Avances en el Diagnóstico y Tratamiento del HSV

8/9/2019 Avances en el Diagnstico y Tratamiento del HSV

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Drogas Antiherpticas2000

1990

1980

1970

1960

1950

Vidarabina

Idoxuridina

Cytosine-arabinosida

Aciclovir

Trifluridina

Valaciclovir

Famciclovir

Foscarnet

Resiquimod

DocosanolCidofovir


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Membrana Celular

Aciclovir

Timidina

Kinase (TK)

Monofosfatode Aciclovir

Trifosfato

de Aciclovir

Prmio Nobel1988


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Anlogos dos NucleosdeosAnlogos dos Nucleosdeos

Mecanismo de AoMecanismo de Ao

A

CV

CCCC

C C C

GGG

G G G

A A A A A

A AT T T

T T

T

T

TA


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Clssico: Valaciclovir X Aciclovir Arch Dermatol. 1998 Feb;134(2):185-91.

A randomized, placebo-controlled comparison of oral valacyclovir and acyclovirin immunocompetent patients with recurrent genital herpes infections. TheValaciclovir International Study Group.

Tyring SK, Douglas JM Jr, Corey L, Spruance SL, Esmann J.

OBJECTIVE: To compare valacyclovir with acyclovircompare valacyclovir with acyclovirin the treatment of recurrentin the treatment of recurrentgenital herpesgenital herpes infection. DESIGN: A multicenter, double-blind, placebo-controlled,randomized study. PATIENTS: One thousand two hundred patientsOne thousand two hundred patients with recurrentgenital herpes simplex infections. INTERVENTIONS: Patients self-initiated oral therapywith 1000 mg of valacyclovir hydrochloride twice daily, 200 mg of acyclovir 5 times daily,or placebo for 5 days. RESULTS: Both drugs were significantly more effective thanplacebo in speeding resolution of herpetic episodes (median duration, 4.8, 4.8, and 5.9days, respectively); the hazards ratios for valacyclovir and acyclovir vs placebo were 1.66

(95% confidence interval [CI], 1.38-2.01) and 1.71 (95% CI, 1.41-2.06) (both P < .001).Similarly, valacyclovir and acyclovir significantly hastened lesion healing (pain durationwas shorter in valacyclovir- and acyclovir-treated patients (median, 2 vs 3 days). Viralshedding stopped 2.55 times faster in patients treated with valacyclovir and 2.24 timesfaster in patients treated with acyclovir than in patients treated with placebo. Abortedepisodes, in which lesions did not progress beyond the macule or papule stage, tendedto occur in more patients treated with valacyclovir (25.9%) or acyclovir (24.8%) than inpatients treated with placebo (19.8%). The nature, severity, and frequency of adverseevents did not differ among the 3 treatment groups. CONCLUSIONS: Twice-dailyTwice-dailyvalacyclovir was as effective and well tolerated in the treatment of recurrent genitalvalacyclovir was as effective and well tolerated in the treatment of recurrent genitalherpes simplex virus infection as 5-times-daily acyclovirherpes simplex virus infection as 5-times-daily acyclovir.
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Tyring%20SK%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Douglas%20JM%20Jr%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Corey%20L%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Spruance%20SL%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Esmann%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Esmann%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Spruance%20SL%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Corey%20L%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Douglas%20JM%20Jr%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Tyring%20SK%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus


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Algumas Vantagens do Valaciclovir

Expert Rev Anti Infect Ther. 2006 Jun;4(3): 367-76.

Valacyclovir for the treatment of genital herpes.

Brantley JS, Hicks L, Sra K, Tyring SK.

Genital herpes is the most prevalent STD infection. While sometimes mild in severity, it canbe a distressing and painful chronic condition. While there is no cure for these conditions,

treatment to alleviate symptoms, suppress recurrences and reduce transmission has beendrastically improved over the past 20 years with the use of guanine nucleoside antivirals,such as valacyclovir, the highly bioavailable prodrug of acyclovir, and famciclovir, a highlybioavailable prodrug of penciclovir. Clinical trials involving approximately 10,000 patients(including patients from nongenital herpes studies, such as herpes zoster) have assessedthe safety and efficacy of valacyclovir in the treatment of initial genital herpes outbreaks,episodic treatment of recurrent episodes and daily suppressive therapy. It was shown thatvalacyclovir has similar efficacy to acyclovir in the episodic and suppressive treatment of

