GB2367242A - Antiviral treatment - Google Patents
Antiviral treatment Download PDFInfo
- Publication number
- GB2367242A GB2367242A GB0023199A GB0023199A GB2367242A GB 2367242 A GB2367242 A GB 2367242A GB 0023199 A GB0023199 A GB 0023199A GB 0023199 A GB0023199 A GB 0023199A GB 2367242 A GB2367242 A GB 2367242A
- Authority
- GB
- United Kingdom
- Prior art keywords
- loop diuretic
- frusemide
- dna
- composition
- viral
- 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.)
- Granted
Links
- 238000011282 treatment Methods 0.000 title claims abstract description 9
- 230000000840 anti-viral effect Effects 0.000 title claims description 11
- 239000002171 loop diuretic Substances 0.000 claims abstract description 19
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229960003883 furosemide Drugs 0.000 claims abstract description 17
- 230000010076 replication Effects 0.000 claims abstract description 5
- NGBFQHCMQULJNZ-UHFFFAOYSA-N Torsemide Chemical compound CC(C)NC(=O)NS(=O)(=O)C1=CN=CC=C1NC1=CC=CC(C)=C1 NGBFQHCMQULJNZ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 108020005202 Viral DNA Proteins 0.000 claims abstract description 4
- 229960005461 torasemide Drugs 0.000 claims abstract description 4
- 230000019522 cellular metabolic process Effects 0.000 claims abstract description 3
- AVOLMBLBETYQHX-UHFFFAOYSA-N etacrynic acid Chemical compound CCC(=C)C(=O)C1=CC=C(OCC(O)=O)C(Cl)=C1Cl AVOLMBLBETYQHX-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229960003199 etacrynic acid Drugs 0.000 claims abstract description 3
- 230000000699 topical effect Effects 0.000 claims abstract description 3
- 208000004449 DNA Virus Infections Diseases 0.000 claims abstract 2
- 239000000203 mixture Substances 0.000 claims description 8
- 230000009885 systemic effect Effects 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- -1 bumetamide Chemical compound 0.000 claims 1
- MAEIEVLCKWDQJH-UHFFFAOYSA-N bumetanide Chemical compound CCCCNC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1OC1=CC=CC=C1 MAEIEVLCKWDQJH-UHFFFAOYSA-N 0.000 abstract description 2
- 229960004064 bumetanide Drugs 0.000 abstract description 2
- 238000007910 systemic administration Methods 0.000 abstract 1
- 238000011200 topical administration Methods 0.000 abstract 1
- 230000005764 inhibitory process Effects 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 6
- 241000700605 Viruses Species 0.000 description 5
- 108020004414 DNA Proteins 0.000 description 4
- 230000009385 viral infection Effects 0.000 description 4
- 241000450599 DNA viruses Species 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 201000004569 Blindness Diseases 0.000 description 2
- 241000282552 Chlorocebus aethiops Species 0.000 description 2
- 208000009889 Herpes Simplex Diseases 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 208000036142 Viral infection Diseases 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000001882 diuretic effect Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010048843 Cytomegalovirus chorioretinitis Diseases 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010019973 Herpes virus infection Diseases 0.000 description 1
- 208000029433 Herpesviridae infectious disease Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- 241000125945 Protoparvovirus Species 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 102000006601 Thymidine Kinase Human genes 0.000 description 1
- 108020004440 Thymidine kinase Proteins 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000001174 ascending effect Effects 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000036983 biotransformation Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 208000001763 cytomegalovirus retinitis Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229930182480 glucuronide Natural products 0.000 description 1
- 150000008134 glucuronides Chemical class 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 210000003501 vero cell Anatomy 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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
- A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
-
- 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
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
- A61K9/0051—Ocular inserts, ocular implants
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The use of a loop diuretic to alter the ionic balance of a living cell to a level that will inhibit the replication of viral DNA without detrimentally affecting cellular metabolism. The loop diuretic used may be selected from frusemide (furosemide), bumetanide, ethacrynic acid or torasemide, and may be adapted for topical or systemic administration. A preferred embodiment provides contact lenses carrying such a loop diuretic, which may be used for the treatment of DNA virus infections of the eye.
Description
ANTIVIRAL TREATMENT
The invention relates to anti-viral treatments and in particular to prophylactic and therapeutic treatments of DNA viral infections such as Herpes virus infections.
Herpes viruses are DNA viruses, having a central core of DNA within a proteinaceous structure. DNA carries the genetic code to reproduce the virus. Viruses must infect a living cell to reproduce. There are numerous viral proteins that are well characterised including important enzymes which act as ideal targets for antiviral chemotherapy.
