WO2007040426A1 - Agent antiviral - Google Patents

Agent antiviral Download PDF

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Publication number
WO2007040426A1
WO2007040426A1 PCT/RU2006/000516 RU2006000516W WO2007040426A1 WO 2007040426 A1 WO2007040426 A1 WO 2007040426A1 RU 2006000516 W RU2006000516 W RU 2006000516W WO 2007040426 A1 WO2007040426 A1 WO 2007040426A1
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WO
WIPO (PCT)
Prior art keywords
remantadine
influenza
iodantipyrine
infection
treatment
Prior art date
Application number
PCT/RU2006/000516
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English (en)
Russian (ru)
Inventor
Vladimir Nikolaevich Hudoley
Original Assignee
Vladimir Nikolaevich Hudoley
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 Vladimir Nikolaevich Hudoley filed Critical Vladimir Nikolaevich Hudoley
Publication of WO2007040426A1 publication Critical patent/WO2007040426A1/fr

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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
    • A61K31/13—Amines
    • 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
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • the invention relates to medicine, specifically to pharmacology, and can be used as an antiviral agent for the treatment and prevention of influenza.
  • Influenza and acute respiratory viral infections take first place in the frequency and number of cases in the world, and make up 95% of all infectious diseases. Up to 500 million people fall ill every year in the world, 2 million of whom die. In Russia, annually from 27.3 to 41.2 million sick flu and other acute respiratory viral infections are recorded. During epidemics, the level of hospitalization increases by 2-5 times. A particularly high level of hospitalization in young children (under the age of 5 years), and in the elderly (over 65 years). Each influenza epidemic is accompanied by increased mortality. Influenza mortality rates in the world are 0.01-0.2%, and average annual losses reach tens of thousands of people across countries, including mainly children of the first years of life (up to 2 years) and elderly people (over 65 years). Influenza collects the largest victims among the elderly population suffering from chronic diseases (high-risk individuals).
  • remantadine in the conventional dosage form has a number of significant drawbacks that limit its use in high dosages for adults and preschool children: 1) the drug is active only against influenza A virus; 2) when taking the drug, side effects are recorded in relation to the central nervous system, liver and kidney cells, the gastrointestinal tract (most often in the elderly); 3) the rapid formation of resistant strains of the virus. In patients from whom the drug-resistant viruses were isolated, there was no clinical deterioration, but the disease lasted longer. In addition, the rapid removal of the drug from the body requires frequent administration to maintain the necessary therapeutic dose, which in turn leads to undesirable side effects.
  • Interferon - a protein produced in the body, has a wide range of antiviral activity, covering, including all known varieties of influenza.
  • interferon inducers - is iodantipyrine.
  • iodantipyrine for the treatment and prevention of tick-borne encephalitis induced in the experiment is known [2].
  • the use of iodantipyrine for the prevention of influenza and other acute respiratory viral infections has become possible due to the identification of its protective properties against influenza viruses and other acute respiratory viral infections [3].
  • side effects from the gastrointestinal tract and central nervous system observed during treatment iodantipyrine limit the possibility of its use for children and the elderly.
  • remantadine contains remantadine as the active substance and as target additives disaccharide, starch, talc, stearic acid and polyvinylpyrrolidone in the following ratio of components, May. %: remantadine 20-50; disaccharide - 30-70; starch - 5-20; talc - 0.3-3; stearic acid - 0.3-1; polyvinylpyrrolidone - 0.5-3 [4].
  • Known pharmaceutical composition containing remantadine from 7.0-33.0 may. % and no-shpu from 13.0 - 53.0 May. % [5].
  • the known preparation has side effects affecting the change in the acidity of the stomach, and its immunomodulatory properties are insufficient for a pronounced antiviral effect.
  • An object of the present invention is to provide a non-toxic drug devoid of side effects and having high antiviral activity.
  • the known antiviral agent containing rimantadine additionally contains iodine tipirin in the following ratio, May. %:
  • remantadine With this simultaneous use of drugs, the dose of remantadine was reduced, which significantly reduces the formation of resistant strains of the influenza virus and enhances the inhibition of the reproduction of influenza A and B viruses [7].
  • the combined use of remantadine and iodantipyrine provides a significant (not less than 4 times) increase in antiviral activity and reduces toxic effects compared with the separate use of these drugs.
