WO2006127482A1 - Therapie au bleu de methylene de maladie virale - Google Patents

Therapie au bleu de methylene de maladie virale Download PDF

Info

Publication number
WO2006127482A1
WO2006127482A1 PCT/US2006/019506 US2006019506W WO2006127482A1 WO 2006127482 A1 WO2006127482 A1 WO 2006127482A1 US 2006019506 W US2006019506 W US 2006019506W WO 2006127482 A1 WO2006127482 A1 WO 2006127482A1
Authority
WO
WIPO (PCT)
Prior art keywords
methylene blue
virus
composition
group
blue
Prior art date
Application number
PCT/US2006/019506
Other languages
English (en)
Inventor
Christopher Wood
Nagy Habib
Original Assignee
Bioenvision, Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Bioenvision, Inc. filed Critical Bioenvision, Inc.
Publication of WO2006127482A1 publication Critical patent/WO2006127482A1/fr

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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention is generally in the area of methods for the treatment of viral diseases, and more specifically relates to the treatment of hepatitis virus using thiazine dyes, and in particular methylene blue, and to the treatment of reactivated viruses using thiazine dyes, and in particular methylene blue.
  • HCV Hepatitis C Virus
  • HCV infection can lead to liver damage, the development of fibrous tissue in the liver, fat deposits in the liver (steatosis), cirrhosis of the liver, and liver cancer.
  • Liver cancer usually develops at later stages of HCV infection, typically after 25-30 years.
  • the type of liver cancer associated with HCV is called primary hepatocellular carcinoma (HCC).
  • HCC primary hepatocellular carcinoma
  • Most DNA virus infections are reactivation-infection, i.e. infections caused by reactivation of the virus that has been dormant after the initial, primary infection months to many years prior to the reactivation. Reactivation can occur when the immune system loses control of the latent virus allowing it to become active. The loss of control occurs when some event or illness results in depressed or suppressed immunity (even if temporary).
  • Examples of such events are acute infection with other viruses (influenza, HIV, etc.), infectious mononucleosis, nerve trauma, physiologic and physical changes (e.g., fever menstruation, and sunlight, immunosuppression, surgery, trauma, toxic exposure, chemotherapy, radiation exposure, extreme acute stress and chronic stress.
  • viruses influenza, HIV, etc.
  • infectious mononucleosis nerve trauma, physiologic and physical changes (e.g., fever menstruation, and sunlight, immunosuppression, surgery, trauma, toxic exposure, chemotherapy, radiation exposure, extreme acute stress and chronic stress.
  • the antiviral compounds acyclovir, valaciclovir and famciclovir are presently available for the treatment of HSV disease.
  • Prophylactic intravenous or oral acyclovir has become a standard of care for HSV seropositive cancer patients during periods of profound immunosuppression.
  • Allogeneic stem cell transplant (SCT) recipients who develop acute graft- versus-host disease usually require a prolonged HSV prophylaxis.
  • SCT Allogeneic stem cell transplant
  • Valaciclovir and famciclovir have an oral bioavailability 3—5 times superior to that of oral acyclovir.
  • oral valaciclovir is commonly used in the prevention of HSV reactivation after SCT.
  • Intravenous acyclovir remains the therapy of choice for severe mucocutaneous or visceral HSV disease in immunocompromised hosts.
  • haploidentical SCT which requires stringent T- and B-cell depletion of the graft to prevent fatal graft-versus-host disease (GVHD)
  • GVHD fatal graft-versus-host disease
  • reactivation of latent human herpes viruses occurred in all 7 evaluable HSV-I- or HSV-2- seropositive patients and these patients did not respond to acyclovir treatment (Langston, A., et al., Blood 99(3):1085-1088 (2002).
  • these drugs can loose their effectiveness over time, have low solubility, and do not always prevent outbreaks of the virus.
  • a method for using thiazine dyes, especially methylene blue, methylene blue derivatives, or pharmaceutically acceptable salts thereof, in an immediate or controlled release formulation, alone or in combination with low levels of light or other drugs, to selectively inactivate or inhibit hepatitis infection, has been developed.
  • Clinical trial results demonstrate efficacy in a human clinical trial for treatment of hepatitis C by oral administration of methylene blue immediate release formulation, in a dosage of 65 mg twice daily, over a period of at least 100 days.
  • a method for using thiazine dyes, especially methylene blue, methylene blue derivatives, or pharmaceutically acceptable salts thereof, in an immediate or controlled release formulation, alone or in combination with low levels of light or other drugs, to prevent or decrease reactivation of viruses, is also described.
  • the preferred class of patient is infected with, or has been exposed to, viruses such as Herpes simplex virus type 1 & 2, Varicella zoster virus, Epstein-Barr virus, Cytomegalovirus, and Herpes virus type 6 & 7, Adenovirus, and Human polyoma viruses, e.g. JC virus and BK virus.
  • viruses such as Herpes simplex virus type 1 & 2, Varicella zoster virus, Epstein-Barr virus, Cytomegalovirus, and Herpes virus type 6 & 7, Adenovirus, and Human polyoma viruses, e.g. JC virus and BK virus.
  • the thiazine dye is administered to a patient experiencing symptoms or
  • thiazine dyes examples are methylene blue, azure A, azure C, toluidine, and thionine.
  • the preferred dye at this time is methylene blue. Since methylene blue absorbs in the red wavelengths, i.e., approximately 670 run, which penetrates tissue much better than other lower wavelengths, light penetrating the skin to the capillaries at the surface can be used to enhance the activity of the dye.
  • Pharmaceutical compositions comprising methylene blue, methylene blue derivatives, or pharmaceutically acceptable salts thereof are described herein. The compositions are preferably administered orally and can be administered as tablets, soft or hard shell capsules, suspension or solutions.
  • compositions further comprise a pharmaceutically acceptable carrier and optionally one or more pharmaceutically acceptable excipients.
  • Suitable excipients include diluents, binders, plasticizers, lubricants, disintegrants, colorants, stabilizers, surfactants, and combinations thereof.
  • the compositions can be formulated for controlled release of the active agent. Suitable controlled release formulations include delayed release, extended release, and combinations thereof.
  • the thiazine dye can be provided in combination with other known antibiotics, anti-inflammatories, antifungals, and antivirals.
  • compositions for oral administration comprising methylene blue, a derivative thereof, or pharmaceutically acceptable salts thereof, in a pharmaceutically acceptable carrier, have been developed.
  • Controlled release dosage form is one for which the drug release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as solutions, ointments, or promptly dissolving dosage forms. Delayed release, extended release, and pulsatile release forms and their combinations are types of controlled release dosage forms.
  • Delayed release dosage form A delayed release dosage form is one that releases a drug (or drugs) at a time other than promptly after administration.
  • Extended release dosage form An extended release dosage form is one that allows at least a twofold reduction in dosing frequency as compared to that drug presented as a conventional dosage form (e.g. as a solution or prompt drug-releasing, conventional solid dosage form).
  • Pulsatile release dosage form A pulsatile release dosage form is one that mimics a multiple dosing profile without repeated dosing and allows at least a twofold reduction in dosing frequency as compared to that drug presented as a conventional dosage form.
  • a pulsatile release profile is characterized by a time period of no release (lag time) followed by rapid drug release.
  • Dibenzo-l,4-thiazines also known as phenothiazines, are a class of thiazine dyes which contain a six-membered heterocycle containing a single nitrogen atom and a single sulfur atom in which two benzene rings are fused to the heterocycle. Phenothiazine was first reported by Bernthsen in 1883 (Bernthsen, Ber. Deut. Chem. Ges., 16, 2896-2904, (1883)).
  • Methylene blue is the most well known example of the phenothiazine dyes.
  • the structure of methylene blue is shown below:
  • Methylene blue is used in a variety of applications such as textiles (for dyeing cellulosic fibers and printing leather), as an anti-oxidant and antiseptic, and in photogalvanic cells based on redox systems.
  • Methylene blue or 3,7-Bis(dimethylamino)-phenothiazin-5-ium chloride, C 16 H 18 ClN 3 S, is a dark green or blue thiazine dye which was first isolated in 1876.
  • Methylene blue is a thiazine dye occurring as dark blue- green crystals which is soluble in water and sparingly soluble in alcohol, forming deep blue solutions.
  • Methylene blue injectable has a pH of 3-4.5. The pK a is between 0 and -1.
  • Methylene blue and its analogues have also been used extensively for staining live and fixed tissues.
  • Derivatives such Azure A, B, and C as well as Taylor's Blue and Toluidine blue are important dyes for the induction of metachromasia, which is the ability of dyes to color different tissue constituents in different colors (Moura et ah, Curr. Drug. Targ., 4, 133-141 (2003)).
  • Toluidine blue is one of the more popular dyes used for staining microorganisms and can also be used for the diagnosis of several diseases (Moulder et ah, Textbook of Microbiology, 19 th Ed., Saunder, Philadelphia, pp. 18 and 47, (1968)).
  • Methylene blue has been approved for oral administration and has been reported to be effective as an antiseptic, disinfectant, and antidote for cyanide and nitrate poisoning.
  • Methylene blue injected intravenously at a dose of 1 mg/kg body weight, is effective in the treatment of methemoglobinemia, a clinical disorder where more than 1% of the hemoglobin in the blood has been oxidized to Fe 3+ .
  • Methylene blue was administered for periods of one week to 19 months to adult humans, with minimal side effects.
  • the 24 h LD 50 for intravenous methylene blue administered as a 3% solution was 42.3 mg/kg with 95% confidence interval limits of 37.3 to 47.9 mg/kg, demonstrating that methylene blue can be safely administered at a dosage of up to at least 15 mg/kg.
  • methylene blue crosses the blood- milk barrier easily.
  • U.S. Patent No. 6,346,529 to Floyd, et al. describes the use of methylene blue and other thiazine dyes to inactivate HIV. It also demonstrates that the effect of the dye on different types of viruses is unpredictable, and that one cannot use results with one virus to predict efficacy with another. See Table 4, comparing efficacy against HIV with a lack of efficacy against Herpes Simplex Virus type 1 and type 2.
