MD995Z - Method for treating Herpes simplex virus type 1 and 2-induced infection - Google Patents
Method for treating Herpes simplex virus type 1 and 2-induced infection Download PDFInfo
- Publication number
- MD995Z MD995Z MDS20150006A MDS20150006A MD995Z MD 995 Z MD995 Z MD 995Z MD S20150006 A MDS20150006 A MD S20150006A MD S20150006 A MDS20150006 A MD S20150006A MD 995 Z MD995 Z MD 995Z
- Authority
- MD
- Moldova
- Prior art keywords
- treatment
- acyclovir
- infection
- herpes
- hsv1
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 30
- 208000015181 infectious disease Diseases 0.000 title claims abstract description 28
- 241000700588 Human alphaherpesvirus 1 Species 0.000 title description 60
- 241000701074 Human alphaherpesvirus 2 Species 0.000 title description 2
- 238000011282 treatment Methods 0.000 claims abstract description 91
- 229960004150 aciclovir Drugs 0.000 claims abstract description 76
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 claims abstract description 74
- 238000012360 testing method Methods 0.000 claims abstract description 17
- 241000700605 Viruses Species 0.000 claims abstract description 14
- 230000000840 anti-viral effect Effects 0.000 claims abstract description 14
- 208000009889 Herpes Simplex Diseases 0.000 claims abstract description 10
- 230000002519 immonomodulatory effect Effects 0.000 claims abstract description 6
- 239000000932 sedative agent Substances 0.000 claims abstract description 6
- 230000000699 topical effect Effects 0.000 claims abstract description 6
- 230000035945 sensitivity Effects 0.000 claims abstract description 5
- 230000000202 analgesic effect Effects 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- 102100040018 Interferon alpha-2 Human genes 0.000 claims abstract description 3
- 108010079944 Interferon-alpha2b Proteins 0.000 claims abstract description 3
- 230000001624 sedative effect Effects 0.000 claims abstract description 3
- 230000000977 initiatory effect Effects 0.000 claims description 12
- 102000006601 Thymidine Kinase Human genes 0.000 claims description 7
- 108020004440 Thymidine kinase Proteins 0.000 claims description 7
- 230000001225 therapeutic effect Effects 0.000 claims description 5
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 4
- 239000011782 vitamin Substances 0.000 claims description 4
- 235000013343 vitamin Nutrition 0.000 claims description 4
- 229940088594 vitamin Drugs 0.000 claims description 4
- 229930003231 vitamin Natural products 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 2
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 2
- 238000001514 detection method Methods 0.000 claims 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 206010019973 Herpes virus infection Diseases 0.000 description 41
- 241001529453 unidentified herpesvirus Species 0.000 description 24
- 210000001744 T-lymphocyte Anatomy 0.000 description 17
- 230000009467 reduction Effects 0.000 description 12
- 239000003550 marker Substances 0.000 description 10
- 108010078049 Interferon alpha-2 Proteins 0.000 description 8
- 208000002193 Pain Diseases 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 238000011835 investigation Methods 0.000 description 8
- 241000700584 Simplexvirus Species 0.000 description 7
- 230000007969 cellular immunity Effects 0.000 description 7
- 238000003759 clinical diagnosis Methods 0.000 description 7
- 238000010166 immunofluorescence Methods 0.000 description 7
- 210000004698 lymphocyte Anatomy 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 238000012332 laboratory investigation Methods 0.000 description 6
- 239000002674 ointment Substances 0.000 description 6
- 230000000306 recurrent effect Effects 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- ZABSXKJOMUONGB-UHFFFAOYSA-N 2-oxo-2-(9-oxofluoren-2-yl)acetaldehyde Chemical compound C1=CC=C2C(=O)C3=CC(C(=O)C=O)=CC=C3C2=C1 ZABSXKJOMUONGB-UHFFFAOYSA-N 0.000 description 5
- 108010050904 Interferons Proteins 0.000 description 5
- 102000014150 Interferons Human genes 0.000 description 5
- 230000003622 anti-hsv Effects 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 238000004113 cell culture Methods 0.000 description 5
- 230000001684 chronic effect Effects 0.000 description 5
- 238000003745 diagnosis Methods 0.000 description 5
- 230000004069 differentiation Effects 0.000 description 5
- 238000011156 evaluation Methods 0.000 description 5
- 238000003771 laboratory diagnosis Methods 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 206010037844 rash Diseases 0.000 description 5
- 230000003612 virological effect Effects 0.000 description 5
- OCOSYMCDPNAWPA-UHFFFAOYSA-N 2,4-dibromo-6-(3,5-dibromo-2,4-dihydroxyphenyl)benzene-1,3-diol Chemical compound OC1=C(Br)C(O)=C(Br)C=C1C1=CC(Br)=C(O)C(Br)=C1O OCOSYMCDPNAWPA-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 206010012735 Diarrhoea Diseases 0.000 description 4
- 206010013082 Discomfort Diseases 0.000 description 4
- 208000029433 Herpesviridae infectious disease Diseases 0.000 description 4
- 206010028813 Nausea Diseases 0.000 description 4
- 208000003251 Pruritus Diseases 0.000 description 4
- 206010037660 Pyrexia Diseases 0.000 description 4
- 206010047700 Vomiting Diseases 0.000 description 4
- 230000002411 adverse Effects 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000003602 anti-herpes Effects 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 230000007803 itching Effects 0.000 description 4
- HZVGIXIRNANSHU-UHFFFAOYSA-N naphthalene-1,2,3,4-tetrone Chemical compound C1=CC=C2C(=O)C(=O)C(=O)C(=O)C2=C1 HZVGIXIRNANSHU-UHFFFAOYSA-N 0.000 description 4
- 230000008693 nausea Effects 0.000 description 4
- 238000002636 symptomatic treatment Methods 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 230000008673 vomiting Effects 0.000 description 4
- 206010010904 Convulsion Diseases 0.000 description 3
- 208000004547 Hallucinations Diseases 0.000 description 3
- 208000000112 Myalgia Diseases 0.000 description 3
- 206010042566 Superinfection Diseases 0.000 description 3
- 229940035676 analgesics Drugs 0.000 description 3
- 239000000730 antalgic agent Substances 0.000 description 3
- 239000003443 antiviral agent Substances 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 230000036461 convulsion Effects 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 229940079322 interferon Drugs 0.000 description 3
- 210000000265 leukocyte Anatomy 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 208000004296 neuralgia Diseases 0.000 description 3
- 229940125723 sedative agent Drugs 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 210000005239 tubule Anatomy 0.000 description 3
- 206010006784 Burning sensation Diseases 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- 206010061598 Immunodeficiency Diseases 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 230000000890 antigenic effect Effects 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 230000001143 conditioned effect Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 206010014599 encephalitis Diseases 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 230000007717 exclusion Effects 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 229940047124 interferons Drugs 0.000 description 2
- 210000001165 lymph node Anatomy 0.000 description 2
- 210000004400 mucous membrane Anatomy 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000011269 treatment regimen Methods 0.000 description 2
- 230000029812 viral genome replication Effects 0.000 description 2
- 235000019154 vitamin C Nutrition 0.000 description 2
- 239000011718 vitamin C Substances 0.000 description 2
- 235000019165 vitamin E Nutrition 0.000 description 2
- 239000011709 vitamin E Substances 0.000 description 2
- UVITTYOJFDLOGI-UHFFFAOYSA-N (1,2,5-trimethyl-4-phenylpiperidin-4-yl) propanoate Chemical compound C=1C=CC=CC=1C1(OC(=O)CC)CC(C)N(C)CC1C UVITTYOJFDLOGI-UHFFFAOYSA-N 0.000 description 1
- SGHTWHQDAWEBOD-YYWUANBLSA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;2-acetyloxybenzoic acid;n-(4-ethoxyphenyl)acetamide;5-ethyl-5-phenyl-1,3-diazinane-2,4,6-trione;phosphoric acid;1,3,7-trimethylpurine-2,6-dio Chemical compound OP(O)(O)=O.CCOC1=CC=C(NC(C)=O)C=C1.CC(=O)OC1=CC=CC=C1C(O)=O.CN1C(=O)N(C)C(=O)C2=C1N=CN2C.C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC SGHTWHQDAWEBOD-YYWUANBLSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 230000004544 DNA amplification Effects 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 206010012218 Delirium Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 208000004898 Herpes Labialis Diseases 0.000 description 1
- 241000700586 Herpesviridae Species 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 1
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010067152 Oral herpes Diseases 0.000 description 1
- 206010068319 Oropharyngeal pain Diseases 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- 241000751100 Pityopus Species 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 206010037898 Rash vesicular Diseases 0.000 description 1
- 208000035415 Reinfection Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical compound NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 235000009470 Theobroma cacao Nutrition 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- HDOVUKNUBWVHOX-QMMMGPOBSA-N Valacyclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCOC(=O)[C@@H](N)C(C)C)C=N2 HDOVUKNUBWVHOX-QMMMGPOBSA-N 0.000 description 1
- WPVFJKSGQUFQAP-GKAPJAKFSA-N Valcyte Chemical compound N1C(N)=NC(=O)C2=C1N(COC(CO)COC(=O)[C@@H](N)C(C)C)C=N2 WPVFJKSGQUFQAP-GKAPJAKFSA-N 0.000 description 1
- 208000012886 Vertigo Diseases 0.000 description 1
- OIRDTQYFTABQOQ-UHTZMRCNSA-N Vidarabine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O OIRDTQYFTABQOQ-UHTZMRCNSA-N 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- AYWLSIKEOSXJLA-UHFFFAOYSA-N [2-[(2-amino-6-oxo-3h-purin-9-yl)methoxy]ethoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound N1C(N)=NC(=O)C2=C1N(COCCOP(O)(=O)OP(O)(=O)OP(O)(O)=O)C=N2 AYWLSIKEOSXJLA-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000011861 anti-inflammatory therapy Methods 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 229940121357 antivirals Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000009534 blood test Methods 0.000 description 1
- 239000012888 bovine serum Substances 0.000 description 1
- 244000240602 cacao Species 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- UOMKBIIXHQIERR-UHFFFAOYSA-N cridanimod Chemical compound C1=CC=C2N(CC(=O)O)C3=CC=CC=C3C(=O)C2=C1 UOMKBIIXHQIERR-UHFFFAOYSA-N 0.000 description 1
- 230000003583 cytomorphological effect Effects 0.000 description 1
- HAAZLUGHYHWQIW-KVQBGUIXSA-N dGTP Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 HAAZLUGHYHWQIW-KVQBGUIXSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 238000000537 electroencephalography Methods 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 229960004396 famciclovir Drugs 0.000 description 1
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 description 1
- 229960005102 foscarnet Drugs 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 229940044627 gamma-interferon Drugs 0.000 description 1
- 229960002963 ganciclovir Drugs 0.000 description 1
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 1
- 210000000609 ganglia Anatomy 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000035931 haemagglutination Effects 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000002443 hepatoprotective effect Effects 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- ZJAOAACCNHFJAH-UHFFFAOYSA-N hydroxycarbonylphosphonic acid Natural products OC(=O)P(O)(O)=O ZJAOAACCNHFJAH-UHFFFAOYSA-N 0.000 description 1
- 230000000544 hyperemic effect Effects 0.000 description 1
- 229960004716 idoxuridine Drugs 0.000 description 1
- 230000007124 immune defense Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 239000002799 interferon inducing agent Substances 0.000 description 1
- 210000001739 intranuclear inclusion body Anatomy 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 238000011005 laboratory method Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000009593 lumbar puncture Methods 0.000 description 1
- DJGAAPFSPWAYTJ-UHFFFAOYSA-M metamizole sodium Chemical compound [Na+].O=C1C(N(CS([O-])(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 DJGAAPFSPWAYTJ-UHFFFAOYSA-M 0.000 description 1
- ZRFIFDFEDPJBII-UHFFFAOYSA-N methyl 2-[4-(2-piperidin-1-ylethoxy)benzoyl]benzoate;hydrochloride Chemical compound Cl.COC(=O)C1=CC=CC=C1C(=O)C(C=C1)=CC=C1OCCN1CCCCC1 ZRFIFDFEDPJBII-UHFFFAOYSA-N 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229960001179 penciclovir Drugs 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 229960000581 salicylamide Drugs 0.000 description 1
- 238000010187 selection method Methods 0.000 description 1
- 231100000873 signs of neurotoxicity Toxicity 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 231100000057 systemic toxicity Toxicity 0.000 description 1
- BSVYJQAWONIOOU-UHFFFAOYSA-N tilorone dihydrochloride Chemical compound Cl.Cl.C1=C(OCCN(CC)CC)C=C2C(=O)C3=CC(OCCN(CC)CC)=CC=C3C2=C1 BSVYJQAWONIOOU-UHFFFAOYSA-N 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000001228 trophic effect Effects 0.000 description 1
- 102000003390 tumor necrosis factor Human genes 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 229940093257 valacyclovir Drugs 0.000 description 1
- 229960002149 valganciclovir Drugs 0.000 description 1
- 231100000889 vertigo Toxicity 0.000 description 1
- 229960003636 vidarabine Drugs 0.000 description 1
- 230000007442 viral DNA synthesis Effects 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
Invenţia se referă la medicină, în special la o metodă de tratament al infecţiei cu Herpes simplex de tip 1 şi 2.Conform invenţiei, metoda constă în efectuarea examenului clinic şi paraclinic al pacientului şi iniţierea tratamentului etiotrop cu aciclovir, precum şi a tratamentelor antiinflamator, sedativ, analgezic, topic, imunomodulator şi vitaminoterapeutic, totodatăîn decurs de 12…24 ore de la examenul clinic se efectuează testul de sensibilitate la aciclovir a tulpinilor de virus prelevate din veziculele herpetice şi în cazul depistării tulpinilor rezistente la aciclovir, acesta se substituie din ziua a doua a tratamentului cu un preparat antiviral cu acţiune timidinkinaza-independentă pe bază de interferon uman recombinant α-2b.The invention relates to medicine, in particular to a method of treating herpes simplex infection type 1 and 2. sedative, analgesic, topical, immunomodulatory and vitamin-therapeutic, at the same time within 12 ... 24 hours from the clinical examination the aciclovir sensitivity test is performed of the virus strains taken from the herpes vesicles and in the case of the aciclovir resistant strains, it is replaced by the day. second treatment with a thymidinkinase-independent antiviral preparation based on recombinant human interferon α-2b.
