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Ganciclovir
Kinds of Ganciclovir Terms modified by Ganciclovir Selected AbstractsViral meningoencephalitis: a review of diagnostic methods and guidelines for managementEUROPEAN JOURNAL OF NEUROLOGY, Issue 8 2010I. Steiner Background:, Viral encephalitis is a medical emergency. The prognosis depends mainly on the pathogen and host immunologic state. Correct immediate diagnosis and introduction of symptomatic and specific therapy has a dramatic influence upon survival and reduces the extent of permanent brain injury. Methods:, We searched the literature from 1966 to 2009. Recommendations were reached by consensus. Where there was lack of evidence but consensus was clear, we have stated our opinion as good practice points. Recommendations:, Diagnosis should be based on medical history and examination followed by CSF analysis for protein and glucose levels, cellular analysis, and identification of the pathogen by polymerase chain reaction amplification (recommendation level A) and serology (level B). Neuroimaging, preferably by MRI, is essential (level B). Lumbar puncture can follow neuroimaging when immediately available, but if this cannot be performed immediately, LP should be delayed only under unusual circumstances. Brain biopsy should be reserved only for unusual and diagnostically difficult cases. Patients must be hospitalized with easy access to intensive care units. Specific, evidence-based, antiviral therapy, acyclovir, is available for herpes encephalitis (level A) and may also be effective for varicella-zoster virus encephalitis. Ganciclovir and foscarnet can be given to treat cytomegalovirus encephalitis, and pleconaril for enterovirus encephalitis (IV class evidence). Corticosteroids as an adjunct treatment for acute viral encephalitis are not generally considered to be effective, and their use is controversial, but this important issue is currently being evaluated in a large clinical trial. Surgical decompression is indicated for impending uncal herniation or increased intracranial pressure refractory to medical management. [source] Synthesis of the stable isotope labeled antiviral nucleoside analog [8- 13C,7,9- 15N2]-ganciclovirJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 13 2006Naiyu Zheng Abstract Ganciclovir, a nucleoside analog of 2,-deoxyguanosine, is a drug used in suicide gene therapy for the treatment of mesothelioma. We required a stable isotope analog of ganciclovir for use in pharmacokinetic studies in order to monitor the systemic exposure of patients to the drug. Therefore, a facile and efficient synthesis of [8- 13C,7,9- 15N2]-ganciclovir, was devised. The synthesis was achieved in 4 steps with 25% total yield using commercially-available [8- 13C,7,9- 15N2]-guanine, without the need for purification of intermediates. The key step of the synthesis involved the coupling of [8- 13C,7,9- 15N2]-guanine with 3-propionyloxy-2-propionyloxy-methoxypropyl propionate. The latter was synthesized from a commercially available dichlorohydrin. Each step of the reaction could be easily monitored by liquid chromatography,mass spectrometry. The structure of the labeled ganciclovir was confirmed using 1H, 13C, and 15N nuclear magnetic resonance spectroscopy. Copyright © 2006 John Wiley & Sons, Ltd. [source] Prevention of CMV disease in pediatric kidney transplant recipients: Evaluation of pp67 NASBA-based pre-emptive ganciclovir therapy combined with CMV hyperimmune globulin prophylaxis in high-risk patientsPEDIATRIC TRANSPLANTATION, Issue 4 2008Edith Renoult Abstract:, A new prevention strategy for CMV infection was evaluated in our pediatric kidney transplant unit. This approach comprises a pre-emptive therapy, based upon the monitoring of CMV pp67 mRNA in whole blood by the qualitative NASBA, combined with prophylactic CMV-IG in high risk (R,/D+) children. Thirty-one kidney transplant children were followed for six months with serial measurements of CMV pp67 mRNA in the blood. The R,/D+ patients were given prophylactic CMV-IG for the first 16 wk after transplantation. I.v. ganciclovir was administered upon CMV detection by NASBA and was discontinued after two consecutive negative results. CMV infection, detected by NASBA, developed in 11 (35%) recipients: one (33%) of the R+/D, patients and 10 (72%) of the R,/D+ patients. CMV disease developed in 9.6% of the patients (3/31), exclusively in the R,/D+ group. These three patients presented concurrently with CMV viremia and disease. It is noteworthy that two of the three patients could not receive a complete course of CMV-IG, and one of the latter two subjects had been treated for acute rejection 15 days before CMV infection. Ganciclovir was given for the 11 cases of primary infection, and for three cases of relapsed CMV infection. pp67 NASBA-based pre-emptive ganciclovir therapy, combined with prophylactic CMV-IG in high-risk patients leads to a lower rate of CMV disease, as long as a complete course of CMV-IG has been administered and ganciclovir is given during the period of treatment for acute rejection in high-risk populations. [source] Long-Term Outcomes of CMV Disease Treatment with Valganciclovir Versus IV Ganciclovir in Solid Organ Transplant RecipientsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2009A. Åsberg Though an important cause of morbidity and mortality in solid organ transplantation (SOT), the long-term outcomes of cytomegalovirus (CMV) disease treatment have not been well studied. In a randomized trial, 321 SOT recipients with CMV disease were followed 1 year after treatment with either twice daily intravenous ganciclovir or oral valganciclovir (for 21 days) followed by once daily valganciclovir until day 49 in all patients. Clinical and viral eradication of CMV disease was similar between groups. Clinical recurrence beyond day 49 was found in 15.1% and virological recurrence in 30.0%, no difference between groups (p > 0.77). In a multivariable logistic regression analysis, the only independent predictor for recurrence was failure to eradicate DNAemia by day 21 (clinical: OR 3.9 [1.3,11.3], p = 0.012; virological: OR 5.6 [2.5,12.6], p < 0.0001). Eight patients developed ganciclovir resistance, with no difference between groups (p = 0.62). Twenty patients (valganciclovir: 11, ganciclovir: 9, p = 0.82) died, 12 due to infections, two involving CMV disease. There were no differences in long-term outcomes between treatment arms, further supporting the use of oral valganciclovir for treatment of CMV disease. Persistent DNAemia at day 21, CMV IgG serostatus and development of resistance may be relevant factors for further individualization of treatment. [source] An Assessment of Herpesvirus Co-infections in Patients with CMV Disease: Correlation with Clinical and Virologic OutcomesAMERICAN JOURNAL OF TRANSPLANTATION, Issue 2 2009A. Humar The effect of herpesvirus co-infections (HHV-6, HHV-7) on cytomegalovirus (CMV) disease and its response to therapy is unknown. We prospectively analyzed herpesvirus co-infections in transplant recipients with CMV disease. All patients received 3 weeks of antiviral therapy. Samples were collected at baseline (day 0) and then day 3, 7, 14 and 21 poststart of therapy. Viral load testing for CMV, HHV-6 and HHV-7 was done using quantitative PCR assays in 302 patients of whom 256 had documented symptomatic CMV viremia. In this subset, day 0 HHV-6 co-infection was present in 23/253 (9.1%) and HHV-7 in 17/253 (6.7%). Including those positive at any time point raised the prevalence to 79/256 (30.9%) for HHV-6 and 75/256 (29.3%) for HHV-7. Viral co-infection did not influence the response of CMV disease to antiviral therapy. Baseline CMV viral loads, time to eradication and risk of recurrence were similar in patients with and without HHV-6 or HHV-7 co-infection. Ganciclovir and valganciclovir had no clear effect on HHV-6 and HHV-7 viremia. In conclusion, herpesvirus co-infections are common in patients with CMV disease but with standard antiviral therapy, no clear clinical effects are discernable. Routine monitoring for viral co-infection in patients with CMV disease is not indicated. [source] Improvement in Long-Term Renal Graft Survival due to CMV Prophylaxis with Oral Ganciclovir: Results of a Randomized Clinical TrialAMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2008V. Kliem Oral ganciclovir prophylaxis and intravenous preemptive therapy are competitive approaches to prevent cytomegalovirus (CMV) disease after renal transplantation. This trial compared efficacy, safety and long-term graft outcome in 148 renal graft recipients randomized to ganciclovir prophylaxis (N = 74) or preemptive therapy (N = 74). Hierarchical testing revealed (i) patients with CMV infection had more severe periods of impaired graft function (creatinine clearancemax-min 25.0 ± 14.2 mL/min vs. 18.1 ± 12.5 mL/min for patients without CMV infection; p = 0.02),(ii) prophylaxis reduced CMV infection by 65% (13 vs. 33 patients; p < 0.0001) but (iii) creatinine clearance at 12 months was comparable for both regimes (54.0 ± 24.9 vs. 53.1 ± 23.7 mL/min; p = 0.92). No major safety issues were observed, and patient survival at 12 months was similar in both groups (5 deaths [6.8%] vs. 4 [5.4%], p = 1.0000). Prophylaxis significantly increased long-term graft survival 4 years posttransplant (92.2% vs. 78.3%; p = 0.0425) with a number needed to treat of 7.19. Patients with donor +/recipient + CMV serostatus had the lowest rate of graft loss following prophylaxis (0.0% vs. 26.8%; p = 0.0035). In conclusion, it appears that routine oral prophylaxis may improve long-term graft survival for most renal transplant patients. Preemptive therapy can be considered in low risk patients in combination with adequate CMV monitoring. [source] Determination of acyclovir in horse plasma and body fluids by high-performance liquid chromatography combined with fluorescence detection and heated electrospray ionization tandem mass spectrometryBIOMEDICAL CHROMATOGRAPHY, Issue 2 2009A. Maes Abstract Two methods are presented for the determination of ,respectively' the plasma protein unbound and total concentration of acyclovir in horse plasma and body fluids: first, a liquid,liquid extraction was performed on plasma, combined with HPLC-fluorescence detection for the total plasma concentration; second a more sensitive method using high-performance liquid chromatography combined with heated electrospray ionization tandem mass spectrometry (LC-HESI-MS/MS) was described for plasma