genital herpes. Valacyclovir is the only antiviral drug approved for a once-daily doseValacyclovir is the only antiviral drug approved for a once-daily doseof suppressive therapy for genital herpesof suppressive therapy for genital herpes, as well as the only antiviral drug US FDAas well as the only antiviral drug US FDAapproved for a 3-day regimen of episodic treatment of recurrent genital herpesapproved for a 3-day regimen of episodic treatment of recurrent genital herpes. Inaddition, valacyclovir is also indicated in the reduction of the sexual transmission of herpessimplex virus infection and for the treatment of herpes labialis. In herpes zoster,In herpes zoster,valacyclovir is more effective than acyclovir or placebo (and as equally effective asvalacyclovir is more effective than acyclovir or placebo (and as equally effective asfamciclovir) in shortening the length and severity of herpes zoster-associated painfamciclovir) in shortening the length and severity of herpes zoster-associated painand postherpetic neuralgiaand postherpetic neuralgia. Valacyclovir has an acceptable safety profile in patients with

herpes simplex and herpes zoster.
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Brantley%20JS%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Hicks%20L%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Sra%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Tyring%20SK%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Tyring%20SK%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Sra%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Hicks%20L%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Brantley%20JS%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus


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Famciclovir para Herpes Genital

Recorrente

Clin Infect Dis. 2006 Jan 1;42(1):8-13.

Single-day, patient-initiated famciclovir therapy for recurrent genital herpes: arandomized, double-blind, placebo-controlled trial.

Aoki FY, Tyring S, Diaz-Mitoma F, Gross G, Gao J, Hamed K.

BACKGROUND: Orally administered antiviral therapy for genital herpes improves the timeto lesion healing and resolves symptoms during an outbreak. Although traditional therapyfor a recurrent episode for healthy adults has consisted of twice-daily dosing for 5 days,recent studies have indicated that shorter courses of antiviral therapy are effective.METHODS: This multicenter, randomized, double-blind, placebo-controlled studycompared single-day, patient-initiated oral famciclovir (1000 mg given twice daily) withplacebo for the treatment of recurrent genital herpes. Patients were instructed to initiate

therapy within 6 h after onset of prodromal symptoms or genital herpes lesions. RESULTS:Famciclovir reduced (P < .001) the time to healing of non-aborted lesions, compared withplacebo. The proportion of patients with aborted lesions was larger in the famciclovir groupthan in the placebo group (23.3% vs. 12.7%; P = .003). Adverse events in the famciclovirgroup were infrequent overall; most were of mild-to-moderate severity and were similar toadverse events in the placebo group. CONCLUSIONS: A single-day regimen of patient-A single-day regimen of patient-initiated famciclovir treatment was well tolerated and safeinitiated famciclovir treatment was well tolerated and safe, and the healing of recurrentgenital herpes lesions occurred approximately 2 days faster than with placebo. Moreover,single-day famciclovir treatment stopped the development or progression of lesions beyondthe papule stage.
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Aoki%20FY%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Tyring%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Diaz-Mitoma%20F%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Gross%20G%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Gao%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Hamed%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Hamed%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Gao%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Gross%20G%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Diaz-Mitoma%20F%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Tyring%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Aoki%20FY%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus


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ANTIVIRAIS

SISTMICOSHERPES SIMPLES

Aciclovir (200mg 5xd) 3-

5d(R) e 7-10d(P)Valaciclovir (500mg 2xd)

3-5d(R) e 7-10d(P)

Famciclovir (125mg 2xd)3-5d(R) e 7-10d(P)

HERPES ZOSTERAciclovir (400-800mg 5

x dia) 7-10 diaValaciclovir (500mg-

1gr 3 x dia) 7-10 dia

Famciclovir (250mg 3x dia) 7-10 dia


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Avaliao por Meta-Anlise daTerapia Supressiva Anti-HSV

J Am Acad Dermatol. 2007 Aug;57(2):238-46.

A meta-analysis to assess the efficacy of oral antiviral treatment to preventgenital herpes outbreaks.

Lebrun-Vignes B, Bouzamondo A, Dupuy A, Guillaume JC, Chosidow O.