Description
Invenţia se referă la medicină, în special la o metodă de tratament al infecţiei cu Herpes simplex de tip 1 şi 2. The invention relates to medicine, in particular to a method of treating Herpes simplex type 1 and 2 infection.
Ţinta tratamentului în infecţia herpetică include: The treatment goals for herpes infection include:
- reducerea severităţii bolii, scăderea contagiozităţii şi a riscului de complicaţii prin inhibarea replicării virusurilor şi stoparea răspândirii infecţiei; - reducing the severity of the disease, decreasing contagiousness and the risk of complications by inhibiting virus replication and stopping the spread of the infection;
- formarea unei apărări imune de o reală valoare prin asigurarea unui răspuns adecvat (Баринский И.Ф., Махмудов Ф.Р. Герпес. Баку, Victory, 2013, p. 10-123; Spânu C., Bîrca Ludmila, Rusu Galina. Infecţia cu Herpes simplex - particularităţi clinico-epidemiologice, de evoluţie, diagnostic, tratament, profilaxie (ghid practic). Chişinău, Tipografia centrală, 2006, p. 23-65). - the formation of a truly valuable immune defense by ensuring an adequate response (Barinsky I.F., Mahmudov F.R. Herpes. Baku, Victory, 2013, p. 10-123; Spânu C., Bîrca Ludmila, Rusu Galina. Herpes simplex infection - clinical and epidemiological features, evolution, diagnosis, treatment, prophylaxis (practical guide). Chisinau, Central Printing House, 2006, p. 23-65).
Aceste obiective pot fi atinse prin: chimioterapie (tratament etiotrop antiherpetic), terapie imunomodulatoare (interferoni, inductori ai interferonogenezei, preparate cu anticorpi antiherpetici, vaccinoterapie), combinarea celor enumerate (chimioterapie+terapie imunomodulatoare) cu tratament antiinflamator, topic, analgezic. Specificul tratamentului etiotrop al infecţiei herpetice este demonstrat în mare măsură de interrelaţia dintre herpes-virusuri (HV) şi organismul uman gazdă caracterizată prin persistenţa îndelungată a virusului în ganglionii nervoşi senzitivi, activizarea lor în cazul diminuării imunităţii specifice şi nespecifice, posibilitatea de reinfectare cu alte tulpini virale de herpes-virusuri. These objectives can be achieved by: chemotherapy (antiherpetic etiotropic treatment), immunomodulatory therapy (interferons, interferonogenesis inducers, antiherpetic antibody preparations, vaccine therapy), combination of the above (chemotherapy + immunomodulatory therapy) with anti-inflammatory, topical, analgesic treatment. The specificity of the etiotropic treatment of herpes infection is largely demonstrated by the interrelation between herpes viruses (HV) and the human host organism characterized by the long-term persistence of the virus in the sensitive nerve ganglia, their activation in case of decreased specific and non-specific immunity, the possibility of reinfection with other viral strains of herpes viruses.
Preparatele antiherpetice constituie 80% din toate preparatele antivirale existente, unele deja au fost abandonate din cauza toxicităţii severe sistemice importante (idoxuridina, vidarabina). Majoritatea substanţelor antivirale utilizate în terapia infecţiilor produse de herpes-virusuri acţionează prin inhibarea sintezei ADN-ului viral şi sunt din punct de vedere chimic analogi nucleozidici ai bazelor purinice sau pirimidinice. Cei mai utilizaţi compuşi în terapia infecţiilor produse de herpes-virusuri sunt aciclovirul şi analogii săi penciclovirul şi ganciclovirul. Valaciclovirul, famciclovirul şi valganciclovirul sunt pro-medicamente cu acelaşi spectru de activitate ca al aciclovirului, dar cu biodisponibilitate orală superioară, ce permite administrarea lor pe cale orală. Se cunoaşte că aciclovirul pentru a deveni activ trebuie supus trifosforilării: prima fosforilare se efectuează prin intermediul enzimei virale timidinkinaza, celelalte două fosforilări sunt realizate de enzimele celulei gazdă, unde ADN-polimeraza virusurilor herpetice include greşit aciclovirul trifosfat în lanţul ADN-ului viral în locul dezoxiguanizintrifosfatului natural, conducând la blocarea replicării virale. Activitatea aciclovirului este strict specifică, deoarece timidinkinaza herpes-virusurilor de mii de ori mai rapid decât cea a celulelor se leagă cu aciclovirul, din care cauză aciclovirul se acumulează doar în celulele infectate cu virus. Antiherpetic drugs constitute 80% of all existing antiviral drugs, some of which have already been abandoned due to severe systemic toxicity (idoxuridine, vidarabine). Most antiviral agents used in the treatment of herpesvirus infections act by inhibiting viral DNA synthesis and are chemically nucleoside analogues of purine or pyrimidine bases. The most widely used compounds in the treatment of herpesvirus infections are acyclovir and its analogues penciclovir and ganciclovir. Valaciclovir, famciclovir and valganciclovir are prodrugs with the same spectrum of activity as acyclovir, but with superior oral bioavailability, which allows their oral administration. It is known that acyclovir must undergo triphosphorylation to become active: the first phosphorylation is carried out by the viral enzyme thymidine kinase, the other two phosphorylations are carried out by host cell enzymes, where the DNA polymerase of herpes viruses mistakenly includes acyclovir triphosphate in the viral DNA chain instead of the natural deoxyguanosine triphosphate, leading to the blocking of viral replication. The activity of acyclovir is strictly specific, because the thymidine kinase of herpes viruses binds to acyclovir thousands of times faster than that of cells, which is why acyclovir accumulates only in cells infected with the virus.
În acest context o problemă extrem de majoră prezintă apariţia rezistenţei la aciclovir, în special la imunodeprimaţi, care poate varia de la 10 până la 40% cauzate de tulpinile de virus Herpes simplex (tip 1⁄2) defecte în timidinkinaze (TK-). În prezent, tratamentul în infecţia cu virusul Herpes simplex (HSV1⁄2) implică (Каримова И. М. Герпесвирусная инфекция (диагностика, клиника, лечение). Медицинское информационное агенство. Москва, 2004, p. 117; Ciufecu Elvira Sînziana. Virusologie medicală, Familia Herpesviridae. Bucureşti, Editura Medicală Naţională, 2003, p. 280-334): In this context, an extremely major problem is the emergence of acyclovir resistance, especially in immunocompromised patients, which can vary from 10 to 40% caused by Herpes simplex virus strains (type 1⁄2) defective in thymidine kinases (TK-). Currently, the treatment of Herpes simplex virus infection (HSV1⁄2) involves (Karimova I. M. Gerpesvirus infection (diagnosis, clinic, treatment). Medical information agency. Moscow, 2004, p. 117; Ciufecu Elvira Sînziana. Medical virusology, Herpesviridae family. Bucharest, National Medical Publishing House, 2003, p. 280-334):
I. Stabilirea diagnosticului clinic, ţinând cont de sediul anatomic al infecţiei şi spectrul evolutiv condiţionat de acest factor cu identificarea anamnesticului maladiei, examenul clinic obiectiv. I. Establishing the clinical diagnosis, taking into account the anatomical site of the infection and the evolutionary spectrum conditioned by this factor, with the identification of the disease history, objective clinical examination.
II. Anamneza epidemiologică. II. Epidemiological history.
III. Iniţierea tratamentului etiotrop şi simptomatic cu declanşarea investigaţiilor de laborator întru confirmarea diagnosticului clinic. III. Initiation of etiotropic and symptomatic treatment with the initiation of laboratory investigations to confirm the clinical diagnosis.
III (a). Conform standardelor existente de tratament al infecţiei cu HSV1⁄2 clinicianul nu trebuie să temporizeze tratamentul etiotrop specific (cu aciclovir) până la sosirea rezultatelor investigaţiilor de laborator. Suspiciunea de tulpină virală rezistentă la aciclovir (TK-) apare pe parcursul tratamentului, adică în absenţa răspunsului clinico-virusologic favorabil după 7...12 zile în primoinfecţie herpetică şi peste 1...3 luni în infecţia herpetică cronică (persistentă). Aşadar, instituirea ,,alternativei terapeutice” în prezent se face în baza răspunsului clinic la tratamentul antiviral, iar alegerea pe criterii de probabilitate statistică. III (a). According to the existing standards of treatment of HSV1⁄2 infection, the clinician should not delay specific etiotropic treatment (with acyclovir) until the results of laboratory investigations are available. The suspicion of acyclovir-resistant viral strain (TK-) appears during treatment, that is, in the absence of a favorable clinical-virological response after 7...12 days in primary herpes infection and after 1...3 months in chronic (persistent) herpes infection. Therefore, the establishment of the "therapeutic alternative" is currently based on the clinical response to antiviral treatment, and the choice is based on statistical probability criteria.
