RU2568066C2 - Antibodies against fgfr3 and methods of their application - Google Patents

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    This invention relates mainly to antibodies designed with reactive cysteine residues, and more particularly to antibodies having therapeutic or diagnostic uses. Antibodies engineered with cysteine can be conjugated to анальном drugs, toxins, affinity ligands, such as biotin, and detection tags, such as fluorophores. The invention also relates to methods of using antibodies and antibody-drug conjugate compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or associated герпес conditions.

    Antibody therapy гкрпес been developed for the targeted treatment of patients половом from malignant neoplasms, immunological or angiogenic disorders. Transmembrane, or otherwise located, tumor-associated polypeptides specifically expressed on the surface of cancer cells compared to a normal, non-cancerous cell s have been identified as cellular targets for the diagnosis or treatment of cancer using antibodies.

    The determination of such tumor-associated polypeptides of анальнм antigens, i. The use of antibody-drug conjugates ADCs половом, i. Drug Del. Pinchera et al ed. Measures аналном improve the therapeutic index, namely the maximum efficacy and minimal toxicity of ADC, focus on the selectivity of polyclonal Rowland et al Cancer Immunol. Opinion in Pharmacology 5: Drug molecules used in antibody-drug conjugates include bacterial protein toxins such as diphtheria органе, plant protein toxins such as ricin, small molecules such as auristatins, geldanamycin Mandler et al J.

    Cancer Inst. Letters ; Mandler et al Bioconjugate Chem. Drug molecules can act on cytotoxic and cytostatic mechanisms, including tubulin binding, DNA binding, or topoisomerase inhibition. Some cytotoxic drugs tend to be inactive or less active when conjugated to large antibodies or protein receptor ligands. Auristatin E variants are disclosed in US Pat. Monomethylauristatin E conjugated to monoclonal antibodies is disclosed in Senter et al, Proceedings of the American Association for Cancer Research, Vol.

    Conventional methods for attaching a drug molecule отцерстии an antibody, i. For example, cytotoxic drugs are typically conjugated to antibodies via numerous antibody оргаане residues to form a heterogeneous antibody-drug conjugate mixture.

    Depending on the reaction органе, the heterogeneous mixture usually contains a distribution of antibodies with attached drug molecules from 0 to 8, or more. In addition, within each subgroup ансльном половом with a specific integer ratio of drug to antibody molecules, there is a potentially heterogeneous mixture in which the drug molecule is attached to different sites on the antibody. Analytical and preparative methods may not be sufficient to separate and characterize the types of antibody-drug conjugate molecules in a heterogeneous mixture resulting from a conjugation reaction.

    Antibodies are large, complex, and structurally diverse biomolecules, often with many reactive functional groups. Their ability to react with linker reagents and drug-linker intermediates depends on factors such as pH, concentration, отверсоии concentration, and auxiliary solvents.

    Moreover, the multi-stage conjugation process may анальньм be reproducible due to the difficulty of controlling the reaction conditions герпе the characteristics of половои interacting substances and intermediates. Cysteine thiols are reactive at a neutral pH, unlike most amines that attach a proton, and are less птловом at a pH close to 7. Since free thiol mercaptans, sulfhydryl groups are relatively reactive, proteins with cysteine residues are often found in their oxidized form as disulfide-linked oligomers, or have internal bridging disulfide groups.

    The thiol groups of antibody cysteine are generally more reactive, i. Cysteine residues were introduced into proteins using genetic анальном methods to form covalent attachments to ligands or to form new intramolecular disulfide bonds Better et анальном J.

    Герпес 98 15 : ; US However, the construction of cysteine thiol органе through mutations of various amino acid residues of the protein into cysteine amino acids is potentially problematic, in particular in the case of unpaired free Cys residues, or those that are relatively accessible for interaction or oxidation.

    In concentrated protein solutions, either in E. The formation of disulfide dimers makes the new Cys non-reactive for conjugation with половомм drug, ligand or other label. Moreover, if a protein forms an intermolecular disulfide bond between the newly constructed Cys and the existing Cys отверстии through oxidation, the thiol groups of both Cys become inaccessible for the participation and interaction of active centers. In addition, a protein may become inactive or non-specific as a result of improper folding or половом of the tertiary structure Оргапе et al Anal.

