agent transport systems
US5840340A (en) 1992-06-15 1998-11-24 Emisphere Technologies, Inc. Proteinoid carriers and methods for preparation and use thereof
US6071538A (en) 1992-06-15 2000-06-06 Emisphere Technologies, Inc. Oral delivery composition comprising supramolecular complex
US6413550B1 (en) 1992-06-15 2002-07-02 Emisphere Technologies, Inc. Proteinoid carriers and methods for preparation and use thereof
US6099856A (en) 1992-06-15 2000-08-08 Emisphere Technologies, Inc. Active agent transport systems
US5811127A (en) 1992-06-15 1998-09-22 Emisphere Technologies, Inc. Desferrioxamine oral delivery system
US6221367B1 (en) 1992-06-15 2001-04-24 Emisphere Technologies, Inc. Active agent transport systems
US5972387A (en) 1992-12-21 1999-10-26 Emisphere Technologies, Inc. Modified hydrolyzed vegetable protein microspheres and methods for preparation and use thereof
US5709861A (en) 1993-04-22 1998-01-20 Emisphere Technologies, Inc. Compositions for the delivery of antigens
US5766633A (en) 1993-04-22 1998-06-16 Emisphere Technologies, Inc. Oral drug delivery compositions and methods
US6100298A (en) 1993-04-22 2000-08-08 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US5955503A (en) 1993-04-22 1999-09-21 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US5643957A (en) 1993-04-22 1997-07-01 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US5958457A (en) 1993-04-22 1999-09-28 Emisphere Technologies, Inc. Compositions for the delivery of antigens
EP0706375A1 (en) * 1993-06-14 1996-04-17 Emisphere Technologies, Inc. Proteinoid carriers
EP0706375A4 (en) * 1993-06-14 1996-11-06 Emisphere Tech Inc Proteinoid carriers
EP0652008A1 (en) * 1993-07-23 1995-05-10 The Minister Of National Defence Of Her Majesty's Canadian Government Liposome-encapsulated ciprofloxacin
EP0726771A4 (en) * 1993-10-26 1997-01-29 Emisphere Tech Inc Desferrioxamine oral delivery system
EP0726771A1 (en) * 1993-10-26 1996-08-21 Emisphere Technologies, Inc. Desferrioxamine oral delivery system
US5792451A (en) 1994-03-02 1998-08-11 Emisphere Technologies, Inc. Oral drug delivery compositions and methods
US5935601A (en) * 1994-04-22 1999-08-10 Emisphere Technologies, Inc. Modified amino acids for drug delivery
US5629020A (en) * 1994-04-22 1997-05-13 Emisphere Technologies, Inc. Modified amino acids for drug delivery
US6180140B1 (en) 1994-04-22 2001-01-30 Emisphere Technologies, Inc. Modified amino acids for drug delivery
US5976569A (en) 1994-09-29 1999-11-02 Emisphere Technologies, Inc. Diketopiperazine-based delivery systems
US6331318B1 (en) 1994-09-30 2001-12-18 Emisphere Technologies Inc. Carbon-substituted diketopiperazine delivery systems
US5989539A (en) 1995-03-31 1999-11-23 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US6090958A (en) 1995-03-31 2000-07-18 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US6428780B2 (en) 1995-03-31 2002-08-06 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US6346242B1 (en) 1995-03-31 2002-02-12 Emishpere Technologies, Inc. Compounds and compositions for delivering active agents
US5650386A (en) 1995-03-31 1997-07-22 Emisphere Technologies, Inc. Compositions for oral delivery of active agents
US5965121A (en) 1995-03-31 1999-10-12 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US6001347A (en) 1995-03-31 1999-12-14 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US5866536A (en) 1995-03-31 1999-02-02 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US6071510A (en) 1995-03-31 2000-06-06 Emisphere Technologies, Inc. Modified amino acids and compositions comprising the same for delivering active agents
US5820881A (en) 1995-04-28 1998-10-13 Emisphere Technologies, Inc. Microspheres of diamide-dicarboxylic acids
US5667806A (en) 1995-06-07 1997-09-16 Emisphere Technologies, Inc. Spray drying method and apparatus
US5824345A (en) 1995-06-07 1998-10-20 Emisphere Technologies, Inc. Fragrances and flavorants
US6100285A (en) 1995-06-07 2000-08-08 Emisphere Technologies, Inc. Method of solubilizing itraconazole
US6461545B1 (en) 1995-06-07 2002-10-08 Emisphere Technologies, Inc. Method of solubilizing and encapsulating itraconazole
US6051258A (en) 1995-06-07 2000-04-18 Emisphere Technologies, Inc. Proteinoid emulsions and methods for preparation and use thereof
US6084112A (en) 1995-09-11 2000-07-04 Emisphere Technologies, Inc. Method for preparing ω-aminoalkanoic acid derivatives from cycloalkanones
US7417022B2 (en) 1996-03-29 2008-08-26 Mhr Institutional Partners Iia Lp Compounds and compositions for delivering active agents
US6375983B1 (en) 1996-06-14 2002-04-23 Emisphere Technologies, Inc. Microencapsulated fragrances and method for preparation
US6313088B1 (en) 1997-02-07 2001-11-06 Emisphere Technologies, Inc. 8-[(2-hydroxy-4-methoxy benzoyl) amino]-octanoic acid compositions for delivering active agents
US5990166A (en) 1997-02-07 1999-11-23 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US8686154B2 (en) 1997-02-07 2014-04-01 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US6242495B1 (en) 1997-02-07 2001-06-05 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US5876710A (en) 1997-02-07 1999-03-02 Emisphere Technologies Inc. Compounds and compositions for delivering active agents
US7553872B2 (en) 1997-02-07 2009-06-30 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US6060513A (en) 1997-02-07 2000-05-09 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US5879681A (en) 1997-02-07 1999-03-09 Emisphere Technolgies Inc. Compounds and compositions for delivering active agents
US5939381A (en) 1997-02-07 1999-08-17 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US5804688A (en) 1997-02-07 1998-09-08 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US5863944A (en) 1997-04-30 1999-01-26 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US5962710A (en) 1997-05-09 1999-10-05 Emisphere Technologies, Inc. Method of preparing salicyloylamino acids
US6960560B2 (en) 1999-12-30 2005-11-01 Gwathmey, Inc. Iron chelator delivery system
WO2001049266A3 (en) * 1999-12-30 2002-03-21 Judith K Gwathemy Iron chelator delivery system
WO2001049266A2 (en) * 1999-12-30 2001-07-12 Gwathemy Judith K Iron chelator delivery system

