SI23311A - Pharmaceutical combination of acetylsalicylic acid and antifungal substance for destroying or inhibition of growth and replication of fungi - Google Patents
Pharmaceutical combination of acetylsalicylic acid and antifungal substance for destroying or inhibition of growth and replication of fungi Download PDFInfo
- Publication number
- SI23311A SI23311A SI201000095A SI201000095A SI23311A SI 23311 A SI23311 A SI 23311A SI 201000095 A SI201000095 A SI 201000095A SI 201000095 A SI201000095 A SI 201000095A SI 23311 A SI23311 A SI 23311A
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- SI
- Slovenia
- Prior art keywords
- pharmaceutical combination
- fungi
- pharmaceutical
- acetylsalicylic acid
- antifungal
- Prior art date
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- A61K31/4196—1,2,4-Triazoles
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Abstract
Description
Farmacevtska kombinacija acetilsalicilne kisline in protiglivne substance za uničevanje ali inhibicijo rasti in replikacije glivA pharmaceutical combination of acetylsalicylic acid and an antifungal substance to kill or inhibit the growth and replication of fungi
Področje izumaFIELD OF THE INVENTION
Predmet izuma je Farmacevtska kombinacija acetilsalicilne kisline in protiglivne substance za uničevanje ali inhibicijo rasti in replikacije gliv. Izum se uvršča na področje protiglivnih substanc, na področje metod uničevanja gliv ali inhibicije rasti in replikacije gliv in na področje zdravil za zdravljenje in preprečevanje glivnih okužb in vivo in in vitro.The subject invention is a pharmaceutical combination of acetylsalicylic acid and an antifungal substance for the destruction or inhibition of fungal growth and replication. The invention relates to the field of antifungal substances, to the field of methods of killing fungi or inhibiting the growth and replication of fungi and to the field of drugs for the treatment and prevention of fungal infections in vivo and in vitro.
Stanje tehnikeThe state of the art
Glive vključno s patogeni so razširjene po celem svetu. So pomembni škodljivci v kmetijstvu in pri pridelavi hrane. V zdravstvu predstavljajo težavo zaradi povečanega števila težkih in težko ozdravljivih okužb, ki so posledica pomanjkanja novih protiglivnih substanc, povečane odpornosti gliv na starejše antimikotike in naraščajočega števila imunsko komprimitiranih pacientov, ki so dovzetnejši za glivne okužbe. Glive pri človeku povzročijo tri vrste kliničnih stanj: infekcije, alergijska stanja ter toksikoze. Imunosupresija ob transplantaciji organov in obolelih z AIDS, opekline in kemoterapija ter diabetična ketoacidoza so glavni predispozicijski faktor za razvoj okužb. Vsa klinična stanja glivnih okužb se lahko pojavijo v lokalni ali sistemski obliki. Od vseh filamentoznih gliv je Aspergillus drugi najpogostejši povzročitelj oportunistične mikoze, najpogosteje pa jo povzroča Candida. Iz rodu Aspergillus je v Evropi najpogostejši povzročitelj aspergiloz gliva A. fumigatus, sledi pa mu A. flavus. Znanih antimikotikov, ki učinkujejo proti glivam, je malo. Njihovo uporabo omejujejo predvsem zelo pogosti stranski učinki, slabo prehajanje zdravila v različna tkiva, ozek antimikotični spekter in neobčutljivost nekaterih gliv za določene antimikotike (Groll in Kolve, 2004; Groll in sod., 1998; Klich, 2007).Fungi including pathogens are widespread worldwide. They are important pests in agriculture and food production. Health care is a problem due to the increased number of severe and difficult to cure infections resulting from the lack of new antifungal substances, increased resistance of fungi to older antifungals, and an increasing number of immunocompromised patients more susceptible to fungal infections. Fungi in humans cause three types of clinical conditions: infections, allergic conditions and toxicosis. Immunosuppression in organ transplantation and AIDS, burns and chemotherapy, and diabetic ketoacidosis are the major predisposing factors for the development of infections. All clinical conditions of fungal infections may occur in local or systemic form. Of all filamentous fungi, Aspergillus is the second most common cause of opportunistic mycosis, most commonly caused by Candida. The genus Aspergillus in Europe is the most common cause of aspergillosis of A. fumigatus, followed by A. flavus. There are few known antifungal antifungals. Their use is limited mainly by very common side effects, poor passage of the drug into different tissues, a narrow antifungal spectrum, and insensitivity of some fungi to certain antifungals (Groll and Kolve, 2004; Groll et al., 1998; Klich, 2007).
Trenutno so v klinični uporabi štirje razredi protiglivnih substanc: polienski antimikotiki, derivati azolov, alilamini ter tiokarbamati in fluoropirimidini. Ciljno mesto prvih treh razredov je ergosterol (Groll in sod., 1998). Azoli inhibirajo lanosterol-demetilazo, starejši azoli (imidazoli) zavirajo še številne druge, na membrano vezane encime, ter biosintezo membranskih lipidov. (Sheehan in sod., 1999). Skupino polienskih antimikotikov sestavlja okrog 200 naravnih makrolidnih antibiotikov, od katerih so le amfotericin B in nistatin razvili za sistemsko zdravljenje glivičnih okužb. Polieni so amfipatične molekule in se vgrajujejo v membrano celic in tvorijo kanale, preko katerih pride do spremenjene prepustnosti, izgube vitalnih citoplazemskih komponent in posledično smrti mikroorganizma (Georgopapadakou in Walsh, 1996). Klinično se uporabljata dve alilaminski protiglivni substanci naftifin in terbinafin, ter tolnaftat, ki je tiokarbamat. Vsi trije so reverzibilni, nekompetitivni inhibitorji skvalen-2,3-epoksidaze. Sintetično izdelani morfolini so kmetijski fungicidi, izjema je le amorolfin, ki se uporablja kot topično zdravilo za zdravljenje nohtnih infekcij. Ehinokandini so nov razred protiglivnih lipopeptidov. Inhibirajo sintezo l,3-p-D-glukana, kije polisaharid v celični steni mnogih patogenih plesni in gliv, v celični steni sesalcev pa ni prisoten (Groll in sod., 2004).There are currently four classes of antifungal agents in clinical use: polyene antifungals, azole derivatives, allylamines, thiocarbamates and fluoropyrimidines. The target site of the first three classes is ergosterol (Groll et al. 1998). Azoles inhibit lanosterol-demethylase, older azoles (imidazoles) inhibit many other membrane-bound enzymes, and membrane lipid biosynthesis. (Sheehan et al., 1999). A group of polyene antifungals consist of about 200 natural macrolide antibiotics, of which only amphotericin B and nystatin have been developed for the systemic treatment of fungal infections. Polyenes are amphipathic molecules and are embedded in the cell membrane and form channels through which altered permeability, loss of vital cytoplasmic components and subsequent death of the microorganism (Georgopapadakou and Walsh, 1996). Clinically, two allylamine antifungal substances naphthyne and terbinafine are used, and tolnaftate, which is thiocarbamate. All three are reversible, non-competitive squalene-2,3-epoxidase inhibitors. Synthetically produced morpholines are agricultural fungicides, with the exception of amorolfine, which is used as a topical treatment for nail infections. Echinocandins are a new class of antifungal lipopeptides. They inhibit the synthesis of l, 3-β-D-glucan, which is a polysaccharide in the cell wall of many pathogenic molds and fungi, and is not present in the mammalian cell wall (Groll et al. 2004).
Ključna slabost antimikotikov je odpornost gliv na protiglivno substanco. O pridobljeni odpornosti na flukonazol med sevi C. albicans so poročali zlasti pri bolnikih, okuženih s HIV. Pridobljena odpornost na amfotericin je zabeležena pri glivah Cryptococcus neoformans in Candida spp., med drugim C. lusitaniae, C. glabrata in C. krusei. Poznamo pa filamentozne glive (Peudalesheria boydii, Scopulariopsis, Fusarium), pa tudi nekatere kvasovke (Trichosporon beigelii, C. lusitanii, C. guiliermondii), ki imajo prirojeno odpornost na amfotericin B (Richter in sod., 2005; Matos in Beovic, 2001).A key weakness of antifungals is the resistance of fungi to antifungal substance. Acquired resistance to fluconazole among C. albicans strains has been reported especially in HIV-infected patients. Acquired amphotericin resistance has been reported in Cryptococcus neoformans and Candida spp., Among others C. lusitaniae, C. glabrata and C. krusei. However, filamentous fungi (Peudalesheria boydii, Scopulariopsis, Fusarium) are known, as well as some yeasts (Trichosporon beigelii, C. lusitanii, C. guiliermondii) that have congenital resistance to amphotericin B (Richter et al., 2005; Matos and Beovic, 2001 ).
Zdravljenje z antimikotiki pogosto spremljajo neželeni stranski učinki. Ketokonazol, ki je zelo lipofilen, se akumulira v maščobnih tkivih. Klinična uporaba amfotericina B je povezana s problemi toksičnosti, kot so: nefrotoksičnost, azotemija, zmanjšana glomerulna filtracija, zmanjšana sposobnost koncentriranja urina, ledvična izguba natrija in kalija, ledvična tubulama acidoza, hipokaliemija, hipomagnezemija, nizek krvni tlak, glavobol, depresija kostnega mozga, leukopenija, hepatitis, hiperlipidemija in hiponatremija, vročina, mrzlica, bolečine v mišicah, anemija in trombocitopenija.Antifungal treatment is often accompanied by side effects. Ketoconazole, which is very lipophilic, accumulates in adipose tissue. Clinical use of amphotericin B is associated with toxicity issues such as: nephrotoxicity, azotemia, decreased glomerular filtration, decreased urine concentration, renal loss of sodium and potassium, renal tubulam acidosis, hypokalemia, hypomagnesemia, low blood pressure, headache, bone marrow depression leukopenia, hepatitis, hyperlipidemia and hyponatremia, fever, chills, muscle pain, anemia and thrombocytopenia.