III (b). Este cunoscută metoda tradiţională, complexă de tratament al infecţiei cu virusul Herpes simplex (HSV1⁄2), care include tratamentul etiotrop specific cu aciclovir (analogii săi), tratamentul local, terapia antiinflamatoare, imunomodulatoare şi tratamentul simptomatic. Frecvent pentru tratamentul local se utilizează ung. Florenal 0,5%, Tebrofen 3,0%, Oxolin 1,0%, Ridoxol 0,5%. Terapia antiinflamatoare include remedii medicamentoase nesteroide: acid acetilsalicilic, salicilamidă, fenilbutazon; imunomodulatoare - interferoni (viferon, giaferon, leucinferon), inductori de interferon (amixin, poludan, ridostin, cicloferon). Se recomandă aplicarea curantilului în termene precoce pentru corecţia microcirculaţiei sangvine, a vitaminelor A, B, C şi E pentru stimularea efectului trofic asupra tegumentelor şi mucoaselor. Cuparea durerii herpetice, postherpetice şi a pruritului se face cu sedative, somnifere şi analgetice (analgin, sedalgin, baralgin, promedol etc.). III (b). The traditional, complex method of treatment of Herpes simplex virus infection (HSV1⁄2) is known, which includes specific etiotropic treatment with acyclovir (its analogues), local treatment, anti-inflammatory, immunomodulatory therapy and symptomatic treatment. Frequently, for local treatment, ointments Florenal 0.5%, Tebrofen 3.0%, Oxolin 1.0%, Ridoxol 0.5% are used. Anti-inflammatory therapy includes non-steroidal medicinal remedies: acetylsalicylic acid, salicylamide, phenylbutazone; immunomodulators - interferons (viferon, giaferon, leucinferon), interferon inducers (amixin, poludan, ridostin, cycloferon). It is recommended to apply curantil in early terms for the correction of blood microcirculation, vitamins A, B, C and E to stimulate the trophic effect on the skin and mucous membranes. Herpetic and postherpetic pain and itching are relieved with sedatives, sleeping pills and analgesics (analgin, sedalgin, baralgin, promedol, etc.).
Durata tratamentului cu utilizarea aciclovirului este de la 7...12 zile pentru primoinfecţie herpetică şi până la 1...3 luni în dependenţă de forma clinică de manifestare: infecţie cronică, latentă, persistentă. Acest tratament etiotropic cu aciclovir sau analogii săi de comun cu tratamentul topic şi simptomatic permite vindecarea bolnavilor, cu excepţia infecţiei herpetice cauzate de HSV1⁄2 rezistent la aciclovir [1,2]. The duration of treatment with acyclovir is from 7...12 days for primary herpes infection and up to 1...3 months depending on the clinical form of manifestation: chronic, latent, persistent infection. This etiotropic treatment with acyclovir or its analogues in combination with topical and symptomatic treatment allows the cure of patients, with the exception of herpes infection caused by acyclovir-resistant HSV1⁄2 [1,2].
Dezavantajele metodei constau în absenţa efectului terapeutic în infecţia herpetică primară şi recidivantă cauzată de virusurile herpetice rezistente la aciclovir (TK-), dezvoltarea efectelor adverse pronunţate (greaţă, vomă, diaree, afectarea rinichilor, convulsii, halucinaţii etc.) pe parcursul administrării îndelungate a aciclovirului, cheltuieli financiare nejustificate. The disadvantages of the method are the absence of therapeutic effect in primary and recurrent herpetic infection caused by acyclovir-resistant herpes viruses (TK-), the development of pronounced adverse effects (nausea, vomiting, diarrhea, kidney damage, convulsions, hallucinations, etc.) during prolonged administration of acyclovir, and unjustified financial expenses.
IV. Diagnosticul de laborator. IV. Laboratory diagnosis.
Tehnicile de laborator utilizate pentru confirmarea diagnosticului clinic al infecţiei cu herpesvirusuri includ: 1) izolarea virusului HSV1⁄2 în cultură de celule HEP-2, Hela, Vero, BSC-21, C1-13, FEO în ou embrionat, prin inoculare animalelor de laborator şi identificarea virusului izolat în reacţia de neutralizare, hemaglutinare, fixare a complementului, 2) examenul prin tehnică imunofluorescentă (EIF) pentru identificarea antigenului virusurilor herpetice (HSV1⁄2) în baza anticorpilor monoclonali şi policlonali, 3) utilizarea reacţiei de amplificare genică PCR şi a tehnicilor de hibridizare pentru evidenţierea şi evaluarea ADN-lui virusului herpetic, 4) analiza imunoenzimatică, realizată prin echipament dotat cu anticorpi monoclonali pentru evidenţierea anti-HSV IgM şi anti-HSV IgG şi evaluarea infecţiei herpetice primare, cronice, recidivante, 5) analiza imunoenzimatică (imunodot) cu utilizarea a două glicoproteine de suprafaţă a virusului HSV - 1 (gG1) şi HSV - 2 (gG2) pentru identificarea formelor subclinice ale infecţiei herpetice şi evaluarea seroconversiei în infecţia herpetică recidivantă, 6) analiza prin Western blot (imunoblot) capabilă de a evidenţia anticorpii din serul pacientului testat către 50 proteine individuale ale virusului herpetic (HSV1⁄2), 7) metoda citomorfologică - examenul microscopic al probelor recoltate din leziuni (cutanate, mucoase, bioptat etc.) care demonstrează celule gigante polinucleare şi incluziuni intranucleare, cunoscute sub numele de celule Unna, dar nu permite diferenţierea de alte virusuri. Suplimentar la cele menţionate pot fi realizate examene complementare (puncţia lombară cu cercetarea lichidului cefalorahidian, Rezonanţa Magnetică Nucleară cerebrală, computer tomografia cerebrală, electroencefalografia, investigaţii ultrasonore) care sunt condiţionate de forma clinică şi sediul infecţiei. În formele recidivante şi severe sunt necesare investigaţii suplimentare de apreciere a statutului imun, în special tisular (CD4 şi CD8 - subpopulaţiile T-limfocitelor), statutului interferonilor (cantitatea totală de interferon, capacitatea leucocitelor de a induce α şi β-interferon, capacitatea T-limfocitelor de a induce γ-interferon), factorul de necroză tumorală. Laboratory techniques used to confirm the clinical diagnosis of herpesvirus infection include: 1) isolation of HSV1⁄2 virus in HEP-2, Hela, Vero, BSC-21, C1-13, FEO cell culture in embryonated egg, by inoculation of laboratory animals and identification of the isolated virus in the neutralization, hemagglutination, complement fixation reaction, 2) examination by immunofluorescence technique (EIF) for identification of herpesvirus antigen (HSV1⁄2) based on monoclonal and polyclonal antibodies, 3) use of PCR gene amplification reaction and hybridization techniques for highlighting and evaluating herpesvirus DNA, 4) immunoenzymatic analysis, performed by equipment equipped with monoclonal antibodies for highlighting anti-HSV IgM and anti-HSV IgG and evaluating primary, chronic, recurrent herpes infection, 5) immunoenzymatic analysis (immunodot) using two surface glycoproteins of the HSV - 1 virus (gG1) and HSV - 2 (gG2) for identifying subclinical forms of herpes infection and evaluating seroconversion in recurrent herpes infection, 6) Western blot analysis (immunoblot) capable of highlighting antibodies in the serum of the tested patient to 50 individual proteins of the herpes virus (HSV1⁄2), 7) cytomorphological method - microscopic examination of samples collected from lesions (skin, mucous membranes, biopsy, etc.) which demonstrate polynuclear giant cells and intranuclear inclusions, known as Unna cells, but does not allow differentiation from other viruses. In addition to those mentioned, complementary examinations can be performed (lumbar puncture with cerebrospinal fluid examination, brain Magnetic Nuclear Resonance, brain computer tomography, electroencephalography, ultrasound investigations) which are conditioned by the clinical form and location of the infection. In recurrent and severe forms, additional investigations are necessary to assess the immune status, especially tissue (CD4 and CD8 - T-lymphocyte subpopulations), interferon status (total amount of interferon, the ability of leukocytes to induce α and β-interferon, the ability of T-lymphocytes to induce γ-interferon), and tumor necrosis factor.
Algoritmul prezentat nu include identificarea şi evaluarea tulpinilor de virus herpetic (HSV1⁄2) rezistente şi sensibile (TK+) la aciclovir. The presented algorithm does not include the identification and evaluation of herpes virus (HSV1⁄2) strains resistant and susceptible (TK+) to acyclovir.
Dezavantajele metodei cunoscute de tratament al infecţiei herpetice etiologic cauzate de HSV1⁄2 ţin de: The disadvantages of the known method of treating herpes infection etiologically caused by HSV1⁄2 are:
- absenţa testului de identificare a tulpinilor de virus Herpes simplex (tip 1⁄2) rezistente la aciclovir defecte în (TK-) în primele (12…24 ore) de iniţiere a tratamentului antiviral etiotrop specific, - absence of the test for the identification of Herpes simplex virus strains (type 1⁄2) resistant to acyclovir defective in (TK-) in the first (12…24 hours) of initiation of specific etiotropic antiviral treatment,
- eşecul tratamentului antiviral cu aciclovir la 40% pacienţi, în special la cei imunodeprimaţi cu infecţie herpetică acută, cronică (recidivantă), - failure of antiviral treatment with acyclovir in 40% of patients, especially in immunocompromised patients with acute, chronic (recurrent) herpetic infection,
- necesitatea modificării spectrului de antivirale etiotropspecifice pentru infecţia herpetică, inclusiv doza de aplicare pe parcursul tratamentului, - the need to modify the spectrum of etiotropic-specific antivirals for herpetic infection, including the application dose during treatment,
- utilizarea neadecvată a aciclovirului în tratamentul infecţiei cu virusul Herpes simplex duce la sporirea procentuală considerabilă a tulpinilor de virus herpetic rezistente la aciclovir, - the inappropriate use of acyclovir in the treatment of Herpes simplex virus infection leads to a considerable increase in the percentage of herpes virus strains resistant to acyclovir,
- sporirea semnificativă a incidenţei reacţiilor adverse; afectarea tranzitorie a funcţiei renale prin cristalizarea aciclovirului în tubii renali, reducerea funcţiei hepatoprotectoare a ficatului, apariţia semnelor de neurotoxicitate, greaţă, vomă, diaree, febră, iritaţie, confuzie, vertij, delir etc., - significant increase in the incidence of adverse reactions; transient impairment of renal function through crystallization of acyclovir in the renal tubules, reduction of the hepatoprotective function of the liver, appearance of signs of neurotoxicity, nausea, vomiting, diarrhea, fever, irritation, confusion, vertigo, delirium, etc.,
- pierderi materiale (financiare) neargumentate suportate de Compania Naţională de Asigurări în Medicină şi pacienţi pe parcursul tratamentului, ce ţin de procurarea medicamentului nominalizat - aciclovir, sau analogilor lui, - unsubstantiated material (financial) losses incurred by the National Health Insurance Company and patients during treatment, related to the procurement of the nominated drug - acyclovir, or its analogues,
- reducerea semnificativă a posibilităţii de izolare şi identificare a sensibilităţii virusului Herpes simplex (HSV1⁄2) la aciclovir în stadiile tardive de evoluţie a infecţiei herpetice. - significant reduction in the possibility of isolating and identifying the sensitivity of the Herpes simplex virus (HSV1⁄2) to acyclovir in the late stages of the evolution of the herpetic infection.
Problema pe care o rezolvă invenţia este sporirea semnificativă a eficacităţii tratamentului specific etiotrop în infecţia cu virusul Herpes simplex HSV1⁄2 manifestată prin revenirea la normă în termeni reduşi a parametrilor clinici şi paraclinici, reducerea semnificativă a duratei de spitalizare şi a efectelor adverse cauzate de administrarea nejustificată a aciclovirului, diminuarea riscului de dezvoltare a complicaţiilor severe postherpetice ca urmare a tratamentului neadecvat şi evitarea cheltuielilor materiale neargumentate. The problem solved by the invention is the significant increase in the effectiveness of specific etiotropic treatment in Herpes simplex virus HSV1⁄2 infection manifested by the rapid return to normal of clinical and paraclinical parameters, the significant reduction in the duration of hospitalization and adverse effects caused by unjustified administration of acyclovir, the reduction in the risk of developing severe postherpetic complications as a result of inadequate treatment and the avoidance of unjustified material expenses.