BACKGROUND: Efficacy of oral antiviral therapies, ie, acyclovir, valacyclovir (VACV),and famciclovir, for suppression of recurrent genital herpes was studied at differentdoses and regimens. METHODS: The selected trials were: parallel randomizedclinical trials testing prophylactic oral antiviral treatment of genital herpes versusplacebo in immunocompetent and nonpregnant patients. RESULTS: FourteenFourteenrandomized clinical trials were selected, including a total of 6158 patientsrandomized clinical trials were selected, including a total of 6158 patients. Theglobal relative risk of developing at least one recurrence during the study was reducedby 47% (95% confidence interval 45%-49%) in antiviral drug groups compared withthe placebo. The best evaluated regimens, with comparable efficacies, were giventwice daily, ie, acyclovir (400 mg twice day), VACV (250 mg twice daily), andfamciclovir (250 mg 2x day), or once day. CONCLUSION: The results of this meta-The results of this meta-analysis confirmed the high clinical efficacy of oral acyclovir, valacyclovir, oranalysis confirmed the high clinical efficacy of oral acyclovir, valacyclovir, orfamciclovir for prophylaxis against recurrent genital herpesfamciclovir for prophylaxis against recurrent genital herpes.
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Lebrun-Vignes%20B%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Bouzamondo%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Dupuy%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Guillaume%20JC%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Chosidow%20O%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Chosidow%20O%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Guillaume%20JC%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Dupuy%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Bouzamondo%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Lebrun-Vignes%20B%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus


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Atividade Anti-HSV da Lisina

J Inherit Metab Dis. 1998 Apr;21(2):103-11.

Varicella and varicella immunity in patients with lysinuric protein intolerance.

Lukkarinen M, Salonen K, Ruuskanen O, Lauteala T, Nuutinen M, Simell O.

Two patients with lysinuric protein intolerance (LPI) had near-fatalTwo patients with lysinuric protein intolerance (LPI) had near-fatalgeneralized varicella infectiongeneralized varicella infection with severe interstitial pneumonitis, hepatitis,decreased platelet count, bleeding and hypoalbuminaemia. Active haemolysisresulted in anaemia and massive haemoglobinuria. Serum lactate dehydrogenaseactivity and ferritin concentration, which in patients with LPI in normalcircumstances exceed the upper reference values 3-folds to 10-fold, increased to >10,000 U/L and > 10,000 micrograms/L, respectively. The patients were treatedwith fresh frozen plasma, red-cell transfusions and intravenous acyclovir for 14days, and recovered clinically in a month. Retrospectively, 3 of the 32 otherRetrospectively, 3 of the 32 otherknown Finnish patients with LPI had had varicella infection that had beenknown Finnish patients with LPI had had varicella infection that had beenmore severe than that in the other children in the family or in subjects in themore severe than that in the other children in the familyor in subjects in theneighbourhood and had led to hospital admissionneighbourhood and had led to hospital admission. We suggest that patientswith LPI who have no varicella zoster antibodies should be treated with acyclovir ifexposed to varicella and should be (re)vaccinated against chickenpox.
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Lukkarinen%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22N%C3%A4nt%C3%B6-Salonen%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Ruuskanen%20O%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Lauteala%20T%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Nuutinen%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Simell%20O%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Simell%20O%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Nuutinen%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Lauteala%20T%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Ruuskanen%20O%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22N%C3%A4nt%C3%B6-Salonen%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Lukkarinen%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus


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L-Lisina Ajuda a Prevenir

Recorrncias do HSVAltern Med Rev. 2006 Jun;11(2):93-101.

Natural remedies for Herpes simplex.

Gaby AR.

Herpes simplex is a common viral infection of the skin or mucousmembranes. The lesions caused by this infection are often painful,burning, or pruritic, and tend to recur in most patients. Short-termtreatment with acyclovir can accelerate the healing of an acute outbreak,and continuous acyclovir therapy is often prescribed for people withfrequent recurrences. While this drug can reduce the recurrence rate by

60-90 percent, it can also cause a wide array of side effects, includingrenal failure, hepatitis, and anaphylaxis. Safe and effective alternativesare therefore needed. There is evidence that certain dietarycertain dietarymodificationsmodifications and natural substances may be useful for treating activemay be useful for treating activeHerpes simplex lesions or preventing recurrencesHerpes simplex lesions or preventing recurrences. Treatmentsdiscussed include lysinelysine, vitamin C, zinc, vitamin E, adenosine

monophosphate, and lemon balm (Melissa officinalis).
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Gaby%20AR%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Gaby%20AR%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus


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Manejo das Recorrencias doHSV

ACV 600 mg/dia

ACV 400 mg/dia

ACV 200 mg/dia

ACV 200 mg seg-sex

ACV 200 mg 3 x sem

L-Lisine 125 mg/dia

L-Lisine 250 mg/dia

L-Lisine 500 mg/dia

L-Lisine 1g/dia

L-Lisine 1g/dia

Restrio Alimentar: Arginina chocolate, sementes e abacaxi. Aumentam a

Disponibilidade de lisina: carne vermelha e laticnios.

