SK287043B6 - Use of brivudine for the treatment of herpes zoster infections or post-herpetic neuralgia - Google Patents
Use of brivudine for the treatment of herpes zoster infections or post-herpetic neuralgia Download PDFInfo
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- SK287043B6 SK287043B6 SK957-2001A SK9572001A SK287043B6 SK 287043 B6 SK287043 B6 SK 287043B6 SK 9572001 A SK9572001 A SK 9572001A SK 287043 B6 SK287043 B6 SK 287043B6
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- brivudine
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- magnesium stearate
- microcrystalline cellulose
- acyclovir
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- ODZBBRURCPAEIQ-PIXDULNESA-N helpin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(\C=C\Br)=C1 ODZBBRURCPAEIQ-PIXDULNESA-N 0.000 title claims abstract description 86
- 229960001169 brivudine Drugs 0.000 title claims abstract description 82
- 206010036376 Postherpetic Neuralgia Diseases 0.000 title claims abstract description 27
- 208000007514 Herpes zoster Diseases 0.000 title claims abstract description 23
- 208000015181 infectious disease Diseases 0.000 title claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 36
- 235000019359 magnesium stearate Nutrition 0.000 claims description 18
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 17
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 9
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 6
- 229940069328 povidone Drugs 0.000 claims description 6
- 229910002012 Aerosil® Inorganic materials 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims description 5
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 4
- 235000013339 cereals Nutrition 0.000 claims description 4
- 229960001375 lactose Drugs 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- 229960001021 lactose monohydrate Drugs 0.000 claims description 4
- 239000008107 starch Substances 0.000 claims description 4
- 235000019698 starch Nutrition 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000004408 titanium dioxide Substances 0.000 claims description 2
- 229920001531 copovidone Polymers 0.000 claims 3
- 229940008126 aerosol Drugs 0.000 claims 2
- 239000000443 aerosol Substances 0.000 claims 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims 1
- 229960003511 macrogol Drugs 0.000 claims 1
- 230000001154 acute effect Effects 0.000 abstract description 7
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 45
- 229960004150 aciclovir Drugs 0.000 description 42
- 239000003826 tablet Substances 0.000 description 15
- 208000002193 Pain Diseases 0.000 description 13
- 239000002994 raw material Substances 0.000 description 9
- 230000008901 benefit Effects 0.000 description 8
- 206010037844 rash Diseases 0.000 description 7
- 208000010201 Exanthema Diseases 0.000 description 6
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 6
- 201000005884 exanthem Diseases 0.000 description 6
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 4
- 230000000840 anti-viral effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229960004396 famciclovir Drugs 0.000 description 4
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 description 4
- HDOVUKNUBWVHOX-QMMMGPOBSA-N Valacyclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCOC(=O)[C@@H](N)C(C)C)C=N2 HDOVUKNUBWVHOX-QMMMGPOBSA-N 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 230000000977 initiatory effect Effects 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 229940093257 valacyclovir Drugs 0.000 description 3
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 description 2
- 208000005298 acute pain Diseases 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 229960001179 penciclovir Drugs 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 231100000444 skin lesion Toxicity 0.000 description 2
- 206010040882 skin lesion Diseases 0.000 description 2
- 231100000046 skin rash Toxicity 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
- 241000700605 Viruses Species 0.000 description 1
- 229940086177 acyclovir 800 mg Drugs 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000009331 sowing Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000000528 statistical test Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000007442 viral DNA synthesis Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 230000001790 virustatic effect Effects 0.000 description 1
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- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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Abstract
Description
Oblasť technikyTechnical field
Predkladaný vynález sa týka použitia brivudínu na liečbu akútnych infekcií herpes zoster a na prevenciu výskytu post-herpetickej neuralgie podávaného lkrát denne.The present invention relates to the use of brivudine for the treatment of acute herpes zoster infections and for preventing the occurrence of post-herpetic neuralgia administered once daily.
Doterajší stav technikyBACKGROUND OF THE INVENTION
V priebehu posledných desiatich rokov sa významne zvýšil počet klinicky účinných liečiv uvedených do chemoterapie vírusových ochorení. Od jeho uvedenia v roku 1982 má acyklovir široké použitie v liečbe akútneho herpesu zoster u imuno-kompetentných pacientov. Hlavnou nevýhodou liečby acyklovirom však je jeho obmedzená biologická dostupnosť, potreba opakovaných a vysokých dávok, čo často spôsobuje jeho nevhodnosť.Over the past decade, the number of clinically effective drugs introduced for chemotherapy of viral diseases has increased significantly. Since its introduction in 1982, acyclovir has been widely used in the treatment of acute herpes zoster in immuno-competent patients. However, the main disadvantage of acyclovir treatment is its limited bioavailability, the need for repeated and high doses, which often makes it unsuitable.