Iz zgoraj opisanega se jasno kaže potreba po novih produktih, ki imajo protiglivno delovanje oziroma po produktih, ki izboljšajo delovanje protiglivne substance in s tem zmanjšajo potrebno terapevtsko učinkovito količino protiglivne substance. Delovanje novega produkta naj bi vplivalo na širok spekter gliv. Produkti naj bi bili uporabni v kombinaciji z drugimi protiglivnimi substancami predvsem, če se aktivnost spremljajoče protiglivne substance izboljša, ker se s tem izboljša učinek terapije in zmanjša potencialna toksičnost protiglivne substance.The above clearly demonstrates the need for new products having antifungal activity, or for products that improve antifungal activity and thereby reduce the required therapeutically effective amount of antifungal substance. The operation of the new product is expected to affect a wide range of fungi. The products should be useful in combination with other antifungal substances, especially if the activity of the accompanying antifungal substance is improved, as this improves the effect of therapy and reduces the potential toxicity of the antifungal substance.
Problem pridobljene odpornosti na antimikotike rešuje uporaba kombinacije več različnih antimikotikov. Odpornosti gliv na določen antimikotik se rešuje tudi s kombiniranjem z drugimi substancami, ki same nimajo ali imajo šibko protiglivno delovanje, kot npr kurkumin ali FK506 (Sharma in sod., 2009; Heitman, 2005).The problem of acquired resistance to antifungals is solved by the use of a combination of several different antifungals. The resistance of fungi to a particular antifungal agent is also resolved by combining it with other substances that do not themselves or have weak antifungal activity, such as curcumin or FK506 (Sharma et al., 2009; Heitman, 2005).
• ·• ·
Izumitelji smo prišli do odkritja, da salicilna kislina in njen derivat acetilsalicilna kislina učinkovito izboljšajo delovanje protiglivnih substanc.The inventors have discovered that salicylic acid and its acetylsalicylic acid derivative effectively improve the action of antifungal substances.
Reference:References:
Georgopapadakou N.H., Walsh T.J. 1996. Minireview, Antifungal agents: Chemoterapeutic targets and immunologic strategies. Antimicrobial agents and chemoterapy, 40, 279-291.Georgopapadakou N.H., Walsh T.J. 1996. Minireview, Antifungal agents: Chemotherapeutic targets and immunologic strategies. Antimicrobial Agents and Chemotherapy, 40, 279-291.
Groll A.H., Kolve H. 2004. Antifungal agents: In vitro susceptibility testing, pharmacodynamics, and prospects for combination therapy. European joumal of clinical microbiology & infectious diseases, 23, 256-270.Groll A.H., Kolve H. 2004. Antifungal agents: In vitro susceptibility testing, pharmacodynamics, and prospects for combination therapy. European Joumal of Clinical Microbiology & Infectious Diseases, 23, 256-270.
Groll A.H., Piscitelli S.C, Walsh T.J. 1998. Clinical pharmacology of systemic antifungal agents: a comprehensive review of agents in clinical use, current investigational compounds, and putative targets for antifungal drug development. Advances in pharmacology, 44, 343500.Groll A.H., Piscitelli S.C, Walsh T.J. 1998. Clinical pharmacology of systemic antifungal agents: a comprehensive review of agents in clinical use, current investigational compounds, and putative targets for antifungal drug development. Advances in Pharmacology, 44, 343500.
Heitman J. 2005 A fungal achilles’ Heel. Science 309, 2175-2176.Heitman J. 2005 A fungal achilles' Heel. Science 309, 2175-2176.
Klich M.A. 2007. Aspergillus flavus: the major producer of aflatoxin. Molecular Plant Pathology, 8(6), 713-722.Klich M.A. 2007. Aspergillus flavus: the major producer of aflatoxin. Molecular Plant Pathology, 8 (6), 713-722.
Matos T, Beovič B. 2001. Odpornost na protiglivna zdravila. Medicinski razgledi, 40, S2, 65-72.Matos T, Beovich B. 2001. Antifungal drug resistance. Medical Views, 40, S2, 65-72.
Richter S.S., Galask R.P., Messer S.A., Hollis R.J., Diekema D.J., Pfaller M.A. 2005 Antifungal susceptibilities of Candida species causing vulvovaginitis and epidemiology of recurrent cases. J Ciin Microbiol 43, 2155-2162.Richter S.S., Galask R.P., Messer S.A., Hollis R.J., Diekema D.J., Pfaller M.A. 2005 Antifungal susceptibilities of Candida species causing vulvovaginitis and epidemiology of recurrent cases. J Ciin Microbiol 43, 2155–2162.
Sharma M., Manoharlal R., Shukla S., Puri N., Prasad T., Ambudkar S.V., Prasad R. 2009 Curcumin modulates efflux mediated by yeast ABC multidrug transporters and is synergistic with antifungals. Antimicrob Agent Chemoter 53: 3256-3265.Sharma M., Manoharlal R., Shukla S., Puri N., Prasad T., Ambudkar S.V., Prasad R. 2009 Curcumin modulates efflux mediated by yeast ABC multidrug transporters and is synergistic with antifungals. Antimicrob Agent Chemoter 53: 3256-3265.
Sheehan D.J., Hitchcock C.A., Sibley C.M. 1999. Current and emerging azole antifungal agents. Clinical Microbiology Reviews, 12, 40-79.Sheehan D.J., Hitchcock C.A., Sibley C.M. 1999. Current and emerging azole antifungal agents. Clinical Microbiology Reviews, 12, 40-79.
Povzetek izumaSummary of the Invention
Izum predstavlja farmacevtsko kombinacijo, ki vsebuje protiglivno substanco in salicilno ali acetilsaliclno kislino, sol ali derivat spojin in se farmacevtska kombinacija po izumu uporablja za uničevanje gliv ali inhibicijo rasti in replikacijo gliv, prednostno patogenih in • · · ·The invention is a pharmaceutical combination containing an antifungal substance and salicylic or acetylsalicylic acid, a salt or a derivative of the compounds, and the pharmaceutical combination of the invention is used to kill fungi or inhibit growth and replicate fungi, preferably pathogenic and • · · ·
oportunistično patogenih gliv. Farmacevtska kombinacija po izumu je namenjena pripravi zdravila za in vivo in in vitro preprečevanje in zdravljenje glivnih okužb pri živalih in človeku in zdravilo vsebuje terapevtsko učinkovitih količino farmacevtske kombinacije. V nadaljevanju je farmacevtska kombinacija namenjena pripravi fitofarmacevtskega pripravka za in vivo in in vitro preprečevanje in zdravljenje glivnih okužb pri rastlinah in pripravek vsebuje fungicidno ali fungistatično učinkovitih količino farmacevtske kombinacije.opportunistic pathogenic fungi. The pharmaceutical combination of the invention is for the preparation of a medicament for in vivo and in vitro prevention and treatment of fungal infections in animals and humans, and the medicament comprises a therapeutically effective amount of a pharmaceutical combination. The following is a pharmaceutical combination for the preparation of a plant protection product for in vivo and in vitro prevention and treatment of fungal infections in plants, and the preparation contains a fungicidally or fungistatically effective amount of a pharmaceutical combination.
Odkritje temelji na spoznanju, da je kombinacija protiglivne substance in salicilne ali acetilsalicilne kisline, sol ali derivat spojin fungicidno ali fungistatično učinkovitejša v boju proti glivnim okužbam kot sama protiglivna substanca. S farmacevtsko kombinacijo po izumu, katere komponente delujejo sinergistično, dosežemo zmanjšano porabo protiglivne substance, boljše terapevtsko učinkovitejše delovanje protiglivne substance, skrajšamo čas zdravljenja, znižamo stroške zdravljenja in v marsikaterem primeru dosežemo fungicidno delovanje farmacevtske kombinacije, kar ne bi bilo mogoče doseči z individualnima komponentama.The discovery is based on the realization that a combination of an antifungal substance and salicylic or acetylsalicylic acid, a salt or a derivative of the compounds, is fungicidally or fungistatically more effective in combating fungal infections than the antifungal substance itself. The pharmaceutical combination according to the invention, whose components act synergistically, results in reduced consumption of antifungal substance, improved therapeutically more effective action of antifungal substance, reduced treatment time, and in many cases achieved the fungicidal action of the pharmaceutical combination, which could not be achieved with individual components. .