Cada etapa do tratamento deve ser continuada por pelo menos 30 dias.


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Publicao Original Sobre o

Uso de IFN + ACVAntiviral Res. 1998 May;38(2):95-106.

Combined effects of interferon-alpha and acyclovir on herpes simplex virus type 1DNA polymerase and alkaline DNase.

Taylor JL, Tom P, O'Brien WJ.

Treatment of cells with combinations of human interferon-alpha (IFN-alpha) and thenucleoside analog, acyclovir (ACV), leads to the synergistic inhibition of herpes simplexvirus type 1 (HSV-1) replication. We have examined the effect of these agents on thereplication of HSV-1 DNA and the synthesis of early viral enzymes to understand themechanism(s) responsible for this synergistic activity. Combination treatment with 100IU/ml IFN-alpha and 5 microM ACV led to HSV-1 DNA levels more than 8-fold lower thanin cells treated with ACV alone, while IFN-alpha treatment alone had no detectable effecton viral DNA synthesis. Steady state levels of DNA polymerase were reduced

approximately 50% by IFN-alpha and 25% by ACV, but combination treatment did notdecrease enzyme levels to an extent greater than the sum of these effects. In contrast, theactivity of another early viral enzyme, alkaline DNase, was reduced less than 20% by IFN-alpha alone or combination treatment and was unaffected by ACV treatment. No decreasein the level of mRNA encoding either enzyme was detected in IFN-alpha-treated cellsalthough ACV treatment reduced polymerase mRNA levels. These studies suggest thatThese studies suggest thatthe synergistic anti-HSV activities of IFN-alpha with ACV could lead to the reductionthe synergistic anti-HSV activities of IFN-alpha with ACV could lead to the reductionin production of viral early enzymesin production of viral early enzymes, especially DNA polymerase.
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Taylor%20JL%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Tom%20P%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22O%27Brien%20WJ%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22O%27Brien%20WJ%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Tom%20P%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Taylor%20JL%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus


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Novas Drogas


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Inibidores da Primase-Helicase do HSV

BAY 57-1293 is a member of the thiazolylsulfonamides, a recently

discovered class of nonnucleosidic compounds with potent

antiherpetic activity in vitro and in vivo, based on a novel

mechanism of action. It inhibited the replication of HSVinhibited the replication of HSV. BAY 57-1293 targets the viral primase-helicase complextargets the viral primase-helicase complex and inhibits itsATPase activity.

BAY 57-1293 is also active against acyclovir-resistant mutantalso active against acyclovir-resistant mutantstrainsstrains which carry mutations in the tkor DNApolgenes. Thecompound showed favorable pharmacokinetics in all speciesinvestigated (mouse, rat, and dog), with an oral bioavailability of

>60% and an elimination half-life of >6 h.

Reading Suggestion: Kleymann G. Helicase primase: targeting the

Achilles heel of HSV. Antivir Chem Chemother 2004;15 (3): 135-40.


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Inibidores da Helicase Primase Antiviral Res. 2007 Jul;75(1):30-5.

The helicase primase inhibitor, BAY 57-1293 shows potent therapeutic antiviral activitysuperior to famciclovir in BALB/c mice infected with herpes simplex virus type 1.

Biswas S, Jennens L, Field HJ.

BAY 57-1293 represents a new class of potent inhibitors of herpes simplex virus (HSV) thattarget the virus helicase primase complex. The present study was conducted using thezosteriform infection model in BALB/c mice. The helicase primase inhibitor, BAY 57-1293 wasshown to be highly efficacious in this model. The beneficial effects of therapy were obtainedrapidly (within 2 days) although the onset of treatment was delayed for 1 day after virusinoculation. The compound given orally, or intraperitoneally once per day at a dose of 15 mg/kgfor 4 successive days was equally effective or superior to a much higher dose of famciclovir(1mg/ml, i.e. approximately 140-200mg/kg/day) given in the drinking water for 7 consecutivedays, which, in our hands, is the most effective method for administering famciclovir to mice. In

contrast to the vehicle-treated infected mice, all mice that received antiviral therapy lookednormal and active with no mortality, no detectable loss of weight and no marked change in earthickness. BAY 57-1293 and famciclovir reduced the virus titers in the skin to below the level ofdetection by days 3 and 7 post infection, respectively. In both BAY 57-1293 and famciclovir-treated mice, infectious virus titers in the ear pinna and brainstem remained below the level ofdetection. Consistent with these findings, BAY 57-1293also showed a potent antiviral effectalso showed a potent antiviral effectin an experiment involving a small number of severely immunocompromisedin an experiment involving a small number of severely immunocompromised athymic-nude BALB/c mice.
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Biswas%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Jennens%20L%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Field%20HJ%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Field%20HJ%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Jennens%20L%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Biswas%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus


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Antivir Chem Chemother. 2007;18(1):35-48. Superior efficacy of helicase-primase inhibitor BAY 57-1293 for herpes

infection and latency in the guinea pig model of human genital herpesdisease.