Toto viedlo k vývoju nového antivírusového liečiva (pencikloviru) a tzv. prekurzorov, ako je napr. valaciklovir (prekurzor acykloviru) famciklovir (prekurzor pencikloviru). Doteraz famciklovir ponúka najvhodnejšiu liečbu akútneho herpesu zoster u starších pacientov, pri dávkovaní troch tabliet alebo kapsúl denne, v porovnaní s piatimi tabletami acykloviru a šiestimi tabletami valacikloviru denne. Famciklovir zmierňuje akútne známky a prejavy herpesu zoster ako acyklovir a poskytuje ochranu pred dlhotrvajúcou bolesťou súvisiacou s infekciou herpes zoster alebo PHN. Pri menej častom podávaní, v nižších dávkach a bez zvýšeného rizika nežiaducich účinkov v porovnaní s acyklovirom, je takáto liečba výhodná a vhodnejšia, najmä u starších pacientov. Odporúčaná denná dávka sa pohybuje medzi 750 mg a 1500 mg (Degreef a ďalší, 1994, Int. J. Antimicrob. Agents, 4, 241-246; Tyring a ďalší, 1995, Ann. Intem. Med., 123, 89-96; Dworkin a ďalší, 1995, Antiviral Res., 26, 344; Dworkin a ďalší, 1996, Pain, 67, 241-251; Dworkin a ďalší, 1998, Antiviral. Res., 33, 73-85).This has led to the development of a new antiviral drug (penciclovir) and the so-called. precursors such as e.g. valaciclovir (precursor of acyclovir) famciclovir (precursor of penciclovir). To date, famciclovir offers the most appropriate treatment for acute herpes zoster in the elderly, at a dose of three tablets or capsules per day, compared to five tablets of acyclovir and six tablets of valaciclovir per day. Famciclovir ameliorates the acute signs and symptoms of herpes zoster such as acyclovir and provides protection against prolonged pain associated with herpes zoster or PHN infection. With less frequent administration, at lower doses and without an increased risk of adverse reactions compared to acyclovir, such treatment is advantageous and more appropriate, especially in the elderly. The recommended daily dose is between 750 mg and 1500 mg (Degreef et al., 1994, Int. J. Antimicrob. Agents, 4, 241-246; Tyring et al., 1995, Ann. Intem. Med., 123, 89-96). Dworkin et al., 1995, Antiviral Res., 26, 344; Dworkin et al., 1996, Pain, 67, 241-251; Dworkin et al., 1998, Antiviral. Res., 33, 73-85).
Brivudín, nukleozidový analóg, je silnou virostatickou látkou so selektívnou aktivitou proti vírusu varicella zoster (VZV) a vírusu herpes simplex typu 1 (HSV-1) (De Clercq a ďalší, 1979, Proc. Natl. Acad. Sci. USA, 76, 2947-2951; De Clerq a ďalší, 1980, J. Infect. Dis, 141, 560-574). Zatiaľ čo syntéza vírusovej DNA je inhibovaná, bunkové funkcie ostávajú väčšinou neovplyvnené. Kontinuálny vývoj brivudínu v priebehu posledných rokov je nasmerovaný na liečbu VZV infekcii u imunokompetentých pacientov.Brivudine, a nucleoside analog, is a potent virostatic agent with selective activity against varicella zoster virus (VZV) and herpes simplex virus type 1 (HSV-1) (De Clercq et al., 1979, Proc. Natl. Acad. Sci. USA, 76, De Clerq et al., 1980, J. Infect. Dis, 141, 560-574). While viral DNA synthesis is inhibited, cellular functions remain largely unaffected. The continuous development of brivudine over recent years has been directed towards the treatment of VZV infection in immunocompetent patients.
Na základe výsledkov množstva nekontrolovaných a kontrolovaných štúdií sa brivudín zaregistroval v Nemecku v r. 1990 na liečbu HSV-1 a VZV infekcií u imunokompetentných pacientov v dávke 125 mg tri alebo štyrikrát denne (De Clerq a ďalší, 1980, Br. Med. J., 281,1178: Tricot a ďalší, 1986, J. Med. Virol., 18, 11-20; Wutzler a ďalší, 1995, J. Med. Virol., 46, 252-257; pozri tiež odbornú informáciu patriacu farmaceutickému produktu Helpin®, ktorý bol na území Nemecka uvedený na trh v r. 1992).Based on the results of a number of uncontrolled and controlled studies, brivudine was registered in Germany in. 1990 for the treatment of HSV-1 and VZV infections in immunocompetent patients at 125 mg three or four times a day (De Clerq et al., 1980, Br. Med. J., 281,1178: Tricot et al., 1986, J. Med. Virol Wutzler et al., 1995, J. Med. Virol., 46, 252-257 (see also the technical information pertaining to the pharmaceutical product Helpin® marketed in Germany in 1992). .
Podstata vynálezuSUMMARY OF THE INVENTION
V najnovších, veľkých mnohonárodných štúdiách uskutočňovaných u imunokompetentných pacientov s herpesom zoster, pri dávkovacom režime 125 mg brivudínu denne počas 7 dní sa prekvapujúco ukázalo, že je štatisticky lepší v porovnaní so štandardnou liečbou acyklovirom podávaným 5x denne 800 mg, vzhľadom na dermatologické ciele (5-Ho-b/0078BC). Sledovanie pacientov vo veku 50 rokov alebo starších, ktorí sa zúčastnili na týchto štúdiách, ktorí po ich ukončení mali PHN, naznačilo významne nižší výskyt PHN po liečbe brivudínom v porovnaní s acyklovirom (5-Ho[a+b+c]PHN/0078BC).Surprisingly, in the latest, large multinational studies conducted in immunocompetent patients with herpes zoster, on a 125 mg daily dose regimen of brivudine for 7 days, it was shown to be statistically superior to standard acyclovir treatment with 800 mg 5x daily relative to dermatological targets (5). -ho-b / 0078BC). The follow-up of patients aged 50 years or older who participated in these studies who had a PHN at the end of the study indicated a significantly lower incidence of PHN after treatment with brivudine compared to acyclovir (5-Ho [a + b + c] PHN / 0078BC) .