Predstavljen izum temelji na odkritju, da se sinergistično delovanje salicilne ali acetilsalicilne kisline in protiglivne substance lahko uporablja za pripravo zdravila za zdravljenje subjekta, ki je okužen z glivami in zagotavlja način za zdravljenje takih infekcij. Prednost izuma je sposobnost zdravljenja glivnih obolenj, ki se jih pojmuje za težko ozdravljive. Dodatna prednost izuma je zdravljenje okužb z glivami, ki so pridobile odpornost na poznane protiglivne substance. V nadaljevanju je prednost zdravljenja s farmacevtsko kombinacijo po izumu, da se zmanjša količina protiglivne substance, ki ima neželene stranske učinke. Prednost zdravljenja s farmacevtsko kombinacijo po izumu je pridobitev na kvaliteti življenja, saj se skrajša trajanje terapije.The present invention is based on the discovery that the synergistic action of salicylic or acetylsalicylic acid and an antifungal substance can be used to prepare a medicament for treating a fungus-infected subject and providing a way of treating such infections. An advantage of the invention is the ability to treat fungal diseases that are considered difficult to cure. An additional advantage of the invention is the treatment of fungal infections that have acquired resistance to known antifungal agents. The following is an advantage of treatment with the pharmaceutical combination according to the invention in order to reduce the amount of antifungal substance having adverse side effects. The advantage of treatment with the pharmaceutical combination of the invention is the acquisition of quality of life as it reduces the duration of therapy.
V nadaljevanju izum vključuje pripravo (i) zdravila ali (ii) fitofarmacevtskega preparata, ki vsebuje farmacevtsko kombinacijo, za preprečevanje in zdravljenje glivnih okužb pri rastlinah, pri živalih in človeku. Farmacevtska kombinacija po izumu se lahko v obliki zdravila uporablja za zdravljenje glivnih okužb ali za dekontaminacijo površin, sterilizacijo medicinske opreme in implantatov. Zdravilo po izumu, ki vsebuje farmacevtsko kombinacijo, je pripravljeno v ustrezni farmacevtski obliki in vsebuje vse potrebne farmacevtske dodatke in po potrebi še dodatne protiglivne substance. Farmacevtska kombinacija po izumu v obliki fitofarmacevtskega preparata z ustreznimi, sprejemljivimi dodatki se uporablja za zdravljenje ali preprečevanje glivnih okužb pri rastlinah. Po izumu je zdravilo, ki vsebuje farmacevtsko kombinacijo, v ustrezni farmacevtski obliki primerni za topično, intravenozno, oralno, • · intramuskulatorno, podkožno, intraperitonalno, intraokulamo, transpulmulamo, transdermalno, aerosolno uporabo in sta aktivni substanci v zdravilu v obliki zmesi ali kot ločeni posamezni komponenti, vendar se uporabljata na način, da se doseže sinergistični učinek zmesi in sta aktivni komponenti ločeni zato, da se izboljša lastnost posameznih komponent.The invention further includes the preparation of (i) a medicament or (ii) a plant protection product containing a pharmaceutical combination for the prevention and treatment of fungal infections in plants, animals and humans. The pharmaceutical combination of the invention can be used in the form of a medicament for the treatment of fungal infections or for decontamination of surfaces, sterilization of medical equipment and implants. The medicament of the invention containing the pharmaceutical combination is prepared in a suitable pharmaceutical form and contains all necessary pharmaceutical additives and, if necessary, additional antifungal agents. The pharmaceutical combination of the invention in the form of a plant protection product with suitable, acceptable additives is used to treat or prevent fungal infections in plants. According to the invention, the medicament containing the pharmaceutical combination is in a suitable pharmaceutical form suitable for topical, intravenous, oral, • intramuscular, subcutaneous, intraperitoneal, intraocular, transpulmonary, transdermal, aerosol administration and the active substances are in the form of a mixture or as a separate individual components, but are used in such a way as to achieve a synergistic effect of the mixture and the active components are separated in order to improve the properties of the individual components.
Dodatno izum predstavlja metodo za uničenje ali inhibicijo rasti gliv, katera vsebuje neposreden kontakt zdravila ali fitofarmacevtskega pripravka, ki vsebuje farmacevtsko kombinacijo, z glivami. Metodo se uporablja in vitro za dekontaminacijo površin in sterilizacijo medicinske opreme in implantatov, in situ sterilizacijo katetrov in intravenoznih vsadkov. Metoda po izumu vključuje ali sočasno aplikacijo aktivnih komponent farmacevtske kombinacije ali ločeno protiglivno in ločeno salicilno ali acetilsalicilno kislino, sol ali derivat spojin, vendar na način, da je učinek enak ali boljši kot ob sočasni aplikaciji in je ločena aplikacija potrebna zaradi izboljšanih lastnosti posameznih komponent.In addition, the invention provides a method of destroying or inhibiting the growth of fungi, which contains direct contact of the drug or plant protection product containing the pharmaceutical combination with the fungi. The method is used in vitro for decontamination of surfaces and sterilization of medical equipment and implants, in situ sterilization of catheters and intravenous implants. The method of the invention involves either the co-administration of the active components of the pharmaceutical combination or the separate antifungal and separate salicylic or acetylsalicylic acid, salt or derivative of the compounds, but in such a way that the effect is the same or better than when co-administered and a separate application is necessary due to the improved properties of the individual components .
Izum predstavlja zdravilo s terapevtsko učinkovito količino farmacevtske kombinacije za terapevtsko ali preventivno zdravljenje pacientov okuženih z glivami.The invention provides a medicament with a therapeutically effective amount of a pharmaceutical combination for the therapeutic or preventive treatment of patients infected with fungi.
Kazalo slikIndex images
Slika 1. Metabolna aktivnost glive A. niger v prisotnosti kombinacije acetilsalicilne kisline in antimikotika amfotericina B, flukonazola, ketokonazola ali klotrimazola. V testu smo uporabili kombinacije acetilsalicilne kisline (končne koncentracije 0, 0.5, 2 mM) in amfotericin (končne koncentracije 0, 0.125, 0.25 mg/1) (A), flukonazol (končne koncentracije 0, 0.5, 1 g/1) (B), ketokonazol (končne koncentracije 0, 5, 10 mg/1), (C) in klotrimazol (končne koncentracije 0, 0.4, 1 mg/1) (D).Figure 1. Metabolic activity of A. niger in the presence of a combination of acetylsalicylic acid and the antifungal agent of amphotericin B, fluconazole, ketoconazole or clotrimazole. The combination of acetylsalicylic acid (final concentrations of 0, 0.5, 2 mM) and amphotericin (final concentrations of 0, 0.125, 0.25 mg / l) (A), fluconazole (final concentrations of 0, 0.5, 1 g / l) (B) were used in the test (B ), ketoconazole (final concentrations 0, 5, 10 mg / l), (C) and clotrimazole (final concentrations 0, 0.4, 1 mg / l) (D).
Slika 2. Inhibicija rasti kvasovke S. cerevisiae. Prirast biomase v prisotnosti kombinacije acetilsalicilne kisline (0, 2, 5 mM) in klotrimazola (0, 0.2, 0.5 mg/1) [A].Figure 2. Inhibition of S. cerevisiae yeast growth. Biomass increment in the presence of a combination of acetylsalicylic acid (0, 2, 5 mM) and clotrimazole (0, 0.2, 0.5 mg / l) [A].
Slika 3. Mikroskopske slike glive A. niger v prisotnosti protiglivne substance in acetilsalicilne kisline. Razrast glive v gojišču brez dodatka farmacevtske kombinacije [A]; z dodatkom 25 μΜ amiodarona in 0.5 mM acetilsalicilne kisline [B]; z dodatkom 0.4 mg/1 klotrimazola in 0.5 mM acetilsalicilne kisline [C].Figure 3. Microscopic images of A. niger in the presence of antifungal substance and acetylsalicylic acid. Growth of the fungus in the culture medium without the addition of a pharmaceutical combination [A]; with the addition of 25 μΜ amiodarone and 0.5 mM acetylsalicylic acid [B]; with the addition of 0.4 mg / l clotrimazole and 0.5 mM acetylsalicylic acid [C].
Slika 4. Metabolna aktivnost glive A. niger v prisotnosti salicilne kisline (A) in acetilsalicilne kisline (B).Figure 4. Metabolic activity of A. niger in the presence of salicylic acid (A) and acetylsalicylic acid (B).
Podroben opis izumaDETAILED DESCRIPTION OF THE INVENTION
Če ni definirano drugače, imajo vsi tukaj uporabljeni tehnični in znanstveni izrazi enak pomen, kot je splošno sprejeto med strokovnjaki. Terminologija, ki je uporabljena v opisu izuma, je namenjena opisovanju določenega dela izuma in ne omejevanju izuma. V opisu izuma in v zahtevkih je opis v ednini, vendar izum vključuje tudi množino, ki pa ni poudarjena zaradi lažjega razumevanja.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as is generally accepted by one of skill in the art. The terminology used in the description of the invention is intended to describe a particular part of the invention and not to limit the invention. In the description of the invention and in the claims, the description is in the singular, but the invention also includes a plural, which is not emphasized for ease of understanding.
