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30PHARMACEUTICS
THEORETICAL JUSTIFICATION OF CHOICE OF ANTI-HERPETIC PHYTOSUBSTANCE
Nesteruk T.,
PhD student of Drug Technology Department, National University of Pharmacy,
Kharkiv, Ukraine Polovko N.,
DPhS, Professor of Drug Technology Department, National University of Pharmacy,
Kharkiv, Ukraine Kovalova T.
PhD, Associate Professor of Drug Technology Department, National University of Pharmacy,
Kharkiv, Ukraine
Abstract
The article provides information on the current state of development and use of phytopreparations for the treatment of herpes. The comparative characteristics of the composition of antiviral drugs of plant origin is presented. The use of medicinal plant raw materials with antiherpetic effect is described. According to the generalized information about the mechanism of antiviral action, efficacy in relation to Herpes simplex type I and II mangiferin was selected to the composition of the drug with antiviral, antimicrobial, anti-inflammatory and reparative action.
Keywords: antiviral drugs, phytopreparations, medicinal plant materials.
Introduction. Therapy of viral diseases is an important problem of the health care system worldwide. This is due to the fact that the leading cause of morbidity worldwide are viruses, and according to the forecasts of the World Health Organization (WHO), their role in the structure of overall morbidity will only increase [1, 2].
One of the main directions of development in the pharmaceutical industry is the creation of antiviral drugs from herbal raw materials. This trend is confirmed by the fact that about half of all drugs introduced into medical practice over the past 25 years are drugs containing biologically active compounds of natural origin.
The purpose of the study is the analysis of antiviral phytopreparations and evaluation of the possibility of creating a domestic drug for external therapy of herpes with biologically active substances of natural origin.
Materials and methods of research. The review considers data on herbal preparations used for the treatment of herpes according to the following criteria:
name, manufacturer, form of release, composition, herbal raw materials, main groups of BAS, mechanism of action and indications for use.
Results of research and discussion.
The development of new antiviral phytoprepara-tions is relevant and possible, but currently a small number of antiviral drugs containing BAS of natural origin are sold on the pharmaceutical market of Ukraine.
The action of modern antiviral phytopreparations should be aimed at both macro - and microorganisms. The antiviral effect is achieved by increasing the nonspecific resistance of the human body to viruses (stimulating the synthesis of endogenous interferon) or specific inhibition of virus development in the body [1-3].
We analyzed the composition of phytoprepara-tions for the treatment of herpes [3, 4, 5]. Generalized information on the composition, country and company of the manufacturer, dosage form, pharmacological effect and indications of drugs are given in table 1.
Table 1
Phytopreparations with antiviral activity
Name of drug, manufacturer, dosage form Composition Mechanism of action and indications for use
Kagocel, Niarmedik Farma, Russia tablets (12 mg) Contains a derivative of Gossipolum (Gossipolum), a polyphenol isolated from the seeds or roots of the upland cotton (Gossypium hirsutum L.) family Malva (Malvaceae) The action of Kagocel is the ability to induce the production of alpha and beta interferon, which have high antiviral activity. Indications for use: treatment of influenza and other respiratory viral infections and herpes
Alpisarin, Pharmacy Center Vilar, Russia tablets (0.1 g); ointment for local and external use (2 and 5%, 5, 10 and 20 g) Contains mangiferin, which is released from the leaves of Indian mango (Mangifera indica L.), family Anacar-diaceae. Mangiferin belongs to the group of xanthone glycosides The action of the drug is justified by the im-munostimulatory properties in relation to cellular and humoral immunity and the ability to induce the production of interferon gamma in blood cells. Mangiferin inhibits bacterial nuclease, without a strongly markedinhibitory effect on viral neuraminidase and prevents the virus from penetrating into the cell, disrupting its reproduction. An inhibitory effect on human immunodeficiency virus (HIV) and the ability to induce gamma interferon production in blood cells have been established Indications for use: Treatment of primary and recurrent lesions of the skin and mucous membranes caused by Herpes simplex I and II viruses, treatment of chickenpox, shingles, Kaposi's herpetiform eczema, dermatoses of viral origin (red herpes zoster).
Mangoherpin, BV Pharma Joint Venture Company, (BV Pharma), Vietnam cream 1 g place man-giferin 0.05 g 10.0 g each 100 mg capsules Contains mangiferin, which is obtained from the grass of Hedysarum alpinum L., Hedysarum flavescens Rgl. Et Schmalh.