Podstatou vynálezu je preto použitie brivudínu na výrobu farmaceutického prostriedku na liečenie infekcií herpes zoster alebo post-herpetickej neuralgie podaním 50 až 300 mg účinnej látky lx denne.Accordingly, the present invention provides the use of brivudine for the manufacture of a pharmaceutical composition for the treatment of herpes zoster infections or post-herpetic neuralgia by administering 50 to 300 mg of active ingredient 1x daily.
Brivudín preto prekvapujúco poskytuje možnosť liečby u pacientov s herpesom zoster podávaním jednej 125 mg tablety denne, namiesto vysokých a častých dávkovacích schém acykloviru, valacikloviru alebo famcikloviru. Podávanie jednej 125 mg tablety denne je dokonca ešte prekvapujúcejšie, ak sa zváži, že predtým sa podľa schémy podávalo 125 mg 4 x denne, ako bolo registrované v Nemecku v r. 1990 na liečbu HSV-1 a VZV infekcií u imunosuprimovaných pacientov. Pri podávaní podľa schémy lx denne sa dosiahol ďalší prekvapujúci výsledok: zníženie výskytu postherpetickej neuralgie.Therefore, surprisingly, brivudine provides treatment options in patients with herpes zoster by administering one 125 mg tablet per day, instead of high and frequent dosing schedules of acyclovir, valaciclovir or famciclovir. The administration of one 125 mg tablet per day is even more surprising if it is considered that 125 mg four times a day was previously administered according to the scheme, as registered in Germany in the year. 1990 for the treatment of HSV-1 and VZV infections in immunosuppressed patients. When administered once daily, a surprising result was achieved: a reduction in the incidence of postherpetic neuralgia.
Klinické skúšanieClinical investigation
Na stanovenie účinnosti a bezpečnosti brivudínu u imunokompetentných dospelých pacientov sa v súčasnosti uskutočnili tri veľké pivotné štúdie (štúdie 5-Ho-a, 5-Ho-b a 5-Ho-c) v súlade s požiadavkami Správnej klinickej praxe. Všetky štyri štúdie boli prospektivne, podľa multicentrického, dvojito-slepého, randomizovaného paralelného návrhu štúdie.To assess the efficacy and safety of brivudine in immunocompetent adult patients, three large pivotal studies (5-Ho-a, 5-Ho-b and 5-Ho-c) are currently conducted in accordance with Good Clinical Practice requirements. All four studies were prospectively, according to a multi-center, double-blind, randomized, parallel design study.
Pacienti sa sledovali 35 dní, aby sa zhodnotilo zmiznutie kožného exantému a fázy akútnej bolesti. Všetci pacienti boli imunokompetentní. Do štúdie boli zahrnutí iba dospelí pacienti starší ako 18 rokov.Patients were followed for 35 days to assess the disappearance of the skin rash and the phase of acute pain. All patients were immunocompetent. Only adult patients over 18 years of age were included in the study.
Primárnym parametrom na stanovenie účinnosti vo všetkých troch štúdiách bol „čas od začiatku liečby po poslednú erupciu nových pľuzgierov“. Tento parameter je paralelný s replikáciou vírusu v koži, a preto opisuje virostatický potenciál liečiva. Toto je v literatúre uznávané a považuje sa za najspoľahlivejší klinický prejav s ohľadom na iné kožné príznaky. Ďalšími parametrami na stanovenie vymiznutia kožného exantému boli „čas od začiatku liečby po začiatok tvorby chrást “, „čas od začiatku liečby po ukončenie tvorby chrást“ a „čas od začiatku liečby po odpadnutie chrást“. Sledovalo sa aj rozšírenie kožných lézií a výskyt iných komplikácií.The primary efficacy endpoint in all three studies was "time from initiation of treatment to the last eruption of new blisters". This parameter is parallel to the replication of the virus in the skin and therefore describes the virostatic potential of the drug. This is recognized in the literature and is considered to be the most reliable clinical manifestation with respect to other skin symptoms. Other parameters for assessing the disappearance of skin rash were "time from start of treatment to start of rash", "time from start of treatment to end of rash", and "time from start of treatment to rash". Widespread skin lesions and other complications were also studied.
V literatúre sa za najčastejší parameter na stanovenie prínosu antivírusovej liečby pri herpes zoster považuje trvanie kožného exantému a intenzita bolesti v akútnej fáze infekcie. Neskôr sa však stáva pri stanovení prínosu antivírusovej liečby dôležitejšou postherpetická neuralgia. Preto na predbežné stanovenie možného účinku brivudínu z hľadiska zníženia výskytu postherpetickej neuralgie sa uskutočnilo doplnkové retrospektívne dvojito slepé sledovanie pacientov vo veku 50 rokov a viac, ktorí boli zahrnutí do sledovaní po skončení štúdie.In the literature, the duration of cutaneous rash and pain intensity in the acute phase of infection is considered to be the most common parameter to determine the benefit of antiviral therapy in herpes zoster. Later, however, postherpetic neuralgia becomes more important in determining the benefits of antiviral therapy. Therefore, an additional retrospective double-blind follow-up of patients aged 50 years and over who were included in the post-study follow-up was performed to pre-determine the possible effect of brivudine in reducing the incidence of postherpetic neuralgia.
