WO2005025565A1 - Composition microbicide comportant un ligand du petit sillon eventuellement en association avec un compose anti-vih, et son application a la prophylaxie des maladies sexuellement transmissibles - Google Patents

Composition microbicide comportant un ligand du petit sillon eventuellement en association avec un compose anti-vih, et son application a la prophylaxie des maladies sexuellement transmissibles Download PDF

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Publication number
WO2005025565A1
WO2005025565A1 PCT/IB2004/002923 IB2004002923W WO2005025565A1 WO 2005025565 A1 WO2005025565 A1 WO 2005025565A1 IB 2004002923 W IB2004002923 W IB 2004002923W WO 2005025565 A1 WO2005025565 A1 WO 2005025565A1
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compound
distamycin
composition according
pharmaceutical composition
hiv
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PCT/IB2004/002923
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Fabrizio Marcucci
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Need Pharmaceuticals S.R.L.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • 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
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/731—Carrageenans
    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/795—Polymers containing sulfur
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/40—Peroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses

Definitions

  • the object of the present invention is a microbicide composition and its use 5 in the prophylaxis of the sexually transmitted diseases. BACKGROUND OF THE ART It is known that the problem of sexually transmitted diseases is very felt and hard to be solved. In recent times, the problem has been made worse due to the HIV infection (human immunodeficiency virus), the sexual route being 10 one of the most dangerous and least easily controlled transmission means.
  • These products might be used by vaginal or rectal application, upon or just before sexual contact, and should protect 25 against most of the so-called sexually transmitted diseases of viral origin, such as for example AIDS, herpes genitalis, of bacterial origin, such as gonorrhea, either or protozoan or fungine ridge, such as trichomoniasis and candidiasis, respectively.
  • sexually transmitted diseases of viral origin such as for example AIDS, herpes genitalis, of bacterial origin, such as gonorrhea, either or protozoan or fungine ridge, such as trichomoniasis and candidiasis, respectively.
  • products having antiviral activity are known for local topical 30 use, which are employed in the treatment of the sexually transmitted diseases of viral origin, limitedly to herpes genitalis and which are employed by application on external genitals.
  • Products with antibacterial activity are also known, which are also used by local application and are active towards the sexually transmitted diseases of bacterial origin
  • the products exhibited a good activity in the treatment of already existing infections, i.e. an activity that can be defined as being curative, but they cannot be used in the prevention of said sexually transmitted diseases.
  • microbicide products capable of carrying out an a- priori antiviral/antibacterial activity
  • a- priori antiviral/antibacterial activity generally being defined as microbicide products
  • the microbicides currently studied and experimented for prophylactic use in the sexually transmitted diseases do not offer such a wide coverage as desired, and they further do not afford sufficient characteristics of safety, physical and chemical stability of the base product.
  • the problem is that of identifying a class of microbicide products active as antivirals, antibacterials, antiprotozoans, and antifungals, such as to ensure a wide protection in the case of sexually transmitted diseases, which are stable, suitable to vaginal and/or rectal application, and can be also easily used by less culturally developed populations.
  • the object of the present invention is to provide a composition having microbicide activity to be applied by vaginal and/or rectal route, which is stable over time and easy to use.
  • composition comprising at least one "Minor Groove Binder” (MGB) compound and at least one anti-HIV compound.
  • MGB Minimum Groove Binder
  • Minor Groove Binder is meant a compound that is able to bind (through a non-covalent binding) to the DNA at the minor groove.
  • said “Minor Groove Binder” (MGB) compound is selected from, though not being limited to: Distamycin A, Mithramycin, Congocidine, Hoechst 33258, Pentamidine, Furamidine, analogues of bis-distamycin and bis-netropsine, diarylamidine and diarylamidossime, such as DB-2898.