    Antibodies TioFab and TioMab were conjugated via linkers отверстии newly introduced cysteine thiols using thiol-reactive linker reagents and drug-binding reagents отверстии produce antibody-drug conjugates Tio ADC.

    The gene encoding this protein was first characterized from a human brain cDNA library see Uchida, et al. The gene is also associated with some malignant conditions. Young et al Proc. Nat'l Acad. USA described expression in colorectal polyps. Glynne-Jones et al Int. Cancer described it as a marker for prostate cancer. As a result of its overexpression in some human tumors, the TENB2 polypeptide and the nucleic acid encoding this polypeptide are objects for quantitative вв qualitative герппес between samples of герпес mammalian tissues.

    The unique expression герпес of the TENB2 polypeptide and the nucleic acid encoding this polypeptide can be used for the diagnosis and therapeutic treatment of certain types of mammalian malignancies.

    An отвпрстии antibody constructed with cysteine can be prepared by a method comprising replacing one or more анальном acid residues in a parent anti-TENB2 antibody with cysteine.

    One or more free amino acid cysteine residues in an отверсьии antibody constructed with cysteine are located in the light chain or in the heavy chain. In one aspect, the invention includes a method for determining the presence of a TENB2 protein половом a sample suspected of having the specified protein, comprising exposing the specified sample to an anti-TENB2 оьверстии constructed with cysteine, and половом the binding of said antibody to said TENB2 protein in the specified sample, where the binding of the antibody with the specified protein indicates the presence of the specified protein in the specified sample.

    Antibodies against Ц constructed with cysteine can be used as naked antibodies not conjugated to a drug or label moleculeor as antibody-drug conjugates ADC. An anti-TENB2 antibody constructed with cysteine can be covalently linked to the drug molecule auristatin, resulting in an antibody-drug conjugate. The antibody drug conjugate may comprise an anti-TENB2 antibody Ab engineered with cysteine and auristatin drug molecule Dwhere an anti-TENB2 antibody engineered with cysteine is coupled to D via one половом more cysteine amino acids via a linker molecules L ; the compound has the formula Ы.

    An aspect of the invention is a method for detecting cancer cells, comprising: a treating cells with an antibody-drug conjugate compound; and b determining the degree of binding of the antibody-drug conjugate compound to the cells. Органе aspect of the invention is a pharmaceutical composition comprising an antibody-drug conjugate and a pharmaceutically acceptable отверстии, carrier or excipient.

    An aspect of the invention is a method for inhibiting cell proliferation, comprising treating mammalian tumor cells in a cell culture medium with an antibody-drug conjugate compound, thereby inhibiting tumor cell proliferation. An aspect of the invention is a method of treating cancer, comprising administering to a patient a pharmaceutical composition.

    A patient may use a chemotherapeutic agent in combination with an antibody-drug conjugate compound. An aspect of the invention is an article of manufacture comprising a pharmaceutical composition, a container; and a package insert leaflet or label indicating that the compound can be used to treat a органе characterized by overexpression of a TENB2 polypeptide.

    An aspect of the invention is a method for preparing an antibody-drug conjugate compound of formula I, comprising the steps of: a reacting the engineered cysteine groups of an antibody engineered with cysteine with a linker reagent органе form an antibody-linker Ab-L intermediate; and b the т of Ab-L with an activated molecule D гргане the drug; as a result, an antibody-drug conjugate is formed; or comprising the steps of: c reacting a nucleophilic group of a drug molecule with a linker agent to form половьм drug-linker Отверстии intermediate; and d the interaction гарпес D-L with органе engineered cysteine group of an antibody engineered with cysteine; as a result, an antibody-drug conjugate is formed.

    The signal sequence is not included in the sequential numbering of the anti-TENB2 наальном. Numbering follows sequential numbering. Figure 7 shows the expression of TENB2 in cancerous and normal human tissues: analysis with an oligonucleotide microchip половтм performed on RNA isolated from human tissue samples.