Tabuľka 1 uvádza klinické skúšania u imunokompetentných pacientov s herpesom zoster. Predchádzajúce nekontrolované štúdie u imunokomprimovaných pacientov, ktoré poskytli prvý dôkaz o možnom prínose brivudínu, nebudú uvádzané.Table 1 presents clinical trials in immunocompetent patients with herpes zoster. Previous uncontrolled studies in immunocompressed patients that provided first evidence of the potential benefit of brivudine will not be reported.
Tabuľka 1Table 1
Prehľad klinických štúdiíOverview of clinical trials
Tieto klinické štúdie sú uvedené v chronologickom poradí.These clinical studies are listed in chronological order.
Štúdia 5-Ho-aStudy 5-Ho-a
Keďže koncentrácie brivudínu v plazme u človeka, ktorý dostáva 125 mg lx denne sú 10 až 50-násobkami IC50 pre klinické kmene vírusu Varicella zoster a okrem toho farmakokinetické dáta u človeka ukázali, že koncentrácie brivudínu v plazme sa udržiavajú nad IC50 24 h po podaní 125 mg brivudínu v jednej dávke, vyslovil sa rozumný predpoklad, že podanie 125 mg brivudínu lx denne by bolo na liečbu herpesu zoster postačujúce.Since plasma concentrations of brivudine in humans receiving 125 mg once daily are 10 to 50 times the IC 50 for clinical strains of Varicella zoster virus, and in addition, human pharmacokinetic data have shown that plasma concentrations of brivudine are maintained above IC 50 24 h after administration. 125 mg of brivudine per dose, it was reasonable to assume that administering 125 mg of brivudine once daily would be sufficient to treat herpes zoster.
Štúdia 5-Hoa, štúdia fázy II, sa uskutočnila u 642 pacientov, preto hodnotila podávanie 125 mg brivudínu lx denne počas 7 dní v porovnaní s podávaním 5 x 800 mg acykloviru počas 7 dní spôsobom prieskumu. Pridali sa dve štúdie s podávaním brivudínu lx denne v dávkach 62,5 mg a 32,25 mg počas 7 dní, aby sa tiež stanovila účinnosť nižších dávok.The 5-Hoa study, a Phase II study, was conducted in 642 patients and therefore evaluated the administration of 125 mg brivudine once daily for 7 days compared to the administration of 5 x 800 mg acyclovir for 7 days by the survey method. Two studies with Brivudine once daily at 62.5 mg and 32.25 mg for 7 days were added to also determine the efficacy of lower doses.
Táto štúdia ukázala, že podávanie 1 x 125 mg brivudínu počas 7 dní u pacientov s akútnym herpesom zoster je rovnako účinné ako liečba 5 x 800 mg acykloviru počas 7 dní vzhľadom na primárny parameter „čas od začiatku liečby po posledný vznik nových pľuzgierov“, ako aj vzhľadom na všetky sekundárne parametre, vrátane „času od začiatku liečby po vymiznutie bolesti (intenzita slabá alebo žiadna) ako klinicky relevantnejší sekundárny parameter. Štatistická analýza primárneho parametra účinnosti a parametra bolesti poukázala na nie horší výsledok dosiahnutý podávaním 1 x 125 mg brivudínu v porovnaní s acyklovirom. Pre parameter „čas od začiatku liečby po úplné chrasty“ sa prieskumom dosiahla výhodnosť. Grafické znázornenie pomerov rizika vypočítané z Cox proporčného modelu rizika pre 1 x 125 mg brivudínovej skupiny v porovnaní s 5 x 800 mg acyklovirovej skupiny je na obr. 1.This study showed that administration of 1 x 125 mg of brivudine for 7 days in patients with acute herpes zoster is as effective as treatment of 5 x 800 mg of acyclovir for 7 days due to the primary parameter "time from start of treatment to last blistering" also with respect to all secondary parameters, including "the time from initiation of treatment to the disappearance of pain (intensity little or no) as a more clinically relevant secondary parameter. Statistical analysis of the primary efficacy and pain parameters showed no worse outcome achieved with 1 x 125 mg brivudine compared to acyclovir. For the parameter "time from the start of treatment to full rattles", the survey achieved advantage. A graphical representation of the risk ratios calculated from the Cox proportional risk model for the 1 x 125 mg brivudine group as compared to the 5 x 800 mg acyclovir group is shown in FIG. First
Brivudín má lineárnu závislosť dávky a účinku. Výhodnosť v porovnaní s placebom sa demonštrovala štatistickou a klinickou významnosťou u imunokompetentných pacientov s infekciou herpes zoster. Liečba brivudínom dávkou 1 x 125 mg počas najmenej 7 dní je prinajmenšom rovnako účinná ako liečba 5 x 800 mg acykloviru počas 7 dní vzhľadom na výskyt pľuzgierov a akútnu bolesť. Tieto výsledky, spolu s predchádzajúcimi farmakokinetickými úvahami, viedli k výberu brivudínu 125 mg lx denne ako liečby voľby.Brivudine has a linear dose-effect relationship. Advantage compared to placebo was demonstrated by statistical and clinical significance in immunocompetent patients with herpes zoster infection. Treatment with brivudine at a dose of 1 x 125 mg for at least 7 days is at least as effective as a treatment of 5 x 800 mg acyclovir for 7 days due to the occurrence of blisters and acute pain. These results, together with previous pharmacokinetic considerations, led to the selection of brivudine 125 mg once daily as the treatment of choice.