  • said anti-HIV compound is selected from, though not being limited to: surfactant agents such as Nonoxynol-9, sodium dodecyl-sulphate, C31G, benzalconium chloride, antibiotics such as magainin, protegrin, oxidizing agents such as chlorhexidine, hydrogen peroxide, anti-HIV and anti-CD4 antibodies, reverse transcriptase inhibitors such as Tenofovir, UC781 , Nevirapine etc., inhibitors of HIV attack and/or fusion to cells such as Suradista analogues, anionic polymers (PRO 2000), Carragenin, Polystyrene Sulfonate, Cyanovirin.
  • surfactant agents such as Nonoxynol-9, sodium dodecyl-sulphate, C31G, benzalconium chloride
  • antibiotics such as magainin, protegrin
  • oxidizing agents such as chlorhexidine
  • hydrogen peroxide anti-HIV and anti-CD4 antibodies
  • said MGB compound is Distamycin A
  • said anti-HIV compound is comprised among the products belonging to the Suradista class.
  • Distamycin A is a natural product having antibiotic activity, particularly a fungicide activity for application in the agricultural or veterinary field, obtained from Streptomyces distallicus such as described in US 3,190,801.
  • Said anti-HIV compound belonging to the Suradista class is a compound similar to the above Distamycin, for use as a drug for the treatment of AIDS, Acquired ImmunoDeficiency Syndrome caused by HIV virus type 1 and 2, such as described in Drug Data Report, Vol.20, No.9, 1995-1999 (Prous Science) with code NSC-651016.
  • the activity of each component is recognized for the treatment of an already existing disease, when the infection has already developed and is symptomatic, both in the case of the antibiotic and AIDS.
  • Both products exhibit their known antibiotic and antiviral activity, though not preventively but only after the onset of the disease, and cause the regress of the latter mainly in the case of Distamycin A antibiotic, as well as a partial deactivation of the virus or inhibition of the viral activity in the case of those compounds belonging to the Suradista class.
  • the composition according to the invention has a microbicide activity; it is particularly active towards viruses, bacteria, protozoans, fungus and is advantageously employed as a microbicide in the prophylaxis of the sexually transmitted diseases, such as for example those due to: Herpes simplex virus (HSVI II), hepatitis B and : C virus , Papilloma virus, Trichomonas vaginalis, Treponema pallidum, Neisseria gonorrheae, Chlamydia trachomatis, Candida albicans, human immunodeficiency virus (HIV) type 1 and 2.
  • HSV human immunodeficiency virus
  • the composition according to the invention is effective in preventing those sexually transmitted diseases which are generally caused by the above mentioned organisms and is thus employed in the prophylaxis, i.e. at a preventive stage before the onset of the disease.
  • the composition is sinergically active in the prevention of the sexually transmitted pathologies caused indifferently by viruses, bacteria, protozoans, fungus.
  • the composition according to the invention is suitable to be administered by vaginal and/or rectal route prior to sexual contact and carries out its protective function by countering the initial action of viruses, bacteria and other microrganisms responsible for the major sexually transmitted diseases thus allowing to counter the onset of the disease.
  • the most appreciable advantage is thus due to the fact that said compositions are not used after the emergence of the pathology but, as stated above, at a preventive stage, and inhibit the onset thereof.
  • composition according to the invention does not represent a cure, it is rather a preventive treatment, a prophylaxis which prevents contracting the disease and avoids that a subject may fall ill and need to be cured.
  • Another advantage deriving from the use of the microbicide composition according to the present invention is that the female partner is able to autonomously select and use the product prior to sexual intercourse. In this case, above all in the underdeveloped countries, the problem of a poor, if any, condom use by the male partner would be obviated.
  • composition according to the invention can also provide adding at least a further component having contraceptive activity, thereby allowing to achieve two targets: carrying out a preventive prophylactic activity towards the sexually transmitted diseases and at the same time performing a contraceptive activity, even a partial one, if desired.
  • compositions comprising a therapeutically and/or prophylactically effective dose of a microbicide composition comprising at least a "Minor Groove Binder” (MGB) compound and at least an anti HIV compound, in admixture with pharmaceutically acceptable carriers and/or excipients.
  • MGB Minor Groove Binder
  • Said pharmaceutical compositions are advantageously prepared in the form of cream, gel, tablets, bougies or other system suitable for vaginal and/or rectal application and are employed in the prophylaxis of the sexually transmitted diseases.