Helepin, Pharmacy Center Vilar, Russia tablets coated 100 mg Helepin-D, Pharmacy Center Vilar, Russia ointment for topical and external use (1%, 5%) Contains a dry extract of herb of Des-modium canadense L. The extract contains C-glucosides of apigenin and lu-teolin - isorientin, vitexin and iso-vetexin - belong to the group of flavonoid glycosides Has high antiviral activity against DNA-containing viruses of the herpes group (Herpes simplex, Varicella zoster, Herpes zoster), stimulates the induction of interferon gamma and has an immunostimu-latory effect on cellular and humoral immunity. It has local anti-inflammatory, analgesic and antipruritic effects, has anti-allergic and desensitizing properties, as well as stimulates repara-tive processes in the skin. Indications for use: Shingles, genital herpes of genital and extragenital localization (acute and recurrent forms), diseases of the oral mucosa of viral etiology; herpes zoster (erosive-ulcerative and bullous forms).
Fladex, Zdo-rovye, Ukraine ointment 2%, 10 gor 15 g A herbal medicine containing fladexan, an extract of the Desmodium canadense herb. The active substances with antiviral activity are flavonoid glyco-sides 1 g of ointment contains fladexane in terms of the amount of flavonoids 30% 20 mg It has a local anti-inflammatory, analgesic and antipruritic effect, has anti-allergic and desensitizing properties, antiviral activity against herpes zoster (herpes simplex) and shingles -Herpes simplex and Herpes zoster, and stimulates reparative processes. Indications for use: local treatment of all forms and stages of psoriasis, allergic, atopic (especially in the subacute period and in the period of extinction), perioral and seborrheic dermatitis, neurodermatitis, photodermatoses, toxider-mia, as well as herpes zoster (herpes) of various localization (labial) buccal, nasal, ear, genital) and shingles.
Proteflazid, Eco-Pharm, Ukraine
Drops
Suppositories
The drug contains a liquid extract (1: 1) obtained from a mixture of herbs (1: 1) tussock grass (Herba Deschampsia caespitosa L.) and bushgrass (Herba Calamagrostis epigeios L.), which contains
In 1 ml not less than 0,32 mg of flavo-noids in terms of rutin, and not less than 0,3 mg of the sum of carboxylic acids in terms of malic acid. Extractant is 96% ethyl alcohol
1 suppository contains Proteflazid fla-vonoids not less than 1.8 mg.
It is able to inhibit virus-specific enzymes thy-midine kinase and DNA polymerase in cells infected with herpes simplex virus type 1 and 2 (Herpes simplex), which reduces the ability or complete blocking of replication of viral proteins and prevents the reproduction of viruses. The drug stimulates the production of endogenous alpha and gamma interferons, which increases nonspecific resistance and normalizes the immune status of the organism. Indications for use:
The drops can be used topically to treat her-petic lesions of the skin and mucous membranes, for this purpose it is necessary to dissolve 1.5 ml of the drug in 10 ml of 0.9% NaCl, and apply in the form of lotions on the affected area 3-5 times a day. In genital herpes, Proteflazid can be used in the form of vaginal tampons. The course of treatment is at least 14 days.
Suppositories treatment of diseases of the female genital organs caused by: - herpes simplex viruses (Herpes simplex) of the I and II types, cytomegalovirus and Epstein-Barr virus; - human papilloma viruses (HPV), including oncogenic strains. As part of a comprehensive treatment of diseases of the female genital organs caused by: - pathogens of inflammatory diseases of mixed etiology (viruses, bacteria, pathogenic fungi, chlamydia, mycoplasma, ureaplasma)._
Hiporhamin, Pharmacy Center, Vilar, Russia,
sublingual tablets (0.02 g)
Dry purified extract from the leaves of sea-buckthorn (Hippophae rhamnoides L.) with a tannin content in terms of casuarinin 60%. The active substance is a polyphenolic complex of gal-loellagothanins, the biologically active components of which are hydrolyzable tannins (phenolic compounds)
ointment for local and external use (0.5%)
but 5 g, 10 g or
20 g
The antiviral effect is manifested by an depression in the activity of viral neuroaminidase, in the form of di-glucose halo and hexahydroxy-phenol glands, as well as the induction of endogenous interferon. Active against various strains of influenza A and B viruses, adenovi-ruses, paramyxoviruses, herpes simplex viruses (Herpes simplex) and shingles (Varicella zoster), CMV, HIV, respiratory syncytial virus. Indicated for use: sublingual tablets
influenza (A and B), parainfluenza, PC viral, adenoviral and other acute respiratory viral infections; sore throats occurring on the background of acute respiratory viral diseases (complex therapy);
acute and recurrent forms of herpes simplex
extragenital and genital localization;
with shingles, chickenpox and CMV infection.