Štúdia 5-Ho-bStudy 5-Ho-b
Štúdia fázy III sa uskutočnila u 1227 pacientov, aby sa poskytla potvrdzujúca štatistika na porovnanie 1 x x 125 mg brivudínu počas 7 dní a 5 x 800 mg acykloviru počas 7 dní u imunokompetentných pacientov s herpesom zoster. Podskupina pacientov vo veku 50 rokov a viac sa tiež hodnotila oddelene.A Phase III study was conducted in 1227 patients to provide confirmatory statistics to compare 1 x x 125 mg brivudine for 7 days and 5 x 800 mg acyclovir for 7 days in immunocompetent patients with herpes zoster. A subgroup of patients aged 50 years or more was also evaluated separately.
Grafická prezentácia rizikových pomerov vypočítaná z Cox proporčného modelu rizika pre skupinu 1 x x 125 mg brivudínu v porovnaní s 5 x 800 mg acykloviru je uvedená na obr. 2.A graphical presentation of the risk ratios calculated from the Cox proportional risk model for the 1 x 125 mg brivudine group as compared to 5 x 800 mg acyclovir is shown in FIG. Second
Štúdia 5-Ho-c: Zníženie trvania liečbyStudy 5-Ho-c: Reduction of treatment duration
Kvôli stanoveniu účinnosti trojdňovej liečby brivudínom 125 mg lx denne u pacientov s herpesom zoster sa uskutočnila ďalšia veľká štúdia za presného použitia toho istého návrhu štúdie ako v štúdii 5- Ho-b. Brivudín 125 mg lx denne počas 3 dní (s pokračovaním placeba počas 4 dní) sa porovnal s acyklovírom 800 mg 5x denne počas 7 dní.To determine the efficacy of three-day treatment with brivudine 125 mg once daily in patients with herpes zoster, another large study was conducted using exactly the same study design as in study 5-Ho-b. Brivudine 125 mg once daily for 3 days (with placebo continued for 4 days) was compared to acyclovir 800 mg 5 times daily for 7 days.
Celkovo sa zahrnulo 1336 pacientov. Výsledky ukazujú, že tento dávkovací režim brivudínu nie je pre primárnu premennú účinnosti horší v porovnaní s liečbou acyklovirom v štandardnej dávke. Lepšiu vhodnosť liečby však nebolo možné stanoviť.A total of 1336 patients were enrolled. The results show that this brivudine dosing regimen is not worse for the primary efficacy variable compared to treatment with acyclovir at standard dose. However, better treatment suitability could not be determined.
Tieto údaje so skráteným trvaním liečby preto podporujú názor, že brivudín je naozaj účinný pri liečbe podávaný raz denne pri herpese zoster u imunokompetentných dospelých a podporujú platnosť výsledkov získaných v predchádzajúcich štúdiách.Therefore, these shortened treatment data support the view that brivudine is truly effective in once-daily treatment for zoster herpes in immunocompetent adults and support the validity of the results obtained in previous studies.
Primárna premenná účinnostiPrimary efficacy variable
Pre primárny parameter lepšej vhodnosti bolo možné stanoviť výhodnosť brivudínovej skupiny v porovnaní s acyklovirom. Použitie konfirmačných testov bolo štatisticky významné na úrovni 5 %. Odhadnutý pomer rizika bol 1,14 (pre „Per Protokol populáciu“), s naznačovaním 14 % lepšieho účinku ( cieľ sa dosiahol skôr) u pacientov liečených 1 x 125 mg brivudínu v porovnaní s pacientmi liečenými acyklovirom. Zodpovedajúca deskriptívna priemerná hodnota pre „čas od začiatku liečby po posledný výsev pľuzgierov herpesu zoster“ bola o 25 % nižšia pre brivudín (priemer: 13,5 h) ako pre acyklovir (priemer: 18,0 h).For the primary parameter of better suitability, it was possible to determine the advantageousness of the brivudine group over acyclovir. The use of confirmatory tests was statistically significant at 5%. The estimated risk ratio was 1.14 (for the Per Protocol population), suggesting a 14% better effect (target achieved earlier) in patients treated with 1 x 125 mg brivudine compared to patients treated with acyclovir. The corresponding descriptive mean value for "time from start of treatment to last sowing of herpes zoster blisters" was 25% lower for brivudine (mean: 13.5 h) than for acyclovir (mean: 18.0 h).
Preto sa pre primárnu premennú účinnosti brivudínovej liečby potvrdzujúco demonštrovalo, že je štatisticky významne lepšia ako liečba acyklovirom.Therefore, for the primary efficacy variable of brivudine treatment, it has been shown to be statistically significantly superior to that of acyclovir.
Sekundárne premenné účinnostiSecondary efficiency variables
Štatistické testy pre všetky sekundárne premenné účinnosti vrátane klinicky relevantných parametrov bolesti, ukázali ekvivalenciu 1 x 125 mg brivudínu s 5 x 800 mg acykloviru.Statistical tests for all secondary efficacy variables, including clinically relevant pain parameters, showed an equivalence of 1 x 125 mg brivudine with 5 x 800 mg acyclovir.