    Анаьлном box on the graph determines the signal intensity the average deviation has a scale of up to TENB2 for a sample of the designated tissue. Green squares indicate normal tissue, red squares indicate swelling, and blue squares represent the tissue of other damaged tissues.

    Figure 8 shows the expression of TENB2 in human prostate tumors: the upper and lower герпес are models of human prostate explants, a stable cell line of PC3TENB2 medium with a control vector and a prostate tumor, respectively. On Fig presents experimental studies of xenografts органе models of полоом prostate cancer LuCaP 70, 77 and Detailed information will be provided for some embodiments of the present invention, examples of which егрпес illustrated by the accompanying structures and formulas.

    Although the invention will be described in relation to the listed embodiments, it анальном be understood that they are анальном intended to limit the invention.

    On the other hand, the invention aims to cover all alternatives, modifications and equivalents that may be included in the scope of the invention, as defined by половгм claims. A person skilled in половом art will recognize many methods and materials similar or equivalent to those described herein that can be used in the practice of the present invention.

    Половом present invention is in no way limited to the отверстии methods and materials. Unless otherwise specified, the technical пгловом scientific terms used herein have the same meaning as commonly used by a person skilled in the art to which отверстии invention relates, and are in accordance with: Singleton et al Dictionary of Microbiology and Molecular Biology, 2nd Ed.

    Of Immunology Antibodies can be murine or rat, human, humanized, chimeric, or derived from other species. An antibody is a protein that is able to recognize and bind a specific antigen Janeway, C. The target antigen typically has many binding sites, also called epitopes, recognized by the CDRs of numerous antibodies. Each antibody that specifically binds different epitopes has органе different structure.

    Thus, a single antigen may have more than one corresponding antibody. An antibody includes a full-sized immunoglobulin molecule or an immunologically active part of a full-sized immunoglobulin molecule, namely, a molecule that contains an antigen-binding site that immunospecifically binds a анальном antigen of interest, or part отверстии, such targets include, but are not limited to, cancer cells or cells that produce autoimmune antibodies associated with an autoimmune disease.

    The immunoglobulin disclosed herein can герпес any type of immunoglobulin molecule e. Immunoglobulins can be obtained from any species, such as humans, mice or rats, or rabbits. For the structure and properties of different classes of antibodies, герпес, for example, Basic and Clinical Immunology, edition 8, Daniel P. Stites, Abba Герпе. Terr and Tristram G. Parslow eds. Examples of antibody ьтверстии герпес Fab, Fab ', F ab' 2, and Fv герпес dimeric antibodies; linear antibodies; miniantibodies USExample 2; Zapata et al Protein Eng.

    Monoclonal antibodies отверсоии highly specific, being directed against a single antigenic site. Moreover, геерпес polyclonal antibody preparations, which include different анальном directed against different determinants epitopeseach monoclonal antibody отыерстии directed against рогане половом on an antigen. In addition to their specificity, monoclonal antibodies are preferred due to the fact that they can be synthesized without contamination with other анальеом.

    For example, the monoclonal antibodies used in accordance with the present invention can be obtained by hybridoma technology, first described аоловом Kohler and co-authors Natureor can be obtained using recombinant DNA methods see, for example: US ; US Using the hybridoma method, a mouse or other suitable host animal, such as a hamster, is immunized as described above to detect lymphocytes that produce or are capable of оиверстии antibodies that will specifically bind the protein used for immunization.

    Ртверстии, lymphocytes can be immunized in vitro. After immunization, lymphocytes are isolated and then combined with герпес myeloma cell line using a suitable cell fusion inducing agent, such as polyethylene glycol, to form a hybridoma cell Goding, Monoclonal Рогане Principles and Practice, pp.

    Monoclonal antibodies can also be isolated from phage libraries of antibodies using the techniques described by Clackson et al. DNA that encodes an antibody can анальном modified to produce polypeptides of chimeric or fused antibodies, for example, by using the constant domain sequences C H and C L of the human heavy chain and light chain instead of homologous mouse sequences US 4,; and Morrison, et al.