  • the claimed ratio of iodantipirin and remantadine allows you to get a drug with high therapeutic activity that does not cause side effects in patients when it is taken. It was shown for the first time that the studied pharmacological composition in the proposed ratios exerts a pronounced antiviral effect in the treatment, prophylactic, therapeutic and prophylactic regimens of the experimental model of influenza infection. The authors did not find in the literature they analyzed information about the antiviral activity of the proposed pharmaceutical composition with the indicated ratio of the components. Empirically established new properties and possibilities of using the claimed funds. Thus, the proposed solution meets the criteria of the invention of "novelty”, “inventive step”, "industrial applicability”.
  • influenza virus was performed on 495 non-inbred mice weighing 22-25 g; in immunological studies, 160 non-inbred male mice were used, as well as 40 BALB / s mice weighing 18-20 g. Animals were kept on a normal diet in vivarium conditions. The experiments were performed using test viruses obtained from the State Virus Collection of the Museum of Strains of the Institute of Virology of the Russian Academy of Medical Sciences: influenza A virus (Aichi / 2/68), adapted for reproduction in lungs of mice with a titer of 5.0 Ig LD 5 o.
  • Example 1 of a specific experiment The effect of the individual components of the pharmaceutical composition of iodantipyrine and remantadine on the course of the flu in the experiment was investigated.
  • the animals were divided into groups receiving iodantipyrine at doses of 12.5, 25, 50, 100, 250 and 500 mg / kg and remantadine at doses of 25, 12.5, 6.25 and 3.0 mg / kg.
  • the control group consisted of untreated animals infected with the influenza virus.
  • the indicators of the effectiveness of the treatment were: a decrease in the mortality rate of mice compared to the control group during the period of maximum death, as well as an increase in the average duration of the incubation period.
  • mice treated with 4-iodantipyrine the maximum protective effect (survival rate of 33.3% of animals) was observed with therapeutic and prophylactic administration at a dose of 250 mg / kg (Table 1). A higher concentration (500 mg / kg) of 4-iodantipyrine did not enhance the protective effect. Concentrations of 4-iodantipyrine of 100 mg / kg or less did not provide reliable protection of animals from influenza infection compared with the control group. sing. Remantadine at a dose of 25 mg / kg showed survival only
  • the therapeutic and prophylactic effect of the combined use of doses of 4-iodo-antipyrine and remantadine was also investigated in a model of experimental influenza infection.
  • Animals of the experimental groups received combined treatment with iodantipyrine and remantadine in the following doses: 100 and 25 mg / kg; 50 and 12.5 mg / kg; 25 and 6.25 mg / kg; 12.5 and 3 mg / kg; 6 and 1.5 mg / kg; 3 and 0.75 mg / kg, respectively.
  • mice The presence of influenza virus in the lungs of mice was determined on the 1st, 3rd, 5th, 7th day from the moment of infection. For this purpose, lungs were taken from 5 mice and 10-11-day-old chicken embryos were infected with the prepared 20% suspension. Virus concentration was evaluated in Ig EIDso / 0.2 ml.
  • the blood serum of experimental mice was examined for the presence of interferon and antihemagglutinins.
  • Interferon activity U / ml was determined by titration of blood sera in a Z-929 cell culture versus 100 TCD 5 o / O, l ml of air force in accordance with generally accepted methods and the content of antihemagglutinins.
  • Serum interferon was detected in mice of the control group (infected with the virus), starting from the 1st day of the experiment, with a maximum content (80 U / ml) by the 3rd day, and from the 5th day of infection its content sharply decreased.
  • a similar pattern was observed with the separate administration of 4-iodo-antipyrine (100 mg / kg) and remantadine (25 mg / kg).
  • the introduction of the pharmaceutical composition (4-iodantipyrine at a dose of 100 mg / kg, remantadine at a dose of 25 mg / kg) contributed to a more stable production of interferon during the 7 days of the experiment, which can be a fairly good prognostic sign (Table 5).
  • inventive antiviral agent can be widely used as a pharmaceutical composition for the treatment and prevention of influenza.
  • an antiviral agent has a pronounced antiviral activity in therapeutic and prophylactic regimens.
  • the proposed tool is a pharmaceutical composition containing iodantipyrine and remantadine in the following ratios, May. %: iodantipyrine - 23 - 97, remantadine - 3 - 67, surpasses them in efficiency.
  • reducing the dose of remantadine can reduce the occurrence of side symptoms.
  • influenza virus in the lung tissue of mice treated separately and combined with 4-dodipyrine (100 mg / kg) and remantadine (25 mg / kg)