Also Published As

Publication number Publication date
BE893559A (en) 1982-12-20
IT8248659A0 (en) 1982-06-17
JPS5823619A (en) 1983-02-12
PH18342A (en) 1985-06-05
ZA824327B (en) 1984-01-25
NZ201010A (en) 1986-02-21
US4397867A (en) 1983-08-09

Similar Documents

Publication Publication Date Title
US4397867A (en) Treatment of arthritic complaints
AU617678B2 (en) Prostaglandin-lipid formulations
US5262168A (en) Prostaglandin-lipid formulations
US9770414B2 (en) Sustained release formulation of methotrexate as a disease-modifying antirheumatic drug (DMARD) and an anti-cancer agent
US5186941A (en) Vesicle formulation for the controlled release of therapeutic agents
EP0126580A2 (en) Vesicle formulations for the controlled release of therapeutic agents
EP2344132A2 (en) Liposomal systems comprising sphingomyelin
RU2005115956A (en) METHOD FOR TREATING INSULIN RESISTANCE, ADULTS DIABETES AND METABOLIC SYNDROME X
JPS62181225A (en) Anesthetic medicine composition
EP0072234B1 (en) Pharmaceutical formulations containing antimony
EP0726763B1 (en) Methods of treatment using unilamellar liposomal arachidonic acid metabolite formulations
US20050008664A1 (en) Compositions and methods related to lipid:emodin formulations
US5811118A (en) Methods of treatment using unilamellar liposomal arachidonic acid metabolite formulations
CA2547866C (en) Farnesyl dibenzodiazepinone formulation
Williams et al. The suppression of rat collagen-induced arthritis and inhibition of macrophage derived mediator release by liposomal methotrexate formulations
Williams et al. Suppression of adjuvant-induced arthritis by liposomally conjugated methotrexate in the rat
Williams et al. Interleukin‐1β (IL‐1β) inhibition: a possible mechanism for the anti‐inflammatory potency of liposomally conjugated methotrexate formulations in arthritis
JPH11510184A (en) Use of sulfamic acid derivatives, acylsulfonamides or sulfonyl carbamates for the manufacture of a medicament for reducing lipoprotein levels
EP0300806B1 (en) Opioid analgesic liposomal delivery-release system
KR20200037879A (en) Dosage regime for apolipoprotein formulations
GB2143433A (en) Methotrexate ointment
WO1988007851A1 (en) Liposome entrapped n-methyl-d-aspartate receptor blockers
WO1988007852A1 (en) Liposome entrapped magnesium
JPH0211515A (en) Pharmaceutical preparation containing ferbinac
AU2013203682B2 (en) Liposome comprising at least one cholesterol derivative

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19820616

AK Designated contracting states

Designated state(s): CH DE FR GB LI LU NL SE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19860222

RIN1 Information on inventor provided before grant (corrected)

Inventor name: BLAKE, DAVID RUSSELL, DR.