Baumeister J, Fischer R, Eckenberg P, Henninger K,Ruebsamen-Waigmann H, Kleymann G.

The efficacy of BAY 57-1293, a novel non-nucleosidic inhibitor of herpes simplexvirus 1 and 2 (HSV-1 and HSV-2), bovine herpesvirus and pseudorabies virus, wasstudied in the guinea pig model of genital herpes in comparison with the licenseddrug valaciclovir (Valtrex). Early therapy with BAY 57-1293 almost completelysuppressed the symptoms of acute HSV-2 infection, and reduced virus sheddingand viral load in the sacral dorsal root ganglia by up to three orders of magnitude,resulting in decreased latency and a greatly diminished frequency of subsequentrecurrent episodes. In contrast, valaciclovir showed only moderate effects in this

set of experiments. Compared with valaciclovir, BAY 57-1293 halved the timenecessary for complete healing. Moreover, the onset of action was fast, so thatonly very few animals developed new lesions after treatment commenced. Finally,in a study addressing the treatment of recurrent disease in animals whose primaryinfection had remained untreated BAY 57-1293 was efficient in suppressing theepisodes. In summary, superior potency and efficacy of BAY 57-1293 oversuperior potency and efficacy of BAY 57-1293 overstandard treatment with valaciclovir was demonstratedstandard treatment with valaciclovir was demonstrated in relevant animalmodels of human genital herpes disease in terms of abrogating an HSV infection,

reducing latency and the frequency of subsequent recurrences.

Inibidores da Helicase Primase
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Baumeister%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Fischer%20R%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Eckenberg%20P%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Henninger%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Ruebsamen-Waigmann%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Kleymann%20G%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Kleymann%20G%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Ruebsamen-Waigmann%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Henninger%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Eckenberg%20P%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Fischer%20R%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Baumeister%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus


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VACINAS ANTI-HERPTICAS:

MITO OU REALIDADE?

Prof. Dr. Omar Lupi


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Escherichia coli

plasmdeo

SV40CMV


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A Engenharia Gentica Deve Muito

aos Vrus Bacterifagos

Plasmdeo


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Plasmdeo

pcDNA3.1/HisA,B,C

PCMV T7His6EKBGH f1 SV40N SV40 ColE1 AmppA ori ori pA

PCMV = Permite a expresso em qualquer clula de mamferosT7= Fornece a orientao correta para a transcrio do plasmdeo

His6= Permitir a purificao da protena recombinante com Nq++

EK=Permite remover a etiqueta de polihistidina c/ enteroquinase

BGHpA=Transcrio eficiente do RNAmF1ori = Permitir o resgate do DNA de hlice simplesSV40ori-N-SV40pA=transcrio do gene p/ resistncia neomicinaColE1 = replicon que permitir replicao eficaz na E.coli

Amp = Gene que codifica resistncia -lactamase na E.coli


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Cerebral

Pele

Nasal

Vaginal

0 10 20 30 4Perodo de Acompanhamento

(dias)

Sobrevida infeco Herptica


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Cerebral

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Vaginal


(dias)



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Cerebral

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Cerebral

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Vaginal

0 10 20 30 4

Sobrevida infeco HerpticaSobrevida infeco Herptica

Perodo de Acompanhamento

(dias)


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Cerebral

0 10 20 30 4



(dias)

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(dias)


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Desenho do Estudo O protocolo envolveu 284 pacientes HIV e HSV-2 negativos, checados por

Western-blot (WB).

Os pacientes foram contactados por rdio e jornais aps aprovao doComit de tica da University of Texas.

Receberam imunizao de forma randomizada e duplo-cega: Vacina (gB2-gC2-gD2+ MF59) ou Placebo (tampo citrato + MF59).

Imunizao IM no incio do acompanhamento e reforos c/ 1 e 3 meses(30g de cada glicoptna). Tempo total de acompanhamento de 9 meses,reavaliados a cada 3 sem.