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (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

La présente invention relève du domaine de la médecine et plus particulièrement de la pharmacologie et peut être utilisée sous la forme d'un agent antiviral pour le traitement et la prévention de la grippe. Cette invention vise à produire un agent médicinal non toxique qui est dépourvu d'effets secondaires et qui présente une forte activité antivirale. Pour ce faire, cet agent antiviral contient également de 3 à 67 % en masse de rémantadine et de 23 à 97 % en masse de iodoantipyrine.
PCT/RU2006/000516 2005-10-05 2006-10-04 Agent antiviral WO2007040426A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
RU2005130751/15A RU2005130751A (ru) 2005-10-05 2005-10-05 Противовирусное средство
RU2005130751 2005-10-05

Publications (1)

Publication Number Publication Date
WO2007040426A1 true WO2007040426A1 (fr) 2007-04-12

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/RU2006/000516 WO2007040426A1 (fr) 2005-10-05 2006-10-04 Agent antiviral

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RU (1) RU2005130751A (fr)
WO (1) WO2007040426A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2305249A1 (fr) * 2008-06-17 2011-04-06 Vladimir Nikolaevich Hudoley Produit à effet stabilisant la membrane

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2175548C2 (ru) * 1998-04-20 2001-11-10 Товарищество с ограниченной ответственностью "Тисет" Средство для профилактики гриппа и других острых респираторных вирусных инфекций
RU2185822C2 (ru) * 2000-08-01 2002-07-27 Общество с ограниченной ответственностью "Фармаген" Препарат для лечения и профилактики вирусных заболеваний
RU2229877C1 (ru) * 2003-02-25 2004-06-10 ГУ Научно-исследовательский институт гриппа РАМН Средство для лечения гриппа
UA6474U (en) * 2004-08-26 2005-05-16 Valentyn Petrovych Liapin Method for medical rehabilitation of young wrestlers after recurrent anginas

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2175548C2 (ru) * 1998-04-20 2001-11-10 Товарищество с ограниченной ответственностью "Тисет" Средство для профилактики гриппа и других острых респираторных вирусных инфекций
RU2185822C2 (ru) * 2000-08-01 2002-07-27 Общество с ограниченной ответственностью "Фармаген" Препарат для лечения и профилактики вирусных заболеваний
RU2229877C1 (ru) * 2003-02-25 2004-06-10 ГУ Научно-исследовательский институт гриппа РАМН Средство для лечения гриппа
UA6474U (en) * 2004-08-26 2005-05-16 Valentyn Petrovych Liapin Method for medical rehabilitation of young wrestlers after recurrent anginas

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE MEDLINE [online] KOZELETSKAYA K.N. ET AL.: "Demonstration of influenza virus reproduction stages sensitive to remantadine", XP003011366, Database accession no. (7189620) *
VIROLOGIE, vol. 31, no. 1, January 1980 (1980-01-01) - March 1980 (1980-03-01) *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2305249A1 (fr) * 2008-06-17 2011-04-06 Vladimir Nikolaevich Hudoley Produit à effet stabilisant la membrane
EP2305249A4 (fr) * 2008-06-17 2011-11-23 Vladimir Nikolaevich Hudoley Produit à effet stabilisant la membrane

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Publication number Publication date
RU2005130751A (ru) 2007-04-10

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