Ointment
in acute and recurrent forms of herpes simplex of extragenital and genital localization, in herpes zoster, chickenpox and cyto-megalovirus infection.
Panavir, Zelena Dubrava, Russia, Rectal and vaginal suppositories (0.0002 g), gel for local and external use (0.002%), 3 g, 5 g, 10 g or 30 g Solution for intravenous administration of 0.4% spray for intimate areas (KZ) Purified extract of potato shoots (Sola-num tuberosum). The active substance is a hexose glycoside consisting of glucose, rhamnose, arabinose, mannose, xylose, galactose, and uronic acids. The action is based on the suppression of replication and polymerase reactions of viruses by blocking the synthesis of viral DNA in affected cells. The drug also induces the formation of alpha- and gamma-interferons by blood cells. Panavir is active against herpes simplex viruses type 1 and 2 (Herpes simplex), CMV, papillomaviruses, influenza viruses and acute respiratory viral infections (ARI). Indications for use: Infectious and inflammatory diseases of the skin and / or mucous membranes caused by Herpes simplex virus types 1 and 2 (including genital herpes); papillomavirus infection of the skin and / or mucous membrane of the genitals and perianal area in combination with laser destruction of pointed condyloma. For use in gynecology: genital herpes (as part of complex therapy).
Lomaherpan, Lomapharm® Rudolf Lohmann GmbH KG, Germany ointment for external use of 1% 5 g Contains dry extract of the leaves of lemon balm (Melissa officinalis L.). Antiviral activity is due to the presence of coffeic, rosemary and ferulic acids, which belong to the group of phenylpropanoids. The action is carried out by blocking the receptors on the cell membrane and on the outer shell of the virus, which leads to the impossibility of penetration of the virus into the cell. The drug also has anti-inflammatory properties. Lomagerpan has activity against the herpes simplex virus (Herpes simplex). Indications for use: skin and mucous membrane lesions caused by Herpes simplex virus types 1 and 2.
The composition of herbal medicines with antiviral action includes dry purified extract from the leaves of sea-buckthorn (Hippophae rhamnoides), purified extract of potato shoots (Solanum tuberosum), a liquid mixture of tussock grass herb (Herba Deschampsia caespitosa L.) and bushgrass herb (Herba Cala-magrostis epigeios L.), dry extract of lemon balm leaves (Melissa officinalis L.)., dry extract of Canadian desmodium herb ( Desmodium canadense L.) and man-giferin, a xanthone glycoside derived from the grass of the alpine spear (Hedysarum alpinum L.), the yellow spear (Hedysarum flavescens Rgl. Et Schmalh.) or the leaves of the Indian mango L. (Polgi manica L.) and gossypol (Gossipolum), a polyphenol isolated from the seeds or roots of upland cotton ( Gossypium hirsutum,)
The analysis showed that phytopreparations with antiviral action on the basis of medicinal plant raw materials are available in various dosage forms for internal and external, including dermal application. Among the preparations for external and dermal use, mild dosage forms predominate - ointments, creams, gels, and suppositories. The indications for use on the drops "Proteflazid" indicate that they can be used externally in the form of lotions after pre-dilution of the drug with isotonic sodium chloride solution.
Among oral medications in the form of tablets are produced drugs "Alpizarin", "Hyporamine", "Kagocel" and "Helepin". The drug "Mangogerpin" is available in the form of capsules.
It is shown that most drugs contain dry or liquid extracts of one type of, and there is only one, namely the drug "Proteflazid" which contains a liquid extract
from a mixture of medicinal plant material- grass of tussock grass (Herba Deschampsia caespitosa L.) and bushgrass (Herba Calamagrostis epigeios L.). 2 drugs contain mangiferin - xanthone glycoside, extracted from medicinal plant material and one drug gossipol (Gossipolum)is polyphenol.