Rozšírenie kožných lézií (brivudín: 1; acyklovir: 2) a ďalšie komplikácie (brivudín: 0; acyklovir: 6) sa vyskytli u menej ako 1 % pacientov v obidvoch skupinách.The spread of skin lesions (brivudine: 1; acyclovir: 2) and other complications (brivudine: 0; acyclovir: 6) occurred in less than 1% of patients in both groups.
Podskupinová analýza u pacientov vo veku 50 rokov a viac poskytla podobné výsledky, ako sa získali v celej populácii, s 18 % lepším účinkom liečby pre primárny parameter účinnosti u pacientov liečených brivudínom v porovnaní s pacientmi liečenými acyklovirom.A subgroup analysis in patients aged 50 years or more gave similar results to that obtained in the entire population, with an 18% better treatment effect for the primary efficacy parameter in patients treated with brivudine compared to patients treated with acyclovir.
Prednosť brivudínu oproti acykloviru sa pre primárnu premennú účinnosti mohla demonštrovať porovnávacou štatistikou. Nie horšia liečba mohla byť demonštrovaná na 5 % hladine významnosti pre všetky sekundárne premenné vrátane parametrov bolesti.The preference of brivudine over acyclovir could be demonstrated by comparative statistics for the primary efficacy variable. No inferior treatment could be demonstrated at a 5% significance level for all secondary variables including pain parameters.
Pre subpopuláciu pacientov vo veku 50 rokov a viac sa zistila dokonca väčšia výhodnosť vzhľadom na primárny parameter pre brivudín v porovnaní s acyklovirom.For the subpopulation of patients aged 50 years or more, even greater advantage was found with respect to the primary parameter for brivudine compared to acyclovir.
Sledovanie postherpetickej neuralgie po štúdiiPost-herpetic neuralgia following study
Na sledovanie výskytu postherpetickej neuralgie (PHN) u pacientov vo veku 50 rokov a starších sa uskutočnili sa dve retrospektívne sledovania po štúdii za dvojito slepých podmienok v súlade s GCP:To monitor the incidence of postherpetic neuralgia (PHN) in patients 50 years of age and older, two retrospective follow-ups were conducted following a double-blind study in accordance with GCP:
1. vybraných zo štúdií 5- Ho-a a 5-Ho-b (7 dní brivudín vs 7 dní acyklovirová liečba)1. selected from the 5-Ho-a and 5-Ho-b studies (7 days brivudine vs 7 days acyclovir treatment)
2. vybraných zo štúdie 5-Ho-c (3 dni brivudín vs 7 dní acyklovirová liečba)2. selected from the 5-Ho-c study (3 days brivudine vs 7 days acyclovir treatment)
Pacienti, ktorí v sledovaní prostredníctvom telefónu hlásili bolesť súvisiacu s herpesom zoster po skončení štúdie, boli pozvaní do centra a boli vyšetrení riešiteľom štúdie, aby sa potvrdil výskyt PHN a zodpovedali sa otázky súvisiace s charakteristikami bolesti. PHN sa definovala ako bolesť v dermatómoch postihnutých herpesom zoster po skončení jednotlivej štúdie (pacienti mali ukončiť štúdie 5-Ho-a, 5-Ho-b a 5-Ho-c, keď všetky chrasty odpadli alebo na 35. deň od začiatku liečby, podľa toho, kedy sa bolesť po prvýkrát vyskytla).Patients who reported herpes zoster pain following study follow-up were invited to the center and examined by the investigator to confirm PHN and to answer questions related to pain characteristics. PHN was defined as pain in herpes zoster-affected dermatomas after completion of a single study (patients should have completed 5-Ho-a, 5-Ho-b, and 5-Ho-c studies when all the rattles had dropped or on day 35 after initiation of treatment) depending on when the pain first occurred).
Štúdie sa uskutočnili za slepých podmienok (ani pacienti, ani riešitelia ešte nevedeli, aká liečba bola použitá počas štúdií 5-Ho-a, 5-Ho-b a 5-Ho-c), čo silno podporuje validitu výsledkov štúdií.The studies were conducted under blind conditions (neither patients nor investigators had yet known what treatment was used during the 5-Ho-a, 5-Ho-b and 5-Ho-c studies), which strongly supports the validity of the study results.
SK 287043 Β6SK 287043 Β6
1. Sledovanie PHN po štúdii po 7-dňovej liečbe brivudínom1. Follow-up of PHN following study after 7-day treatment with brivudine
Veľká vzorka 608 mužov a žien vo veku 50 rokov a viac zo štúdií 5-Ho-a, 5-Ho-b a 5-Ho-c sa znovu retrospektívne hodnotila (medzi 8 až 17 mesiacmi po liečbe), aby sa stanovila výhodnosť brivudínu v prevencii výskytu postherpetickej neuralgie. V skupine pacientov predtým liečených 125 mg brivudínu počas 7 dní sa u 32,7 % zaznamenalo postihnutie postherpetickou neuralgiou po ukončení štúdie, kým v skupine liečenej acyklovirom to bolo 43,5 %. Teda, relatívne riziko výskytu postherpetickej neuralgie bolo o 25 % nižšie v skupine 125 mg brivudínu v porovnaní s acyklovirovou skupinou. Toto bolo štatisticky významné zníženie a možno ho považovať za klinicky relevantnú výhodu brivudínu.A large sample of 608 men and women aged 50 years or more from the 5-Ho-a, 5-Ho-b, and 5-Ho-c studies were re-evaluated retrospectively (between 8 to 17 months after treatment) to determine the benefit of brivudine in preventing the occurrence of postherpetic neuralgia. In the group of patients previously treated with 125 mg of brivudine for 7 days, 32.7% experienced postherpetic neuralgia after completion of the study, compared with 43.5% in the acyclovir group. Thus, the relative risk of postherpetic neuralgia was 25% lower in the 125 mg brivudine group compared to the acyclovir group. This was a statistically significant reduction and can be considered a clinically relevant benefit of brivudine.