  • compositions according to the invention are not noxious for the organism, do not cause lactobacilli growth inhibition within the vaginal tract, which are responsible for the preservation of the proper acid level in the vagina, and represent a valid defence against the sexually transmitted diseases such as, as stated above, those due to: herpes virus, hepatitis B and C virus , Papilloma virus, Trichomonas vaginalis, Treponema pallidum, Neisseria gonorrheae, Chlamydia trachomatis, Candida albicans, human immunodeficiency virus (HIV) of type 1 and 2.
  • herpes virus hepatitis B and C virus
  • Papilloma virus Trichomonas vaginalis
  • Treponema pallidum Neisseria gonorrheae
  • Chlamydia trachomatis Chlamydia trachomatis
  • Candida albicans human immunodeficiency virus (HI
  • a pharmaceutical composition with microbicide activity comprises a "Minor Groove Binder” (MGB) such as Distamycin A as the active ingredient.
  • MGB Minimum Groove Binder
  • Said composition exhibits a surprising microbicide action and is advantageously employed in the prophylactic treatment of sexually transmitted diseases, particularly those due to: Herpes simplex virus, hepatitis B and C virus , Papilloma virus, Trichomonas vaginalis, Treponema pallidum, Neisseria gonorrheae, Chlamydia trachomatis, Candida albicans, human immunodeficiency virus (HIV) of type 1 and 2.
  • pharmaceutical compositions comprising a therapeutically and/or prophylactically effective dose of Distamycin A as the active ingredient, in admixture with pharmaceutically acceptable carriers and/or excipients.
  • Said pharmaceutical compositions are advantageously prepared in the form of cream, gel, tablets, bougies or other system suitable for vaginal and/or rectal application and are used in the prophylaxis of sexually transmitted diseases. Particularly, they are employed prior to the onset of the pathology and therefore they carry on a preventive action by countering and preventing the onset of the pathology, rather than a therapeutic activity towards an already existing and emerged pathology.
  • Several pharmaceutical compositions according to the invention which are given by way of non-limiting examples, are described below.
  • Distamycin A Activity of Distamycin A in combination with Suradista towards HSV-1.
  • the activity of Distamycin towards HSV-1 and 2 is discussed for example in Antiviral Chemistry & Chemotherapy. 1997: 8(3):243-254 and in Anti-cancer Drug Design. 1986: 1 : 235-244.
  • the antiviral activity of Distamycin A whether alone or in combination with Suradista assayed towards HSV-1 until the maximum concentration of 100 ⁇ M for both compounds has been determined by using a culture of the virus HSV-1 strain HF in HEp-2 cells (epithelial cells derived from human laryngeal cancer). The cells are infected with 1000 DI 50 (1 Dl 50 corresponding to the Dose Infecting 50% of cells after 72 hour incubation at 37°C).
  • the antiviral activity is determined after 72 hour incubation of the infected cells (2 x 10 5 cells/mL) with various concentrations of Distamycin A either alone or in combination with Suradista by microscopic observation of the cytopathic effect being induced by HSV-1.
  • the Clso i.e. the concentration inhibiting the viral cytopathic effect by 50% is obtained by correlating the compound concentration to the corresponding measure of the cytopathic effect.
  • the CI 50 obtained with Distamycin A was 11.7 ⁇ M.
  • the addition of Suradista until a concentration of 100 ⁇ M has not affected the activity of Distamycin A (CI 50 : 12.1 ⁇ M in the presence of 100 ⁇ M Suradista). Activity of Distamycin A in combination with Suradista towards HSV-2.
  • the antiviral activity of Distamycin A either alone or in combination with Suradista assayed until the maximum concentration of 100 ⁇ M for both compounds towards HSV-2 has been determined by using a culture of HSV- 2 virus isolated from pathologic material and grown in human fibroblasts.
  • the cells (2 x 10 5 celIs/mL in 6-well plates; 1 mL/well) are infected with such viral concentrations as to cause the formation of 20-30 plaques of cytopathic activity per each well.
  • the antiviral activity is determined after 72 hour incubation of the infected cells (2 x 10 5 cells/mL) with various concentrations of Distamycin A either alone or in combination with Suradista by microscope observation of the cytopathic effect being induced by HSV-2.
  • the Cl 50 i.e. the concentration inhibiting the viral cytopathic effect by 50% is determined by correlating the compound concentration with the corresponding measure of the cytopathic effect.
  • the CI 50 obtained with Distamycin A was 35 ⁇ M.
  • the addition of Suradista to a concentration of 100 ⁇ M has not affected the activity of Distamycin A (CI 50 : 41 ⁇ M in the presence of 100 ⁇ M Suradista).