Predstavljen izum se nanaša na odkritje, da salicilna oziroma acetilsalicilna kislina, soli in derivati spojine izboljšajo delovanje protiglivne substance in se lahko kot farmacevtska kombinacija protiglivne substance in salicilne oziroma acetilsalicilne kisline, soli in derivatov spojin uporablja za pripravo (i) zdravila ali (ii) fitofarmacevtskega pripravka za zdravljenje subjekta: človeka, živali ali rastline, ki je okužen z glivami in zagotavlja način zdravljenje takih infekcij. Po izumu je sinergistična farmacevtska kombinacija protiglivne substance in salicilne oziroma acetilsalicilne kisline uporabna za pripravo zdravila za in vivo preprečevanje in zdravljenje okužb z glivami, prednostno patogenimi in oportunistično patogenimi glivami in in vitro za dekontaminacijo površin in sterilizacijo medicinske opreme in implantatov. V nadaljevanju po izumu je sinergistična farmacevtska kombinacija protiglivne substance in salicilne oziroma acetilsalicilne kisline uporabna za pripravo fitofarmacevtskega preparata za in vivo preprečevanje in zdravljenje okužb z glivami pri rastlinah.The present invention relates to the discovery that salicylic or acetylsalicylic acid, salts and derivatives of a compound enhance the action of an antifungal substance and can be used as a pharmaceutical combination of an antifungal substance and salicylic or acetylsalicylic acid for the preparation of (i) a drug or (ii) of a plant protection product for the treatment of a subject: a human, animal or plant infected with fungi and providing a way of treating such infections. According to the invention, a synergistic pharmaceutical combination of antifungal substance and salicylic or acetylsalicylic acid is useful for the preparation of a medicament for the in vivo prevention and treatment of fungal infections, preferably pathogenic and opportunistic pathogens and in vitro for decontamination of surfaces and sterilization of medical equipment and implants. In the following, the synergistic pharmaceutical combination of an antifungal substance and salicylic or acetylsalicylic acid is useful for the preparation of a plant protection product for the in vivo prevention and treatment of fungal infections in plants.
Izraz protiglivna substanca se nanaša na antimikotik ali fungicid' in predstavlja protiglivno substanco, ki se jo uporablja za preprečevanje in zdravljenje okužb z glivami. Izraz antimikotik se nanaša na substanco, ki zavira rast in replikacijo gliv ali povzroči uničenje glivne celice in je substanca izbrana iz skupine (i) polienskih antimikotikiov, kot so: natamicin, rimocidin, filipin, nistatin, amfotericin B, kandicin; (ii) azolnih antimikotikov, kot so: mikonazol, ketokonazol, klotrimazol, ekonazol, bifonazol, butokonazol, fentikonazol, izokonazol, oksikonazol, sertaconazol, sulkonazol, tiokonazol, pramikonazol; (iii) triazolnih antimikotikov, kot so: flukonazol, itrakonazol, izavukonazol, ravukonazol, posakonazol, vorikonazol, terkonazol; (iv) alilaminskih antimikotikov, kot so: terbinafin, amorolfin, naftidin, butenafin; ali (v) ehinokandinov, kot so: anidulafungin, kaspofungin, mikaiungin; in drugi, kot so: amiodarone, terbinafine, ciklopiroks, pimaricin, flucitosin, allylamintiokarbamati, grizeofulvin, haloprogin. Izraz protiglivna substanca se nanaša tudi na proteine, ki inhibirajo rast gliv, kot so: PAF, AFP, rastlinski defenzini in drugi protiglivni • * peptidi in proteini. Izraz fungicid' se nanaša na kemična sredstva, ki se uporabljajo za zatiranje gliv v fitofarmacevtiki in so lahko kontaktni, polsistemični in sistemični.The term antifungal substance refers to an antifungal or fungicide 'and is an antifungal substance used to prevent and treat fungal infections. The term antifungal refers to a substance that inhibits the growth and replication of fungi or causes destruction of a fungal cell and the substance is selected from the group (i) of polyene antifungal agents such as: natamycin, rimocidin, Filipin, nystatin, amphotericin B, candicine; (ii) azole antifungals such as: miconazole, ketoconazole, clotrimazole, econazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxyconazole, sertaconazole, sulconazole, thioconazole, pramiconazole; (iii) triazole antifungals such as: fluconazole, itraconazole, isavuconazole, ravuconazole, posaconazole, voriconazole, terconazole; (iv) allylamine antifungals such as: terbinafine, amorolfin, naphtidine, butenafine; or (v) echinocandins, such as: anidulafungin, caspofungin, mikaiungin; and others, such as: amiodarone, terbinafine, cyclopyrox, pimaricin, flucytosine, allylamintiocarbamates, grizofulvin, haloprogin. The term antifungal substance also refers to proteins that inhibit the growth of fungi, such as: PAF, AFP, plant defensins and other antifungal peptides and proteins. The term fungicide refers to chemical agents used to control fungi in plant protection products, which may be contact, semi-systemic and systemic.
Predstavljeni izum se prednostno nanaša na odkritje, da salicilna kislina oziroma acetilsalicilna kislina, ki je derivat salicilne kisline, soli ali derivati spojin, izboljšajo fungicidno ali fungistatično delovanje protiglivne substance, kar se kaže z zmanjšano potrebno terapevtsko učinkovito količino protiglivne substance pri preprečevanju in zdravljenju glivnih okužb.The present invention preferably relates to the discovery that salicylic acid or acetylsalicylic acid, which is a derivative of salicylic acid, salts or derivatives of compounds, improves the fungicidal or fungistatic action of an antifungal substance, as evidenced by the reduced therapeutically effective amount of an antifungal substance in the prevention and treatment of fungi infections.
Izraz ustrezne soli, derivati se nanaša na soli ali derivate salicilne kisline in acetilsalicilne kisline, ki je tudi derivat salicilne kisline, ki bistveno ne spremenijo funkcije spojine, ji pa npr. povečajo topnost, dostopnost v tkivo, izboljšajo ali spremenijo presnovo, razgradnjo ali izločanje iz telesa in drugo. Funkcija salicilne kisline in acetilsalicilne kisline po izumu je sinergistično delovanje skupaj s protiglivno substanco pri zdravljenju in preprečevanju glivnih okužb.The term corresponding salts, derivatives, refers to salts or salicylic acid and acetylsalicylic acid derivatives, which is also a salicylic acid derivative that does not substantially alter the function of the compound, e.g. increase solubility, accessibility to tissue, improve or modify metabolism, breakdown or elimination from the body, and more. The function of salicylic acid and acetylsalicylic acid according to the invention is a synergistic action together with an antifungal substance in the treatment and prevention of fungal infections.
Izraz sinergističen predstavlja izboljšavo fungicidne ali fungistatične terapevtske učinkovitosti protiglivne substance v prisotnosti salicilne oziroma acetilsalicilne kisline. Izraz terapevtska učinkovitost se nanaša na uspešen klinični rezultat in ni nujno, da zahteva, da farmacevtska kombinacija uniči 100% organizmov vključenih v infekcijo. Uspešnost je odvisna od intenzivnosti glivne okužbe na mestu infekcije in se nanaša na izboljšanje stanja okužbe. Terapevtska učinkovitost je odvisna tudi od stanja osebka in je pri zdravem osebku potrebna manjša količina farmacevtske kombinacije kot pri osebku, ki ima oslabljen imunski odziv. Po izumu je terapevtsko učinkovita količina protiglivne substance v prisotnosti salicilne oziroma acetilsalicilne kisline v farmacevtski kombinaciji izuma nižja kot v primeru zdravljenja samo s protiglivno substanco.The term synergistic represents an improvement in the fungicidal or fungistatic therapeutic efficacy of an antifungal substance in the presence of salicylic or acetylsalicylic acid. The term therapeutic efficacy refers to a successful clinical outcome and does not necessarily require the pharmaceutical combination to destroy 100% of the organisms involved in the infection. Success depends on the intensity of the fungal infection at the site of infection and refers to the improvement of the infection status. The therapeutic efficacy also depends on the condition of the subject and in a healthy subject a smaller amount of the pharmaceutical combination is required than in a subject having a weakened immune response. According to the invention, the therapeutically effective amount of the antifungal substance in the presence of salicylic or acetylsalicylic acid in the pharmaceutical combination of the invention is lower than in the case of treatment with the antifungal substance alone.
Izum se nanaša na farmacevtsko kombinacijo za pripravo zdravila ali fitofarmacevtskega preparata za preprečevanje ali zdravljenje okužb, ki jih povzročajo patogene in oportunistično patogene kvasovke in filamentozne glive.The invention relates to a pharmaceutical combination for the preparation of a medicament or a plant protection product for the prevention or treatment of infections caused by pathogenic and opportunistic pathogenic yeasts and filamentous fungi.
Izraz glivne okužbe se nanaša na okužbe s filamentoznimi glivami in kvasovkami pri rastlinah, živalih in človeku in tudi na materialih, tekočinah in površinah. Izraz gliva se nanaša na mikroorganizme iz kraljestva gliv, prednostno na kvasovke in filamentozne glive, ki so rastlinski ali živalski patogeni in oportunistični patogeni. V skupino patogenih in oportunistično patogenih gliv se uvrščajo glive iz rodov: Candida, prednostno C. albicans, C. glabrata, C. krusei, C. laurentii, C. parapsilosis, C. tropicalis, C. lusitaniae, C. kefyr, C.The term fungal infection refers to infections with filamentous fungi and yeasts in plants, animals and humans, as well as in materials, liquids and surfaces. The term fungus refers to microorganisms from the kingdom of fungi, preferably yeast and filamentous fungi, which are plant or animal pathogens and opportunistic pathogens. The pathogenic and opportunistic pathogenic fungi include fungi of the genus Candida, preferably C. albicans, C. glabrata, C. krusei, C. laurentii, C. parapsilosis, C. tropicalis, C. lusitaniae, C. kefyr, C.