  • U.S. Patent No. 5,545,516 to Wagner describes the inactivation of extracellular enveloped viruses in blood and blood components by phenthiazin-5-ium dyes plus light.
  • the described process inactivates pathogenic contaminants in whole blood, plasma, cellular blood components, by adding a phenthiazin-5-ium dye(s) thereto and irradiating the dye-containing composition with light of wavelengths from 560 to 800 nm or red light, such that they are suitable for transfusion.
  • the conditions for treating blood products in a laboratory, and the availability of a radiant light source are quite different from the conditions required to treat a patient with a chronic viral conditions such as hepatitis C.
  • R 1 , R 2 , R 4 , R 5 , and R 7 are independently selected from the group consisting of hydrogen, linear, branched or cyclic alkyl, aryl, substituted aryl, alkoxy, thioalkoxy, alkylamino, nitro, amino and halogen;
  • R 3 and R 6 are independently selected from the group consisting of -O, -NH 2 , -NHR 8 , and -NRgR 10 wherein R 8 -R 10 is a linear, branched or cyclic hydrocarbon or R 9 and R 10 together with the nitrogen atom to which they are attached form an optionally substituted 5-, 6-, or 7-membered ring, optionally containing one or more heteroatoms selected from non-peroxide oxy (-O-), thio (-S-), sulfmyl (-SO-), sulfonyl (-SO 2 -), or amine (-NR-), where R is hydrogen; linear, branched, or
  • thiazine dyes examples include, but are not limited to, methylene blue, methyl methylene blue, dimethyl methylene blue, azure A, azure B, azure C, methylene green, new methylene blue, Taylor's Blue, Toluidine Blue O, and thionine. These dyes are all commercially available from a number of different sources. Symmetrical 3,7- fe(dialkylamino)phenothiazin-5-ium derivatives which may be useful are described in Moura et ah, Current Drug Targets, Vol. 4, 133-141 (2003).
  • phenoxazine dyes in which the sulfur atom of the thiazine ring is replaced by an oxygen atom, may also be used. Examples of phenoxazine dyes include Nile Blue and its derivatives.
  • Methylene blue and its derivatives typically exist as the chloride or bromide salts; however, other anions can be used to stabilize the positive charge on the molecule.
  • Suitable anions include inorganic anions such sulfate, sulfamte, phosphate, nitrate, and nitrite; and organic anions such as acetate, propionate, succinate, glycolate, lactate, malate, tartarate, citrate, ascorbate, pamoate, maleate, hydroxymaleate, phenylacetate, glutamate, benzoate, salicylate, sulfanilate, 2-acetoxybenzoate, fumarate, tolunesulfonate, naphthalenesulfonate, methanesulfonate, ethane disulfonate, oxalate, and isethionate salts.
  • the activity of the dye can be enhanced further by irradiation with light or by derivatization with compounds such as antisense mRNA.
  • the thiazine dye can also be provided in combination with other therapeutic, prophylactic or diagnostic agents.
  • methylene blue or a derivative of methylene blue can be administered adjunctively with other active compounds such as analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptics, antihistamines, antimigraine drugs, antimuscarinics, anxioltyics, sedatives, hypnotics, antipsychotics, bronchodilators, anti asthma drugs, cardiovascular drugs, corticosteroids, dopaminergics, electrolytes, gastro-intestinal drugs, muscle relaxants, nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics and anti-narcoleptics.
  • active compounds such as analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptics, antihistamines, antimigraine drugs, antimuscarinics, anxioltyics, sedatives, hypnotics, antipsychotics, bronchodilators,
  • Suitable anti-inflammatory agents include, but are not limited to, cortisone, hydrocortisone, betamethasone, dexamethasone, fluocortolone, prednisolone, triamcinolone, indomethacin, sulindac.
  • the formulation can include other antiinfectives such as antibiotics, antifungals, other antivirals, amoebicidal, trichomonocidal, to treat viral or secondary infections.
  • Suitable antibiotics include, but are not limited to, beta-lactam antibiotics, chloramphenicol, rifampin, clarithromycin, adriamycin, erythropoietin, neomycin, gramicidin, bacitracin, sulfonamides, and nalidixic acid.
  • Suitable anti-fungals include, but are not limited to, voriconazole (Vfend®), azoles, imidazoles, polyenes, posaconazole, fluconazole, itraconazole, amphotericin B, 5-fluorocytosine, miconazole, and ketoconazole.
  • Suitable antivirals include, but are not limited to, acyclovir, amantadine, rimantadine, nevirapine, cidofovir
  • Vistide.TM. trisodium phosphonoformate (Foscarnet.TM.), famcyclovir, pencyclovir, valacyclovir, zidovudine (AZT, Retrovir.TM.), didanosine (dideoxyinosine, ddl, Videx.TM.), stavudine (d4T, Zerit.TM.), zalcitabine (dideoxycytosine, ddC, Hivid.TM.) , nevirapine (Viramune.TM.), lamivudine (Epivir.TM., 3TC), saquinavir (Invirase.TM., Fortovase.TM.), ritonavir (Norvir.TM.), nelfinavir (Viracept.TM.), efavirenz (Sustiva.TM.), abacavir (Ziagen.TM.) , amprenavir (Agenerase.TM.) in
  • Formulations may be prepared using a pharmaceutically acceptable carrier composed of materials that are considered safe and effective and may be administered to an individual without causing undesirable biological side effects or unwanted interactions.
  • the carrier is all components present in the pharmaceutical formulation other than the active ingredient or ingredients.
  • carrier includes, but is not limited to, diluents, binders, lubricants, disintegrators, fillers, and coating compositions. Carrier also includes all components of the coating composition which may include plasticizers, pigments, colorants, stabilizing agents, and glidants.
  • the delayed release dosage formulations may be prepared as described in standard references such as "Pharmaceutical dosage form tablets", eds. Liberman et. al.
  • the coating material may contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilization agents, pore formers and surfactants.
  • Optional pharmaceutically acceptable excipients present in the drug- containing tablets, beads, granules or particles include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants.
  • Diluents also referred to as "fillers,” are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules.
  • Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar.
  • Binders are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet or bead or granule remains intact after the formation of the dosage forms.
  • Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactos e and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone.
  • Lubricants are used to facilitate tablet manufacture.
  • suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil.
  • Disintegrants are used to facilitate dosage form disintegration or
  • breakup after administration, and generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as cross- linked PVP (Polyplasdone XL from GAF Chemical Corp).
  • cross- linked PVP Polyplasdone XL from GAF Chemical Corp.
  • Stabilizers are used to inhibit or retard drug decomposition reactions which include, by way of example, oxidative reactions.
  • Surfactants may be anionic, cationic, amphoteric or nonionic surface active agents.
  • Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions.
  • anionic surfactants include sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2- ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate.
  • Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine.
  • nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, poryglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG- 150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide.
  • amphoteric surfactants include sodium N-dodecyl-.beta.-alanine, sodium N-lauryl-.beta.-iminodipropionate, myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.
  • the tablets, beads, granules, or particles may also contain minor amount of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents, or preservatives.
  • the compounds can be administered as tablets, hard or soft shell capsules, suspensions or solutions.
  • Devices with different drug release mechanisms can be combined in a final dosage form comprising single or multiple units. Examples of multiple units include multilayer tablets, capsules containing tablets, beads, granules, etc.
  • an immediate release portion can be added to the extended release system by means of either applying an immediate release layer on top of the extended release core using coating or compression process or in a multiple unit system such as a capsule containing extended and immediate release beads.
  • Extended Release Formulations can be added to the extended release system by means of either applying an immediate release layer on top of the extended release core using coating or compression process or in a multiple unit system such as a capsule containing extended and immediate release beads.
  • Extended release formulations are generally prepared as diffusion or osmotic systems, for example, as described in "Remington - The science and practice of pharmacy” (20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000).
  • a diffusion system typically consists of two types of devices, reservoir and matrix, and is well known and described in the art.
  • the matrix devices are generally prepared by compressing the drug with a slowly dissolving polymer carrier into a tablet form.
  • the three major types of materials used in the preparation of matrix devices are insoluble plastics, hydrophilic polymers, and fatty compounds.
  • Plastic matrices include, but not limited to, methyl acrylate-methyl methacrylate, polyvinyl chloride, and polyethylene.
  • Hydrophilic polymers include, but are not limited to, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and carbopol® 934, polyethylene oxides.
  • Fatty compounds include, but are not limited to, various waxes such as carnauba wax and glyceryl tristearate.
  • extended release formulations can be prepared using osmotic systems or by applying a semi-permeable coating to the dosage form.
  • the desired drug release profile can be achieved by combining low permeable and high permeable coating materials in suitable proportion.
  • Extended release tablets containing hydrophilic polymers are prepared by techniques commonly known in the art such as direct compression, wet granulation, or dry granulation processes. Their formulations usually incorporate polymers, diluents, binders, and lubricants as well as the active pharmaceutical ingredient.
  • the usual diluents include inert powdered substances such as any of many different kinds of starch, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.
  • Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful.