  • EXAMPLE 2 Activity of Distamycin A on various species of bacteria, fungus, protozoans, and viruses.
  • the minimum inhibiting concentration (MIC) of Distamycin A on bacteria and fungus has been determined according to the procedures of National Committee for Clinical Laboratory Standards (NCCLS), Documents M7-A4 (1997), M11-A4 (1997), M27-T (1995).
  • the tested microrganisms included: Staphylococcus aureus, S.epidermidis, Streptococcus pyogenes, Escherichia coli, Enterococcus faecalis, E. faecium, Neisseria gonorrheae, Candida albicans, Chlamydia trachomatis, Ureoplasma urealyticum.
  • Distamycin A The activity of Distamycin A towards the motility of Trichomonas vaginalis has been determined in Loche medium additioned with 10% bovine serum. Distamycin A at a concentration of 10 mg/L inhibits the motility of the protozoan after 4 hour contact.
  • Distamycin A Activity of Distamycin A in combination with Suradista towards bacteria, fungus, protozoans and viruses.
  • the presence of Suradista at a concentration of 512 mg/L does not interfere with the exhibited activity of Distamycin A towards bacteria, fungus protozooms and viruses being described in Example 2 (Table 1).
  • Distamycin A was 2.7 ⁇ M. Distamycin A, until a concentration of 1 mM, does not interfere with the Suradista anti-HIV activity.
  • Distamycin A and Suradista either alone or in combination, do not exhibit any direct antibacterial activity towards Lattobacillus acidophylus.
  • Cytotoxicity measure is indicative of the tolerability and toxicity of compounds designated as microbicide in the prevention of sexually transmitted diseases.
  • the cytotoxic activity of Distamycin A and Suradista has been determined by using the following human cell lines: HepG2 (hepatocellular carcinoma) e HeLa (cervix epithelioid carcinoma), according to MTT method. Both compounds, whether tested alone or in combination, at 1 mM maximum concentration have not induced any cytotoxicity after 24 hour incubation (IC 50 : > 1 mM).
  • EXAMPLE 7 Distamycin A in gel form The composition contains Distamycin A at the possible concentrations ranging from 0.01 to 4 %.
  • the formulation contains for example a gelling agent, a preserving agent, a wetting agent.
  • gelling agents and their concentrations thereof are: Carbomer 934P (0.5-2%), cetostearic alcohol (10%), hydroxyethylcellulose (0.1-0.5%), hydroxymethylcellulose, polyoxymethylene- or polyoxypropylene-based copolymer (15-50%), sodium carboxymethylcellulose (4-6%).
  • wetting agents and their concentrations thereof are: propylene glycol (15%), glycerine (10-20%), sorbitol (3-15%).
  • preserving agents and their concentrations thereof are: methyl parabenzoate (0.1-0.2%), propyl parabenzoate (0.02- 0.1 %), propylene glycol (5-80%).
  • the composition contains Distamycin A in combination with Suradista at the possible respective concentrations ranging from 0.01 and 4 %.
  • the ratio of Distamycin A and Suradista can range between 1 :5 e 5%, preferably between 1 :2 and 2:1 , preferably about 1 :1.
  • the formulation contains the same ingredients as the composition with Distamycin A alone.
  • Distamycin A in the form of a cream contains Distamycin A at the possible concentrations ranging from 0.01 and 4 %.
  • the formulation contains for example an emulsifying agent, a preserving agent, an aqueous base.
  • emulsifying agents and their concentrations thereof are: cetyl stearyl alcohol (2-5%), cetyl alcohol (2-5%), polyethylenglycol extended, polysorbate 60 (1-10%).
  • preserving agents and their concentrations thereof are: methyl parabenzoate (0.1-0.2%), propyl parabenzoate (0.02-0.1%), propylene glycol (5-80), benzyl alcohol (1%).
  • aqueous bases are: spermaceti, stearic acid (1-20%).
  • Distamycin + Suradista in the form of a cream
  • the composition contains Distamycin A in combination with Suradista at the respective possible concentrations ranging from 0.01 to 4 %.
  • the ratio of Distamycin A and Suradista can range between 1 :5 and 5%, preferably between 1 :2 and 2:1 , preferably about 1 :1.
  • the formulation contains the same ingredients as the composition with Distamycin A alone.
  • EXAMPLE 9 Distamycin A in the form of tablets/capsules
  • the composition contains Distamycin A at the possible concentrations ranging from 0.01 and 4 %.
  • the formulation contains for example: cellulose (0-100%), hydroxypropylmethylcellulose (2-10%), methylcellulose (2-10%), crospovidone (2-5%), magnesium stearate (0,25-5%), corn starch (5-25%), lactic acid (0.05-6%), colloidal silicon dioxide (2-10%),
  • the composition contains Distamycin A in combination with Suradista at the respective possible concentrations ranging between 0.01 and 4 %.
  • the ratio of Distamycin A and Suradista can be between 1 :5 and 5%, preferably between 1 :2 and 2:1 , preferably about 1 :1.
  • the formulation contains the same ingredients of the composition with Distamycin A alone.