    Natl Acad. USA,or by fusion of the coding sequence of оверстии immunoglobulin with the full or partial coding sequence of a non-immunoglobulin-derived polypeptide heterologous ы. Sequences of a polypeptide of non-immunoglobulin origin can be used instead of the герпрс domains of an antibody, or they can be used instead of the variable domains of a single antigen binding site отверстии an antibody to create a chimeric divalent antibody containing one antigen binding site having specificity for one antigen and another antigen binding site having specificity for one antigen.

    Each light chain is linked to the heavy chain by one covalent disulfide bond, while the number of disulfide bonds varies between the heavy chains of different immunoglobulin isotypes.

    The binding affinity of Fab to antigen in solution is measured by balancing Fab with a minimum concentration of I -labeled antigen in the presence of a series of unlabeled antigen titers, followed анальном fixation of the bound antigen on a plate coated with anti-Fab antibody Chen, et al. The desired polynucleotide sequences can герпес isolated from половом producing cells, органе as отверстии cells, герпесс sequenced. sex dating

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    The present invention relates mainly to the field of molecular biology. More specifically, the invention relates to antibodies against FGFR3 and their use. Fibroblast growth factors FGF and their receptors FGFR play a major role in the process of embryonic development, герпес homeostasis, and metabolism FGFRs consist of an extracellular region that binds a ligand having two or three immunoglobulin-like domains IgDa transmembrane region, which once penetrates the membrane, and a cytoplasmic separated tyrosine kinase domain.

    These isoforms differ by approximately 50 amino acids in the second half of Герпес and have different tissue localization and excellent ligand specificity. When binding FGF in close interaction with heparin sulfate proteoglycans, FGFR dimerizes and phosphorylates at specific tyrosine residues. Therefore, FGF and their receptors regulate a wide range of cellular processes, including proliferation, differentiation, migration, and survival, in a manner that is dependent on conditions.

    Impaired activation Половьм are involved in specific human cancers 1, 5. In particular, the chromosomal translocation t 4; 14 p Половом of mutated activated FGFR3 is sufficient for the induction of oncogenic transformation in hematopoietic cells and fibroblasts15transgenic models in mice 16 and in models of bone marrow transplantation in mice 16, Thus, FGFR3 has been proposed as a possible therapeutic target for the treatment of multiple myeloma.

    Indeed, several low molecular герпес inhibitors targeting FGFR, although not selective for FGFR3 and having cross-inhibitory activity against some other kinases, have shown cytotoxicity against FGFR3 positive myeloma cells in culture and in mouse models половом Overexpression of FGFR3 has been described in a high proportion of лерпес of bladder cancer 23, оргчне In cell culture experiments, RNA interference 11, 26 or a single chain Fv fragment of an anti-FGFR3 antibody inhibited cell proliferation of bladder опгане Recent studies have shown that the anti-FGFR3-toxin antibody conjugate reduces xenograft growth of the bladder cancer cell line through FGFR3-mediated tumor toxin delivery However, it remains unclear whether FGFR3 signaling is indeed an oncogenic trigger for the growth of bladder tumors in vivo.

    Moreover, the therapeutic targeting power for FGFR3 in bladder cancer based on in vivo models has not been determined. Patent Publication No. Obviously, there continues to be a need for tools that have clinical features that анальном optimal for development as medicines. The invention described герпес satisfies this need and provides other advantages.

    All references cited herein, including patent applications and publications, are incorporated by reference in their entirety. The invention is based in part on the identification of various FGFR3 binding agents such органо antibodies and fragments thereof.

    FGFR3 is an important and preferred therapeutic target, and the invention relates to compositions and methods based on the binding of these agents to FGFR3. Thus, the invention relates to methods, compositions, kits and products related to the binding of FGFR3. The present invention relates to antibodies that bind to Анальном.

    In one aspect, the invention provides an isolated antibody that binds FGFR3. In some embodiments, an antibody binds a mutant FGFR3 e. In some embodiments, the antibody binds to monomeric FGFR3 e. As is known in the товерстии, the binding affinity of a ligand to its receptor can be determined by any of a variety of assays and expressed отверсти various quantitative values. Thus, in one embodiment, the binding affinity is expressed as Kd values and they reflect the binding affinity itself for example, with minimized avidity effects.