<* · • · guilliermondii, C. dubliniensis·, Cryptococcus, prednostno C. neoformans, C. albidus, C. gattii; Aspergillus, prednostno A. flavus, A. fumigatus, A. clavatus, A. niger, A. nidulans, A. terreus, A. sydowi, A. glaucus, A. oryzae, A. ustus, A. versicolor; Histoplasma, prednostno Histoplasma capsulatum; Paracoccidioides, prednostno P. brasiliensis; Sporothrix, prednostno Sporothrix schenckii; Blastomyces, prednostno B. dermatitidis; Paecilomyces prednostno P. lilacinus, P. variotii; Pneumocystis, prednostno P. jirovecii; Stachybotrys, prednostno S. chartarum; Malassezia, prednostno M. jurfur; Pityrisporum, prednostno P. ovalae; Coccidioides, Fonsecaea, Cladosporium, Basidiobolus, Conidiobolus, Rhizopus, Rhizomucor, Mucor, Absidia, Mortierella, Cunninghamella, Saksenaea, Trychophyton, prednostno T. rubrum, T. tonsurans T. mentagrophytes, T. soudanense, T. verrucosum, T. ajelloi, T. concentricum, T. equinum, T. erinacei, T. flavescens, T. gloriae, T. interdigitale, T. megnini, T. phaseoliforme, T. schoenleini, T. simii, T. terrestre, T. tonsurans, T. vanbreuseghemii, T. violaceum, T. yaoundei·, Microsporum, prednostno M. canis, M. gypseum, M. audouini, M. gallinae, M. ferrugineum, M. distortum, M. nanum, M. cookie, M. vanbreuseghemii·, Epidermophyton, prednostno E. floccosum, E. stockdaleae; Trichosporon, Fusarium, prednostno F. oxysporum, F. šolani, F. semitectum, Scytalidium, prednostno S. dimidiatum, S. hyalinum, S. infestans, S. japonicum, S. lignicola; Penicillium, Actinomyceees, Cochliobolus; Scopulariopsis, prednostno S. brevicaulis, S. candida, S. koningii, S. acremonium, S. flava, S. cinerea, S. trigonospora, S. brumptii, S. chartarum, S. fusca, S. asperula; Alternaria, prednostno A. alternate, A. chartarum, A. dianthicola, A. geophilia, A. infectoria, A. stemphyloides, A. teunissima; Curvularia, prednostno C. brachyspora, C. clavata, C. geniculata, C. lunata, C. pallescens, C. senegalensis, C. verruculosa; Chaetomium prednostno C. atrobrunneum, C. funicola, C. globosum, C. strumarium. Izraz glive se nanaša na kvasovke in filamentozne glive, ki pri zdravem preiskovancu ne povzročajo obolenja, pri imunokompromitiranih preiskovancu pa te glive lahko povzročijo obolenja. Izraz glive se nanaša tudi na glive, ki so rastlinski patogeni in so Fusarium spp., Thielaviopsis spp., Verticillium spp., Rhizoctonia spp., Phakospora pachyrhizi Sydow, Puccinia spp., Magnaporthe spp. e.g. Magnaporthe grisea, Ustilago spp. e.g. Ustilago mydis,<* · • · guilliermondii, C. dubliniensis ·, Cryptococcus, preferably C. neoformans, C. albidus, C. gattii; Aspergillus, preferably A. flavus, A. fumigatus, A. clavatus, A. niger, A. nidulans, A. terreus, A. sydowi, A. glaucus, A. oryzae, A. ustus, A. versicolor; Histoplasma, preferably Histoplasma capsulatum; Paracoccidioides, preferably P. brasiliensis; Sporothrix, preferably Sporothrix schenckii; Blastomyces, preferably B. dermatitidis; Paecilomyces preferably P. lilacinus, P. variotii; Pneumocystis, preferably P. jirovecii; Stachybotrys, preferably S. chartarum; Malassezia, preferably M. jurfur; Pityrisporum, preferably P. ovalae; Coccidioides, Fonsecaea, Cladosporium, Basidiobolus, Conidiobolus, Rhizopus, Rhizomucor, Mucor, Absidia, Mortierella, Cunninghamella, Saksenaea, Trychophyton, preferably T. rubrum, T. tonsurans T. mentagrophytes, T. soudanum, T. arucoscosense, T. arucoscosense, T. arucoscosense T. concentricum, T. equinum, T. erinacei, T. flavescens, T. gloriae, T. interdigitale, T. megnini, T. phaseoliforme, T. schoenleini, T. simii, T. terrestre, T. tonsurans, T. vanbreuseghemii, T. violaceum, T. yaoundei ·, Microsporum, preferably M. canis, M. gypseum, M. audouini, M. gallinae, M. ferrugineum, M. distortum, M. nanum, M. cookie, M. vanbreuseghemii · , Epidermophyton, preferably E. floccosum, E. stockdaleae; Trichosporon, Fusarium, preferably F. oxysporum, F. scholi, F. semitectum, Scytalidium, preferably S. dimidiatum, S. hyalinum, S. infestans, S. japonicum, S. lignicola; Penicillium, Actinomyceees, Cochliobolus; Scopulariopsis, preferably S. brevicaulis, S. candida, S. koningii, S. acremonium, S. flava, S. cinerea, S. trigonospora, S. brumptii, S. chartarum, S. fusca, S. asperula; Alternaria, preferably A. alternate, A. chartarum, A. dianthicola, A. geophilia, A. infectoria, A. stemphyloides, A. teunissima; Curvularia, preferably C. brachyspora, C. clavata, C. geniculata, C. lunata, C. pallescens, C. senegalensis, C. verruculosa; Chaetomium preferably C. atrobrunneum, C. funicola, C. globosum, C. strumarium. The term fungus refers to yeast and filamentous fungi that do not cause disease in a healthy subject, but in immunocompromised subjects, these fungi can cause disease. The term fungus also refers to fungi that are plant pathogens and are Fusarium spp., Thielaviopsis spp., Verticillium spp., Rhizoctonia spp., Phakospora pachyrhizi Sydow, Puccinia spp., Magnaporthe spp. e.g. Magnaporthe grisea, Ustilago spp. e.g. Ustilago mydis,
Uncinula necator, Plasmopara viticola, Pseudopezicula tracheiphila, Botrytis spp. e.g. Botrytis cinerea, Phomopsis viticola.Uncinula necator, Plasmopara viticola, Pseudopezicula tracheiphila, Botrytis spp. e.g. Botrytis cinerea, Phomopsis viticola.
Izraz obolenje se nanaša na bolezensko stanje, ki ga povzročajo okužbe s kvasovkami in filamentoznimi glivami. Izraz obolenje se nanaša na površinska obolenja, ki so omejena na okužbo kože, nohtov in las; podkožna obolenja, kot so dermatitisi, ki so okužbe podkožnih • · • · tkiv in bližnje strukture; sistemska obolenja, ki so okužbe notranjih organov: pljuč, jeter, srca, centralnega živčnega sistema, gastrointestinalnega trakta in oportunistična obolenja, okužbe imunokomprimitiranih pacientov tudi z nepatogenimi glivami. Obolenja se izražajo v obliki mikoz, kandidoz, sistemskih mikoz, histoplazmoze, blastomikoze, kokidiomikoze in parakokidiomikoze, vnetij, rdečic, prhljaja, atletskega stopala, kandidoze ust in vagine, dermatitisa, ekcema, onikomikoza, aspergilloze, histoplazmoze, pljučnice, poškodbe dihal in glavobola, astme. Izraz obolenje se nanaša na obolenje, ki ga povzročajo glive pri živalih, in človeku, prednostno pri čebelah in vretenčarjih; predvsem ptičih, perutnini, sesalcih; predvsem kopitarji, zajci, zveri, mačke, primati, človek.The term disease refers to a disease condition caused by yeast infections and filamentous fungi. The term disease refers to superficial diseases that are restricted to infection of the skin, nails and hair; subcutaneous diseases such as dermatitis, which are infections of subcutaneous tissues and adjacent structures; systemic diseases that are infections of the internal organs: lungs, liver, heart, central nervous system, gastrointestinal tract and opportunistic diseases, infections of immunocompromised patients with non-pathogenic fungi. The diseases are expressed in the form of mycoses, candidiasis, systemic mycoses, histoplasmosis, blastomycosis, coccidiomycosis and paracoccidiomycosis, inflammations, redness, dandruff, athletic foot, candidiasis of the mouth and vagina, dermatitis, eczema, onychomycosis, aspergillosis, aspergillosis, aspergillosis , asthma. The term disease refers to a disease caused by fungi in animals and humans, preferably in bees and vertebrates; mainly birds, poultry, mammals; especially equidae, rabbits, beasts, cats, primates, man.
Izraz zdravljenje povzema preventivno in terapevtsko zdravljenje. In vitro metoda zdravljenja se nanaša na uničenje in inhibicijo rasti in replikacije gliv preko prenosa farmacevtske kombinacije po izumu na z glivo okuženo mesto.The term treatment refers to preventive and therapeutic treatment. The in vitro method of treatment relates to the destruction and inhibition of the growth and replication of fungi by transferring a pharmaceutical combination of the invention to a fungal infected site.
Izum predstavlja zdravilo, ki vsebuje farmacevtsko kombinacijo po izumu za zdravljenje glivnih okužb in zdravilo vsebuje farmacevtsko kombinacijo v učinkovitih količinah, da inhibirajo ali uničijo glivne celice.The invention provides a medicament containing a pharmaceutical combination of the invention for the treatment of fungal infections, and a medicament comprising a pharmaceutical combination in effective amounts to inhibit or destroy fungal cells.