These include DNA polymerase and thymidine kinase which are needed for DNA replication. The replication of viral DNA is essential for virus infectivity. It is known that infecting viruses can alter the natural ionic balances of a living cell in the course of their replication.
We have discovered that a loop diuretic can be used for an antiviral effect against
DNA viruses.
According to this invention in one aspect there is provided the use of a loop diuretic acting to alter the natural ionic balance of a living cell to a level less than that which will affect cellular metabolism detrimentally but sufficient to inhibit replication of viral DNA.
In another aspect the invention provides a composition useful for the treatment of virus infections in subjects, comprising an effective anti-viral amount of a loop diuretic and a suitable carrier.
The loop diuretic may be selected from a wide range of available agents. Preferably the loop diuretic is any one or more of frusemide, bumetanide, ethacrynic acid or torasemide. According to our studies the loop diuretics mediate their antiviral effects through alteration to the cellular concentration of ions, cellular ionic balances, cellular ionic milieu and electrical potentials.
Frusemide is an anthrilic acid derivative, chemically 4-chloro-N-furfuryl-5- sulfamoylanthranilic acid. It is practically insoluble in water at neutral pH, however is freely soluble in alkali. Frusemide exerts its physiological effect by inhibition of the transport of chloride ions across cell members. Frusemide is a loop diuretic with a short duration of action. It is used for treating oedema due to hepatic, renal, or cardiac failure and treating hypertension. The bioavailability of frusemide is between 60% to 70% and it is primarily excreted by filtration and secretion as unchanged
drug. Frusemide acts on the Na+/K+/2Cl-cotransfonner. For its diuretic effect, its predominant action is in the ascending limb of the loop of Hennie in the kidney. Loop diuretics markedly promote K+ excretion, leaving cells depleted in intracellular potassium. This may lead to the most significant complication of long term systemic frusemide usage namely a lowered serum potassium. We postulate that it is this action however which makes frusemide a candidate for use as an agent against DNA viral infections.
Recent evidence suggests that the major biotransformation product of frusemide is a glucuronide. Frusemide is extensively bound to plasma proteins, mainly albumin.
Plasma concentrations ranging from 1 to 400 mcg/ml are 91-99% bound in healthy individuals. The unbound fraction ranges between 2.3-4. 1% at therapeutic concentrations. The terminal half life of frusemide is approximately 2 hours, and it is predominantly excreted in the urine.
The invention is applicable to Herpes and other DNA viruses such as parvoviruses; papoviruses; adenoviruses; hepadnoviruses and poxviruses.
The compositions of the invention may be adapted for external or internal administration. The formulations may be adapted for slow release. Topical and systemic applications are likely to be the most useful. Other ingredients may be present, provided that they do not compromise the anti-viral activity.
A preferred embodiment of this invention is the use of local concentrations of a loop diuretic as a highly effective treatment of virus infections of the eye. Recurrent
Herpes infections of the cornea in man is the most common viral cause of blindness.
The use of contact lenses carrying e. g. impregnated with a loop diuretic would be a safe and efficient method for creating high intracellular concentrations to prevent or treat the disease. A depot application of a loop diuretic applied intra-occularly would be a suitable method for the treatment of cytomegalovirus retinitis, a major cause of blindness in patients suffering with AIDS.
In order that the invention may be well understood it will now be described by way of illustration only with reference to the following example:
EXAMPLE
In vitro bioassays were undertaken to follow the anti-viral activity of a diuretic compound.
The therapeutic compositions were applied to African green monkey kidney and BHK1 veros cells infected with type 2 herpes simplex virus (strains 3345 and 180) at low, intermediate, and high multiplicities of infection (MOI). Inhibition of virus replication was scored on the scale: no inhibition 20% inhibition + 40% inhibition ++ 60% inhibition +++ 80% inhibition ++++ 100% inhibition +++++ T denotes drug toxicity.
The following results were obtained using African green monkey kidney cells and type 2 herpes simplex strain 3345:
Inhibition of hsv2
Multiplicity of infection (Dose of virus) Effect of frusemide
High
Medium ++
Low ++
The experiment was repeated using BHK1 vero cells and type 2 herpes simplex strain 180. Similar results were obtained.
These results show the antiviral effect of frusemide at Imgjml.
Claims (7)
- CLAIMS 1. Use of a loop diuretic acting to alter the natural ionic balance of a living cell to a level less than that which will affect cellular metabolism detrimentally but sufficient to inhibit replication of viral DNA.
- 2. Use according to Claim 1, wherein the loop diuretic is one or more of frusemide, bumetamide, ethacyrnic acid or torasemide.
- 3. A composition useful for the treatment of DNA virus infections in subjects, comprising an effective anti-viral amount of a loop diuretic and a suitable carrier.