Soroconverso analisada atravs da mensurao de Ac neutralizantespara o HSV-2 (Reao de microneutralizao dependente decomplemento) e de Ac ligantes para gB-C-D do HSV-2 (ELISA).

Cultura viral foi realizada nos casos clnicos suspeitos.


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Vacinao Antiherptica

Resposta Imune Celular e


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Resposta Imune Celular eHumoral


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Homens vacinados

Homens placebo

Mulheres

vacinadasMulheres

PlaceboHomens

vacinadosHomens

lacebo

Ttulos de Acs Neutralizadores


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Situao Atual Vacinas anti-HSV

A vacina muito imunog-nica ebem tolerada. A tec-nologiaenvolvida segura e bemdominada.

A excelente resposta no sexo

feminino parece dever-se afisiopatogenia prpria do HSV-2nas mulheres.

Uma vacinao antiherpti-caeficaz dever ser feita, com pelomenos, 3 doses.

H proteo cruzada para herpeslabial.

A vacina parece eficaz no controledas crises mas no na proteocontra novos casos de herpesgenital.

A via IM pode no ser a mais

adequada. Imunizao via mucosa(intra-nasal) pode ser mais efetiva.

Imunidade humoral parece no sersuficiente, isolada-mente, paraconferir imunidade ao HSV-2.

S


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Update em Vacina Anti-HSV Curr Opin Investig Drugs. 2006 Feb;7(2):136-41.

Vaccines for herpes simplex virus infections.

Koelle DM.

Infections with herpes simplex virus (HSV) type 1 (HSV-1) and type 2 (HSV-

2) can have serious medical consequences. Although antiviral medicationscan suppress symptomatic disease, asymptomatic shedding andtransmission, they neither cure nor alter the natural history of HSVinfections. Manipulation of the immune response is one potential method todecrease disease burden. Current research on prophylactic and therapeuticvaccination approaches is discussed in this review, with a focus oncompounds that have entered clinical trials or that display novelcompositions or proposed mechanisms of action. One such vaccine is an

alum and monophosphoryl lipid A-adjuvanted subunit glycoprotein D2vaccine that has demonstrated activity in the prevention of HSV-2has demonstrated activity in the prevention of HSV-2infection and disease in HSV-uninfected women in a phase III clinicalinfection and disease in HSV-uninfected women in a phase III clinicaltrial.trial. Further confirmatory clinical trials of this vaccine are currentlyunderway. Other vaccine formats also in development include attenuatedlive or replication-incompetent HSV-2 strains and technologies that targetvirus-specific CD8 T-cell responses.
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Koelle%20DM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Koelle%20DM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus


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Hum Vaccin. 2007 Jun 3;3(6).

Effectiveness and Efficiency of Imperfect Therapeutic HSV-2 Vaccines.

Schwartz EJ, Bodine EN, Blower S.

Background: Efforts are currently underway to develop therapeutic vaccines for HerpesSimplex Virus type 2 (HSV-2). Methods: We use a mathematical model to predict the

potential public health impact of imperfect, therapeutic HSV-2 vaccines. We evaluatevaccine effectiveness and efficiency for the general population in the United States whereHSV-2 prevalence is currently 22%. We assume that therapeutic vaccines will produce twotherapeutic benefits in vaccinated infected-individuals: (1) the rate of viral reactivation willdecrease (hence infected-individuals will experience fewer viral shedding episodes), and (2)the average length of the viral shedding episodes will be shortened. In addition, we assumethat therapeutic vaccines will benefit uninfected individuals by reducing viral shedding in(and hence transmission from) vaccinated infected-individuals. Results: Our predictionsOur predictionsshow that therapeutic vaccines could substantially reduce HSV-2 epidemics byshow that therapeutic vaccines could substantially reduce HSV-2 epidemics by

reducing new infections by 77% and preventing 0.84 new infections for eachreducing new infections by 77% and preventing 0.84 new infections for eachvaccinated individual.vaccinated individual. These vaccines could prevent 212,600 (median; IQR, 156,064-288,558) new infections after only one year. We show that increased effectiveness andefficiency are more strongly correlated with a vaccine-induced reduction in transmissionprobability than with either of the two therapeutic benefits that accrue directly to the infectedindividuals (specifically, the reduction in episode length and number of episodes).Conclusions: We suggest that current vaccine development efforts target mechanisms thatreduce viral shedding (thereby reducing transmission) thus providing both a beneficialtherapeutic and a beneficial epidemic-level impact. Our results also demonstrate that

therapeutic vaccines would be substantially more useful than prophylactic vaccines forepidemic control.