  • Typical tablet binders include substances such as starch, gelatin and sugars such as lactose, fructose, and glucose. Natural and synthetic gums, including acacia, alginates, methylcellulose, and polyvinylpyrrolidine can also be used. Polyethylene glycol, hydrophilic polymers, ethylcellulose and waxes can also serve as binders.
  • a lubricant is necessary in a tablet formulation to prevent the tablet and punches from sticking in the die. The lubricant is chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.
  • Extended release tablets containing wax materials are generally prepared using methods known in the art such as a direct blend method, a congealing method, and an aqueous dispersion method.
  • a congealing method the drug is mixed with a wax material and either spray- congealed or congealed and screened and processed.
  • Delayed Release Formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in the acid environment of the stomach, and soluble in the neutral environment of small intestines.
  • the delayed release dosage units can be prepared, for example, by coating a drug or a drug-containing composition with a selected coating material.
  • the drug-containing composition may be, e.g., a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core” dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule.
  • Preferred coating materials include bioerodible, gradually hydrolyzable, gradually water- soluble, and/or enzymatically degradable polymers, and may be conventional "enteric" polymers.
  • Enteric polymers as will be appreciated by those skilled in the art, become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as the dosage form passes through the gastrointestinal tract, while enzymatically degradable polymers are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly in the colon.
  • Suitable coating materials for effecting delayed release include, but are not limited to, cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate, and other methacrylic resins that are commercially available under the tradename Eudragit ® . (Rohm Pharma; Westerstadt, Germany), including Eudragit ® . L30D-55 and L100-55 (soluble at pH 5.5 and above), Eudragit ®
  • the preferred coating weights for particular coating materials may be readily determined by those skilled in the art by evaluating individual release profiles for tablets, beads and granules prepared with different quantities of various coating materials. It is the combination of materials, method and form of application that produce the desired release characteristics, which one can determine only from the clinical studies.
  • the coating composition may include conventional additives, such as plasticizers, pigments, colorants, stabilizing agents, glidants, etc.
  • a plasticizer is normally present to reduce the fragility of the coating, and will generally represent about 10 wt. % to 50 wt. % relative to the dry weight of the polymer.
  • typical plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetyl citrate, castor oil and acetylated monoglycerides.
  • a stabilizing agent is preferably used to stabilize particles in the dispersion.
  • Typical stabilizing agents are nonionic emulsifiers such as sorbitan esters, polysorbates and polyvinylpyrrolidone. Glidants are recommended to reduce sticking effects during film formation and drying, and will generally represent approximately 25 wt. % to 100 wt. % of the polymer weight in the coating solution.
  • One effective glidant is talc.
  • Other glidants such as magnesium stearate and glycerol monostearates may also be used.
  • Pigments such as titanium dioxide may also be used.
  • Small quantities of an anti-foaming agent such as a silicone (e.g., simethicone), may also be added to the coating composition.
  • Such methods include, but are not limited to, the following: coating a drug or drug-containing composition with an appropriate coating material, typically although not necessarily incorporating a polymeric material, increasing drug particle size, placing the drug within a matrix, and forming complexes of the drug with a suitable complexing agent.
  • the delayed release dosage units may be coated with the delayed release polymer coating using conventional techniques, e.g., using a conventional coating pan, an airless spray technique, fluidized bed coating equipment (with or without a Wurster insert), or the like.
  • a conventional coating pan e.g., an airless spray technique, fluidized bed coating equipment (with or without a Wurster insert), or the like.
  • Pharmaceutical Dosage Forms Tablets, eds. Lieberman et al. (New York: Marcel Dekker, Inc., 1989), and Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, ⁇ .sup.th Ed. (Media, PA: Williams & Wilkins, 1995).
  • a preferred method for preparing extended release tablets is by compressing a drug-containing blend, e.g., blend of granules, prepared using a direct blend, wet-granulation, or dry-granulation process.
  • Extended release tablets may also be molded rather than compressed, starting with a moist material containing a suitable water-soluble lubricant. However, tablets are preferably manufactured using compression rather than molding.
  • a preferred method for forming extended release drug-containing blend is to mix drug particles directly with one or more excipients such as diluents (or fillers), binders, disintegrants, lubricants, glidants, and colorants.
  • a drug-containing blend may be prepared by using wet-granulation or dry-granulation processes.
  • Beads containing the active agent may also be prepared by any one of a number of conventional techniques, typically starting from a fluid dispersion.
  • a typical method for preparing drug-containing beads involves dispersing or dissolving the active agent in a coating suspension or solution containing pharmaceutical excipients such as polyvinylpyrrolidone, methylcellulose, talc, metallic stearates, silicone dioxide, plasticizers or the like.
  • the admixture is used to coat a bead core such as a sugar sphere (or so-called "non-pareil”) having a size of approximately 60 to 20 mesh.
  • An alternative procedure for preparing drug beads is by blending drug with one or more pharmaceutically acceptable excipients, such as microcrystalline cellulose, lactose, cellulose, polyvinyl pyrrolidine, talc, magnesium stearate, a disintegrant, etc., extruding the blend, spheronizing the extrudate, drying and optionally coating to form the immediate release beads.
  • the dye can be continuously delivered to a patient over an extended period of time using a controlled release polymeric implant or implantable pump.
  • Polymeric implants are generally manufactured from polymers which degrade in vivo over a known period of time. Examples of useful polymers include polyanhydrides, polylactic acid, polyorthoester, and ethylene vinyl acetate. These devices are also commercially available. Alza Corporation, Palo Alta, CA, and Nova Pharmaceuticals, Baltimore, MD, both manufacture and distribute biodegradable controlled release polymeric devices.
  • the thiazine dyes can also be delivered using techniques known to those skilled in the art of drug delivery to target specific cell types or to enhance the activity of the dye. For example, a procedure utilizing injection of photoactive drugs for cancer treatment is described by Edelson, et al., in New England J. Med. 316. 297-303 (1987). Thiazine dyes can be specifically delivered to macrophages, a site of high hepatitis virus concentration in hepatitis virus patients, using techniques such as liposome delivery. Liposomes are generally described by Gregoriadis, Drug Carriers in Biology and Medicine Ch. 14, 287-341 (Academic Press, NY, 1979).
  • Liposome compositions are commercially available from companies such as the Liposome Company, Inc., Princeton, NJ. Release of compounds from liposomes ingested by macrophages is described by Storm, et al., in Biochim.Biophys.Acta 965, 136-145 (1988). III. Methods of Treatment
  • Hepatitis is inflammation of the liver.
  • viruses cause viral hepatitis. They are named the hepatitis A, B, C, D, and E viruses.
  • viruses A, B, C, D, E, G and transfusion transmitted virus (TTV) are recognized in the hepatitis virus alphabet.
  • Hepatitis G virus and TTV probably do not cause liver disease in humans.
  • Hepatitis A and E usually cause a self-limiting hepatitis followed by complete recovery but occasionally cause fulminant hepatic failure.
  • Hepatitis B and C are major public health problems worldwide due to their sequelae of chronic hepatitis, cirrhosis and primary liver cancer.
  • Chronic hepatitis C is a particular health issue for Western Europe already, accounting for 40% of end-stage cirrhosis and 30% of liver transplants. The contribution of hepatitis C to chronic liver disease is predicted to rise in the future. Vaccines can prevent hepatitis A and B. Interferon alpha is effective treatment in 25-30% of patients with chronic hepatitis B or C. The prospects for treating chronic hepatitis B have been improved by the introduction of reverse transcriptase inhibitors. Lamivudine is the first drug of this class to be licensed. The optimal use of these new drugs is currently being studied. The success rate for treating chronic hepatitis C can be raised to about 40% with combination therapy of interferon alpha and ribavirin.
  • viruses cause acute or short-term viral hepatitis.
  • the hepatitis B, C, and D viruses can also cause chronic hepatitis, in which the infection is prolonged, sometimes lifelong.
  • Other viruses may also cause hepatitis, but they have yet to be discovered and they are obviously rare causes of the disease.
  • Hepatitis A is primarily spread through food or water contaminated by feces from an infected person. Rarely, it spreads through contact with infected blood. Hepatitis A is prevented by a vaccine; by avoiding tap water when traveling internationally and practicing good hygiene and sanitation. Hepatitis A usually resolves on its own over several weeks. Hepatitis B is spread through contact with infected blood, through sex with an infected person, and from mother to child during childbirth. Hepatitis B can be prevented by a vaccine and treated with alpha interferon, peginterferon, lamivudine, or adefovir dipivoxil.
  • Acute hepatitis B usually resolves on its own. Very severe cases can be treated with lamivudine.
  • Hepatitis C is a viral infection of the liver.
  • the virus, HCV 5 is a major cause of acute hepatitis and chronic liver disease, including cirrhosis and liver cancer.
  • HCV is spread primarily by direct contact with human blood.
  • the major causes of HCV infection worldwide are use of unscreened blood transfusions, and re-use of needles and syringes that have not been adequately sterilized.
  • Current means for treating chronic hepatitis C is with peginterferon alone or in combination treatment with peg-interferon and the drug ribavirin.
  • Acute hepatitis C treatment is recommended if it does not resolve within 2 to 3 months.