Esenţa invenţiei constă în efectuarea examenului clinic şi paraclinic al pacientului şi iniţierea tratamentului etiotrop cu aciclovir, precum şi a tratamentelor antiinflamator, sedativ, analgezic, topic, imunomodulator şi vitaminoterapeutic, totodată în decurs de 12…24 ore de la examenul clinic se efectuează testul de sensibilitate la aciclovir a tulpinilor de virus prelevate din veziculele herpetice şi în cazul depistării tulpinilor rezistente la aciclovir, acesta se substituie din ziua a doua a tratamentului cu un preparat antiviral cu acţiune timidinkinaza-independentă pe bază de interferon uman recombinant α-2b. The essence of the invention consists in performing the clinical and paraclinical examination of the patient and initiating etiotropic treatment with acyclovir, as well as anti-inflammatory, sedative, analgesic, topical, immunomodulatory and vitamin therapeutic treatments, at the same time, within 12…24 hours of the clinical examination, the acyclovir sensitivity test of the virus strains taken from the herpetic vesicles is performed and in the case of detecting strains resistant to acyclovir, it is substituted from the second day of treatment with an antiviral preparation with thymidine kinase-independent action based on recombinant human interferon α-2b.
Invenţia se referă la o nouă abordare a metodelor de tratament al infecţiei herpetice în baza diagnosticului prezumtiv precoce (realizat în 12…24 ore) care permite diferenţierea tulpinilor de virus herpetic în (TK+) şi (TK-). The invention refers to a new approach to the treatment methods of herpes infection based on early presumptive diagnosis (performed within 12…24 hours) which allows the differentiation of herpes virus strains into (TK+) and (TK-).
Rezultatul invenţiei constă în obţinerea unei eficacităţi sporite în tratamentul etiotrop specific al infecţiei herpetice, demonstrată prin revenirea la parametrii normali într-un interval de timp redus (comparativ cu metoda prototip) a indicilor clinici şi paraclinici, excluderea utilizării nejustificate a aciclovirului (derivaţiilor săi), care poate dezvolta efecte adverse extrem de nedorite (greaţă, vomă, diaree, convulsii, cristalizarea aciclovirului în tubii renali, halucinaţii etc.), reducerea riscului de avansare a infecţiei herpetice în forme severe (encefalite), urmare a absenţei răspunsului virusologic scontat la tratamentul cu aciclovir, diminuarea semnificativă a duratei de spitalizare a pacienţilor, inclusiv a suportului material. The result of the invention consists in obtaining increased efficacy in the specific etiotropic treatment of herpes infection, demonstrated by the return to normal parameters in a reduced time interval (compared to the prototype method) of clinical and paraclinical indices, the exclusion of unjustified use of acyclovir (its derivatives), which can develop extremely undesirable adverse effects (nausea, vomiting, diarrhea, convulsions, crystallization of acyclovir in the renal tubules, hallucinations, etc.), the reduction of the risk of progression of herpes infection to severe forms (encephalitis), as a result of the absence of the expected virological response to treatment with acyclovir, the significant reduction of the duration of hospitalization of patients, including material support.
Soluţionarea acestei probleme, privind sporirea eficacităţii tratamentului în infecţia cu virusul Herpes simplex, se datorează includerii acestui modul original de diferenţiere a virusurilor herpetice în HSV1⁄2 (TK+) şi HSV (TK-) în primele 12…24 ore de la iniţierea investigării clinice a pacientului, care face posibilă modificarea în timp real a tratamentului antiviral cu dezvoltarea unui răspuns clinico-virusologic de tratament al infecţiei herpetice cu HSV1⁄2 (TK+); HSV1⁄2 (TK-) susţinut. The solution to this problem, regarding the increase in the effectiveness of treatment in Herpes simplex virus infection, is due to the inclusion of this original module for differentiating herpes viruses into HSV1⁄2 (TK+) and HSV (TK-) in the first 12…24 hours from the initiation of the patient's clinical investigation, which makes it possible to modify the antiviral treatment in real time with the development of a sustained clinical-virological response to the treatment of herpes infection with HSV1⁄2 (TK+); HSV1⁄2 (TK-).
Toate aceste argumente ne permit să afirmăm că prin aplicarea metodei propuse se soluţionează o importantă problemă clinico-virusologică, obţinând rezultate terapeutice şi epidemiologice benefice, însoţite de ameliorarea indicilor clinici şi paraclinici cu un impact pozitiv asupra diminuării morbidităţii prin infecţiile herpetice. All these arguments allow us to state that by applying the proposed method, an important clinical-virological problem is solved, obtaining beneficial therapeutic and epidemiological results, accompanied by the improvement of clinical and paraclinical indices with a positive impact on reducing morbidity from herpetic infections.
În continuare prezentăm metodologia propusă pentru diferenţierea tulpinilor de virus Herpes simplex în HSV1⁄2, aciclovir sensibile (TK+) şi HSV1⁄2 aciclovir rezistente (TK-), unde procesul tehnologic include mai multe etape. Next, we present the proposed methodology for differentiating Herpes simplex virus strains into HSV1⁄2, acyclovir sensitive (TK+) and HSV1⁄2 acyclovir resistant (TK-), where the technological process includes several steps.
Etapa 1. Concomitent cu examenul clinic primar al pacientului cu diagnosticul prezumtiv ,,infecţie herpetică”, conţinutul veziculelor indiferent de localizare (herpes labial, genital, ocular etc.) în volum de 0,1 ml se inoculează în culturi celulare Vero, HEp-2 cu monostrat format, cultivate special pe lamele de sticlă (destinate pentru tehnicile de imunofluorescenţă), unde mediul de cultură Eagle + ser bovirn (10%) a fost suplimentat cu aciclovir în concentraţie inhibitoare, când IC-50=2,0-5,0, µg/ml. După 12…24 ore lamelele cu substrat celular deja fixat se prelucrează cu anticorpi monoclonali anti-HSV1⁄2 marcaţi cu fluoresceină (BIO-RAD, Pathfinder, SUA) pentru evidenţierea markerilor antigenici ai virusurilor herpetice HSV1⁄2 la microscopul de ultimă generaţie în regim automatizat Leica 2500 DM, Germania. Stage 1. Simultaneously with the primary clinical examination of the patient with the presumptive diagnosis of "herpetic infection", the contents of the vesicles regardless of location (labial, genital, ocular herpes, etc.) in a volume of 0.1 ml are inoculated into Vero, HEp-2 cell cultures with a formed monolayer, specially cultivated on glass slides (intended for immunofluorescence techniques), where the Eagle culture medium + bovine serum (10%) was supplemented with acyclovir in inhibitory concentration, when IC-50=2.0-5.0, µg/ml. After 12…24 hours, the slides with already fixed cellular substrate are processed with monoclonal anti-HSV1⁄2 antibodies labeled with fluorescein (BIO-RAD, Pathfinder, USA) to highlight the antigenic markers of the HSV1⁄2 herpes viruses on the latest generation microscope in automated mode Leica 2500 DM, Germany.
Etapa 2. Aceeaşi procedură realizată prin infectarea culturilor celulare Vero, HEp-2 cu conţinut vezicular de la pacienţii nominalizaţi şi prelucrarea ulterioară prin tehnici de imunofluorescenţă pentru evidenţierea markerilor antigenici ai virusului herpetic HSV1⁄2 în absenţa soluţiei de aciclovir în concentraţie IC>2,0 µg/ml. Stage 2. The same procedure performed by infecting Vero, HEp-2 cell cultures with vesicular content from nominated patients and subsequent processing by immunofluorescence techniques to highlight antigenic markers of the herpes virus HSV1⁄2 in the absence of acyclovir solution at an IC concentration of >2.0 µg/ml.
Etapa 3. Procedură similară primului test, deosebindu-se prin inocularea concomitentă a conţinutului veziculelor recoltate de la pacienţii cu infecţie herpetică în volum de 0,1 ml şi a serurilor de neutralizare a activităţii infecţioase a virusului herpetic HSV1⁄2 de asemenea în volum de 0,1 ml (obţinute la Institutul de virusologie ,,D.I. Ivanovski”), Moscova, Federaţia Rusă, în culturi celulare. Stage 3. Procedure similar to the first test, differing by the simultaneous inoculation of the contents of vesicles collected from patients with herpes infection in a volume of 0.1 ml and of sera neutralizing the infectious activity of the herpes virus HSV1⁄2 also in a volume of 0.1 ml (obtained at the Institute of Virology "D.I. Ivanovski"), Moscow, Russian Federation, into cell cultures.
Etapa 4. Ultimul test-martor, similar primului, a inclus toate elementele enumerate de identificare a virusului herpetic HSV1⁄2 şi de evidenţiere a posibilelor tulpini aciclovir-rezistente în culturile celulare nominalizate, dar inoculate cu placebo (0,1 ml ser fiziologic). Stage 4. The last control test, similar to the first, included all the listed elements for identifying the herpes virus HSV1⁄2 and highlighting possible acyclovir-resistant strains in the nominated cell cultures, but inoculated with placebo (0.1 ml of physiological serum).
Tabelul 1 Table 1
Interpretarea rezultatelor obţinute prin tehnici de imunofluorescenţă privind diferenţierea tulpinilor de HSV1⁄2 în TK+ şi TK-, după metodologia propusă de autori în timp de 12…24 ore Interpretation of the results obtained by immunofluorescence techniques regarding the differentiation of HSV1⁄2 strains into TK+ and TK-, according to the methodology proposed by the authors within 12…24 hours
Testele utilizate Infecţie herpetică (IH) cu virusurile HSV 1⁄2 *IH cu virusul HSV, TK- ** IH cu virusul HSV,TK+ *** Absenţa IH cu HSV Test -1 Test -2 Test -3 Test -4 (+) (+) (-) (-) (-) (+) (-) (-) (-) (-) (-) (-)Tests used Herpes infection (HI) with HSV 1⁄2 viruses *HI with HSV virus, TK- ** HI with HSV virus, TK+ *** Absence of HI with HSV Test -1 Test -2 Test -3 Test -4 (+) (+) (-) (-) (-) (+) (-) (-) (-) (-) (-)
Remarcă: * pacient cu infecţie herpetică (IH), etiologic cauzată de virusul HSV1⁄2, rezistent la tratamentul cu aciclovir; ** pacient cu IH determinată de HSV1⁄2 sensibil la tratamentul cu aciclovir, *** absenţa infecţiei herpetice la pacienţii investigaţi. Note: * patient with herpes infection (HI), etiologically caused by the HSV1⁄2 virus, resistant to acyclovir treatment; ** patient with HI determined by HSV1⁄2 sensitive to acyclovir treatment, *** absence of herpetic infection in the investigated patients.
Pentru aprobarea metodei propuse de tratament al infecţiei cu virusul Herpes simplex s-au efectuat investigaţii clinice şi paraclinice pentru aprecierea eficacităţii metodei originale de tratament în clinicile de boli infecţioase la copii şi adulţi ,,Spitalul clinic municipal de boli contagioase la copii”, Spitalul clinic de boli infecţioase „T. Ciorbă”, Chişinău. Pe parcursul perioadei de studiu au fost examinaţi 85 bolnavi în vârstă de la 2 până la 18 ani cu diagnosticul clinic prezumtiv - infecţie herpetică labială. To approve the proposed method of treatment of Herpes simplex virus infection, clinical and paraclinical investigations were carried out to assess the effectiveness of the original treatment method in the infectious diseases clinics for children and adults, "Municipal Clinical Hospital for Contagious Diseases in Children", "T. Ciorba" Clinical Hospital for Infectious Diseases, Chisinau. During the study period, 85 patients aged 2 to 18 years with the presumptive clinical diagnosis of labial herpes infection were examined.