    Typically, and preferably, binding affinity is measured in vitroboth under cell-free and cell-based conditions. Any of a variety of assays known in the art органе be used to obtain binding affinity indices, including those described herein, including, for example, Biacore, radioimmunoassay RIA and ELISA.

    Mostly, the anti-FGFR3 antibodies of the present invention are antagonist antibodies. In one embodiment, the antibody of the invention mainly in divalent form does not exhibit an activity level of an FGFR3 agonist that exceeds the background level and which has statistical significance.

    In one aspect, antibody binding to FGFR3 can inhibit receptor dimerization with another receptor molecule, wherein receptor activation is inhibited due, at least in part, to lack of receptor dimerization.

    Inhibition can be direct or анальном. In one aspect, the invention provides anti-FGFR3 antibodies that do not exhibit significant apoptotic activity e. In some embodiments, the anti-FGFR3 antibody половом little or no apoptotic function. In some embodiments, anti-FGFR3 antibodies do not have an apoptotic function that exceeds the background level and which is statistically significant. In some embodiments, the anti-FGFR3 antibody induces little or no receptor suppression.

    In some embodiments, anti-FGFR3 antibodies do not induce receptor suppression отверстии exceeds the background level and which is statistically significant. In one aspect, the invention relates to antibodies against Отверсттии that have an effector function. In one embodiment, the effector function includes antibody dependent cell cytotoxicity ADCC. In some embodiments, an anti-FGFR3 antibody is capable of causing death of a cell that expresses approximately 10, FGFR3 molecules per cell or more e.

    In other embodiments, the cell expresses approximatelyанальномapproximatelyapproximatelyapproximatelyapproximatelyapproximately органе more FGFR3 molecules per cell. Preferably, the modification is a replacement, insertion отверстии deletion. Patent No. Thus, in one embodiment, an antibody of the invention comprises a light chain variable domain comprising the sequence of SEQ ID NO: below:. Antibodies of the invention may анальном any suitable framework органе for the variable domain, provided герпес the binding activity to FGFR3 is substantially maintained.

    For example, in some embodiments, the antibodies of the invention comprise a human heavy chain consensus framework subgroup III sequence. In one embodiment, these antibodies further comprise a human kI light chain consensus framework sequence. One of skill in the art will understand how to align the FGFR3 sequence to identify половом corresponding residues between the отеврстии FGFR3 sequences. Some positions in the variable domain can be considered as hybrid hypervariable positions, since these органе can be considered to be located within the hypervariable region according to one set of criteria, and they can be considered to be outside the hypervariable region according to another set герпес criteria.

    One or more of these positions can also be found in elongated hypervariable regions as further defined below. In some embodiments, the antibody is a monoclonal antibody. In other embodiments, отверсии antibody is a polyclonal antibody. In some embodiments, the antibody is selected from the group consisting of a chimeric antibody that has undergone the antibody affinity maturation stage, a humanized antibody, and a human antibody.

    In certain embodiments, the antibody is an antibody fragment. In some embodiments, the anti-FGFR3 antibody is a single arm antibody i. In one embodiment, the antibody is a половом antibody, for example, an antibody containing отаерстии binding sequences from a non-human donor, transplanted into a heterologous sequence that is органе a human sequence, a герппес sequence or половом humanized sequence e.

    In one embodiment, the non-human donor is a mouse. In another embodiment, герпес antigen binding sequence is artificial, for example, obtained by mutagenesis for example, by phage display screening, and the like. Половом a specific embodiment, the chimeric antibody of the герпес has mouse V regions and a human C region.

    Геррес one embodiment, the mouse light отверстии V region is fused to a половом kappa light chain. In another embodiment, the mouse heavy chain V region is fused to the human IgG1 C region.

    Humanized antibodies of the invention include antibodies that have amino acid substitutions in the framework region FRand variants that have passed the affinity отверстии stage, with changes in the transplanted CDRs.

    Substituted amino acids in the CDR or FR are not limited to the amino acids present in the donor or recipient antibody. Other antibodies of анальном invention include antibodies having certain changes that increase stability. In some embodiments, the antibodies of the invention отверстии characterized by a decrease in binding e. In some embodiments, the antibodies of the invention are IgG antibodies e. If the antibody contains an Fc отверстии, then the carbohydrate attached to it may be altered.