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  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Engineering & Computer Science (AREA)
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  • Inorganic Chemistry (AREA)
  • AIDS & HIV (AREA)
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Abstract

Composition microbicide et son application à la prophylaxie des maladies sexuellement transmissibles.
PCT/IB2004/002923 2003-09-12 2004-09-08 Composition microbicide comportant un ligand du petit sillon eventuellement en association avec un compose anti-vih, et son application a la prophylaxie des maladies sexuellement transmissibles WO2005025565A1 (fr)

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IT001754A ITMI20031754A1 (it) 2003-09-12 2003-09-12 Composizione microbicida.
ITMI2003A001754 2003-09-12

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WO2005025565A1 true WO2005025565A1 (fr) 2005-03-24

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Cited By (9)

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Publication number Priority date Publication date Assignee Title
WO2007049771A1 (fr) 2005-10-28 2007-05-03 Ono Pharmaceutical Co., Ltd. Compose contenant un groupe basique et son utilisation
WO2007058322A1 (fr) 2005-11-18 2007-05-24 Ono Pharmaceutical Co., Ltd. Composé contenant un groupe basique et son utilisation
US7417158B2 (en) 2003-12-05 2008-08-26 The University Of North Carolina At Chapel Hill Cationic substituted benzofurans as antimicrobial agents
US7432278B2 (en) 2004-03-08 2008-10-07 The University Of North Carolina At Chapel Hill Dicationic imidazo[1,2-a]pyridines and 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridines as antiprotozoal agents
US7517893B2 (en) 2005-05-20 2009-04-14 The University Of North Carolina At Chapel Hill Bichalcophenes and their prodrugs as antiprotozoal agents
US7825279B2 (en) 2003-11-24 2010-11-02 The University Of North Carolina At Chapel Hill Fused ring dicationic anti-protozoan agents and their prodrugs
US7951827B2 (en) 2005-05-05 2011-05-31 The University Of North Carolina At Chapel Hill Synthesis and antiprotozoal activity of dicationic 3,5-diphenylisoxazoles
US7964619B2 (en) 2005-06-03 2011-06-21 The University Of North Carolina At Chapel Hill Teraryl components as antiparasitic agents
US8101636B2 (en) 2005-06-03 2012-01-24 The University Of North Carolina At Chapel Hill Linear dicationic terphenyls and their aza analogues as antiparasitic agents

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US3190801A (en) * 1956-12-12 1965-06-22 Farmaceutici Italia Antibiotic distamycin and method of production
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Patent Citations (2)

* Cited by examiner, † Cited by third party
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US3190801A (en) * 1956-12-12 1965-06-22 Farmaceutici Italia Antibiotic distamycin and method of production
EP0312222A1 (fr) * 1987-10-14 1989-04-19 Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo Traitement de maladies virales

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