Diagnosticul clinic prezumtiv de infecţie herpetică labială a fost confirmat prin investigaţii paraclinice: evidenţierea markerilor Ag HSV1⁄2 şi Ag HSV1⁄2 în elementele de structură ale sângelui (limfocite, leucocite şi eritrocite) la bolnavii din ambele loturi prin tehnici de imunofluorescenţă cu anticorpi monoclonali, marcaţi cu fluoresceină. Ponderea bolnavilor cu infecţie herpetică, etiologic cauzată de HSV ″ confirmată prin tehnicile nominalizate a constituit 85,9%. Ulterior bolnavii au fost repartizaţi în două loturi martor şi experimental, fiind completate succesiv, odată cu internarea lor în staţionar, care au inclus 43 şi, respectiv, 42 pacienţi. Loturile au fost formate după metoda selecţiei aleatorii, iar studiul a fost realizat prin metoda dublu-orb. În lotul martor tratamentul iniţiat după examenul primar clinic a inclus aciclovir 15 mg/kg per os, de 5 ori/zi, timp de 7...12 zile suplimentat cu ung. Florenal 0,5%, Tebrofen 3,0% şi Oxolin 1,0% local şi cu administrare de vitamine din grupa B, acid ascorbic, în unele cazuri după necesitate au fost aplicate sedative şi analgetice. Supravegherea clinică şi investigaţiile paraclinice efectuate la sfârşitul curei de tratament demonstrează că la o pondere considerabilă de bolnavi 85,7% din lotul martor s-au redus semnificativ termenele de apariţie a noi erupţii veziculoase, însoţite de simptome de arsură şi prurit, constituind în medie 3,7± 0,2 zile faţă de 10,7±0,5 zile identificate la 6 (14,3%) pacienţi din acelaşi lot, ulterior identificaţi ca rezistenţi la tratamentul cu aciclovir (TK-). Acest grup de pacienţi, în număr de 6, de asemenea a punctat un număr semnificativ de recidive 5 (cazuri) cu termene prelungite de disconfort general (dureri, mialgii, nevralgii etc.) până la 12, inclusiv absenţa procesului de epitelizare (tab. 2). The presumptive clinical diagnosis of labial herpes infection was confirmed by paraclinical investigations: highlighting the Ag HSV1⁄2 and Ag HSV1⁄2 markers in the structural elements of the blood (lymphocytes, leukocytes and erythrocytes) in patients from both groups by immunofluorescence techniques with monoclonal antibodies, labeled with fluorescein. The share of patients with herpetic infection, etiologically caused by HSV ″ confirmed by the nominated techniques was 85.9%. Subsequently, the patients were divided into two control and experimental groups, being completed successively, with their hospitalization, which included 43 and, respectively, 42 patients. The groups were formed according to the random selection method, and the study was conducted by the double-blind method. In the control group, the treatment initiated after the primary clinical examination included acyclovir 15 mg/kg per os, 5 times/day, for 7...12 days supplemented with ointment. Florenal 0.5%, Tebrofen 3.0% and Oxolin 1.0% locally and with administration of vitamins from group B, ascorbic acid, in some cases sedatives and analgesics were applied as needed. Clinical surveillance and paraclinical investigations performed at the end of the treatment course demonstrate that in a considerable proportion of patients 85.7% of the control group the time of appearance of new vesicular eruptions, accompanied by symptoms of burning and itching, was significantly reduced, constituting an average of 3.7± 0.2 days compared to 10.7±0.5 days identified in 6 (14.3%) patients from the same group, later identified as resistant to acyclovir treatment (TK-). This group of patients, numbering 6, also showed a significant number of relapses 5 (cases) with prolonged periods of general discomfort (pain, myalgia, neuralgia, etc.) up to 12, including the absence of the epithelialization process (tab. 2).
La 5 din cei 6 pacienţi, de asemenea au fost atestate suprainfecţii bacteriene, ceea ce a dus la o creştere a duratei de manifestare a erupţiilor, durata medie a spitalizării constituind 16…19 zile. In 5 of the 6 patients, bacterial superinfections were also observed, which led to an increase in the duration of the eruptions, with the average duration of hospitalization being 16…19 days.
Tabelul 2 Table 2
Indicii clinici de bază evidenţiaţi la pacienţii cu infecţie herpetică labială după aplicarea tratamentului existent nemodificat Basic clinical indices highlighted in patients with labial herpes infection after applying the existing treatment without modification
Nr. Indici Lotul martor - 43 bolnavi P IH cu HSV1⁄2 TK+ IH cu HSV1⁄2 TK- 37(86,1%) 6(13,9%) Abs M±m Abs M±m 1 Durata spitalizării 9…10 8,5±0,3 18…21 20,5±0,3 <0,05 2 Termenele de apariţie a erupţiilor noi (zile) 3…4 3,7±0,2 9…12 10,7±0,5 3 Numărul recidivelor (cazuri ) 2 5 4 Termenele dispariţei disconfortului general (dureri, nevralgii, mialgii etc.) (zile) 6…7 6,4±0,3 14…16 13,4±0,7 5 Suprainfecţii bacteriene (cazuri) 1 6 6 Termenele de epitelizare (zile) 15…17 16±1,0 25…30 27,3±1,0 No. Indices Control group - 43 patients P IH with HSV1⁄2 TK+ IH with HSV1⁄2 TK- 37(86.1%) 6(13.9%) Abs M±m Abs M±m 1 Duration of hospitalization 9…10 8.5±0.3 18…21 20.5±0.3 <0.05 2 Time of appearance of new eruptions (days) 3…4 3.7±0.2 9…12 10.7±0.5 3 Number of relapses (cases) 2 5 4 Time of disappearance of general discomfort (pain, neuralgia, myalgia, etc.) (days) 6…7 6.4±0.3 14…16 13.4±0.7 5 Bacterial superinfections (cases) 1 6 6 Time of epithelialization (days) 15…17 16±1.0 25…30 27.3±1.0
Remarcă: Monitorizarea clinică şi a unor indici paraclinici a fost efectuată în termen de până la 3…6 luni. Note: Clinical monitoring and some paraclinical indices were performed for up to 3…6 months.
Durata spitalizării pentru bolnavii cu infecţie herpetică, rezistenţi la tratamentul cu aciclovir (TK-) a constituit de la 18 până la 21 zile, comparativ cu 9…10 zile, interval caracteristic pentru bolnavii care au răspuns la tratamentul cu aciclovir. În paralel cu monitorizarea clinico-virusologică s-a efectuat testarea unor indici ai imunităţii celulare la finele curei de tratament cu aciclovir, prin utilizarea analizei imunoenzimatice Capcelia (BIORAD) SUA cu aprecierea numărului total de limfocite şi a subclaselor T-helper şi T-supresor. Rezultatele examinării paraclinice a bolnavilor din lotul martor sunt expuse în tab. 3. The duration of hospitalization for patients with herpes infection, resistant to acyclovir treatment (TK-) was from 18 to 21 days, compared to 9…10 days, a characteristic interval for patients who responded to acyclovir treatment. In parallel with the clinical-virological monitoring, testing of cellular immunity indices was performed at the end of the acyclovir treatment course, using the Capcelia (BIORAD) immunoenzymatic analysis USA with the assessment of the total number of lymphocytes and the T-helper and T-suppressor subclasses. The results of the paraclinical examination of patients in the control group are presented in tab. 3.
Tabelul 3 Table 3
Indicii paraclinici de bază la bolnavii cu infecţie herpetică labială examinaţi în lotul martor după tratamentul existent, nemodificat Basic paraclinical indices in patients with labial herpes infection examined in the control group after existing, unchanged treatment
Nr. Indicii imunităţii celulare Lotul martor - 43 bolnavi P IH cu HSV1⁄2 TK+ IH cu HSV1⁄2 TK- 37 (86,1%) 6 (13,9%) Abs M±m Abs M±m 1 2 3 4 T-limfocite total T-limfocite (helperi) T-limfocite (supresori) Indicele T-helperi/T-supresori 37 1,1±0,1 0,81±0,07 0,29±0,02 2,79±0,03 6 1,2±0,1 0,65±0,06 0,50±0,04 1,3±0,2 <0,05No. Cellular immunity indices Control group - 43 patients P IH with HSV1⁄2 TK+ IH with HSV1⁄2 TK- 37 (86.1%) 6 (13.9%) Abs M±m Abs M±m 1 2 3 4 Total T-lymphocytes T-lymphocytes (helpers) T-lymphocytes (suppressors) T-helper/T-suppressor index 37 1.1±0.1 0.81±0.07 0.29±0.02 2.79±0.03 6 1.2±0.1 0.65±0.06 0.50±0.04 1.3±0.2 <0.05
Remarcă: Valorile indicilor paraclinici sunt exprimate astfel, spre exemplu T-limfocite (helper) =0,81± 0,07x109/L. Note: The values of paraclinical indices are expressed as follows, for example T-lymphocytes (helper) =0.81± 0.07x109/L.
Evaluarea rezultatelor obţinute demonstrează că la bolnavii cu infecţie herpetică labială, care au răspuns la tratamentul cu aciclovir (TK+) după 7…12 zile s-a înregistrat o sporire a numărului de T-limfocite helper şi o reducere a T-limfocitelor supresoare, comparativ cu indicii analogi la bolnavii care au fost identificaţi ca rezistenţi la aciclovir (TK-). Indicatorul T-helper / T-supresor de asemenea reflectă această tendinţă, pentru bolnavii care au răspuns la tratamentul cu aciclovir. The evaluation of the obtained results demonstrates that in patients with herpes labialis infection, who responded to acyclovir treatment (TK+) after 7…12 days, an increase in the number of T-helper lymphocytes and a reduction in T-suppressor lymphocytes was recorded, compared to analogous indices in patients who were identified as acyclovir resistant (TK-). The T-helper / T-suppressor indicator also reflects this trend, for patients who responded to acyclovir treatment.
Identificarea markerului Ag HSV1⁄2 prin tehnici de imunofluorescenţă în elementele de structură ale sângelui (leucocite, limfocite, eritrocite) la bolnavii din lotul martor, care au răspuns la tratamentul cu aciclovir după 12 zile a demonstrat o reducere semnificativă a incidenţei de la 85,9% (37) până la 39,5% (17). P<0,05. Identification of the HSV1⁄2 Ag marker by immunofluorescence techniques in the structural elements of the blood (leukocytes, lymphocytes, erythrocytes) in patients in the control group who responded to acyclovir treatment after 12 days demonstrated a significant reduction in incidence from 85.9% (37) to 39.5% (17). P<0.05.
La cei 6 bolnavi rezistenţi la tratamentul cu aciclovir, marcherii Ag HSV1⁄2 au fost identificaţi până şi după tratament. In the 6 patients resistant to acyclovir treatment, HSV1⁄2 Ag markers were identified even after treatment.
Investigarea clinică şi paraclinică a pacienţilor din lotul experimental cu infecţie herpetică labială, în număr de 42 bolnavi, a inclus aceiaşi parametri, cu excepţia că la iniţierea examenului clinic şi a diagnosticului de laborator pentru confirmarea infecţiei cu HSV1⁄2 a fost inclusă metodologia de diferenţiere a tulpinilor de virus Herpes simplex în TK+ şi TK- (tab. 1). Includerea testului de apreciere a sensibilităţii la aciclovir a tulpinilor de virus HSV1⁄2 concomitent cu iniţierea examenului clinic ne-a permis să identificăm din start timp de 12…24 ore 5 pacienţi cu infecţie herpetică, rezistenţi la tratamentul cu aciclovir (TK-). Astfel a devenit real, începând cu ziua a doua de tratament, de a substitui produsul antiviral aciclovir cu viferon - 500.000 pentru bolnavii cu infecţie herpetică labială, cauzată de HSV1⁄2 (TK-), nemodificând tratamentul simptomatic. Viferonul este un produs antiviral, care include interferon IFN - a 2 uman recombinat şi vitaminele E şi C pe ulei de cacao. The clinical and paraclinical investigation of the patients in the experimental group with labial herpes infection, in the number of 42 patients, included the same parameters, except that at the initiation of the clinical examination and laboratory diagnosis to confirm the HSV1⁄2 infection, the methodology for differentiating Herpes simplex virus strains into TK+ and TK- was included (tab. 1). The inclusion of the acyclovir sensitivity assessment test of HSV1⁄2 virus strains simultaneously with the initiation of the clinical examination allowed us to identify from the start for 12…24 hours 5 patients with herpetic infection, resistant to acyclovir treatment (TK-). Thus, it became real, starting with the second day of treatment, to substitute the antiviral product acyclovir with viferon - 500,000 for patients with labial herpes infection, caused by HSV1⁄2 (TK-), without modifying the symptomatic treatment. Viferon is an antiviral product, which includes recombinant human interferon IFN-a 2 and vitamins E and C in cocoa oil.