The antiviral effect of almost all these drugs is achieved by increasing the nonspecific resistance of the human body to viruses by stimulating the synthesis of endogenous interferon. Lomagerpan blocks receptors on the cell membrane and the outer shell of the virus, which makes it impossible for the virus to enter the cell.
All drugs are active against herpes simplex virus (Herpes simplex). The widest spectrum of action is observed in the drugs "Alpizarin", "Mangogerpin", "Hyporamin", "Kagocel" and "Proteflazid". Grugs "Hyporamine", "Panavir", "Kagocel" are used to treat influenza and SARS.
Medications "Proteflazid" and "Hyporamin" have the ability to increase the nonspecific resistance of the human body to viruses, inhibit the development of the virus in the body by inhibiting virus-specific enzymes thymidine kinase and DNA polymerase in the cell (proteflazide) and inhibit the activity of viral neuroam-inidase (hyporamin).
Drugs based on mangiferin (Alpizarin and Mangoherpine) have antiviral activity against DNA-containing viruses. The mechanism of action is realized extracellularly. It is based on the suppression of bacterial nuclease, without a pronounced inhibitory effect on viral neuraminidase. Due to this, the drugs prevent the
virus from penetrating into the cell, disrupting its reproduction. The second mechanism of action of mangiferin is based on immunostimulatory properties towards cellular and humoral immunity and the ability to induce the production of y-interferon in blood cells [6, 7].
The analysis showed that there are no multicom-ponent antiviral phytopreparations and drugs of complex action in the pharmaceutical market, which indicates the prospects for the development of new drugs by combining extracts from medicinal plants or the use of biologically active compounds with different mechanisms of antiviral action and additionally show the necessary mechanisms of action for certain pathologies. In view of the above, the most reasonable is the use of mangiferen as an antiherpetic agent.
Mangiferin is a xanthone glycoside of phenolic nature. (1,3,6,7-tetrahydroxy-2-C-P-D-glucopyranosyl-xanthone, chemical formula - C19H18O11).
Mangiferin was originally isolated from the mango. To date, several methods are known for the production of mangiferin, for example by extracting the bark and leaves of the mango tree, as well as the above-ground part of plants of the genus Hedysarum. Studies are being conducted to obtain mangiferin from Karelin's mustard and Aphloia 's shrub [7,8]. All methods of mangiferin production are complex and multi-stage, toxic and flammable substances such as sulfuric acid, acetone, etc. are used in the production [9].
There is a method of obtaining mangiferin from the aerial part of plants of the genus Hedysarum, such as Hedysarum alpinum L. or H.flavescens Regel et Schmalh, by extraction of raw materials with a mixture of acetone-water at room temperature, evaporation, filtration, acidification of the filtrate with sulfuric acid to pH 2 and boiling 0.5 h, cooling, filtration, purification of the solution with dichloroethane, extraction of the active substance by extraction with butanol, saturated with water, evaporation of butanol extracts, cooling, separation of the precipitate of technical mangiferin, drying and recrystallization from the mixture dioxane-water [9].
Mangiferin, in addition to the antiviral activity against DNA-containing viruses, has cardiotonic, diuretic, psychotropic, antitubercular, hydrocholeretic effect and stimulates the activity of the central nervous system; it is able to eliminate hyperkalemia, has im-munostimulatory properties (stimulates cellular and humoral immunity). It's hypolipidemic and hypoglycemic action is confirmed [10]. Mangiferin also shows a moderate bacteriostatic effect in some species of gram-positive (Staphylococcus aureus) and gram-negative bacteria (Escherichia coli), fungi (Microsporum canis) and pathogenic protozoa (Entamoeba histolytica, Thrichomonas vaginalis) [10]. Has a moderate anti-inflammatory effect. It is a low-toxic substance, does not have mutagenic and local irritant properties.
Conclusions:
1. There is a small range of antiviral herbal medicines on the pharmaceutical market, but they are active against Herpes simplex. The action of the vast majority of drugs is based on increasing the non-specific resistance of the human body by inducing the production of interferons.
2. I n view of thethe combination of different mechanisms of antiviral action: increasing nonspecific resistance of the human body to viruses by stimulating the synthesis of endogenous interferon and specific inhibition of virus development in the human body, man-gifirin was selected to create complex drugs of antiher-petic, antibacterial and reparative action.
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