  • Hepatitis D is also spread through contact with infected blood. This disease occurs only in people who are already infected with hepatitis B. Treatment of chronic hepatitis D is with alpha interferon.
  • Hepatitis E is spread through food or water contaminated by feces from an infected person. There is no vaccine for hepatitis E; the only way to prevent the disease is to reduce the risk of exposure to the virus. Hepatitis E usually resolves on its own over several weeks to months.
  • hepatitis A, B, C, D, or E viruses Some cases of viral hepatitis cannot be attributed to.the hepatitis A, B, C, D, or E viruses. This is called non A-E hepatitis.
  • HCV hepatitis C virus
  • the World Health Organization has declared hepatitis C a global health problem, with approximately 3% of the world's population (roughly 170-200 million people) infected with HCV. In the US, approximately 3 million people are chronically infected, many of whom are still undiagnosed. According to the Sustainable Sciences Institute (SSI) the situation is quite worse in Egypt. Egypt has a population of 62 million and contains the highest prevalence of hepatitis C in the world. The national prevalence rate of HCV antibody positivity was estimated by the Egyptian Ministry of Health (MOHP) in 1999 to be 18.9%. Since 25-30% of individuals clear the infection, the estimated adjusted national prevalence rate is 12% (or 7.2 million people) (MOHP, 1999).
  • Hepatitis C virus was first described in 1989 as the putative viral agent of non-A non-B hepatitis. It is a member of the Flaviviridae family and has been recognized as the major causative agent of chronic liver disease, including chronic active hepatitis, cirrhosis and hepatocellular carcinoma.
  • HCV is a positive RNA virus with a genome containing approximately 9500 nucleotides. It has an open reading frame that encodes a large polyprotein of about 3000 amino acids and is characterized by extensive genetic diversity. HCV has six major genotypes (subtypes): Ia, Ib, 2a, 2b, 3, 4, 5, and 6. Genotypes Ia and Ib, which are the most common in the U.S., are more difficult to treat. Interestingly, genotype 4 represents over 90% of cases in Egypt.
  • HCV liver cirrhosis and liver cancer in Egypt, and indeed, one of the top five leading causes of death.
  • Egypt the major route of exposure appears to be due to medical therapy and inadequate sterilization techniques and supplies.
  • the major risk factor associated with HCV infection is a history of anti-schistosomal injection treatment.
  • Schistosomiasis is a common parasitic disease in Egypt acquired through swimming or wading in contaminated irrigation channels or standing water. Thus, farmers and rural populations are at greatest risk, and this is supported by the higher prevalence rate of HCV in the Nile delta and rural areas. Schistosomiasis can lead to urinary or liver damage over many years.
  • Latent Viruses Clinically important DNA-viral infections are caused by viruses such as Herpes simplex virus type 1 & 2, Varicella zoster virus, Epstein-Barr virus, Cytomegalovirus, and Herpes virus type 6 & 7, Adenovirus, and Human polyoma viruses, e.g. JC virus and BK virus.
  • the papovaviruses (JC and BK) are widely distributed in the human population, as evidenced by the presence of specific antibodies in 70-80% of adult sera.
  • BK virus has been associated with hemorrhagic cystitis and is capable of inducing obstructive renal failure.
  • the JC virus is thought to persist in the kidney, and is reactivated when the host immune system is impaired (e.g., HIV infection, immunosuppressive therapy, pregnancy).
  • progressive multifocal leukoencephalopathy (PML) caused by JC virus may occur when patient receives profound immunosuppressive therapy, such as chemotherapy or radiation.
  • PML progressive multifocal leukoencephalopathy
  • Adenoviruses cause acute disease of the respiratory and gastrointestinal tracts.
  • organ transplant kidney, bone marrow
  • AIDS patients suggests that these infections most probably represent reactivation of a latent adenovirus infection.
  • Pneumonia and hepatitis are the most common infections.
  • Hemorrhagic cystitis occasionally occurs and has been associated with specific serotypes of the virus.
  • Infections in transplant patients caused by adenovirus occur in approximately 17% of patients who receive allogeneic bone marrow transplantation.
  • Reactivation infections by B or C AdV2, AdV5 serotypes are most common. No specific treatment is available.
  • Herpes viruses are a leading cause of human viral disease, second only to influenza and cold viruses. Infection is life long and the viruses are capable of causing overt disease or remaining silent for many years only to be reactivated, for example as shingles.
  • Herpetoviridae There are 25 families in the Herpetoviridae but only six of them are known to infect man with any regularity, Herpes simplex virus Type 1 (HSV-I), Herpes simplex virus Type 2 (HSV-2), Epstein Barr virus (EBV), Cytomegalovirus (CMV), Varicella Zoster Virus (VZV), Human herpes virus 6 (exanthum subitum or roseola infantum), and Human herpes virus 8 (Kaposi's sarcoma-associate herpes virus).
  • HSV-I Herpes simplex virus Type 1
  • HSV-2 Herpes simplex virus Type 2
  • Epstein Barr virus EBV
  • CMV Cytomegalovirus
  • VZV Varicella Zoster
  • Herpes simplex virus HSV
  • HSV-I Herpes simplex virus
  • HSV-2 Herpes simplex 1 and 2 can infect both humans and animals but only humans show symptoms of disease. HSV-I and HSV-2 first infect cells of the mucoepithelia or enter through wounds. They then frequently set up latent infections in neuronal cells. Both types of HSV can also persistently infect macrophages and lymphocytes. A large proportion of the population has evidence of HSV-I infection. In underdeveloped countries, HSV-I antibodies are found in more than 90% of children as a result of poor hygiene. HSV-2 is normally spread sexually. HSV-2 infections are more prevalent later in life as the number of sexual contacts increases. Thus, the lowest rates of infection are found in children and the highest rates in prostitutes among whom as many as 80% are infected with HSV-2.
  • Herpes simplex 1 and 2 are frequently benign but can also cause severe disease. Diseases caused by HSV-I and/or HSV-2 include, oral herpes herpes pharyngitis, herpes keratitis, which is a leading cause of corneal blindness in the United States, herpes whitlow, herpes gladiatorum eczema herpeticum, genital herpes, HSV encephalitis, and HSV meningitis.
  • HSV reactivation of infection often occurs at the same site as the initial infection. There are several agents that seem to trigger reactivation, most of which are stress-related. It also appears that exposure to strong sunlight and perhaps fever can lead to reacitivation. These factors may cause some degree of immune suppression that leads to renewal of virus proliferation in the nerve cell. HSV types 1 and 2 are a common cause of lesions in patients with malignancy. HSV infection results in most cases from reactivation of latent virus. More than 80% of bone marrow transplant (BMT) patients have reactivation of latent HSV residing in the neuronal ganglia. The same is true for patients with leukemia, lymphoma, or solid tumors who receive intensive chemotherapy.
  • BMT bone marrow transplant
  • This reactivation usually occurs within the first 3 weeks after transplantation or chemotherapy and is characterized by ulcerative oral lesions (in 85% of the cases) or genital lesions (in 15% of the cases).
  • Other possible presentations of HSV infection in immunocompromised patients are esophagitis, tracheitis, pneumonitis, and, rarely, encephalitis.
  • pneumonitis When pneumonitis occurs, it may present as a local infiltrate (usually originating from aspiration of the virus from the upper airways) or as a diffuse interstitial infiltrate (from viremia).
  • Varicella-Zoster Virus also known as Herpes Zoster Virus, Human Herpes Virus-3 causes two major diseases, chicken-pox (Varicella), usually in childhood, and shingles, later in life. Shingles (Zoster) is a reactivation of an earlier varicella infection.
  • the Varicella-Zoster virus may be reactivated under stress or with immune suppression.
  • VZV infection in cancer patients can present either as primary infection (chickenpox) or as reactivation (shingles).
  • Children with acute leukaemia who develop varicella are at particularly high risk for VZV pneumonia which may occur in up to one-third of patients with a fatality rate of about 10% (Feldman, S. and Lott, L., Pediatrics 80:465-472 (1987)).
  • Patients with AIDS often exhibit reactivation of varicella infection.
  • Increased reactivation of varicella-zoster virus is also observed in CD34+ allogenic stem cell transplantation (Martino, R., et al., Haematologica.
  • Herpes zoster is most frequently observed among cancer patients with leukaemia or lymphoma and in recipients of autologous or allogeneic stem cell transplants (SCT).
  • SCT autologous or allogeneic stem cell transplants
  • intravenous acyclovir is used for treatment.
  • high-dose oral acyclovir, valaciclovir or famciclovir are often used.
  • these drugs have significant drawbacks as discussed above.
  • VZV reactivation may occur for a prolonged period of time.
  • long-term antiviral drug prophylaxis is not advisable in allograft recipients, since it only delays the occurrence of zoster and carries the potential for induction of VZV resistance.
  • Epstein- Barr Virus occurs worldwide. In the United States, as many as 95% of adults between 35 and 40 years of age have been infected. When infection with EBV occurs during adolescence or young adulthood, it causes infectious mononucleosis 35% to 50% of the time. Although symptoms of infectious mononucleosis usually resolve in one or two months, EBV remains dormant or latent in a few cells in the throat and blood for the rest of the person's life. Periodically, the virus can reactivate. In a few carriers of EBV the emergence of Burkitt's lymphoma and nasopharyngeal carcinoma, two rare cancers is seen.
  • the tumor cells show evidence of EBV DNA and tumor antigens and patients show a much higher level of anti-EBV antibodies than other members of the population. Further evidence that implicates EBV in Burkitt's lymphoma is the observation that EBV can transform B lymphocytes in culture and can produce B cell lymphomas in primates. If cell mediated immunity is suppressed, resolution of the EBV disease may not occur. Uncontrolled viral replication may lead to a severe syndrome with B cell lymphoproliferation, leukopenia and lymphoma. In patients with T cell deficiency X-linked lymphoproliferative disorder may occur. Transplant patients and AIDS patients who are also immunosuppressed may exhibit post-transplant lymphoproliferative disorder.