Aşadar, începând cu ziua a doua de tratament, la cei 5 bolnavi cu infecţie herpetică HSV1⁄2 (TR-) din lotul experimental, produsul antiviral aciclovir a fost substituit cu viferon - 500.000, suplimentat cu ung. Florenal, Tebrofen, Oxolin local şi cu administrarea de vitamine (grupa B), acid ascorbic şi aplicarea după caz a unor sedative şi analgetice pe parcursul a 7…12 zile. Rezultatul eficacităţii metodei de tratament modificate a bolnavilor cu infecţie herpetică labială cu o durată de până la 12 zile sunt expuse în tab. 4. Therefore, starting with the second day of treatment, in the 5 patients with HSV1⁄2 herpes infection (TR-) from the experimental group, the antiviral product acyclovir was substituted with viferon - 500,000, supplemented with Florenal, Tebrofen, Oxolin ointment locally and with the administration of vitamins (group B), ascorbic acid and the application of sedatives and analgesics as appropriate for 7…12 days. The results of the effectiveness of the modified treatment method of patients with labial herpes infection with a duration of up to 12 days are presented in tab. 4.
Tabelul 4 Table 4
Indicii clinici de bază evidenţiaţi la pacienţii din lotul experimental cu infecţie herpetică labială după aplicarea tratamentului etiotrop modificat Basic clinical indices highlighted in patients from the experimental group with labial herpes infection after applying modified etiotropic treatment
Nr. Indici Lotul experimental - 42 bolnavi P IH cu HSV1⁄2 TK+ IH cu HSV1⁄2 TK- 37 (88,1%) 5 (11,9) Abs M±m Abs M±m 1 Durata spitalizării 9…11 8,8±0,3 8…9 7,2±0,3 <0,05 2 Termenele de apariţie a erupţiilor noi (zile) 2…3 3,0±0,2 2…3 3,0±0,2 3 Numărul recidivelor (cazuri) 3 4 Termenele dispariţiei disconfortului general (dureri, nevralgii, mialgii etc.) zile 5…7 6,1±0,3 4…6 5,7±0,3 5 Suprainfecţii bacteriene (cazuri) 1 6 Termenele de epitelizare (zile) 14…16 15,7±1,0 13…15 14,5±1,0No. Indices Experimental group - 42 patients P IH with HSV1⁄2 TK+ IH with HSV1⁄2 TK- 37 (88.1%) 5 (11.9) Abs M±m Abs M±m 1 Duration of hospitalization 9…11 8.8±0.3 8…9 7.2±0.3 <0.05 2 Time of appearance of new eruptions (days) 2…3 3.0±0.2 2…3 3.0±0.2 3 Number of relapses (cases) 3 4 Time of disappearance of general discomfort (pain, neuralgia, myalgia, etc.) days 5…7 6.1±0.3 4…6 5.7±0.3 5 Bacterial superinfections (cases) 1 6 Time of epithelialization (days) 14…16 15.7±1.0 13…15 14.5±1.0
Remarcă: Monitorizarea clinică şi a unor indici paraclinici a fost efectuată în termen de până la 3…6 luni. Note: Clinical monitoring and some paraclinical indices were performed for up to 3…6 months.
Rezultatele obţinute, expuse în tabelul 5, demonstrează că practic nu este o diferenţă semnificativă între valoarea indicilor clinici evidenţiaţi la bolnavii cu infecţie herpetică labială HSV1⁄2 (TK+) şi la pacienţii cu HSV1⁄2 (TK-), ultimii evidenţiaţi ca aciclovir rezistenţi la tratamentul din start cu aciclovir. Contrar lotului martor, indicii din lotul experimental, în special pentru cei 5 bolnavi (TK-), cărora din start li s-a modificat schema de tratament, demonstrează o tendinţă de ameliorare mai rapidă a valorilor indicilor nominalizaţi. Indicii paraclinici evidenţiaţi pentru bolnavii cu infecţie herpetică labială din lotul experimental de asemenea confirmă eficacitatea sporită a metodei de tratament propuse comparativ cu metoda din cadrul celei mai apropiate soluţii. Rezultatele investigaţiilor de laborator ce ţin de statutul imun tisular sunt expuse în tab. 5. The results obtained, presented in Table 5, demonstrate that there is practically no significant difference between the values of the clinical indices shown in patients with labial herpes infection HSV1⁄2 (TK+) and in patients with HSV1⁄2 (TK-), the latter shown to be acyclovir resistant to treatment with acyclovir from the start. Contrary to the control group, the indices in the experimental group, especially for the 5 patients (TK-), whose treatment regimen was modified from the start, demonstrate a tendency for faster improvement of the values of the named indices. The paraclinical indices shown for patients with labial herpes infection in the experimental group also confirm the increased efficacy of the proposed treatment method compared to the method within the closest solution. The results of laboratory investigations related to the tissue immune status are presented in Tab. 5.
Tabelul 5 Table 5
Indicii paraclinici de bază la pacienţii cu infecţie herpetică labială examinaţi în lotul experimental de tratament în varianta propusă Basic paraclinical indices in patients with labial herpes infection examined in the experimental treatment group in the proposed variant
Nr. Indicii imunităţii celulare Lotul experimental - 42 bolnavi P IH cu HSV1⁄2 TK+ IH cu HSV1⁄2 TK- 37 (88,1%) 5 (11,9%) Abs M±m Abs M±m 1 2 3 4 T-limfocite total T-limfocite (helperi) T-limfocite (supresori) Indicele T-helperi /T-supresori 37 1,2±0,1 0,79±0,65 0,27 ±0,02 2,92±0,31 5 1,2±0,1 0,81±0,07 0,28±0,02 2,89 ±0,30 <0,05No. Cellular immunity indices Experimental group - 42 patients P IH with HSV1⁄2 TK+ IH with HSV1⁄2 TK- 37 (88.1%) 5 (11.9%) Abs M±m Abs M±m 1 2 3 4 Total T-lymphocytes T-lymphocytes (helpers) T-lymphocytes (suppressors) T-helper/T-suppressor index 37 1.2±0.1 0.79±0.65 0.27 ±0.02 2.92±0.31 5 1.2±0.1 0.81±0.07 0.28±0.02 2.89 ±0.30 <0.05
Remarcă: Valorile indicilor paraclinici sunt exprimate astfel, spre exemplu T-limfocite total=1,2±0,1x109 /L. Note: The values of paraclinical indices are expressed as follows, for example total T-lymphocytes=1.2±0.1x109 /L.
Astfel, la finele tratamentului (după 7…12 zile) cu aciclovir pentru pacienţii cu infecţie herpetică (TK+) şi cu viferon - 500.000 pentru pacienţii cu virus Herpes simplex HSV1⁄2 (TK-) nu a fost evidenţiată o diferenţă statistic semnificativă între indicii caracteristici pentru statutul imun tisular. În ambele cazuri indicii au revenit în limitele normei în termene similare. Thus, at the end of treatment (after 7…12 days) with acyclovir for patients with herpes infection (TK+) and with viferon - 500,000 for patients with Herpes simplex virus HSV1⁄2 (TK-) no statistically significant difference was revealed between the indices characteristic of tissue immune status. In both cases, the indices returned to normal within similar time frames.
Identificarea markerului Ag HSV1⁄2 prin tehnici de imunofluorescenţă cu anticorpi monoclonali anti HSV1⁄2 marcaţi cu fluoresceină la finele tratamentului (după 7…12 zile) a demonstrat o reducere semnificativă a prezenţei markerului nominalizat în elementele de structură ale sângelui bolnavilor cu infecţie herpetică de la 85,9% (36) până 38% (17) P=0,05. Markerul Ag HSV1⁄2 a fost identificat după tratamentul etiotrop cu viferon - 500.000 iniţiat practic după examenul clinic la 2 bolnavi din 5 testaţi prezumtiv şi apreciaţi ca aciclovir rezistenţi (TK-). Identification of the HSV1⁄2 Ag marker by immunofluorescence techniques with monoclonal anti-HSV1⁄2 antibodies labeled with fluorescein at the end of treatment (after 7…12 days) demonstrated a significant reduction in the presence of the named marker in the structural elements of the blood of patients with herpes infection from 85.9% (36) to 38% (17) P=0.05. The HSV1⁄2 Ag marker was identified after etiotropic treatment with viferon - 500,000 initiated practically after the clinical examination in 2 patients out of 5 presumptively tested and assessed as acyclovir resistant (TK-).
Algoritmul tratamentului etiotrop existent al infecţiei cu virusul Herpes simplex, tip 1⁄2 este următorul: The existing etiotropic treatment algorithm for Herpes simplex virus infection, type 1⁄2, is as follows:
I. Examenul clinic al pacientului cu infecţie herpetică (prima zi); I. Clinical examination of the patient with herpetic infection (first day);
II. Iniţierea tratamentului cu aciclovir (începând cu prima zi). Diagnosticul de laborator (12…48 ore); II. Initiation of acyclovir treatment (starting on the first day). Laboratory diagnosis (12…48 hours);
III. Evaluarea tratamentului etiotrop (simptomatic după 7…12 zile); III. Evaluation of etiotropic treatment (symptomatic after 7…12 days);
IV. Modificarea tratamentului în urma eşecului cauzat de virusul herpetic aciclovir rezistent. Iniţierea unui nou tratament cu un alt antiviral, inclusiv viferon, timidinkinază - independent (după 7…12 zile); IV. Modification of treatment following failure caused by acyclovir-resistant herpes virus. Initiation of a new treatment with another antiviral, including viferon, thymidine kinase - independently (after 7...12 days);
V. Evaluarea tratamentului etiotrop antiherpes (simptomatic) după 14…24 zile iniţiat cu alt produs antiviral - foscarnet. V. Evaluation of etiotropic antiherpes treatment (symptomatic) after 14…24 days initiated with another antiviral product - foscarnet.
Algoritmul tratamentului etiotrop propus al infecţiei cu virusul Herpes simplex, tip 1⁄2 este următorul: The proposed etiotropic treatment algorithm for Herpes simplex virus infection, type 1⁄2, is as follows:
I. Examenul clinic al pacientului cu infecţie herpetică (prima zi); I. Clinical examination of the patient with herpetic infection (first day);
II. Iniţierea tratamentului cu aciclovir (începând cu prima zi). Diagnosticul de laborator (12…48 ore). Diferenţierea tulpinilor de virus herpetic în aciclovir sensibile (TK+) şi rezistente (TK-) după metoda propusă în 12…24 ore; II. Initiation of acyclovir treatment (starting on the first day). Laboratory diagnosis (12…48 hours). Differentiation of herpes virus strains into acyclovir sensitive (TK+) and resistant (TK-) according to the proposed method within 12…24 hours;
III. Modificarea tratamentului iniţiat cu aciclovir după 24 ore urmare a identificării tulpinilor de virus herpetic aciclovir rezistente (TK-). Substituirea aciclovirului cu un alt produs antiviral etiotrop, inclusiv viferon, timidinkinază - independent; III. Modification of treatment initiated with acyclovir after 24 hours following the identification of acyclovir-resistant (TK-) herpes virus strains. Substitution of acyclovir with another etiotropic antiviral product, including viferon, thymidine kinase - independently;
IV. Evaluarea tratamentului etiotrop (simptomatic) după 7…12 zile. IV. Evaluation of etiotropic (symptomatic) treatment after 7…12 days.