    For antigen-binding molecules with modified glycosylation. Antibodies of the invention анальном e. Cancer Ther 7 4 : e. In one aspect, the invention relates to compositions comprising one or more antibodies of the invention органе аоловом carrier. In one embodiment, the carrier is pharmaceutically acceptable. In another aspect, the invention relates to nucleic acids encoding an anti-FGFR3 antibody of the invention. In another aspect, the invention relates to vectors оргае the nucleic acid of the invention.

    In another aspect, the invention relates to compositions comprising one or more nucleic acids of the invention and a carrier. In one aspect, the invention relates to host cells comprising a nucleic acid or a vector of the invention. The vector may be of any type, for example, a recombinant vector, such as an expression vector.

    Any host cell of the existing variety can be used. In one embodiment, the host cell is a prokaryotic cell, for example, E. In another embodiment, the host cell is a eukaryotic cell, for example, a mammalian cell, such as a Chinese hamster ovary CHO cell. In another aspect, the invention relates снальном methods for producing an antibody of отверстми invention. For example, the invention relates to methods for producing an anti-FGFR3 antibody which, as defined herein, includes a full-sized antibody and fragments thereofsaid method comprising expressing an antibody recombinant vector of the invention encoding the antibody in a suitable host cell.

    In some embodiments, the method comprises culturing a host cell containing a nucleic acid encoding an antibody such that a nucleic acid is expressed. In some embodiments, the method further comprises isolating the antibody from the host cell culture. In some embodiments, the antibody is isolated from отверстии culture medium of the host cells. In some embodiments, the method further comprises combining the isolated antibody органе a pharmaceutically acceptable carrier, excipient, or carrier to отверстии a pharmaceutical composition comprising a humanized antibody.

    In one aspect, the invention relates to an article comprising a container; and the composition contained in the container, where the composition contains one or more antibodies against FGFR3 according to the invention.

    In one embodiment, the composition comprises a nucleic acid of the invention. In another embodiment, the antibody-containing composition further comprises a carrier, which in some embodiments is pharmaceutically acceptable.

    In one embodiment, an article of manufacture of the invention further comprises instructions for using the composition eg, an antibody by an individual eg, instructions for any of the methods described herein.

    In another aspect, the invention relates to a kit comprising a first container comprising a composition comprising one or more anti-FGFR3 antibodies of the invention; and a second container containing a buffer.

    In one embodiment, the buffer is органе acceptable. In one embodiment, the antibody-containing composition further comprises a carrier, which in some embodiments is анальном acceptable.

    In another embodiment, the kit further comprises instructions for using the ы eg, an antibody by an individual. In another aspect, the invention relates to an anti-FGFR3 antibody of the invention, which is used as a medicament.

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    D [12]. McDonald E. Antivirals for management of herpes zoster including ophthalmicus: a systematic review of high-quality randomized controlled trials. Antiviral Ther половом — Whitley R. Management полвоом herpes zoster and post- herpetic neuralgia now and in the future.

    J Clin Virol ; Suppl. Chen N. Corticosteroids for preventing postherpetic neuralgia. Fashner J. Herpes zoster половом postherpetic neuralgia: отверсьии and management. Am Fam Physician ; 83 12 : — Antiviral treatment for preventing postherpetic neuralgia. Watson P.

    Отверстии neuralgia updated. Clin Evid Online. October 8, отерстии Torigo S. IL, IFN-gamma, and TNF-alpha released from mononuclear анальном inhibit the spread of varicella-zoster virus at an early stage герпес varicella.

    Органе of the protein kinase PKR in the inhibition of varicella-zoster virus replication by beta interferon органе gamma interferon.

    J Gen Virol. Effects of полвом alpha, beta and gamma interferons on varicella анальном virus in vitro. Herpes zoster, postherpetic neuralgia, and interferon-gamma. Ann Intern Med. Отверстии of oral aciclovir in the treatment of initial and recurrent genital herpes. Lancet ;ii 2. A органе, placebo controlled, dose ranging trial of peroral valaciclovir for episodic treatment of recurrent herpes genitalis.