Update em Vacina Anti-HSV
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Schwartz%20EJ%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Bodine%20EN%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Blower%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Blower%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Bodine%20EN%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Schwartz%20EJ%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus


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HERPESVIRUS, CLULAS-TRONCO ETERAPIA GENTICA

Clulas-Tronco


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Cultura clulas-tronco

feto

skin liver neurons heart eyes etc

Clulas-Tronco


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HSV como Vetor de EngenhariaGentica em Ds Cardacas

Cell Transplant. 2006;15(1):67-74.

Engineered cell therapy for sustained local myocardial delivery of nonsecreted proteins.

Bian J, Kiedrowski M, Mal N, Forudi F, Penn MS.

Novel strategies for the treatment of congestive heart failure have taken the form of gene and cellNovel strategies for the treatment of congestive heart failure have taken the form of gene and celltherapy to induce angiogenesistherapy to induce angiogenesis, optimize calcium handling by cardiac myocytes, or regeneratedamaged myocardial tissue. Arguably both gene- and cell-based therapies would be benefited by havingthe ability to locally deliver specific transcription factors and other usually nonsecreted proteins to cells inthe surrounding myocardial tissue. The herpes simplex virus type 1 (HSV-1)The herpes simplex virus type 1 (HSV-1)has been shown tohas been shown tomediate protein intercellular trafficking to mammalian cells and finally localize into the nucleus,mediate protein intercellular trafficking to mammalian cells and finally localize into the nucleus,which makes it a useful cargo-carrying functional protein in cell-based gene therapy.which makes it a useful cargo-carrying functional protein in cell-based gene therapy. While VP22has been studied as a means to modulate tumor growth, little is known about the distribution andtransport kinetics of VP22 in the heart and its potential application in combination with autologous celltransplantation for the delivery of proteins to myocardial tissue. The aim of this study was to evaluate the

efficacy of VP22 fusion protein intercellular trafficking combined with autologous cell transplantation inthe heart. In an in vitro study untransfected rat heart cells were cocultured with stably transfected ratcardiac fibroblasts (RCF) with fusion constructs of VP22. The control experiment was untransfected ratheart cells co-plated with RCF stably transfected with enhanced green fluorescence protein (eGFP). TheLewis rat model was selected for in vivo study. In the in vitro studies there was a 14-fold increase in thenumber of GFP-positive cells 48 h after initiating coculture with VP22-eGFP RCF compared to eGFPRCF. The VP22-eGFP area consisted of eGFP-positive endothelium, smooth muscle cells, and cardiacmyocytes with delivery to an area of approximately 1 mm2 of myocardial tissue. Our data suggest aviable strategy for the delivery of proteins that are not naturally secreted or internalized, and provide thefirst insight into the feasibility and effectiveness of cell-penetrating proteins combined with celltransplantation in the heart.
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Bian%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Kiedrowski%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Mal%20N%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Forudi%20F%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Penn%20MS%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Penn%20MS%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Forudi%20F%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Mal%20N%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Kiedrowski%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Bian%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus


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Benthocodon pedunculata

Aequorea vitoria

GreenFluorescent

protein (GFP)


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Infeco Experimental comInfeco Experimental com


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Infeco Experimental comInfeco Experimental comTrypanosoma cruziTrypanosoma cruzi == DD

ChagasChagasTrypanosoma cruziTrypanosoma cruzi

BALBBALB/c mice/c mice

D ChagasD Chagascronicacronica CT fluorescentesCT fluorescentes

modificdas pelomodificdas peloHSVHSV

C T M difi d l HSV D t t d


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Anti GFP + Anti Myosine

C-T Modificadas pelo HSV Detectadas noTecido Cardaco (15 dias)


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0

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300

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500

0 2 4 6 8

Months after Treatment

Inflammatorycells/mm

2

Saline

SC

INFLAMAINFLAMACAOCAO

0

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30

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50

0 2 4 6 8

Months After Treatment

Fibroticare a/

mm

2

Saline

SC

FIBROSFIBROSEE

Reduo da Miocardite em RatosTratados com C-T modificadas pelo HSV

HSV Auxilia Tratamento de Gliomas


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HSV Auxilia Tratamento de Gliomas

Malignos Cerebrais sem Cirurgia Mol Ther. 2007 Jul;15(7):1373-81.