  • herpes simplex virus there are no drugs available to treat Epstein-Barr virus. This may reflect the absence of a thymidine kinase encoded by this virus (drugs such as acyclovir that are active against herpes simplex are activated by the viral thymidine kinase).
  • Cytomegalovirus (CMV) infection is found in a significant proportion of the population. By college age, about 15% of the US population is infected and this rises to about half by 35 years of age. The virus is spread in most secretions, particularly saliva, urine, vaginal secretions and semen. Cytomegalovirus infection is therefore sexually transmitted. It can also spread to a fetus in a pregnant woman and to the newborn via lactation. In the hospital, the virus can also be spread via blood transfusions and transplants. In third world countries with more crowded conditions, the virus is found in a much higher proportion of the population than in western countries.
  • Cytomegalovirus causes no symptoms in children and at most mild disease in adults. However, CMV infections can decrease blood cell count, resulting in dangerous neutropenia or slight but persistent thrombocytopenia. It can also induce organ specific diseases, like CMV hepatitis, pneumonitis, or GI infections. Of these, the most deadly infection is known to be CMV pneumonitis. CMV pneumonitis occurs in 15% of patients with CMV reactivation. CMV is the most common viral cause of congenital disease. Up to one in forty newborns in the United States are infected by the virus. Abnormalities include microcephaly, rash, brain calcification and hepatosplenomegaly. These may result in hearing loss (bilateral or unilateral) and retardation.
  • CMV CMV
  • the virus may later reactivate, particularly in cases of immunosuppression; indeed, infection by the virus can, itself, be immunosuppressive.
  • Mild forms of the illness may manifest as fever, hepatitis, leukopenia, and thrombocytopenia.
  • Severe forms manifest as interstitial pneumonia (with a mortality rate of 80% to 90%) and gastroenteritis.
  • Patients receiving cytoreductive therapy for acute leukaemia and recipients of allogeneic SCT are at high risk for serious CMV disease following reactivation of virus.
  • CMV pneumonia was reported to occur in 2.9% of patients with a case-fatality rate of 57% (Nguyen Q, et al., Clin Infect Dis 32:539 ⁇ -5(2001)).
  • an immunosuppressive disease e.g. AIDS
  • cytomegalovirus can be a major problem.
  • Reactivation of CMV occurs in approximately 80% of patients who are seropositive before transplantation. Most commonly, infection appears 4 to 10 weeks after transplantation.
  • CMV can cause multiorgan disease after stem cell transplant (SCT), including pneumonia, gastroenteritis, hepatitis, retinitis, and encephalitis.
  • SCT stem cell transplant
  • T-cells and or B-cells are removed from the graft to prevent chronic graft-versus-host disease (GVHD)
  • GVHD chronic graft-versus-host disease
  • Intravenous ganciclovir prophylaxis results in less frequent CMV disease but not in improved survival.
  • Human herpes virus 6 is found worldwide and is found in the saliva of the majority of adults (>90%). It infects almost all children by the age of two. It can set up a latent infection in T cells which can later be reactivated when cells are stimulated to divide. Human herpes virus-6 has two forms, HHV-6A and HHV-6B. The latter causes exanthem subitum, otherwise known as roseola infantum. Symptoms include fever and sometimes upper respiratory tract infection and lymphadenopathy. In adults, primary infection is associated with a mononucleosis. This virus may co-infect HIV-infected T4 lymphocytes exacerbating the replication of HIV. Patients with HIV have a higher infection rate than the normal population.
  • HHV-6 has been associated with a number of neurological disorders, including encephalitis and seizures. It has been postulated to play a role in multiple sclerosis and chronic fatigue immunodeficiency syndrome. Cell-mediated immunity is essential in control, although infection is life-long, and the virus can reactivate in patients who are immunosuppressed.
  • Human herpes virus 7 is found in the saliva of the majority of the adult population (>75%). Most people acquire the infection as children and it remains with them for the rest of their lives. It is similar to HHV-6 and may be responsible for some cases of exanthem subitum.
  • nucleoside analog drugs used to treat herpes infections, many of which are of high specificity since they take advantage of the activation of the drug by a viral enzyme, thymidine kinase.
  • the best known of the nucleoside analogs is acycloguanosine (acyclovir) but there are other approved drugs including famciclovir and valacyclovir. All of these nucleoside analogs suffer from the appearance of resistant herpes mutants. It should be noted that these drugs act against the replicating virus (they are incorporated into the DNA as it is copied) and therefore they are ineffective against latent virus.
  • Herpes B is a simian virus found in old world monkeys such as macaques but it can be a human pathogen in people who handle monkeys (monkey bites are the route of transmission). In humans, the disease is much more problematic than it is in its natural host. Indeed, about 75% of human cases result in death with serious neurological problems (encephalitis) in many survivors. There is also evidence that the disease can be passed from a monkey-infected human to another human. In vitro the virus is sensitive to both Acyclovir and Ganciclovir and these are recommended for therapy. Their efficacy is unknown.
  • Hepatitis B is spread through contact with infected blood, through sex with an infected person, and from mother to child during childbirth. Hepatitis B can be prevented by a vaccine and treated with alpha interferon, peginterferon, lamivudine, or adefovir dipivoxil. Acute hepatitis B usually resolves on its own. Very severe cases can be treated with lamivudine.
  • Reactivation of hepatitis B has been described under a variety of circumstances. Reactivation can occur spontaneously (Davis GL, et al., Gastroenterology 86:230-235 (1984) and Fattovich G, et al., Liver 10:141- 146 (1990)); under impaired immune status, e.g. presence of malignancies or after chemotherapy (Hoofhagle JH 5 et al. 5 Ann.Intern.Med. 96:447-449 (1982) and Martin BA, et al., Bone Marrow Transplant 15:145-148 (1995)) and in patients with AIDS (Vento S, et al., Lancet i:332-333 (1989)); following transplantation, e.g.
  • HBV hepatitis B virus
  • HBV hepatitis B virus
  • the drug is preferably administered orally, although it can also be administered by injection.
  • the preferred dosage range for methylene blue is 30 to 180 mg twice a day, more preferably between 60 and 130 mg twice a day, for an immediate release formulation.
  • An equivalent dosage can be administered in a controlled release formulation. In some cases it may be desirable to administer the formulation using a dosage escalation regime to reach a desired maintenance level.
  • the appropriate in vivo dosage can be determined by extrapolation from in vitro levels, assuming the usual blood volume for adult humans is approximately 10, and taking into account the 74% oral absorption and 75% excretion of that absorbed over a period of time, and assuming the lower therapeutic index in darkness than in light.
  • the formulation can also be administered as spray dried particles, for intranasal or pulmonary administration, with or without a surfactant or other carrier.
  • the method described herein does not require administration of exogenous light, although the results may be enhanced by exposure to light in addition to that normally transmitted through the skin. Exposure to light can occur with exposure to sun light, a tanning light, or even incandescent light.
  • the drug can be administered prior to or following reactivation of the virus.
  • the drug can be administered for an effective period of time to clear the viral infection, which can be from days to months to years. Suitable lengths of treatment for viral reactivation infections include, but are not limited to, 4 weeks (about 1 month), 12 weeks (about 3 months), 24 weeks (about 6 months), 48 weeks (about 1 year), or even longer as necessary.
  • patients are treated from 3 to 6 months.
  • patients are treated for at least 50 days (about two months) up to 48 weeks.
  • compositions should be administered for an effective period of time, for example, for at least one month.
  • Combination Therapy with Radiation or other Drugs does not require administration of exogenous light, although the results may be enhanced by exposure to light in addition to that normally transmitted through the skin. Exposure to light can occur with exposure to sun light, a tanning light, or even incandescent light.
  • Combination therapy can be sequential, meaning treatment with one agent first followed by treatment with a second agent, or it can be simultaneous, meaning treatment with both agents at the same time. If the combination therapy is sequential, administration of a second agent occurs within a reasonable time after administration of the first agent. If the combination therapy is simultaneous, both agents can be administered at the same time in the same dosage form or in separate dosage forms. The exact regimen will depend on the severity of the disorder and the response to the treatment.
  • Example 1 Clinical Trial to Demonstrate efficacy in reduction in hepatitis C viral load by administration of oral methylene blue. This was an open label study of methylene blue assessing its effectiveness in reducing serum viral load and treating the symptoms associated with chronic hepatitis C. Clinical Study:
  • the study was to evaluate the effectiveness of Methylene Blue in reducing the viral titer and alleviating the related symptoms of chronic Hepatitis C infection.
  • the study design was an open label study to assess the reduction of viral titres in patients over a 24 week treatment period and subsequent 4 week follow-up period.
  • the dose was 65mg of Methylene Blue twice daily in the capsules.
  • the type of subjects were male and female subjects aged between 18 and 70 with proven chronic hepatitis C, 60% with and 40% without cirrhosis, who are refractory to, unwilling, or unable to take interferon/ ribavarin therapy. A total of 60 subjects were enrolled to ensure that 40 completed the treatment period.
  • the primary endpoint was change in Hepatitis C viral titers during treatment and after the treatment period.
  • the secondary endpoints were to reduce hepatic inflammation (measured as an improvement in liver function tests) in patients with chronic hepatitis C.
  • the primary efficacy parameters were (1) Overall reduction in hepatitis C viral titer after the period of treatment, (2) Early Viral Response (EVR) rate as defined as ⁇ 2 Cog reduction in viral count after 90 days of treatment, (3) the Sustained Viral Reduction (SVR) after 6 months of treatment in patients who obtained an EVR.
  • EVR Early Viral Response

