EP3687541A1 - Compositions and methods for treatment of bowen's disease and related diseases - Google Patents
Compositions and methods for treatment of bowen's disease and related diseasesInfo
- Publication number
- EP3687541A1 EP3687541A1 EP17925688.8A EP17925688A EP3687541A1 EP 3687541 A1 EP3687541 A1 EP 3687541A1 EP 17925688 A EP17925688 A EP 17925688A EP 3687541 A1 EP3687541 A1 EP 3687541A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- pharmaceutical composition
- chloroquine
- pharmaceutically acceptable
- metronidazole
- subject
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
Definitions
- the present invention relates generally to the field of skin diseases and more specifically to compositions and methods for the treatment of Bowen' s disease and related diseases.
- Bowen' s disease and related diseases such as recurrent respiratory papillomatosis (RRP) are rare diseases, for which the medical need has not yet been met, and require drugs to cure or treat them.
- Stage 1 melanoma is a disease which is often initially treated by surgery. Each of these diseases would benefit from new treatments.
- Bowen' s disease may also be identified as an orphan disease, referring to a disease or condition that affects fewer than 200,000 people and, as a result, is often overlooked as providing sufficient incentive to researchers and enterprises to develop pharmaceuticals for treatment.
- Bowen's disease (also known as "squamous cell carcinoma in situ") is a very early form of skin cancer.
- the main visible symptom is a red, scaly patch on the skin.
- Bowen's disease involved abnormal growth of the squamous cells, in the outermost layer of skin. Sometimes, the cancerous cells spread along the skin's surface, but it is usually very slow- growing and may not change for years. Occasionally (in 3-5% of patients), Bowen's disease infiltrates the deeper layers of skin and turns into a more serious type of skin cancer.
- the disease is manageable and there is only a risk if it is left undiagnosed or untreated.
- Recurrent respiratory papillomatosis is also known as "laryngeal papillomatosis". It is caused by HPV, typically HPV6 and 11, and involves formation of generally nonmalignant tumors on the larynx or vocal chords, but can spread to the trachea, bronchi and even to the lungs. This rare disease is typically fatal and can require large numbers of surgeries per year to keep the airway open. Children can contract RRP in the birth canal from vaginal delivery when mothers have active cases of condyloma, and adults also contract the disease.
- Stage I malignant melanoma (sometimes called a localized melanoma) is a cancer in epidermis (the outer layer of the skin) and/or the dermis (upper part of the inner layer of skin), but which has not spread to lymph nodes or anywhere else in the body.
- An important feature of melanoma is the thickness of the melanoma ("Breslow thickness," which is measured in millimeters). Based on the thickness of the tumor, a melanoma is categorized into 3 main groups: (1) thin melanomas, where the thickness is less than or equal to 1 mm; (2) intermediate thickness melanomas, where the thickness is between 1 mm to 4 mm; and (3) thick melanomas, where the thickness is greater than 4 mm.
- Thicker melanomas have a greater chance of spread to sites beyond the initial tumor and a greater chance of recurrence.
- Stage 1 melanoma is often treated with surgery. The patient would undergo an operation to remove a larger area of healthy tissue around the melanoma. This removal of surrounding tissue is called a wide local excision. The amount of tissue removed in a wide local excision depends on the thickness of the melanoma. While this is a small operation, alternative non- surgical remedies would be desirable in treating melanomas detected at such an early stage.
- the current disclosure provides compositions and methods for the treatment of Bowen's disease, recurrent respiratory papillomatosis (RRP) and melanoma (at stage 1).
- the present disclosure resides in the discovery that one or a combination of the known compounds chloroquine and amodiaquine, or pharmaceutically acceptable salts thereof, all of which have been used previously as antimalarial agents and/or to treat disorders of the immune system, also have utility in treating Bowen's disease, recurrent respiratory papillomatosis (RRP) and melanoma (at stage 1). In some cases, one or a combination of these compounds can be effectively used in further combination with an antibiotic such as metronidazole.
- the current disclosure provides compositions that comprise one or more of chloroquine, amodiaquine, and metronidazole; and methods of using these compositions for the treatment of Bowen's disease. In a further aspect, the current disclosure provides methods of using compositions comprising metronidazole for the treatment of Bowen's disease.
- compositions that comprise one or more of chloroquine, amodiaquine, and metronidazole, and methods of using these compositions for the treatment of recurrent respiratory papillomatosis (RRP).
- RRP recurrent respiratory papillomatosis
- compositions that comprise one or more of chloroquine, amodiaquine, and metronidazole; and methods of using these compositions for the treatment of stage 1 melanoma.
- compositions that comprise one or more active ingredients from the group consisting of chloroquine, amodiaquine, and an antibiotic.
- the antibiotic is metronidazole.
- the disclosure provides methods of using these compositions for the treatment of Bowen's disease.