Modificarea schemei de tratament al infecţiei herpetice cu HSV1⁄2 în baza includerii unui element nou propus în diagnosticul de laborator, care ne permite în timp de 12…24 ore diferenţierea tulpinilor de virus Herpes simplex HSV1⁄2 în TK+ şi TK-, oferă posibilitatea de a iniţia tratamentul etiotrop practic peste 12…24 ore după realizarea examenului clinic, contrar 7…12 zile, urmare a algoritmului existent de tratament. The modification of the treatment regimen for herpes infection with HSV1⁄2 based on the inclusion of a new element proposed in laboratory diagnosis, which allows us to differentiate the Herpes simplex virus strains HSV1⁄2 into TK+ and TK- within 12…24 hours, offers the possibility of initiating etiotropic treatment practically 12…24 hours after the clinical examination, contrary to 7…12 days, following the existing treatment algorithm.
Rezultatele obţinute demonstrează că modificarea metodei cunoscute (prototip) de tratament cu aciclovir al infecţiei cu HSV1⁄2, prin includerea la etapa iniţială de examinare clinică a unui modul nou de diagnostic pentru diferenţierea virusurilor herpetice HSV1⁄2 în sensibile (TK+) şi rezistente (TK-) a dus la sporirea semnificativă a eficacităţii tratamentului comparativ cu metoda cunoscută. Acest efect benefic include: revenirea la parametrii normali într-un interval de timp cu mult mai redus a indicilor clinici şi paraclinici, excluderea utilizării nejustificate a produsului antiviral etiotrop - aciclovir, care poate dezvolta efecte adverse nedorite (cristalizarea aciclovirului în tubii renali, vomă, greaţă, diaree, somnolenţă, halucinaţii, convulsii, ameţeli etc.), reducerea riscului de avansare a infecţiei cu herpes în forme severe (encefalite), cronice, latente urmare a absenţei răspunsului virusologic scontat la tratamentul cu aciclovir, diminuarea semnificativă a duratei de spitalizare a pacienţilor, inclusiv a costului tratamentului. The results obtained demonstrate that the modification of the known (prototype) method of acyclovir treatment of HSV1⁄2 infection, by including at the initial stage of clinical examination a new diagnostic module for differentiating HSV1⁄2 herpes viruses into sensitive (TK+) and resistant (TK-) led to a significant increase in the effectiveness of the treatment compared to the known method. This beneficial effect includes: the return to normal parameters in a much shorter time interval of clinical and paraclinical indices, the exclusion of the unjustified use of the etiotropic antiviral product - acyclovir, which can develop undesirable adverse effects (crystallization of acyclovir in the renal tubules, vomiting, nausea, diarrhea, drowsiness, hallucinations, convulsions, dizziness, etc.), the reduction of the risk of progression of herpes infection to severe (encephalitis), chronic, latent forms due to the absence of the expected virological response to acyclovir treatment, the significant reduction in the duration of hospitalization of patients, including the cost of treatment.
Pentru ilustrarea eficacităţii tratamentului infecţiei herpetice labiale, etiologic cauzate de virusul Herpes simplex prezentăm următoarele cazuri clinice. To illustrate the effectiveness of the treatment of labial herpes infection, etiologically caused by the Herpes simplex virus, we present the following clinical cases.
Exemplul 1. Bolnavul B., 2 ani 7 luni, a fost internat pe data de 18.10.2014 cu acuze la senzaţie de arsuri, dureri, usturime la faţă în regiunea buzelor, disconfort, slăbiciune generală, febră 38,1°C. În regiunea labială (subnazală) au fost identificate multiple vezicule cu lichid transparent, care au apărut pe parcursul ultimelor 12…24 ore. Ganglionii limfatici periferici erau măriţi în volum. În anamneză s-a stabilit apariţia în premieră a acestei patologii. Investigaţiile de laborator realizate în primele 24…48 ore au identificat prezenţa markerului Ag HSV-1 în elementele de structură ale sângelui şi în lichidul vezicular, markerul anti-HSV-1 igM a fost negativ, iar anti-HSV-1 igG pozitiv. Concomitent prin testul propus s-a demonstrat că tulpina virusului herpetic HSV-1 este sensibilă la aciclovir (TK+). În urma investigaţiilor efectuate s-a stabilit diagnosticul clinic de infecţie herpetică primară, etiologic cauzată de HSV-1 (TK+). În continuare pacientul a fost testat la markerii paraclinici: hemoleucograma (18.10.2014) Hb-106 g/L, Er-3,5x1012/L, leuc-6,0x109/L, nes-2%, segm-60%, eoz-1%, limf-28%, mon-9%, VSH-12 mm/oră şi repetat (22.10.2014) Hb-128 g/L, Er-4,5x1012/L, leuc-5,1x109/L, nes-0%, segm-35%, eoz-2%, limf-55%, mon-8%, VSH-10 mm/oră; urograma şi coprograma fiind în limitele normei. Example 1. Patient B., 2 years 7 months old, was admitted on 18.10.2014 with complaints of burning sensation, pain, stinging of the face in the lip region, discomfort, general weakness, fever 38.1°C. In the labial (subnasal) region, multiple vesicles with transparent liquid were identified, which appeared during the last 12…24 hours. The peripheral lymph nodes were enlarged in volume. The anamnesis established the first appearance of this pathology. Laboratory investigations performed in the first 24…48 hours identified the presence of the HSV-1 Ag marker in the structural elements of the blood and in the vesicular fluid, the anti-HSV-1 igM marker was negative, and the anti-HSV-1 igG was positive. At the same time, the proposed test demonstrated that the HSV-1 herpes virus strain is sensitive to acyclovir (TK+). Following the investigations, the clinical diagnosis of primary herpetic infection, etiologically caused by HSV-1 (TK+), was established. The patient was further tested for paraclinical markers: hemoleukogram (18.10.2014) Hb-106 g/L, Er-3.5x1012/L, leuk-6.0x109/L, nes-2%, segm-60%, eoz-1%, lymph-28%, mon-9%, ESR-12 mm/hour and repeated (22.10.2014) Hb-128 g/L, Er-4.5x1012/L, leuk-5.1x109/L, nes-0%, segm-35%, eoz-2%, lymph-55%, mon-8%, ESR-10 mm/hour; urogram and coprogram were within normal limits.
Testarea indicilor imunităţii celulare prin analiza imunoenzimatică (Capcelia-BIORAD) a evidenţiat următoarele: T-limfocite(total)-0,6/x109; T-limfocite (helperi)-0,31x109; T-limfocite (supresori)-0,29x109, T-helperi /T-supresori-1,06. S-a instituit tratamentul cu ung. Florenal 0,5%, ung. Herpevir 2,5%, aplicaţii topice şi aciclovir, 15 mg/kg, per os, de 5 ori/zi, timp de 7 zile. Ca rezultat al tratamentului apariţia de noi vezicule herpetice s-a stopat peste 48 ore, iar erupţiile au dispărut peste 5…6 zile, concomitent dispărând şi acuzele locale. Identificarea markerului Ag HSV-1 în elementele structurale ale sângelui după finalizarea tratamentului a demonstrat absenţa acestuia. Markerii anti-HSV1⁄2 igM şi anti-HSV1⁄2 igG în serul bolnavului au rămas nemodificaţi. Indicii imunităţii celulare au demonstrat următoarele: T-limfocite (total)-1,2x109/L, T-limfocite (helperi)-0,80x109/L, T-supresor-0,29x109/L; T-helperi/T-supresori-2,75. Supravegherea clinică pe parcursul perioadei de până la 3 luni a pacientului nu a evidenţiat apariţia de recidive. Testing of cellular immunity indices by immunoenzymatic analysis (Capcelia-BIORAD) revealed the following: T-lymphocytes (total) - 0.6/x109; T-lymphocytes (helpers) - 0.31x109; T-lymphocytes (suppressors) - 0.29x109, T-helpers /T-suppressors - 1.06. Treatment was initiated with Florenal ointment 0.5%, Herpevir ointment 2.5%, topical applications and acyclovir, 15 mg/kg, orally, 5 times/day, for 7 days. As a result of the treatment, the appearance of new herpetic vesicles stopped after 48 hours, and the eruptions disappeared after 5...6 days, simultaneously disappearing local complaints. Identification of the HSV-1 Ag marker in the structural elements of the blood after the completion of the treatment demonstrated its absence. The anti-HSV1⁄2 igM and anti-HSV1⁄2 igG markers in the patient's serum remained unchanged. Cellular immunity indices demonstrated the following: T-lymphocytes (total)-1.2x109/L, T-lymphocytes (helpers)-0.80x109/L, T-suppressor-0.29x109/L; T-helpers/T-suppressors-2.75. Clinical surveillance during the period of up to 3 months of the patient did not reveal the occurrence of relapses.