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Virology (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne un procédé d'utilisation de colorants thiazine, en particulier du bleu de méthylène ou des dérivés de bleu de méthylène, dans une préparation à libération immédiate ou commandée, seule ou en combinaison avec de faibles niveaux de lumière ou avec d'autres médicaments, de façon à sélectivement inactiver ou inhiber une infection hépatique. Un essai clinique a démontré l'efficacité sésame humain d'un traitement de l'hépatite C par administration orale d'une préparation à libération immédiate de bleu de méthyle, dans une dose de 65 mg deux fois par jour, pendant une durée d'au moins 100 jours. Cette invention concerne aussi un procédé d'utilisation de colorants thiazine, en particulier de bleu de méthylène ou de dérivés de bleu de méthylène, dans une préparation à libération immédiate ou commandée, seule ou en combinaison avec de faibles niveaux de lumière ou avec d'autres médicaments, afin de prévenir ou de réduire la réactivation de virus. La classe préférée de patient est infectés par des virus, ou exposée à des virus, tels que le virus Herpès simplex de type 1 et 2, le virus varicella zoster, le virus Epstein-Barr, le cytomégalovirus, le virus herpès de type 6 et 7, l'adénovirus et des virus polyoma humains, par exemple le virus JC et le virus BK. Dans un mode de réalisation de l'invention le colorant thiazine est administré à un patient souffrant de symptômes ou d'une maladie causée par la réactivation d'un virus. Dans un mode préféré de réalisation le colorant thiazine est administré un patient à risque ou souffrant de symptômes ou d'une maladie causée par la réactivation d'un virus, avant ou pendant une immunosuppression ou une chimiothérapie.
PCT/US2006/019506 2005-05-20 2006-05-19 Therapie au bleu de methylene de maladie virale WO2006127482A1 (fr)