Določitev terapevtsko učinkovite količine farmacevtske kombinacije protiglivne substance in motilca protonske homeostaze je poznana strokovnjaku s področja. Terapevtsko učinkovita količina farmacevtske kombinacije po izumu vsebuje manjšo količino protiglivne substance zaradi sočasne ali zaporedne administracije salicilne ali acetilsalicilne kisline. Farmacevtska kombinacija lahko poleg farmacevtske kombinacije protiglivne substance in salicilne kisline ali acetilsalicilne kisline, soli ali derivatov spojine vsebuje tudi druga zdravila.One skilled in the art will determine the therapeutically effective amount of a pharmaceutical combination of an antifungal substance and a proton homeostasis disruptor. The therapeutically effective amount of the pharmaceutical combination according to the invention contains a smaller amount of antifungal substance due to the simultaneous or sequential administration of salicylic or acetylsalicylic acid. The pharmaceutical combination may contain, in addition to the pharmaceutical combination of the antifungal substance and salicylic acid or acetylsalicylic acid, salts or derivatives of the compound.
Učinkovitejše delovanje protiglivne substance v farmacevtski kombinaciji se vidi z zmanjšano učinkovito količino protiglivne substance, kije potrebna za popolno odstranitev ali inhibicijo replikacije in rasti gliv. Uporaba nekaterih protiglivnih substanc je omejena zaradi njihove sistemske toksičnosti ali visokih stroškov zdravljena s tako protiglivno substanco. Zniževanje koncentracije protiglivnih substanc s salicilno ali acetilsalicilno kislino, soljo ali derivatom spojin je potrebno zaradi zniževanja stranskih učinkov in stroškov, kar omogoča širšo uporabo farmacevtske kombinacije. Zdravilo po izumu je pripravljeno na način, da zagotavlja hitrejše ali učinkovitejše fungistatične ali fungicidne učinke, kot bi jih dosegli ob uporabi same protiglivne substance. Zdravilo, ki vsebuje farmacevtsko kombinacijo po izumu lahko izniči odpornost gliv na protiglivno substanco, oziroma spremeni fungistatično delovanje protiglivne substance v fungicidno. Pri tem je v farmacevtski kombinaciji • · učinkovita količina protiglivne substance zmanjšana zaradi sinergističnega delovanja komponent farmacevtske kombinacije.The more effective action of an antifungal substance in a pharmaceutical combination is seen by the reduced effective amount of the antifungal substance required for complete removal or inhibition of fungal replication and growth. The use of certain antifungal substances is limited by their systemic toxicity or the high cost of treating such antifungal substance. Reducing the concentration of antifungal substances with salicylic or acetylsalicylic acid, salt or derivative of the compounds is necessary in order to reduce the side effects and costs, thus making the pharmaceutical combination more widely used. The medicament of the invention is formulated to provide faster or more effective fungistatic or fungicidal effects than would be achieved with the use of the antifungal substance itself. A medicament containing the pharmaceutical combination of the invention may degrade the fungal resistance of the antifungal substance or change the fungistatic action of the antifungal substance into a fungicidal one. In this case, in the pharmaceutical combination, the effective amount of the antifungal substance is reduced due to the synergistic action of the components of the pharmaceutical combination.
Zdravilo lahko vsebuje aktivni substanci: protiglivno substanco in salicilno ali acetilsalicilno kislino v farmacevtski kombinaciji po izumu, v obliki zmesi ali posamezni aktivni komponenti ločeno, pod pogojem, da sta substanci zdravila uporabljeni na način, ki zagotavlja, da ločeni substanci dosežeta učinke na mestu glivne okužbe, ki so enaki sinergističnim učinkom zmesi. Aktivni komponenti v zdravilu sta ločeni zaradi izboljšane stabilnosti ločenih komponent in lažje uporabe predvsem po ločenih poteh. Posamezni komponenti farmacevtke kombinacije po izumu, to sta protiglivna substanca in salicilna ali acetilsalicilna kislina, lahko poteka v različnih farmacevtskih oblikah. Farmacevtska kombinacija, ki zagotavlja sočasno administracijo protiglivne substance in acetilsalicilne kisline je pričakovano učinkovitejša, z močnejšim fungistatičnim ali fungicidnim učinkom in vivo v primerjavi z administracijo posamične substance farmacevtske kombinacije po izumu. Izraz fungistatični učinek” opisuje inhibirano rast in razmnoževanje gliv, izraz fungicidni učinek” pa se nanaša na uničenje gliv.The drug may contain active substances: an antifungal substance and salicylic or acetylsalicylic acid in the pharmaceutical combination of the invention, in the form of a mixture or individual active component, provided that the drug substances are used in a manner that ensures that the separate substances achieve effects at the fungal site infections equal to the synergistic effects of the mixture. The active components in the drug are separated because of the improved stability of the separate components and their ease of use especially in separate routes. The individual components of the pharmaceutical combination of the invention, i.e. the antifungal substance and salicylic or acetylsalicylic acid, may be present in different pharmaceutical forms. A pharmaceutical combination that provides concomitant administration of an antifungal substance and acetylsalicylic acid is expected to be more effective, with a stronger fungistatic or fungicidal effect in vivo than administration of a single substance of the pharmaceutical combination of the invention. The term fungistatic effect "describes the inhibited growth and reproduction of fungi, and the term fungicidal effect" refers to the destruction of fungi.
Izum, farmacevtska kombinacija, omogoča uničenje ali inhibicijo rasti gliv na način neposrednega kontakta farmacevtske kombinacije z glivo. Ta metoda se lahko uporablja in vitro, kot na primer v fitofarmacevtiki, dekontaminaciji tekočin in površin ali za sterilizacijo kirurških in drugih medicinskih orodij in implantatov, vključno s protetiko, in situ sterilizacijo katetrov, intravenoznih vsadkov.The invention, a pharmaceutical combination, enables the destruction or inhibition of fungal growth by direct contact of the pharmaceutical combination with the fungus. This method can be used in vitro, such as in plant protection, decontamination of fluids and surfaces, or for the sterilization of surgical and other medical tools and implants, including prosthetics, in situ sterilization of catheters, intravenous implants.
Izum v nadaljevanju obsega pripravo zdravila, ki vsebuje farmacevtsko kombinacijo za zdravljenje infekcije z glivami. Zdravilo je v poljubni farmacevtski obliki in vsebuje potrebne farmacevtske dodatke.The invention further comprises the preparation of a medicament comprising a pharmaceutical combination for the treatment of fungal infection. It is in any pharmaceutical form and contains the necessary pharmaceutical additives.
Farmacevtska oblika je oblika, v katero vgradimo učinkovino, farmacevtsko kombinacijo po izumu in se nanaša na prašek, suspenzija, emulzija, raztopina, pasta, krema, mazilo, gel, losjon, liniment, farmacevtske oblike za injiciranje, infuzijske farmacevtske oblike, tableta, kapsula, svečka, transdermalni obliž, terapevtski sistem, tinktura, perkolat, izvleček. Izraz farmacevtska dopolnila se nanaša na dodatke v farmacevtski formulaciji oziroma zdravilu, ki olajšajo, izboljšajo vnos aktivnih substanc, farmacevtske kombinacije po izumu na mesto okužbe in so del farmacevtske oblike. Farmacevtska dopolnila vključujejo ustrezna redčila, adjuvanse, nosilce. Administracija aktivne učinkovine je lahko topična, intravenozna, oralna ali intramuskulatoma, preko aerosola, podkožna, intraperitonalna, intraokulama, transpulmulama, transdermalna.The pharmaceutical form is the form in which the active ingredient, the pharmaceutical combination of the invention is incorporated, and relates to powder, suspension, emulsion, solution, paste, cream, ointment, gel, lotion, liniment, pharmaceutical dosage forms, infusion dosage forms, tablet, capsule. , suppository, transdermal patch, therapeutic system, tincture, percolate, extract. The term pharmaceutical additives refers to additives in a pharmaceutical formulation or drug that facilitate, enhance the uptake of active substances, pharmaceutical combinations of the invention at the site of infection, and form part of a pharmaceutical form. Pharmaceutical supplements include suitable diluents, adjuvants, carriers. Administration of the active substance may be topical, intravenous, oral or intramuscular, via aerosol, subcutaneous, intraperitoneal, intraocular, transpulmin, transdermal.
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Farmacevtska kombinacija po izumu je lahko administriran skupaj z drugimi zdravili. Farmacevtska kombinacija lahko vsebuje eno ali več protiglivnih substanc z salicilno ali acetilsalicilno kislino.The pharmaceutical combination of the invention may be administered together with other medicaments. The pharmaceutical combination may contain one or more antifungal substances with salicylic or acetylsalicylic acid.
Izum se nanaša tudi na fitofarmacevtski pripravek v ustrezni obliki in z ustreznimi dodatki in je namenjen za preprečevanje ali zdravljenje glivnih okužb pri rastlinah. Izum se nanaša na metodo uporabe farmacevtske kombinacije v obliki zdravila ali fitofarmacevtskega pripravka za uničevanje gliv ali inhibicijo rasti in reprodukcije gliv in se uporablja v fitofarmacevtiki in dekontaminaciji tekočin in površin ali za sterilizacijo kirurških in drugih medicinskih orodij in implantatov, vključno s protetiko, in situ sterilizacijo katetrov, intravenoznih vsadkov.The invention also relates to a plant protection product in a suitable form and with appropriate additives and is intended to prevent or treat fungal infections in plants. The invention relates to a method of using a pharmaceutical combination in the form of a drug or plant protection product for the destruction of fungi or inhibiting the growth and reproduction of fungi, and is used in the plant protection and decontamination of liquids and surfaces or for the sterilization of surgical and other medical tools and implants, including prosthetics, in situ sterilization of catheters, intravenous implants.