- the disclosure also provides methods of using these compositions for the treatment of RRP.
- the disclosure further provides methods of using these compositions for the treatment of stage 1 melanoma.
- chloroquine IUPAC name: (RS)-N'-(7- chloroquinolin-4-yl)-N,N-diethyl-pentane-l,4-diamine
- hydroxychloroquine IUPAC name: (RS)-2-[ ⁇ 4-[(7-chloroquinolin-4-yl)amino]pentyl ⁇ (ethyl)amino]ethanol
- amodiaquine IUPAC name: 4-[(7-chloroquinolin-4-yl)amino]-2-
- Chloroquine is commercially available as the pharmaceutically acceptable salt chloroquine phosphate, and may be purchased in solid (tablet) form from a wide variety of sources such as Ohm Laboratories, Inc of North Brunswick, N.J., U.S.A., while a ready-made aqueous solution may be purchased from a wide variety of sources, including Sal Parenterals (P) Ltd., of India, or Scott Edil Pharmacia Ltd., of Jhannajri, India.
- Hydroxychloroquine in solid (tablet) form, is commercially available as the pharmaceutically acceptable salt hydroxychloroquine sulfate, and may be purchased from a wide variety of sources such as West- Ward Pharmaceutical Corporation of Eatontown, N.J., U.S.A.
- Amodiaquine, in solid (tablet) form is commercially available as the pharmaceutically acceptable salt amodiaquine hydrochloride, and may be purchased from a wide variety of sources, including Parke, Davis & Company, a division of Pfizer Inc., headquartered in New York, N.Y., U.S.A.
- compositions of the disclosure comprise an antibiotic.
- the antibiotic is metronidazole.
- Metronidazole is a nitroimidazole antibiotic and antiprotozoal medication. It can be given via oral or parenteral (including topical, intravenous, and intravaginal) administration. Metronidazole has been marketed under the names METROGEL, FLAGYL, NORITATE, METROCREAM, ROSADAN, and METROLOTION, among others.
- the molecular structure of metronidazole (IUPAC name: 2-(2-methyl-5-nitro-lH-imidazol-l-yl)ethanol) is provided below, as Formula IV.
- compositions of the disclosure comprise either chloroquine (Formula I) alone or amodiaquine (Formula III) alone as the active ingredient, or chloroquine combined with amodiaquine, or chloroquine combined with metronidazole (Formula IV), or amodiaquine combined with metronidazole, or chloroquine combined with both amodiaquine and metronidazole, as the active ingredients.
- the methods of the disclosure comprise, in certain embodiments, administering the pharmaceutical compositions of the disclosure comprising the active ingredient or ingredients to a subject such as a human being using one or more of the specific routes of administration, which include direct topical (epicutaneous) administration, in forms such as gel, douche, cream, lotion, solution, spray, soap or other bathing apparatus; transdermal administration, in the form of a patch; transmucosal administration (also known as pharmaceutical pessary delivery) through the vagina or rectum, in the form, for example, of an ovule or a suppository, including a vaginal suppository; respiratory administration, such as delivery via inhalation through the nostrils and nasal passages of aerosol droplets produced, for example, with the aid of a nebulizer; and infusion under the skin in the form of an intra-epidermal injection.
- routes of administration include direct topical (epicutaneous) administration, in forms such as gel, douche, cream, lotion, solution, spray, soap or other bath
- compositions and methods of the disclosure will be illustratively described hereinafter with reference to topical, transmucosal, oral and other routes of administration, it should be understood that the disclosure is not limited to the specific cases described, but extends also to the use of other compatible routes for administering pharmaceutical compositions according to the disclosure, as will be evident to those skilled in the art, including but not limited to other topical and/or parenteral routes, such as buccal, conjunctival, endotracheal, intramuscular, intravascular, laryngeal, or ophthalmic, or even enteral (oral) routes, any one or more of which may be used.
- topical and/or parenteral routes such as buccal, conjunctival, endotracheal, intramuscular, intravascular, laryngeal, or ophthalmic, or even enteral (oral) routes, any one or more of which may be used.
- Suitable formulations for any route of administration that is ultimately selected are known and are described in well-known texts, including for example Remington, The Science and Practice of Pharmacy, 21st edition, 2005, Mack Publishing Company, Easton, Pa., and therefore such formulations may easily be prepared by those of ordinary skill in the art. It is well understood, however, that proper dosages of any medication may vary from one individual to another, depending on many factors such as the intensity of the affliction and the selected route of administration, as well as the weight, age and gender of the subject or patient. Therefore, the effective dosages of the pharmaceutical compositions of the present disclosure should be determined by a specialist in this matter, such as a medical doctor or other health care provider, depending on these and other parameters. Nevertheless, for the sake of illustration only, exemplary formulations, preparation procedures and dosages, for topical, transmucosal, and other routes of administration, are provided herein for the sake of guidance.