Exemplul 2. Bolnavul G., 2 ani 3 luni, a fost internat pe data 15.10.2014 cu acuze severe de dureri, prurit, senzaţie de usturime, febră 37,6 °C, disconfort, slăbiciune generală însoţite de multiple vezicule cu lichid transparent localizate în regiunea perinazală a feţei, apărute recent în ultimele 12…24 ore. În anamneză a acuzat prezumtiv suportarea unei infecţii respiratorii acute însoţite de febră, dureri de cap şi în gât, nas înfundat, ochi înroşiţi (hiperemiaţi), disconfort general. Ganglionii limfatici periferici erau măriţi în volum. Maladia a evoluat cu recidive şi remisii, acum recidivând a 4-a oară. Din anamneză s-a constatat că acutizarea posibil este legată de statutul imun compromis. Prezumtiv a fost stabilit diagnosticul ,,infecţie herpetică nazo-labială”. Investigaţiile de laborator efectuate în primele 12…24 ore au identificat prezenţa markerului Ag HSV-1 în elementele de structură ale sângelui şi în lichidul veziculelor, markerul anti-HSV 1 IgM a fost negativ, iar anti-HSV 1 IgG pozitiv. Concomitent prin testul propus la etapa primară, în primele 12…24 ore de examinare clinică a bolnavului prin teste paraclinice s-a demonstrat că tulpina virusului herpetic HSV-1 este rezistentă la aciclovir (TK-). Astfel diagnosticul clinic a fost formulat în următoarea redacţie: ,,infecţie herpetică nazo-labială recidivantă, etiologic cauzată de HSV-1, rezistent la aciclovir (TK-)”. În continuare pacientul a fost examinat la următorii marcheri paraclinici: hemoleucograma (16.10.2014) Hb-137 g/L, Er-4,5x1012/L, Leuc-6,3x109/L, neseg-2%, segm-50%, eoz-4%, limf-38%, mon-6%, VSH-12 mm/oră; examenul biochimic al sângelui ureea-5,29 mmol/L, creatinina-68,4 mmol/L, ALT-13,4U/L, AST-66,2U/L, bilirubina generală-6,1 µmol/L, amilaza-56,0U/L; urograma şi coprograma (în normă). Indicii imunităţii celulare: T-limfocite(total)-0,80x109; T-limfocite (helperi)-0,48x109; T-limfocite (supresori)- 0,35x109; T- helperi /T-supresori -1,37. Luând în consideraţie rezistenţa tulpinii de HSV-1 la aciclovir evidenţiată în primele 12…24 ore de la examinarea clinică s-a instituit tratamentul cu aplicarea ung. Florenal 0,5%, Tebrofen, Oxolin şi etiopatogenic cu viferon-500.000 UA/1supp., per rectum, de 2 ori /zi, timp de 10 zile, cura repetată. Acuzele la dureri, prurit, disconfort au dispărut peste 3…4 zile, erupţiile peste 5…6 zile. Investigaţiile de laborator după finalizarea tratamentului au demonstrat următoarele: absenţa markerului Ag HSV-1 în elementele de structură ale sângelui, anti-HSV1⁄2 IgM pozitiv şi anti HSV 1⁄2 IgG-pozitiv. Indicii imunităţii celulare au prezentat următoarele valori: T-limfocite (total)-1,2x109; limfocite (helperi)-0,84x109; limfocite (supresori)-0,33x109; T-helperi/T-supresori-2,55. Supravegherea clinică pe parcursul perioadei de până la 3 luni a pacientului nu a evidenţiat apariţia de noi recidive. Example 2. Patient G., 2 years 3 months old, was admitted on 15.10.2014 with severe complaints of pain, itching, burning sensation, fever 37.6 °C, discomfort, general weakness accompanied by multiple vesicles with clear fluid located in the perinasal region of the face, recently appeared in the last 12…24 hours. In the anamnesis, he alleged suffering from an acute respiratory infection accompanied by fever, headache and sore throat, stuffy nose, red (hyperemic) eyes, general discomfort. The peripheral lymph nodes were enlarged in volume. The disease evolved with relapses and remissions, now relapsing for the 4th time. From the anamnesis, it was found that the exacerbation is possibly related to the compromised immune status. The diagnosis of “naso-labial herpetic infection” was presumptively established. Laboratory investigations carried out in the first 12…24 hours identified the presence of the HSV-1 Ag marker in the structural elements of the blood and in the fluid of the vesicles, the anti-HSV 1 IgM marker was negative, and anti-HSV 1 IgG was positive. At the same time, through the test proposed at the primary stage, in the first 12…24 hours of clinical examination of the patient, paraclinical tests demonstrated that the HSV-1 herpes virus strain is resistant to acyclovir (TK-). Thus, the clinical diagnosis was formulated in the following wording: "recurrent naso-labial herpetic infection, etiologically caused by HSV-1, resistant to acyclovir (TK-)". The patient was further examined for the following laboratory markers: hematology (16.10.2014) Hb-137 g/L, Er-4.5x1012/L, Leuc-6.3x109/L, non-seg-2%, segm-50%, eoz-4%, lymph-38%, mon-6%, ESR-12 mm/hour; biochemical blood test urea-5.29 mmol/L, creatinine-68.4 mmol/L, ALT-13.4U/L, AST-66.2U/L, total bilirubin-6.1 µmol/L, amylase-56.0U/L; urogram and coprogram (normal). Cellular immunity indices: T-lymphocytes (total)-0.80x109; T-lymphocytes (helpers)-0.48x109; T-lymphocytes (suppressors) - 0.35x109; T-helpers/T-suppressors -1.37. Taking into account the resistance of the HSV-1 strain to acyclovir evidenced in the first 12…24 hours after the clinical examination, treatment was instituted with the application of Florenal 0.5% ointment, Tebrofen, Oxolin and etiopathogenic with viferon-500,000 UA/1 supp., per rectum, 2 times / day, for 10 days, repeated course. Complaints of pain, itching, discomfort disappeared after 3…4 days, rashes after 5…6 days. Laboratory investigations after the completion of the treatment demonstrated the following: absence of the HSV-1 Ag marker in the structural elements of the blood, anti-HSV1⁄2 IgM positive and anti HSV 1⁄2 IgG-positive. Cellular immunity indices showed the following values: T-lymphocytes (total) - 1.2x109; lymphocytes (helpers)-0.84x109; lymphocytes (suppressors)-0.33x109; T-helpers/T-suppressors-2.55. Clinical surveillance during the period of up to 3 months of the patient did not reveal the appearance of new relapses.
Astfel, includerea modului de diferenţiere a tulpinilor de virus herpetic HSV1⁄2 în (TK+) şi (TK-) la etapa de examinare primară a bolnavului (în primele 12…24 ore) din start face posibilă modificarea algoritmului tratamentului, favorizând în continuare o evoluţie favorabilă a procesului patologic, o recuperare mai rapidă a bolnavilor cu o reducere semnificativă a duratei de manifestare a principalelor semne clinice şi paraclinice în lotul experimental comparativ cu lotul martor. Thus, including the differentiation method of HSV1⁄2 herpes virus strains into (TK+) and (TK-) at the stage of the patient's primary examination (in the first 12…24 hours) from the start makes it possible to modify the treatment algorithm, further favoring a favorable evolution of the pathological process, a faster recovery of patients with a significant reduction in the duration of manifestation of the main clinical and paraclinical signs in the experimental group compared to the control group.
1. Герпесвирусная инфекция. Под редакцией В.П. Малого. Москва, Медицинская практика, 2009, p. 36-57 1. Herpesvirus infection. Under the editorship of V.P. Small. Moscow, Medical practice, 2009, p. 36-57
2. Исаков В.А., Архипова Е.И., Исаков Д.В. Герпесвирусные инфекции человека (руководство для врачей). Санкт-Петербург, 2006, p. 276-282 2. Isakov V.A., Arkhipova E.I., Isakov D.V. Herpesvirus infections of a person (guide for doctors). Saint Petersburg, 2006, p. 276-282
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MDS20150006A MD995Z (en) | 2015-01-27 | 2015-01-27 | Method for treating Herpes simplex virus type 1 and 2-induced infection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MDS20150006A MD995Z (en) | 2015-01-27 | 2015-01-27 | Method for treating Herpes simplex virus type 1 and 2-induced infection |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| MD995Y MD995Y (en) | 2016-01-31 |
| MD995Z true MD995Z (en) | 2016-08-31 |
Family
ID=55235465
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MDS20150006A MD995Z (en) | 2015-01-27 | 2015-01-27 | Method for treating Herpes simplex virus type 1 and 2-induced infection |
Country Status (1)
| Country | Link |
|---|---|
| MD (1) | MD995Z (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU491387A1 (en) * | 1974-07-18 | 1975-11-15 | Всесоюзный Научно-Исследовательский Институт Лекарственных Растений | Flavonoid compounds exhibiting antiherpetic activity |
| SU1246005A1 (en) * | 1984-07-13 | 1986-07-23 | Московский научно-исследовательский институт вирусных препаратов | Method of estimating pharmacological activity of chemical drugs for curing genital herpes |
| SU1530189A1 (en) * | 1988-04-15 | 1989-12-23 | Научно-Исследовательский Институт Эпидемиологии И Микробиологии Им.Почетного Акад.Н.Ф.Гамалеи | Method of treatment of recurring herpes simplex |
| SU1720649A1 (en) * | 1981-08-06 | 1992-03-23 | Институт Биоорганической Химии Ан Узсср | Antiherpetic remedy "megosine" |
| MD1051C2 (en) * | 1996-12-02 | 1999-05-31 | Centrul National Stiintifico-Practic De Igiena Si Epidemiologie Al Ministerului Sanatatii Din Republica Moldova | Antiherpetic remedy |
| MD1473F2 (en) * | 1998-06-02 | 2000-05-31 | Centrul National Stiintifico P | Antiherpetic remedy |
| RU2492861C1 (en) * | 2012-05-29 | 2013-09-20 | Закрытое акционерное общество "Вектор-Медика" (ЗАО "Вектор-Медика") | Method of treating recurrent genital herpes with chronic fatigue symptoms |
-
2015
- 2015-01-27 MD MDS20150006A patent/MD995Z/en not_active IP Right Cessation
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU491387A1 (en) * | 1974-07-18 | 1975-11-15 | Всесоюзный Научно-Исследовательский Институт Лекарственных Растений | Flavonoid compounds exhibiting antiherpetic activity |
| SU1720649A1 (en) * | 1981-08-06 | 1992-03-23 | Институт Биоорганической Химии Ан Узсср | Antiherpetic remedy "megosine" |
| SU1246005A1 (en) * | 1984-07-13 | 1986-07-23 | Московский научно-исследовательский институт вирусных препаратов | Method of estimating pharmacological activity of chemical drugs for curing genital herpes |
| SU1530189A1 (en) * | 1988-04-15 | 1989-12-23 | Научно-Исследовательский Институт Эпидемиологии И Микробиологии Им.Почетного Акад.Н.Ф.Гамалеи | Method of treatment of recurring herpes simplex |
| MD1051C2 (en) * | 1996-12-02 | 1999-05-31 | Centrul National Stiintifico-Practic De Igiena Si Epidemiologie Al Ministerului Sanatatii Din Republica Moldova | Antiherpetic remedy |
| MD1473F2 (en) * | 1998-06-02 | 2000-05-31 | Centrul National Stiintifico P | Antiherpetic remedy |
| RU2492861C1 (en) * | 2012-05-29 | 2013-09-20 | Закрытое акционерное общество "Вектор-Медика" (ЗАО "Вектор-Медика") | Method of treating recurrent genital herpes with chronic fatigue symptoms |
Non-Patent Citations (2)
| Title |
|---|
| Герпесвирусная инфекция. Под редакцией В.П. Малого. Москва, Медицинская практика, 2009, p. 36-57 * |
| Исаков В.А., Архипова Е.И., Исаков Д.В. Герпесвирусные инфекции человека (руководство для врачей). Санкт-Петербург, 2006, p. 276-282 * |
Also Published As
| Publication number | Publication date |
|---|---|
| MD995Y (en) | 2016-01-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| LAWRENCE et al. | Genital herpes simplex virus infections: current concepts in diagnosis, therapy, and prevention | |
| Whitley et al. | Clinical management of herpes simplex virus infections: past, present, and future | |
| Blough et al. | Successful treatment of human genital herpes infections with 2-deoxy-D-glucose | |
| Azher et al. | Herpes simplex keratitis: challenges in diagnosis and clinical management | |
| Piperi et al. | Management of oral herpes simplex virus infections: The problem of resistance. A narrative review | |
| Whitley et al. | Pathogenesis and disease | |
| Dworkin et al. | Recommendations for the management of herpes zoster | |
| Chou et al. | Ganciclovir ophthalmic gel 0.15% for the treatment of acute herpetic keratitis: background, effectiveness, tolerability, safety, and future applications | |
| Yeung-Yue et al. | Herpes simplex viruses 1 and 2 | |
| Fontenelle et al. | Effect of topical ophthalmic application of cidofovir on experimentally induced primary ocular feline herpesvirus-1 infection in cats | |
| Miller et al. | Effect of prophylactic valacyclovir on the presence of human herpesvirus DNA in saliva of healthy individuals after dental treatment | |
| Mustafa et al. | Herpes simplex virus infections, Pathophysiology and Management | |
| Thurman et al. | Herpes simplex virus and HIV: genital infection synergy and novel approaches to dual prevention | |
| Desai et al. | A rare case of varicella-zoster virus reactivation following recovery from COVID-19 | |
| US20220088403A1 (en) | Methods And Compositions For Treating Coronavirus | |
| Ivanov et al. | Antivirals for the treatment of Monkeypox: utilization in the general and HIV-positive population and gaps for research. A short narrative review | |
| Stoopler et al. | Update on herpesvirus infections | |
| Mehrmal et al. | Diagnostic methods and management strategies of herpes simplex and herpes zóster infections | |
| Goodman et al. | Prospective double-blind evaluation of topical adenine arabinoside in male herpes progenitalis | |
| Lewin et al. | Surveillance for feline herpesvirus type 1 mutation and development of resistance in cats treated with antiviral medications | |
| Spertus et al. | Effects of orally administered raltegravir in cats with experimentally induced ocular and respiratory feline herpesvirus-1 infection | |
| Diaz-Mitoma et al. | Detection of viral DNA to evaluate outcome of antiviral treatment of patients with recurrent genital herpes | |
| Ikematsu et al. | Clinical outcome of laninamivir octanoate hydrate for influenza in the 2013–2014 Japanese season | |
| Stiles et al. | Effects of λ-carrageenan on in vitro replication of feline herpesvirus and on experimentally induced herpetic conjunctivitis in cats | |
| Koh et al. | Zosteriform herpes simplex |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FG9Y | Short term patent issued | ||
| MK4Y | Short term patent expired |