2. Sledovanie PHN po štúdii po 3-dňovej liečbe brivudínom2. Follow-up of PHN following study after 3-day treatment with brivudine
Štúdia zahŕňala pacientov vo veku 50 rokov alebo starších, ktorí dostávali trojdňovú liečbu brivudínom 125 mg alebo štandardnú sedemdňovú dávkovaciu schému acykloviru v štúdii 5-Ho-c. Pacienti boli dotazovaní medzi 3 až 8 mesiacmi po liečbe.The study included patients 50 years of age or older who received 3-day treatment with brivudine 125 mg or the standard 7-day acyclovir dosing schedule in the 5-Ho-c study. Patients were interviewed between 3 and 8 months after treatment.
Výsledky ukazujú, že výskyt postherpetickej neuralgie u pacientov, ktorí dostávali trojdňovú liečbu brivudínom 125 mg x denne je porovnateľný ako u pacientov, ktorí dostávali acyklovir v štandardnej dávke počas 7 dní (41,6 vs 39,7 %).The results show that the incidence of postherpetic neuralgia in patients receiving 3-day treatment with brivudine 125 mg x daily is comparable to patients receiving acyclovir at a standard dose for 7 days (41.6 vs 39.7%).
Tieto ďalšie údaje podporujú dôkaz, že brivudín 125 mg, podávaný lx denne iba 3 dni, nie je pri liečbe herpesu zoster horší ako acyklovir.These additional data support the evidence that brivudine 125 mg, given once daily only for 3 days, is not inferior to acyclovir in the treatment of herpes zoster.
Prehľad obrázkov na výkresochBRIEF DESCRIPTION OF THE DRAWINGS
Obrázok 1 znázorňuje pomery* rizika a jednostranný dolný 95 % konfidenčný interval. Porovnávalo sa 1 x 125 mg brivudínu vs 5 x 800 mg acykloviru (na populáciu podľa protokolu). * Označuje pomery rizika vypočítané z Cox regresie s kovariátmi. Pomer rizika väčší ako 1 naznačuje lepší liečebný účinok brivudínu vs acyklovir. J Dolná hranica jednostranného 95 % konfidenčného intervalu nad 0,8 hodnotou (prerušovaná čiara) ukazuje nie horšiu vhodnosť a nad 1,0 hodnotou (plná čiara) ukazuje výhodnosť 1 x 125 mg brivudínu vs 5 x 800 mg acykloviru.Figure 1 shows the risk ratios * and the one-sided lower 95% confidence interval. 1 x 125 mg brivudine vs 5 x 800 mg acyclovir (per protocol population) were compared. * Indicates risk ratios calculated from Cox regression with covariates. A risk ratio greater than 1 indicates a better therapeutic effect of brivudine vs acyclovir. J The lower limit of the one-sided 95% confidence interval above 0.8 (dashed line) shows no inferior suitability and above 1.0 value (solid line) shows a preference of 1 x 125 mg brivudine vs 5 x 800 mg acyclovir.
Obrázok 2 znázorňuje pomery* rizika a jednostranný dolný 95 % konfidenčný interval. Porovnávalo sa 1 x 125 mg brivudínu vs 5 x 800 mg acykloviru (na populáciu podľa protokolu). * Označuje pomery rizika vypočítané z Cox regresie s kovariátmi. Pomer rizika väčší ako 1 naznačuje lepší liečebný účinok brivudínu vs acyklovir. f Dolná hranica jednostranného 95 % konfidenčného intervalu nad 0,8 hodnotou (prerušovaná čiara) ukazuje nie horšiu vhodnosť a nad 1,0 hodnotou (plná čiara) ukazuje výhodnosť 1 x 125 mg brivudínu vs 5 x 800 mg acykloviru.Figure 2 shows the risk ratios * and the one-sided lower 95% confidence interval. 1 x 125 mg brivudine vs 5 x 800 mg acyclovir (per protocol population) were compared. * Indicates risk ratios calculated from Cox regression with covariates. A risk ratio greater than 1 indicates a better therapeutic effect of brivudine vs acyclovir. f The lower limit of the one-sided 95% confidence interval above 0.8 (dashed line) shows no inferior suitability and above 1.0 value (solid line) shows a preference of 1 x 125 mg brivudine vs 5 x 800 mg acyclovir.
Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION
Nasledovné príklady predkladaného vynálezu možno považovať za nie limitujúce príklady.The following examples of the present invention may be considered as non-limiting examples.