Bystander Killing of Malignant Glioma by Bone Marrow-derived Tumor-InfiltratingProgenitor Cells Expressing a Suicide Gene.

Miletic H, Fischer Y, Litwak S, Giroglou T, Waerzeggers Y, Winkeler A, Li H,Himmelreich U, Lange C, Stenzel W, Deckert M, Neumann H, Jacobs AH,von Laer D.

Adult stem cells are promising cellular vehicles for therapy of malignant gliomas as theyhave the ability to migrate into these tumors and even track infiltrating tumor cells.However, their clinical use is limited by a low passaging capacity that impedes large-scale production. In the present study, a bone marrow-derived, highly proliferativesubpopulation of mesenchymal stem cells (MSCs)-here termed bone marrow-derivedtumor-infiltrating cells (BM-TICs)-was genetically modified for the treatment of malignantglioma. Upon injection into the tumor or the vicinity of the tumor, BM-TICs infiltrated solidparts as well as the border of rat 9L glioma. After intra-tumoral injection, BM-TICs

expressing the thymidine kinase of herpes simplex virus (HSV-tk) and enhanced greenfluorescent protein (BM-TIC-tk-GFP) were detected by non-invasive positron emissiontomography (PET) using the tracer 9-[4-[(18)F]fluoro-3-hydroxymethyl)butyl]guanine([(18)F]FHBG). A therapeutic effect was demonstrated in vitro and in vivo by BM-TICsexpressing HSV-tk through bystander-mediated glioma cell killing. Therapeutic efficacywas monitored by PET as well as by magnetic resonance imaging (MRI) and stronglycorrelated with histological analysis. In conclusion, BM-TICs expressing a suicide geneBM-TICs expressing a suicide genewere highly effective in the treatment of malignant glioma in a rat modelwere highly effective in the treatment of malignant glioma in a rat model and

therefore hold great potential for the therapy of malignant brain tumors in humans.
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Miletic%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Fischer%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Litwak%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Giroglou%20T%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Waerzeggers%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Winkeler%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Li%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Himmelreich%20U%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Lange%20C%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Stenzel%20W%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Deckert%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Neumann%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Jacobs%20AH%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22von%20Laer%20D%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22von%20Laer%20D%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Jacobs%20AH%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Neumann%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Deckert%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Stenzel%20W%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Lange%20C%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Himmelreich%20U%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Li%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Winkeler%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Waerzeggers%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Giroglou%20T%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Litwak%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Fischer%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Miletic%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus


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TERAPIA GENTICA COM HSV

HSV

ACV/GCV


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HSV Auxilia C-T a Prevenir AVC

J Cell Physiol. 2007 Nov;213(2):341-7.

Adult mesenchymal stem cells for tissue engineering versus regenerative medicine.

Caplan AI.

Adult mesenchymal stem cells (MSCs) can be isolated from bone marrow or marrow aspirates

and because they are culture-dish adherent, they can be expanded in culture while maintainingtheir multipotency. The MSCs have been used in preclinical models for tissue engineering ofbone, cartilage, muscle, marrow stroma, tendon, fat, and other connective tissues. Thesetissue-engineered materials show considerable promise for use in rebuilding damaged ordiseased mesenchymal tissues. Unanticipated is the realization that the MSCs secrete a largespectrum of bioactive molecules. These molecules are immunosuppressive, especially for T-cells and, thus, allogeneic MSCs can be considered for therapeutic use. In this context, thesecreted bioactive molecules provide a regenerative microenvironment for a variety of injuredadult tissues to limit the area of damage and to mount a self-regulated regenerative response.

This regenerative microenvironment is referred to as trophic activity and, therefore, MSCsappear to be valuable mediators for tissue repair and regeneration. The natural titers of MSCsthat are drawn to sites of tissue injury can be augmented by allogeneic MSCs delivered via thebloodstream. Indeed, human clinical trials are now under way to use allogeneic MSCs fortreatment of myocardial infarcts, graft-versus-host disease, Crohn's Disease, cartilage andmeniscus repair, stroke, and spinal cord injury. This review summarizes the biological basis forthe in vivo functioning of MSCs through development and aging.

DESENHO DO ESTUDO 1
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Caplan%20AI%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Caplan%20AI%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus


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DESENHO DO ESTUDO 1

DESENHO DO ESTUDO 2


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DESENHO DO ESTUDO 2

animais tratados com C T com


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Peso corporal Consumo de alimento e gua

animais tratados com C-T comaqueles tratados com placebo


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Avances en el Diagnóstico y Tratamiento del HSV

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