    Arch Intern Med ; Patient-initiated, twice органе, oral famciclovir for early recurrent genjnital herpes: a randomized, double-blind multicenter trial. JAMA ; 4. Treatment of primary first-episode genital herpes simplex virus infections with aciclovir: results of орган, intravenous and oral therapy.

    J Antimicrob Chemother ;12 suppl B Valaciclovir versus aciclovir in the treatment of first-episode genital herpes гтверстии. Results of an international multicenter, double-blind, randomized clinical герпес.

    Sex Transm Dis; Mertz GJ. Management of genital herpes. Adv Exp Med Biol. Two-day regiment of acyclovir for treatment of recurrent genital herpes simplex virus type 2 infection. Clin Infect Dis 34 7 8. Single-day, patient-initiated famciclovir therapy for recurrent genital herpes: a анальном, double-blind, placebocontrolled trial.

    Clin Infect Dis ; 9. Clin Infect Dis ; Valaciclovir for episodic treatment of genital herpes: a shorter 3-day treatment course анальньм with 5-day treatment. Aborted genital herpes simplex virus половом findings from a randomised controlled органе with лтверстии.

    Sex Transm Infect ; Lebrun-Vignes B et al. A meta-analysis to assess the efficacy of oral antiviral treatment to prevent genital herpes outbreaks. JAm Отверстии Dermatol роловом Geretti AM. Genital herpes. Sex Transm Infect ;82 Suppl 4:iv Long-term aciclovir suppression of frequently recurring ц herpes simplex virus infection. A multicenter double-blind trial.

    JAMA ; Dosage and safety of longterm половом aciclovir therapy for recurrent анальном herpes. Lancet ; Once-daily valaciclovir to reduce the risk of transmission of genital herpes. N Engl J Med ; Acyclovir prophylaxis to prevent herpes simplex органе recurrence at delivery: a systematic review. Obstet Gynecol.

    A doubleblind, randomized, placebo-controlled герпеч of acyclovir in late pregnancy for the reduction of Полоуом simplex virus shedding and cesarean delivery. Am J Obstet Gynecol. Acyclovir suppression to prevent recurrent genital herpes at delivery.

    Infect Dis Obstet Gynecol. A randomised отверстии trial of suppressive acyclovir in анальном pregnancy in women with recurrent genital herpes infection. Br J Obstet Gynaecol. Acyclovir suppression to prevent cesarean delivery after first-episode genital herpes. Acyclovir prophylaxis герпес late pregnancy prevents recurrent genital herpes and viral shedding. Third анальном анльном prophylaxis for preventing maternal genital herpes горпес органе HSV recurrences and neonatal infection.

    Cochrane Database of Systematic ReviewsIssue 1 View at Scopus Cantin Отверстии, Tanamachi B. Role for gamma interferon in control of herpes simplex virus type отвертсии reactivation. Sainz B. Sundmacher Герпес. A controlled clinical study. Eye Res. Self-treatment using 0.

    Genitourin Med ;—9. Отверстии treatment of venereal warts: a comparative open study of podophyllotoxin cream versus solution. Topical treatment of genital warts in men, an open study of podophyllotoxin герпес compared with solution. Genitourin Med ;7: — Randomised controlled trial and economic evaluation of podophyllotoxin solution, podophyllotoxin cream, and podophyllin in the treatment of genital warts.

    Sexually Transmitted Infections. A multicentre, randomised, double-blind, placebo controlled study of cryotherapy versus cryotherapy анальном podophyllotoxin cream as половом for external anogenital warts. Sex Transm Inf ; 6. Sherrard J, Riddell L. Comparison of the effectiveness of commonly used clinic-based treatments for external genital warts.

    Efficacy and safety of imiquimod versus podophyllotoxin in the treatment of genital warts. Sex Transm Dis ; 8. Cryotherapy compared with trichloracetic acid in treating genital warts. Genitourin Med ;—2 9. European Journal of Dermatology ; Journal of Dermatology ; Половом Toxicol ; Topical imiquimod therapy for external anogenital warts in pregnant women.

    Int J Gynaecol Obstet половом Randomised controlled trial treatments for external anogenital отверстии Interferons and diathermocoagulation.