- compositions of the disclosure comprising one or more of chloroquine, amodiaquine and metronidazole as the only active ingredient(s) are to be administered topically (epicutaneously), in the form of a gel or a spray
- the compositions may comprise chloroquine and/or amodiaquine and/or metronidazole plus optional non- active ingredients.
- the non-active ingredients may comprise sodium carboxymethylcellulose, a preservative (for example, methylparaben, for example at 0.5%), purified water, Versatile gel base, as well as ethyl alcohol and peppermint spirit oil, and the gel form may additionally comprise lidocaine jelly or ointment, while the spray form may additionally comprise lidocaine as a 2% solution.
- non-active ingredients are conventional and are available commercially from a wide variety of sources.
- the non-active ingredients are exemplary only, but are included for the following purposes: the lidocaine functions as an analgesic, the ethyl alcohol functions as an antiseptic, while the peppermint spirit oil functions to provide a pleasing odor.
- the compositions of the disclosure comprising one or more of chloroquine, amodiaquine and metronidazole are also provided in suppository and douche forms.
- the suppository forms may comprise chloroquine and/or amodiaquine and/ or metronidazole plus optional non-active ingredients.
- the douche forms may comprise chloroquine and/or amodiaquine and/ or metronidazole plus optional non-active ingredients.
- the non-active ingredients in the suppository form may comprise Polybase (for example, containing PEG 400, PEG 8000 and Polysorbate 80), and citric acid, while the non-active ingredients in the douche form may comprise purified water for irrigation, sodium chloride (for example 0.9%, or normal saline), citric acid, a preservative (for example, sodium benzoate).
- Polybase for example, containing PEG 400, PEG 8000 and Polysorbate 80
- citric acid while the non-active ingredients in the douche form may comprise purified water for irrigation, sodium chloride (for example 0.9%, or normal saline), citric acid, a preservative (for example, sodium benzoate).
- compositions for the gel, suppository and douche forms may be prepared as set forth in the Formulation Examples below.
- the gel forms of these medications may be administered to a subject as follows:
- the affected areas are first cleaned with one or more alcohol swabs. Thereafter, an amount of the gel approximately equal to the surface area of each affected area (or an amount equal to the surface area of the tip of a finger) is applied to the affected area, after which that area may optionally be covered with a sterile bandage.
- the gel form may be administered to the subject in the foregoing manner once or twice a day, for approximately one to four weeks, until return of the affected area(s) to a normal skin appearance.
- the spray forms of these medications may be administered to a subject in the same manner, although the dosage may be two puffs applied to the affected areas once or twice daily.
- the suppository forms for vaginal administration of these compositions may be administered to a subject by placing the "bullet", or suppository, into the vagina.
- the suppository form for vaginal administration may be administered to the subject once or twice a day, for approximately one to four weeks, until return of the affected area(s) to a normal skin appearance.
- the suppository form for vaginal administration may be administered before or at bedtime.
- the douche forms for vaginal or oral administration of these compositions may be administered vaginally using a bottle or other suitable apparatus. It may also be administered orally, where needed, by gargling of the douche solution. Either form (as appropriate) may be administered to the subject once or twice a day, for approximately one to four weeks.
- the term "pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
- pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
- the pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
- the pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
- such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile may be used.
- nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile may be used.
- Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.
- the formulation percentage range covers from 2.5% to 25% of the active ingredient, whether it is one active ingredient or two active ingredients, or a mixture of three active ingredients.
- Bowen's disease squamous cell carcinoma in situ
- other related diseases like RRP and melanoma (at stage one).
- Chloroquine phosphate pure powder 10% equals to 7 grams
- Sodium Carboxymethylcellulose is 1.2 grams
- the composition may be prepared by adding the chloroquine, amodiaquine and metronidazole, and then adding each of the non-active ingredients, in the sequence listed above, sufficient to make a total of approximately 60 gm of the gel. The gel form may then be transferred to a tube or other appropriate container.
- Vaginal Suppository Formula 1
- vaginal suppository composition Sufficient to make 24 bullet shaped vaginal suppositories. To be applied vaginally at bedtime for about 14 days.
- the vaginal suppository composition may be prepared by adding the chloroquine (and metronidazole if included), and then adding each of the non-active ingredients, in the sequence listed above, sufficient to make the suppository.
- Citric acid powder 1.5 grams Sufficient to make 24 bullet shaped vaginal suppositories. To be applied vaginally at bedtime for about 14 days.
- the vaginal suppository composition may be prepared by adding the amodiaquine and metronidazole, and then adding each of the non-active ingredients, in the sequence listed above, sufficient to make the suppository.
- Chloroquine douche in 4.5 oz (133 ml). To be applied vaginally or orally (for gargling) at bedtime for about 14 days.