Spodaj so navedeni primeri postopkov, načrtovani z namenom ilustracije inovacije. Opisi primerov nimajo namena omejevanja inovacije in naj se razumejo v smislu demonstracije inovacije.Below are examples of procedures designed to illustrate innovation. Case descriptions are not intended to limit innovation and should be understood in terms of demonstrating innovation.
Primeri izvedbePerformance examples
Primer 1. Test inhibicije rastiExample 1. Growth inhibition test
Učinek farmacevtske kombinacije smo testirali na glivah iz vrste Aspergillus v tekočem gojišču. Spore smo gojili preko noči (od 16 do 24 h) v sintetičnem tekočem gojišču po Voglu pri 30 °C. Gojišče po Voglu je vsebovalo različne kombinacije antimikotika in acetilsalicilne kisline. Za pozitivno kontrolo smo uporabili glivo, ki je rastla v gojišču brez dodatkov farmacevtske kombinacije. Metoda ΧΤΤ, ki se uporablja za določanje metabolne aktivnosti glivnih celic in njihovo preživetje, je opisana spodaj.The effect of the pharmaceutical combination was tested on Aspergillus fungi in liquid medium. The spores were grown overnight (from 16 to 24 h) in a synthetic liquid medium at Vogel at 30 ° C. The Vogel medium contained various combinations of antifungal and acetylsalicylic acid. For positive control, we used a fungus grown in culture medium without the addition of a pharmaceutical combination. The method ΧΤΤ used to determine the metabolic activity of fungal cells and their survival is described below.
Priprava suspenzije spor in gojiščPreparation of suspension of spores and media
Suspenzije spor smo pripravili v 0.1% (m/v) raztopini Tween 80. Suspenzijo spor končnih koncentracije 105 spor/ml smo uporabili za inokulacijo tekočega gojišča po Voglu. Gojišče po Voglu vsebuje: 8.5 mM of sodium citrate dihydrate (Ε^^ΡΕΟγ)), 36.8 mM KH2PO4, 25.0 mM NH4NO3, 0.7 mM CaCl2.2H2O, 0.8 mM MgSO4.7H2O, pH 6.0, 0.2 ml kovine v sledovih (34.3 mM EDTA, 15.3 mM ZnSO4.7H2O, 8 mM MnCl2.4H20, 1.6 mM CoC12.6H2O, 1.3 mM CuSO4.5H2O, 0.2 mM (NH4)6Mo7O24.4H20, 10 mM CaCl2.2H2O, 3.6 mM FeSO4.7H2O; pH 6.5), 20 μΜ D-biotin in 2% (w/v) glukoze. Protiglivne substance (amiodaron 2 mM v DMSO, amfotericin 0,04 g/1 DMSO, klotrimazol 1 g/1 DMSO, flukonazol 40 g/1 DMSO, ketokonazol 5 g/1 metanola) in, acetilsalicilna kislina v vodi smo raztopili v pripadajočih topilih v • c ustreznih koncentracijah. 0.2 ml spor v gojišču smo odpipetirali v luknjice mikrotitrske plošče (uporabljali smo plošče s 96 luknjicami). K raztopini spor smo dodali farmacevtsko kombinacijo. Gojišče s sporami brez farmacevtske kombinacije smo uporabili kot kontrolo rasti (100% rast). Sledila je 24 uma inkubacija pri 37° C.Spore suspensions were prepared in 0.1% (w / v) Tween 80 solution. Spores of final concentrations of 10 5 spores / ml were used to inoculate liquid medium according to Vogel. The Vogel medium contains: 8.5 mM sodium citrate dihydrate (Ε ^^ ΡΕΟγ)), 36.8 mM KH2PO4, 25.0 mM NH4NO3, 0.7 mM CaCl 2 .2H 2 O, 0.8 mM MgSO4.7H 2 O, pH 6.0, 0.2 ml metal trace (34.3 mM EDTA, 15.3 mM ZnSO 4 .7H 2 O, 8 mM MnCl 2 .4H 2 0, 1.6 mM CoC1 2 .6H 2 O, 1.3 mM CuSO 4 .5H 2 O, 0.2 mM (NH4) 6Mo 7 O 2 4.4H 2 0, 10 mM CaCl 2 .2H 2 O, 3.6 mM FeSO 4 .7H 2 O; pH 6.5), 20 μΜ D-biotin and 2% (w / v) glucose. Antifungals (amiodarone 2 mM in DMSO, amphotericin 0.04 g / 1 DMSO, clotrimazole 1 g / 1 DMSO, fluconazole 40 g / 1 DMSO, ketoconazole 5 g / 1 methanol) and acetylsalicylic acid in water were dissolved in the respective solvents v • c appropriate concentrations. Pipette 0.2 ml of culture medium spores into the wells of a microtiter plate (96-well plates were used). A pharmaceutical combination was added to the spore solution. Dispute medium without pharmaceutical combination was used as growth control (100% growth). This was followed by 24 μm incubations at 37 ° C.
Z ΧΤΤ metodo smo določali prisotnost živih celic. ΧΤΤ reagent prehaja celično membrano in se v aktivnih mitohondrijih pretvori v obarvano spojino. Pripravili smo raztopini ΧΤΤ in menadiona. ΧΤΤ smo raztopili v vroči vodi s končno koncentracijo 1 g/1. Menadion smo raztopili v acetonu v koncentraciji 10 mM, ter ga nato redčili v razmerju 1:10 s fiziološko raztopino. Končna ΧΤΤ raztopina vsebuje ΧΤΤ reagent (koncentracija 0.6 g/1; končna koncentracija v luknjici 0.2 g/1) in menadion (koncentracija 75 μΜ, končna koncentracija v luknjici 25 μΜ).The presence of live cells was determined by the ΧΤΤ method. ΧΤΤ The reagent crosses the cell membrane and is converted to the colored compound in active mitochondria. Solutions and menadione were prepared. ΧΤΤ was dissolved in hot water at a final concentration of 1 g / l. Menadion was dissolved in acetone at a concentration of 10 mM, and then diluted 1:10 with saline. The final solution contains a reagent (concentration 0.6 g / l; final concentration in the hole 0.2 g / l) and menadion (concentration 75 μ koncent, final concentration in the hole 25 μΜ).
V vsako luknjico smo dodali 100 μΐ ΧΤΤ raztopine. Nato smo ploščo inkubirali pri 30° C, tokrat 4 ure. Po inkubaciji smo iz vsake luknjice odpipetirali 100 μΐ raztopine v novo prozorno mikrotitrsko ploščo, v kateri smo potem na mikročitalcu Bio-Tek® PowerWave XS izmerili absorbanco raztopine pri valovni dolžini 450 nm.100 μΐ ΧΤΤ of solution was added to each well. The plate was then incubated at 30 ° C, this time for 4 hours. After incubation, 100 μΐ of the solution was pipetted from each well into a new clear microtiter plate, whereupon the absorbance of the solution was measured at a wavelength of 450 nm on a Bio-Tek® PowerWave XS micro reader.
Na Sliki 1 so predstavljeni rezultati kombinacije acetilsalicilne kisline (0, 0.5, 2 in 4 mM) in antimikotikov amfotericina, flukonazola, ketokonazola in klotrimazola. Kljub temu, da amfotericin in acetilsalicilna kislina delujeta sinergistično pa v nobeni od testiranih kombinacij nismo dosegli fungicidnega delovanja. Kombinacija 0.5 mM acetilsalicilne in 1 g/1 flukonazola inhibira rast 99%. Višje koncentracij farmacevtske kombinacije pa so fungicidne. Enako velja za farmacevtsko kombinacijo acetilsalicilne kisline in klotrimazola, ki je fungicidna pri koncentraciji 2 mM acetilsalicilne kisline in 1 mg/1 klotrimazola. Nekaj slabše rezultate smo dosegli s kombinacijo acetilsalicilne kisline in ketokonazola, ki pa še vedno deluje sinergistično.Figure 1 presents the results of the combination of acetylsalicylic acid (0, 0.5, 2 and 4 mM) and the antifungals of amphotericin, fluconazole, ketoconazole and clotrimazole. Although amphotericin and acetylsalicylic acid act synergistically, in none of the tested combinations did fungicidal activity be achieved. A combination of 0.5 mM acetylsalicylic and 1 g / l fluconazole inhibits growth of 99%. Higher concentrations of the pharmaceutical combination are fungicidal. The same applies to the pharmaceutical combination of acetylsalicylic acid and clotrimazole, which is fungicidal at a concentration of 2 mM acetylsalicylic acid and 1 mg / l of clotrimazole. Somewhat worse results were achieved with the combination of acetylsalicylic acid and ketoconazole, which still works synergistically.
Slika 4 predstavlja inhibicijo metabolizma glive A. niger v prisotnosti salicilne in acetilsalicilne kisline. Rezultati kažejo, da sta tako salicilna kot tudi acetilsalicilna kislina, derivat salicilne kisline, sposobna inhibirat rast glive.Figure 4 presents the inhibition of the metabolism of A. niger in the presence of salicylic and acetylsalicylic acid. The results show that both salicylic and acetylsalicylic acid, a derivative of salicylic acid, are capable of inhibiting fungal growth.