Príklad 1Example 1
Tablety 125 mg brivudínu s okamžitým uvoľňovaním125 mg brivudine immediate-release tablets
245,0245.0
Príklad 2Example 2
245,0245.0
Príklad 3Example 3
245,0245.0
Príklad 4Example 4
245,0245.0
Príklad 5Example 5
250,0250.0
Príklad 6Example 6
250,0250.0
SK 287043 Β6SK 287043 Β6
Príklad 7Example 7
250,0250.0
Príklad 8Example 8
Kapsuly s okamžitým uvoľňovanímImmediate release capsules
250,0250.0
Príklad 9Example 9
Poťahované tablety s okamžitým uvoľňovanímImmediate release film-coated tablets
256,0256.0
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| ES2239527B1 (en) * | 2004-03-01 | 2006-11-16 | M. Cruz Fernandez Gonzalez | PHARMACOLOGICAL COMPOSITION OF TOPICAL USE FOR THE TREATMENT OF HERPES ZOSTER. |
| CN113712928A (en) * | 2021-09-29 | 2021-11-30 | 重庆市力扬医药开发有限公司 | Brivudine drug absorbed through oral mucosa |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0104857A1 (en) * | 1982-09-28 | 1984-04-04 | Beecham Group Plc | Deoxyuridine compounds, methods for preparing them and their use in medicine |
| IT1170232B (en) * | 1983-10-31 | 1987-06-03 | Anna Gioia Stendardi | THERAPEUTIC COMPOSITIONS WITH ANTI-VIRAL ACTIVITY |
| US5446031A (en) * | 1991-04-24 | 1995-08-29 | Yamasa Shuyu Kabushiki Kaisha | 1-β-D-arabinofuranosyl-(E)-5-(2-halogenovinyl)uracil derivatives |
| WO1997025989A1 (en) * | 1996-01-19 | 1997-07-24 | Glaxo Group Limited | Use of valaciclovir for the manufacture of a medicament for the treatment of genital herpes by a single daily application |
-
2001
- 2001-01-03 IT IT2001MI000009A patent/ITMI20010009A1/en unknown
- 2001-04-25 IE IE20010413A patent/IE20010413A1/en not_active IP Right Cessation
- 2001-05-01 GB GB0110682A patent/GB2370771A/en not_active Withdrawn
- 2001-05-11 HR HR20010345A patent/HRPK20010345B3/en not_active IP Right Cessation
- 2001-05-29 CH CH00987/01A patent/CH695662A5/en not_active IP Right Cessation
- 2001-06-28 SE SE0102309A patent/SE0102309L/en not_active Application Discontinuation
- 2001-06-29 FR FR0108596A patent/FR2818907B1/en not_active Expired - Lifetime
- 2001-06-29 DK DKPA200101019A patent/DK177084B1/en not_active IP Right Cessation
- 2001-07-02 NL NL1018431A patent/NL1018431C2/en not_active IP Right Cessation
- 2001-07-03 FI FI20011446A patent/FI20011446A/en not_active Application Discontinuation
- 2001-07-04 SK SK957-2001A patent/SK287043B6/en not_active IP Right Cessation
- 2001-07-04 BE BE2001/0452A patent/BE1014522A5/en not_active IP Right Cessation
- 2001-07-04 CZ CZ20012464A patent/CZ20012464A3/en unknown
- 2001-07-04 UA UA2001074658A patent/UA76402C2/en unknown
- 2001-07-05 PT PT102642A patent/PT102642B/en active IP Right Grant
- 2001-07-05 ES ES200101566A patent/ES2192456B1/en not_active Expired - Fee Related
- 2001-07-05 GR GR20010100322A patent/GR1004012B/en unknown
- 2001-07-05 HU HU0102816A patent/HUP0102816A3/en unknown
- 2001-07-05 PL PL01348480A patent/PL348480A1/en not_active Application Discontinuation
-
2002
- 2002-07-03 AT AT0805702U patent/AT6141U1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| ITMI20010009A0 (en) | 2001-01-03 |
| FR2818907B1 (en) | 2006-05-26 |
| ES2192456A1 (en) | 2003-10-01 |
| PT102642A (en) | 2002-07-31 |
| PL348480A1 (en) | 2002-07-15 |
| CZ20012464A3 (en) | 2002-08-14 |
| DK177084B1 (en) | 2011-07-11 |
| GB2370771A (en) | 2002-07-10 |
| FI20011446A (en) | 2002-07-04 |
| HRPK20010345B3 (en) | 2005-02-28 |
| AT6141U1 (en) | 2003-05-26 |
| DK200101019A (en) | 2002-07-04 |
| CH695662A5 (en) | 2006-07-31 |
| PT102642B (en) | 2003-06-30 |
| SE0102309L (en) | 2002-07-04 |
| IE20010413A1 (en) | 2003-04-16 |
| UA76402C2 (en) | 2006-08-15 |
| HUP0102816A2 (en) | 2002-10-28 |
| FI20011446A0 (en) | 2001-07-03 |
| GB0110682D0 (en) | 2001-06-20 |
| HRP20010345A2 (en) | 2003-08-31 |
| FR2818907A1 (en) | 2002-07-05 |
| SE0102309D0 (en) | 2001-06-28 |
| SK9572001A3 (en) | 2003-03-04 |
| GR20010100322A (en) | 2002-10-08 |
| HUP0102816A3 (en) | 2005-01-28 |
| ES2192456B1 (en) | 2005-02-01 |
| HU0102816D0 (en) | 2001-09-28 |
| GR1004012B (en) | 2002-11-01 |
| ITMI20010009A1 (en) | 2002-07-03 |
| BE1014522A5 (en) | 2003-12-02 |
| NL1018431C2 (en) | 2002-07-05 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK4A | Patent expired |
Expiry date: 20210704 |