Antiviral Therapy (3): Gancyclovir
Mechanism of Action:
Gancyclovir is a synthetic analogue of 2'-deoxy-guanosine. It is first phosphorylated to a deoxyguanosine triphosphate (dGTP) analog. This competitively inhibits the incorporation of dGTP by viral DNA polymerase, resulting in the termination of elongation of viral DNA. Ganciclovir has inhibitory activity against herpesviruses, but its unique characteristic is potent inhibition of CMV replication.
Absorption of the oral form is very limited - about 5% fasting, about 8% with food. It achieves a concentration in the central nervous system of about 50% of the plasma level. About 90% of plasma ganciclovir is eliminated unchanged in the urine, with a half-life of 2-6 hrs, depending on renal function (elimination takes over 24 hours in end-stage renal disease). A prodrug form with improved oral bioavailability (valgancyclovir) has also been developed.
Resistance Mechanisms:
In 1992 the viral kinase responsible for gancyclovir monophosphorylation was identified. A number of mutations responsible for ganciclovir resistance in this UL97 gene have since been documented, and mutation detection resistance assays may therefore be suitable, especially as CMV phenotypic assays are time-consuming. Few studies have examined the contribution of drug resistance to drug failure systematically, but the use of quantitative polymerase chain reaction (PCR) assays to assess blood CMV viral load responses to treatment have proven useful. The U69 protein kinase has been identified in cases of HHV-6 resistant to gancyclovir.
Gancyclovir resistance is rare in gancyclovir-naïve patients but has been recognized clinically by progressive disease and persistent CMV viraemia on therapy. Risk factors include prolonged gancyclovir exposure, primary infection, and higher immunosuppression including use of antilymphocyte globulin. In patients with AIDS receiving gancyclovir for retinitis, resistant CMV is detectable in about 7% by 3 months and in 28% by 9 months. During the HAART era, a 15% frequency of UL97 mutations has been found by 18 months in valgancyclovir recipients. Emergence of resistance, sometimes within several weeks, also occurs with gancyclovir use in stem cell and solid-organ transplant recipients. Gancyclovir-resistant CMV disease developed in 7% of mismatched solid-organ transplant recipients receiving gancyclovir prophylaxis. Mismatched lung transplant recipients are at particular risk for resistance emergence. The transmissibility of gancyclovir-resistant CMV strains is undefined, but patients with such strains may have invasive disease, including retinitis, enteritis, polyradiculopathy, or pneumonia. Foscarnet or cidofovir therapy may benefit patients with gancyclovir-resistant CMV infections.
Clinical Indications:
- Sight-threatening CMV retinitis in severely immunocompromised patients.
- CMV pneumonitis in bone marrow transplant recipients.
- Prevention of CMV disease in bone marrow and solid organ transplant recipients.
- Confirmed CMV retinitis in people with AIDS (intravitreal implant).
It is also used for acute CMV colitis in HIV/AIDS and CMV pneumonitis in immunosuppressed patients.
Toxicity:
Myelosuppression is the principal dose-limiting toxicity of gancyclovir and its prodrug. The most common adverse events are neutropaenia in 24% to 40% and thrombocytopaenia in 15% to 20% of patients with AIDS receiving intravenous gancyclovir or oral valgancyclovir. The risk for these toxicities is lower in transplant recipients. Neutropaenia occurs in approximately one fourth of those receiving oral gancyclovir. Neutropaenia is most commonly observed during the second week of treatment and is reversible in most patients within 1 week after drug cessation. Recombinant granulocyte-macrophage colony-stimulating factor (G-CSF) may be useful in treating gancyclovir-induced neutropaenia.
CNS side effects, ranging in severity from headache to behavioral changes with confusion or psychosis, to convulsions and coma, have been described in 5% to 15% of patients. Up to one third of patients receiving intravenous gancyclovir interrupt or prematurely stop therapy because of bone marrow or CNS toxicity, and catheter-related complications are common. Approximately 25% of valgancyclovir recipients discontinue maintenance therapy within 10 months for toxicity or other reasons. Increased rates of ureaemia occur in transplant recipients receiving intravenous gancyclovir prophylaxis.
Oral valgancyclovir and gancyclovir are associated with diarrhoea and possibly with mild nephrotoxicity. Anaemia, rash, fever, liver function test abnormalities, nausea or vomiting, and eosinophilia have also been reported. Phlebitis at the infusion site may be caused by the alkaline pH of the solution. In the event of massive overdosage, haemodialysis and hydration may be effective in reducing plasma ganciclovir levels. Placement of the intravitreal insert may be associated with visual changes, haemorrhage, infection, and retinal detachment.
Gancyclovir is mutagenic, carcinogenic, and immunosuppressive, and it causes irreversible reproductive toxicity in animals and possibly humans. Teratogenicity, embryotoxicity, testicular atrophy, and bone marrow hypocellularity have been observed in animals at gancyclovir exposures comparable to those in humans. Gancyclovir may be teratogenic in humans (classified in pregnancy category C), and mothers should avoid breast-feeding while receiving gancyclovir or valgancyclovir.
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Estimated retention rates at
Estimated retention rates at 6, 12, and 24 mo were calculated and plotted for each program. Retention was also estimated using Kaplan-Meier curves. In sensitivity analyses we considered best-case, worst-case, and midpoint scenarios for retention at 2 y; the best-case scenario assumed no further attrition beyond that reported, while the worst-case scenario assumed that attrition would continue in a linear fashion. We reviewed 32 publications reporting on 33 patient cohorts (74,192 patients, 13 countries). For all studies, the weighted average follow-up period reported was 9.9 mo, after which 77.5% of patients were retained. Loss to follow-up and death accounted for 56% and 40% of attrition, respectively. Weighted mean retention rates as reported were 79.1%, 75.0% and 61.6 % at 6, 12, and 24 mo, respectively. Of those reporting 24 mo of follow-up, the best program retained 85% of patients and the worst retained 46%. Attrition was higher in studies with shorter reporting periods, leading to monthly weighted mean attrition rates of 3.3%/mo, 1.9%/mo, and 1.6%/month for studies reporting to 6, 12, and 24 months, respectively,
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