- 4. A composition in accordance with Claim 3 adapted for topical application.
- 5. A composition in accordance with Claim 3 adapted for systemic application.
- 6. A composition according to Claim 3,4 or 5, wherein the loop diuretic is one or more of frusemide, bumetamide, ethacrynic acid or torasemide.
- 7. Contact lenses carrying e. g. impregnated with a loop diuretic.
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0023199A GB2367242B (en) | 2000-09-21 | 2000-09-21 | Antiviral treatment |
| EP01967534A EP1322316B1 (en) | 2000-09-21 | 2001-09-21 | Diuretic or sulphonylurea for use in antiviral treatment |
| DE60139134T DE60139134D1 (en) | 2000-09-21 | 2001-09-21 | DIETHETICS OR SULFONYL UREA FOR USE IN ANTIVIRAL TREATMENT |
| PCT/GB2001/004206 WO2002024207A1 (en) | 2000-09-21 | 2001-09-21 | Diuretic or sulphonylurea for use in antiviral treatment |
| US10/380,886 US20040034016A1 (en) | 2000-09-21 | 2001-09-21 | Diuretic or sulphonylurea for use in antiviral treatment |
| AU2001287907A AU2001287907A1 (en) | 2000-09-21 | 2001-09-21 | Diuretic or sulphonylurea for use in antiviral treatment |
| AT01967534T ATE435019T1 (en) | 2000-09-21 | 2001-09-21 | DIURETIC OR SULFONYL UREA FOR USE IN ANTIVIRAL TREATMENT |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0023199A GB2367242B (en) | 2000-09-21 | 2000-09-21 | Antiviral treatment |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB0023199D0 GB0023199D0 (en) | 2000-11-01 |
| GB2367242A true GB2367242A (en) | 2002-04-03 |
| GB2367242B GB2367242B (en) | 2004-07-28 |
Family
ID=9899887
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB0023199A Expired - Fee Related GB2367242B (en) | 2000-09-21 | 2000-09-21 | Antiviral treatment |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2367242B (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2044101A (en) * | 1979-02-22 | 1980-10-15 | Sandoz Ltd | Antihypertensive pharmaceutical compositions |
| EP0068408A1 (en) * | 1980-11-10 | 1983-01-05 | Mochida Pharmaceutical Co., Ltd. | Antiviral compositions and a method for treating virus diseases |
| US4757089A (en) * | 1985-06-14 | 1988-07-12 | Massachusetts Eye And Ear Infirmary | Increasing aqueous humor outflow |
| US5026690A (en) * | 1986-08-02 | 1991-06-25 | Chemische Fabrik Stockhausen Gmbh | Antiviral agent |
| US5650541A (en) * | 1993-04-19 | 1997-07-22 | Alcon Laboratories, Inc. | Ethacrynic acid-like compounds and use thereof to treat glaucoma |
| WO2000010574A1 (en) * | 1998-08-24 | 2000-03-02 | Hadasit Medical Research Services And Development Ltd. | The use of loop diuretics for hiv infection |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2218254T3 (en) * | 1999-12-30 | 2004-11-16 | Henderson Morley Research And Development Limited | COMBINATIONS OF CARDIAC GLYCOSIDES WITH ASA DIURETICS FOR THE TREATMENT OF VIRIC DNA INFECTIONS. |
-
2000
- 2000-09-21 GB GB0023199A patent/GB2367242B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2044101A (en) * | 1979-02-22 | 1980-10-15 | Sandoz Ltd | Antihypertensive pharmaceutical compositions |
| EP0068408A1 (en) * | 1980-11-10 | 1983-01-05 | Mochida Pharmaceutical Co., Ltd. | Antiviral compositions and a method for treating virus diseases |
| US4757089A (en) * | 1985-06-14 | 1988-07-12 | Massachusetts Eye And Ear Infirmary | Increasing aqueous humor outflow |
| US5026690A (en) * | 1986-08-02 | 1991-06-25 | Chemische Fabrik Stockhausen Gmbh | Antiviral agent |
| US5650541A (en) * | 1993-04-19 | 1997-07-22 | Alcon Laboratories, Inc. | Ethacrynic acid-like compounds and use thereof to treat glaucoma |
| WO2000010574A1 (en) * | 1998-08-24 | 2000-03-02 | Hadasit Medical Research Services And Development Ltd. | The use of loop diuretics for hiv infection |
Non-Patent Citations (1)
| Title |
|---|
| Virology; Vol 219, pp 291-294 (1996). Voss et al. * |
Also Published As
| Publication number | Publication date |
|---|---|
| GB0023199D0 (en) | 2000-11-01 |
| GB2367242B (en) | 2004-07-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 20130921 |