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Sten333
01.09.2004, 19:30
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Famciclovir
Structure (Fig. 24): diacetyl ester of 9-(4-hydroxy-3-hydroxymethyl-but-1-yl)-6-deoxyguanine (FCV), Famvir.
Activity spectrum: HSV-1, HSV-2 and VZV.
Mechanism of action: serves as oral prodrug of penciclovir (to which it is converted by hydrolysis of the two acetyl groups and oxidation at the 6-position), then acts as described for penciclovir.
Principal indication(s): HSV-1, HSV-2 and VZV infections.
Administered: orally at 750 mg per day (250 mg tablet every 8 h, three times a day), or 1500 mg per day (500 mg every 8 h).
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Ganciclovir
Structure (Fig. 28): 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG), (GCV), Cymevene, Cytovene.
Activity spectrum: HSV (types 1 and 2), CMV and some other herpesviruses.
Mechanism of action: targeted at the viral DNA polymerase, where it mainly acts as chain terminator, following intracellular phosphorylation to GCV triphosphate and incorporation of GCV monophosphate at the 3′-end of the viral DNA chain. First phosphorylation step is catalyzed by the HSV-encoded thymidine kinase (TK) or CMV-encoded protein kinase (PK), which explains the specificity of ganciclovir for HSV and CMV, respectively.
Principal indication(s): CMV infections, particularly CMV retinitis in immunocompromised (i.e. AIDS) patients (treatment and prevention).
Administered: intravenously at 10 mg/kg per day (2×5 mg/kg, every 12 h) for induction therapy; orally at 3000 mg per day (three times four 250 mg capsules) for maintenance therapy and for prevention; intraocular (intravitreal) implant (Vitrasert*) of 4.5 mg ganciclovir as localized therapy of CMV retinitis.
Valganciclovir Structure (Fig. 29): -valine ester of ganciclovir (VGCV), Valcyte.
Activity spectrum: as for GCV.
Mechanism of action: serves as oral prodrug of GCV, then acts as described for GCV.
Principal indication(s): CMV infections. Oral valganciclovir is expected to replace intravenous ganciclovir in both the therapy and prevention of CMV infections.
Administered: orally at 900 mg per day (two 450 mg tablets daily) for maintenance therapy (900 mg twice daily for induction therapy).
Foscarnet
Structure (Fig. 30): trisodium phosphonoformate, foscarnet sodium, Foscavir.
Activity spectrum: herpesviruses (HSV-1, HSV-2, VZV, CMV, etc.) and also HIV.
Mechanism of action: pyrophosphate analogue, interferes with the binding of the pyrophosphate (diphosphate) to its binding site of the viral DNA polymerase, during the DNA polymerization process.
Principal indication(s): CMV retinitis in AIDS patients, and mucocutaneous acyclovir-resistant (viral TK-deficient) HSV and VZV infections in immunocompromised patients.
Administered: intravenously at 180 mg/kg per day (3×60 mg/kg, every 8 h) for induction therapy of CMV retinitis; intravenously at 120 mg/kg per day (3×40 mg/kg, every 8 h) for maintenance therapy of CMV retinitis and for therapy of acyclovir-resistant mucocutaneous HSV or VZV infections in immunocompromised patients. Dose adjustments for changes in renal function are imperative.
Cidofovir
Structure (Fig. 31): (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC), (CDV), Vistide, Forvade.
Activity spectrum: herpesviruses (HSV-1, HSV-2, VZV, CMV, etc.), papilloma-, polyoma-, adeno- and poxviruses.
Mechanism of action: targeted at the viral DNA polymerase, acts as chain terminator, following intracellular phosphorylation to the diphosphate form, and incorporation at the 3′-end of the viral DNA chain (two sequential incorporations needed for chain termination in the case of CMV DNA synthesis) (Scheme 9).
Principal indications(s): officially licensed for the treatment of CMV retinitis in AIDS patients. Also shown to be effective in the treatment of acyclovir-resistant (viral TK-deficient) HSV infections, recurrent genital herpes, genital warts, CIN-III (cervical intraepithelial neoplasia grade III), laryngeal and cutaneous papillomatous lesions, molluscum contagiosum lesions, orf lesions, adenovirus infections and progressive multifocal leukoencephalopathy (PML).
Administered: intravenously (Vistide) at 5 mg/kg per week during the first 2 weeks, then 5 mg/kg every other week, with sufficient hydration and under cover of probenecid to prevent nephrotoxicity. Can also be administered topically as a 1% gel or cream.
Fomivirsen
Structure (Fig. 32): antisense oligodeoxynucleotide composed of 21 phosphorothioate-linked nucleosides, ISIS 2922, Vitravene.
Activity spectrum: CMV.
Mechanism of action: being complementary in base sequence, it hybridizes with, and thus blocks expression (translation) of, the CMV immediate early 2 (IE2) mRNA.
Principal indication(s): CMV retinitis (in AIDS patients).
Administered : intraocularly (intravitreally).
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01.09.2004, 19:30
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01.09.2004, 19:30
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01.09.2004, 19:30
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01.09.2004, 19:30
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01.09.2004, 19:30
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01.09.2004, 19:30
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