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
US68289105P 2005-05-20 2005-05-20
US60/682,891 2005-05-20
US69709405P 2005-07-07 2005-07-07
US60/697,094 2005-07-07
US71880405P 2005-09-20 2005-09-20
US60/718,804 2005-09-20
US72006605P 2005-09-23 2005-09-23
US72005805P 2005-09-23 2005-09-23
US60/720,066 2005-09-23
US60/720,058 2005-09-23

Publications (1)

Publication Number Publication Date
WO2006127482A1 true WO2006127482A1 (fr) 2006-11-30

Family

ID=37085722

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2006/019506 WO2006127482A1 (fr) 2005-05-20 2006-05-19 Therapie au bleu de methylene de maladie virale

Country Status (1)

Country Link
WO (1) WO2006127482A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007056439A1 (fr) * 2005-11-08 2007-05-18 Collegium Pharmaceutical, Inc. Sels de bleu de méthylène et dérivés de ceux-ci
WO2009048868A1 (fr) * 2007-10-08 2009-04-16 Ondine International Ltd. Procédé de thérapie photodynamique et compositions photosensibilisantes
US8466159B2 (en) 2011-10-21 2013-06-18 Abbvie Inc. Methods for treating HCV
US8492386B2 (en) 2011-10-21 2013-07-23 Abbvie Inc. Methods for treating HCV
US8809265B2 (en) 2011-10-21 2014-08-19 Abbvie Inc. Methods for treating HCV
US8853176B2 (en) 2011-10-21 2014-10-07 Abbvie Inc. Methods for treating HCV
CN110870868A (zh) * 2018-08-31 2020-03-10 成都夸常奥普医疗科技有限公司 包含亚甲蓝类染料、营养素或/和抗肿瘤化合物的药物组合物及其应用
US11192914B2 (en) 2016-04-28 2021-12-07 Emory University Alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto
WO2024115630A1 (fr) * 2022-11-30 2024-06-06 CERNY, Erich Bleu de méthylène destiné à être utilisé en thérapie de l'hépatite b et/ou de l'infection par l'hépatite d