- Optional active ingredient Metronidazole - 6gram/60 ml in which each ml contains 100 mg of Metronidazole.
- the douche composition may be prepared by adding the chloroquine (and metronidazole if included), and then adding each of the non-active ingredients, in the sequence listed above, sufficient to make the suppository.
- EXAMPLE 5 An adult female with Bowen's disease presented with warts. She was first ineffectively treated with a composition in gel form comprising chloroquine as the active ingredient, and further ineffectively treated with a composition in gel form comprising chloroquine and hydroxychloroquine as the active ingredients. However, after two weeks of twice daily treatment with a composition in gel form comprising chloroquine and metronidazole as the active ingredients, the affected skin area returned to normal skin.
- compositions in gel and douche forms comprising chloroquine and metronidazole as the active ingredient each twice a day for 21 days. After 21 days of treatment, the affected skin area returned to normal skin.
- RRPRRP recurrent respiratory papillomatosis
- HPV + and HPV " laryngeal keratinocytes obtained from a recurrent respiratory papillomatosis patient were expanded on Mitomycin C-treated J2 3T3 feeder cell layers in E media with 10 uM Y27632 (ROCK inhibitor). These cells were then plated without feeder layers in 2.5 uM Y27632 and grown until they reached 90% confluency. At this point, fresh E media without Y27632 was added to the cells with increasing concentrations of chloroquine. Chloroquine concentrations used were 0 ug/ml, 2.5 ug/ml, 25 ug/ml, 250 ug/ml, 2.5 mg/ml and 25 mg/ml.
- Chloroquine powder (Sigma) was resuspended at 25 mg/ml in E media and was brought to pH 7 with IN NaOH. Working dilutions were made with full E media. Cells were incubated for two days in chloroquine and then visually inspected for survival, as noted by (a) the presence of cells in the wells and (b) morphology of the cells.
- HPV + and HPV cells were killed at chloroquine concentrations of 250 ug/ml and higher. Both sets of cell survived 25 ug/ml concentrations of chloroquine. Thus, treatment of respiratory HPV infections with chloroquine may be useful.
- ASCUS is defined as an atypical squamous cells of undetermined significance ("ASCUS")- squamous cells are thin and flat and grow on the surface of a healthy cervix.
- ASCUS atypical squamous cells of undetermined significance
- the Pap smear reveals slightly abnormal squamous cells of Bowen' s disease origin, but the changes clearly suggest that precancerous cells are present or may not be present.
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US2017/053223 WO2019059943A1 (en) | 2017-09-25 | 2017-09-25 | Compositions and methods for treatment of bowen's disease and related diseases |
Publications (1)
Publication Number | Publication Date |
---|---|
EP3687541A1 true EP3687541A1 (en) | 2020-08-05 |
Family
ID=65809868
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP17925688.8A Withdrawn EP3687541A1 (en) | 2017-09-25 | 2017-09-25 | Compositions and methods for treatment of bowen's disease and related diseases |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP3687541A1 (en) |
CN (1) | CN111432819A (en) |
CA (1) | CA3077028A1 (en) |
WO (1) | WO2019059943A1 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN113855674A (en) * | 2021-11-05 | 2021-12-31 | 中国科学院动物研究所 | Application of chloroquine |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6916627B2 (en) * | 2002-11-27 | 2005-07-12 | St. Jude Children's Research Hospital | ATM kinase compositions and methods |
TW200711649A (en) * | 2005-06-17 | 2007-04-01 | Combinatorx Inc | Combination therapy for the treatment of immunoinflammatory disorders |
EP2313095A4 (en) * | 2008-07-14 | 2013-04-17 | Univ Colorado | Methods and products for treating proliferative diseases |
WO2012071561A2 (en) * | 2010-11-23 | 2012-05-31 | Alder Biopharmaceuticals, Inc. | Anti-il-6 antibodies for the treatment of anemia |
US20140011839A1 (en) * | 2012-07-03 | 2014-01-09 | Justice E. OBI | Compositions and methods for treating and inhibiting viral infections |
US9770448B1 (en) * | 2016-06-30 | 2017-09-26 | Justice E. OBI | Compositions and methods for treatment of Bowen's disease and related diseases |
-
2017
- 2017-09-25 CN CN201780097005.2A patent/CN111432819A/en active Pending
- 2017-09-25 CA CA3077028A patent/CA3077028A1/en not_active Abandoned
- 2017-09-25 WO PCT/US2017/053223 patent/WO2019059943A1/en unknown
- 2017-09-25 EP EP17925688.8A patent/EP3687541A1/en not_active Withdrawn
Also Published As
Publication number | Publication date |
---|---|
WO2019059943A1 (en) | 2019-03-28 |
CN111432819A (en) | 2020-07-17 |
CA3077028A1 (en) | 2019-03-28 |
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