Kombinacijo acetilsalicilne kisline in klotrimazola na glivi A. flavus (Tabela 1). Obe kombinaciji v uporabljenih koncentracijah delujeta na rast glive sinergistično z 99% inhibicijo rasti.A combination of acetylsalicylic acid and clotrimazole on A. flavus (Table 1). Both combinations at the concentrations used act on the growth of the fungus synergistically with 99% growth inhibition.
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Tabela 1. Inhibicija'rasti gliv A. flavus s farmacevtskima kombinacijama acetilsalicilne kisline in klotrimazola. Za primerjavo smo uporabili gojišče brez komponent in s posameznimi komponentami farmacevtske kombinacije.Table 1. Inhibition of the A. flavus fungus by pharmaceutical combinations of acetylsalicylic acid and clotrimazole. For comparison, the medium without components and with the individual components of the pharmaceutical combination was used.
Primer 2. Konfokalna mikroskopijaExample 2. Confocal microscopy
S pomočjo mikroskopije smo ovrednotili vpliv farmacevtske kombinacije na rast testirane glive. Celice smo barvali z barvilom SynaptoRed in SYTOX. Prvo barvilo barva celične membrane, medtem ko SYTOX slabo prehaja nepoškodovano celično steno in fluorescira samo po vezavi na DNA. Detekcija SYTOX barvila znotraj celice je pokazatelj, da je poškodovana celična membrana.Microscopy was used to evaluate the effect of the pharmaceutical combination on the growth of the test fungus. Cells were stained with SynaptoRed and SYTOX dye. The first dye stains the cell membrane, whereas SYTOX poorly crosses the intact cell wall and fluoresces only after DNA binding. Detection of SYTOX dye inside the cell indicates that the cell membrane is damaged.
Preskusili smo kombinacije amiodarona in acetilsalicilne kisline, klotrimazola in acetilsalicilne kisline. Kot kontrolo smo uporabili glivo A. niger brez dodatka farmacevtske kombinacije. Rezultati so prikazani na sliki 3. Povečave slik so enake povečavi kontrolnega preparata. Primerjava rasti in barvanje s SYTOX jasno kažejo, da je v prisotnosti farmacevtske kombinacije motena rast gliv. Opazi se, da je rast kontrolnega preparata intenzivnejša in se znotraj celična vsebina ne barva s SYTOX barvilom. Farmacevtske kombinacije močno inhibirajo rast. Natančna izvedba posameznih korakov eksperimenta je opisana spodaj.Combinations of amiodarone and acetylsalicylic acid, clotrimazole and acetylsalicylic acid were tested. A. niger fungus without the addition of a pharmaceutical combination was used as a control. The results are shown in Figure 3. Magnifications of images are equal to magnification of the control preparation. Comparison of growth and staining with SYTOX clearly indicate that fungal growth is impaired in the presence of the pharmaceutical combination. It is observed that the growth of the control preparation is more intense and does not stain within the cell contents with SYTOX dye. Pharmaceutical combinations strongly inhibit growth. The exact implementation of the individual steps of the experiment is described below.
Pri delu smo uporabljali konfokalni mikroskop Leica TCS SP5. To je laserski mikroskop postavljen na ogrodje Leica DMI 6000 CS invertnega mikroskopa (Leica Microsystems, Germany). Uporabljali smo imerzijski objektiv s HCX plan apo 63x oil (NA 1.4). Za barvanje smo uporabili barvilo SynaptoRed 2 (Biotium), ki se vzbuja pri 514 nm z argonskim laserjem, emisijo pa smo zbirali med 650 in 700 nm in SYTOX Green, ki se vzbuja pri 488 nm in emitira pri 520 do 540 nm.We used a Leica TCS SP5 confocal microscope at work. This is a laser microscope mounted on a Leica DMI 6000 CS inverted microscope (Leica Microsystems, Germany). We used an immersion lens with HCX plan apo 63x oil (NA 1.4). SynaptoRed 2 (Biotium) dye excited at 514 nm with an argon laser was used for dyeing, and emission was collected between 650 and 700 nm and SYTOX Green excited at 488 nm and emitted at 520 to 540 nm.
Pripravili smo suspenzijo spor s koncentracijo 105 spor/ml v gojišču po Voglu, ki je vsebovalo protiglivno substanco in motilec protonske homeostaze. 0.2 ml omenjene suspenzije smo nacepili na krovno steklo. Preparat smo inkubirali 14 ur na 30° C v vlažni komori. Preparate smo barvali s Synapto Red (barvila celične membrane) in 10 μΐ 0.5 mM barvila Sytox Green, 15 minut pri 30°C.A 10 5 spore / ml spore suspension was prepared in a Vogel medium containing an antifungal substance and a proton homeostasis disruptor. 0.2 ml of said suspension was applied to a glass slide. The preparation was incubated for 14 hours at 30 ° C in a humidified chamber. The preparations were stained with Synapta Red (cell membrane dyes) and 10 μΐ 0.5 mM Sytox Green dye for 15 minutes at 30 ° C.
Primer 3. Inhibicija rasti kvasovkExample 3. Inhibition of yeast growth
Farmacevtske kombinacije smo testirali na kvasovkah Saccharomyces cerevisiae v tekočem gojišču. Kvasovko smo gojili preko noči (od 16 do 24 h) v sintetičnem tekočem gojišču pri 28 °C. Gojišče je vsebovalo različne farmacevtske kombinacije. Kontrolne celice kvasovk smo gojili v gojišču brez farmacevtske kombinacije. Celice kvasovk smo razredčili do optične gostote pri 600 nm 0.04 (OD600). Rast smo spremljali spektrofotometrično. Predstavljeni so rezultati izmerjeni po 8 h inkubacije na 28 °C. Kvasovkam smo dodali farmacevtske kombinacije in spremljali njihovo rast. Rezultati so predstavljeni na sliki 2.The pharmaceutical combinations were tested on the yeast Saccharomyces cerevisiae in liquid medium. The yeast was grown overnight (16 to 24 h) in a synthetic liquid medium at 28 ° C. The medium contained various pharmaceutical combinations. Yeast control cells were grown in culture medium without pharmaceutical combination. Yeast cells were diluted to optical density at 600 nm 0.04 (OD600). The growth was monitored spectrophotometrically. The results presented are measured after 8 h of incubation at 28 ° C. We added pharmaceutical combinations to the yeasts and monitored their growth. The results are presented in Figure 2.
Najhitrejša je bila rast kvasovk, ki smo jih gojili brez prisotnosti dodatkov. Vsi nadaljnji rezultati so preračuni kot odstotek rasti glede na pozitivno kontrolo. Iz rezultatov je razvidno (Slika 2), da farmacevtska kombinacija motilca protonske homeostaze, acetilsalicilne kisline in amfotericina, inhibira rast S. cerevisiae in da je inhibicija rasti veliko boljša od inhibicije rasti v prisotnosti posameznih komponent. Podobne rezultate smo dobili tudi s kvasovko C. albicans (Tabela 3).The fastest growth was the yeast that was grown without additives. All further results are calculated as a percentage of growth relative to the positive control. The results show (Figure 2) that the pharmaceutical combination of proton homeostasis, acetylsalicylic acid and amphotericin inhibits the growth of S. cerevisiae and that growth inhibition is much better than growth inhibition in the presence of individual components. Similar results were obtained with C. albicans yeast (Table 3).
Tabela 3. Rast kvasovke C. albicans v prisotnosti farmacevtske kombinacije amiodarona in acetilsalicilne kisline.Table 3. Growth of C. albicans yeast in the presence of a pharmaceutical combination of amiodarone and acetylsalicylic acid.
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EP3229900A4 (en) * | 2014-12-10 | 2018-11-14 | Devicefarm Inc. | Onychomycosis treatment apparatus and method |
US20170361078A1 (en) * | 2014-12-10 | 2017-12-21 | Devicefarm, Inc. | Onychomycosis treatment system and method |
US10493263B2 (en) * | 2014-12-10 | 2019-12-03 | Devicefarm, Inc. | Onychomycosis treatment system and method |
EP3772961A4 (en) * | 2018-03-26 | 2021-11-24 | UPL Ltd | Fungicidal combinations |
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US6159977A (en) * | 1998-11-16 | 2000-12-12 | Astan, Inc. | Therapeutic anti-fungal nail preparation |
DE10113045A1 (en) * | 2001-03-14 | 2002-09-19 | Tares Gmbh | Fungicide that inhibits secreted lipolytic enzymes, useful for plant protection and clinical use, e.g. acetylsalicylic acid |
NL1019441C1 (en) * | 2001-11-27 | 2003-06-02 | Cornelis Gerardus Maria Rovers | Composition useful for treating superficial mycoses, comprises acetylsalicylic acid and peroxide |
LT2018164T (en) * | 2006-05-12 | 2017-07-10 | Christian Noe | Use of combination preparations comprising antifungal agents |
WO2009051840A2 (en) * | 2007-10-18 | 2009-04-23 | Yale University | Compositions and methods for reducing hepatotoxicity associated with drug administration |
JP2011502143A (en) * | 2007-10-31 | 2011-01-20 | リ、ジン−シク | Bactericidal composition comprising peracid and acetylsalicylic acid |
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EP2605654B1 (en) * | 2010-08-20 | 2023-09-27 | Biotelliga Holdings Limited | Epipyrone a as an anti-microbial agent |
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