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4181128A (en) * 1975-11-28 1980-01-01 Massachusetts Institute Of Technology Virus inactivation applicator and the like
WO1996002268A1 (fr) * 1994-07-15 1996-02-01 Brigham And Women's Hospital Inhibition d'un virus par l'oxyde nitrique
WO1998031219A1 (fr) * 1997-01-21 1998-07-23 The American National Red Cross Decontamination intracellulaire et extracellulaire de sang total et de composants du sang au moyen de colorants amphiphiles phenotiazin-5-ium et de lumiere
US6346529B1 (en) * 1988-10-28 2002-02-12 Oklahoma Medical Research Foundation Antiviral therapy using thiazine dyes
WO2004019682A1 (fr) * 2002-08-28 2004-03-11 Luis Buil Torres Composition pharmaceutique destinee au traitement des infections virales, fongiques et bacteriennes et applications de ladite composition
WO2005082342A1 (fr) * 2004-02-20 2005-09-09 Hofmann Robert F Utilisation d'une formulation therapeutique oxydative ciblee pour traiter des maladies virales
WO2006034219A2 (fr) * 2004-09-17 2006-03-30 The General Hospital Corporation Inactivation de micro-organismes avec des inhibiteurs de resistance a plusieurs medicaments et des phenothiaziniums
WO2006032879A2 (fr) * 2004-09-23 2006-03-30 Wista Laboratories Ltd. Procedes de synthese chimique et de purification de composes diaminophenothiazinium renfermant du chlorure de methylthioninium (mtc)

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4181128A (en) * 1975-11-28 1980-01-01 Massachusetts Institute Of Technology Virus inactivation applicator and the like
US6346529B1 (en) * 1988-10-28 2002-02-12 Oklahoma Medical Research Foundation Antiviral therapy using thiazine dyes
WO1996002268A1 (fr) * 1994-07-15 1996-02-01 Brigham And Women's Hospital Inhibition d'un virus par l'oxyde nitrique
WO1998031219A1 (fr) * 1997-01-21 1998-07-23 The American National Red Cross Decontamination intracellulaire et extracellulaire de sang total et de composants du sang au moyen de colorants amphiphiles phenotiazin-5-ium et de lumiere
WO2004019682A1 (fr) * 2002-08-28 2004-03-11 Luis Buil Torres Composition pharmaceutique destinee au traitement des infections virales, fongiques et bacteriennes et applications de ladite composition
WO2005082342A1 (fr) * 2004-02-20 2005-09-09 Hofmann Robert F Utilisation d'une formulation therapeutique oxydative ciblee pour traiter des maladies virales
WO2006034219A2 (fr) * 2004-09-17 2006-03-30 The General Hospital Corporation Inactivation de micro-organismes avec des inhibiteurs de resistance a plusieurs medicaments et des phenothiaziniums
WO2006032879A2 (fr) * 2004-09-23 2006-03-30 Wista Laboratories Ltd. Procedes de synthese chimique et de purification de composes diaminophenothiazinium renfermant du chlorure de methylthioninium (mtc)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007056439A1 (fr) * 2005-11-08 2007-05-18 Collegium Pharmaceutical, Inc. Sels de bleu de méthylène et dérivés de ceux-ci
WO2009048868A1 (fr) * 2007-10-08 2009-04-16 Ondine International Ltd. Procédé de thérapie photodynamique et compositions photosensibilisantes
US8809265B2 (en) 2011-10-21 2014-08-19 Abbvie Inc. Methods for treating HCV
US8492386B2 (en) 2011-10-21 2013-07-23 Abbvie Inc. Methods for treating HCV
US8680106B2 (en) 2011-10-21 2014-03-25 AbbVic Inc. Methods for treating HCV
US8685984B2 (en) 2011-10-21 2014-04-01 Abbvie Inc. Methods for treating HCV
US8466159B2 (en) 2011-10-21 2013-06-18 Abbvie Inc. Methods for treating HCV
US8853176B2 (en) 2011-10-21 2014-10-07 Abbvie Inc. Methods for treating HCV
US8969357B2 (en) 2011-10-21 2015-03-03 Abbvie Inc. Methods for treating HCV
US8993578B2 (en) 2011-10-21 2015-03-31 Abbvie Inc. Methods for treating HCV
US9452194B2 (en) 2011-10-21 2016-09-27 Abbvie Inc. Methods for treating HCV
US11192914B2 (en) 2016-04-28 2021-12-07 Emory University Alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto
CN110870868A (zh) * 2018-08-31 2020-03-10 成都夸常奥普医疗科技有限公司 包含亚甲蓝类染料、营养素或/和抗肿瘤化合物的药物组合物及其应用
WO2024115630A1 (fr) * 2022-11-30 2024-06-06 CERNY, Erich Bleu de méthylène destiné à être utilisé en thérapie de l'hépatite b et/ou de l'infection par l'hépatite d

Similar Documents

Publication Publication Date Title
US20060264423A1 (en) Methylene Blue Therapy of Viral Disease
WO2006127482A1 (fr) Therapie au bleu de methylene de maladie virale
US11807625B2 (en) Capsid inhibitors for the prevention of HIV
US7635690B2 (en) HIV-1 mutations selected for by β-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine
CA2633603A1 (fr) Combinaison pharmaceutique
AU2013336491A1 (en) Pharmaceutical antiretroviral composition
US8912141B2 (en) Treatment of hepatitis C virus
JP2016528240A (ja) ドルテグラビル、エムトリシタビン及びテノホビルの医薬コンビネーションを有する医薬
JP2015522080A (ja) スタチン、ビグアナイド、およびさらなる薬剤を含む心血管代謝性リスクを減少させるための組成物
US20070123520A1 (en) Methylene blue therapy of avian influenza
US20070105848A1 (en) Methylene Blue Therapy of Parasitic Infections
US20230218663A1 (en) Compositions and methods for treating a sars-cov-2 infection
AU2018239257A1 (en) HIV post-exposure prophylaxis
US7115584B2 (en) HIV-1 mutations selected for by β-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine
Romero‐Cordero et al. Mitochondrial changes associated with viral infectious diseases in the paediatric population
US20240033236A1 (en) Methods of treating herpes viral infection with 4-phenylbutyrate (pba) or a pharmaceutically acceptable salt thereof
WO2000043014A2 (fr) MUTATIONS DE VIH-1 SELECTIONNEES A L'AIDE DE β-2',3'-DIDEHYDRO-2',3'-DIDEOXY-5-FLUOROCYTIDINE
US20220265689A1 (en) Hiv pre-exposure prophylaxis
US20240041854A1 (en) Cold medicine and antiviral medicine
AU2016331073A1 (en) Combination therapy regimen for treatment of HCV
WO2014122537A2 (fr) Compositions pharmaceutiques et méthodes de traitement d'une infection par le virus de l'hépatite c à l'aide d'une combinaison d'hydroxychloroquine et de ribavirine
WO2016164625A1 (fr) Compositions et méthodes de traitement d'une infection par vhc
Filon Antiviral Therapy for Progressive Multifocal Leukoencephalopathy
Hakimi Therapeutical Aspects of Hepatitis C infections
CN1152259A (zh) 硫代乙烯酮衍生物用于预防或治疗乙型肝炎的用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: RU

122 Ep: pct application non-entry in european phase

Ref document number: 06770697

Country of ref document: EP

Kind code of ref document: A1