and for body fluids analysis. To obtain the unbound concentration of acyclovir in plasma, a simple deproteinization step using a Microcon® filter was performed. Ganciclovir was used as an internal standard. Analysis was carried out on an Inertsil 5 ODS-3 column for the HPLC-fluorescence method. For the LC-HESI-MS/MS method a PLRP-S column was used. The limit of quantification (LOQ) for the total concentration was set at 50 and 2 ng mL,1 for the HPLC-fluorescence method and the LC-HESI-MS/MS method, respectively. The limit of quantification for the unbound concentration was set at 5 ng mL,1 and at 2 ng mL,1 for body fluids. The methods were successfully used to perform pharmacokinetic and clinical studies in horses after intravenous and oral dosage of acyclovir and its prodrug valacyclovir. Copyright © 2008 John Wiley & Sons, Ltd. [source] Retrovirus-mediated transfer of the herpes simplex virus thymidine kinase and enhanced green fluorescence protein genes in primary T lymphocytesBRITISH JOURNAL OF HAEMATOLOGY, Issue 4 2000Sabrina Di Florio The EGFP-tk retroviral vector, encoding enhanced green fluorescent protein (EGFP) and the herpes simplex virus thymidine kinase (HSV-tk) packaged in a Phoenix amphotropic cell line, was used to transduce healthy donor T lymphocytes. Infection yielded a mean of 41·8 ± 9·3% SD (range 31·1,48·4%) EGFP-positive cells and a mean of 92 ± 2% SD (range 90,94%) after cell sorting. EGFP expression remained stable for 30 d after infection. The entire gene transfer procedure had no significant effect on lymphocyte subsets and slightly reduced clonogenicity. Ganciclovir (gcv) treatment (1 µg/ml × 10 d) killed all EGFP-positive cells in the transduced and transduced/sorted populations, but had no effect on untransduced controls. Our results show that primary T lymphocytes can be transduced using an EGFP-tk vector that yields a homogeneous infected population without affecting lymphocyte subsets, function and clonogenicity. [source] Efficacy of systemic ganciclovir as a therapeutic strategy for cytomegalovirus-associated anterior uveitis in immunocompetent patientsACTA OPHTHALMOLOGICA, Issue 2009M ANGI Purpose Cytomegalovirus (CMV)-associated anterior uveitis is a newly recognized entity that accounts for half of patients with Posner-Schlossman syndrome. To date, the therapeutic management of these patients remains controversial. The aim of this study was to assess the efficacy of systemic Ganciclovir as a treatment for PCR-proven CMV-associated hypertensive anterior uveitis. Methods Retrospective interventional study of 27 consecutive patients treated in a single centre between 2002 and 2008. Main outcome measures included intraocular pressure (IOP) and anterior chamber inflammation. Results All patients responded to systemic Ganciclovir, with mean IOP dropping from 32 to 14 mmHg (p<0,05). Relapses occurred in 50% of cases within one year from the first antiviral course. Repeated treatment allowed control of the disease in 75% of cases (follow-up range: 12-78 months). Conclusion Ganciclovir is effective but remains a suspensive therapeutic strategy. [source] Synthesis and Characterization of a C(6) Nucleoside Analogue for the in vivo Imaging of the Gene Expression of Herpes Simplex Virus Type-1 Thymidine Kinase (HSV1 TK)CHEMISTRY & BIODIVERSITY, Issue 3 2006Anass Johayem Abstract The synthesis and biological evaluation of ,6-(1,3-dihydroxyisobutyl)thymine' (DHBT; 1), which corresponds to 6-[3-hydroxy-2-(hydroxymethyl)propyl]-5-methylpyrimidine-2,4(1H,3H)-dione, is reported. DHBT (1) was designed as a new substrate for herpes simplex virus type-1 thymidine kinase (HSV1 TK). The compound was found to be exclusively phosphorylated by HSV1 TK, and to exhibit good binding affinity (Ki,=,35.3±1.3,,M). Cell-proliferation assays with HSV1-TK-transduced human osteosarcoma cells (143B-TK+-HSV1-WT) and with both human-thymidine-kinase-1-negative (143B-TK,) and non-transduced parental (MG-63) cells indicate that 1 is less cytotoxic than the standard drug Ganciclovir. Thus, DHBT (1) represents a promising precursor of a nontoxic reporter probe for the monitoring of HSV1 TK gene expression by means of positron-emission tomography (PET). [source] Anti-cytomegalovirus prophylaxis in solid-organ transplant recipientsCLINICAL MICROBIOLOGY AND INFECTION, Issue 7 2006M. E. Falagas Abstract Ganciclovir and its prodrug, valganciclovir, are more effective than acyclovir in preventing cytomegalovirus (CMV) infection and disease in solid-organ transplant recipients. However, the indirect effects of prophylactic use of ganciclovir and acyclovir are comparable, and the greater effectiveness of ganciclovir may be compensated for by less drug-related toxicity with acyclovir or valacyclovir. No conclusive data exist concerning the best technique and duration of surveillance for CMV infection in patients for whom active surveillance for late-onset CMV should be performed, i.e., those reaching the end of prophylaxis. Only large randomised controlled trials, with long follow-up periods, will provide definitive conclusions regarding the comparative prophylactic roles of the major antiviral agents in this population, and how their use fits with a strategy of active surveillance and pre-emptive therapy. [source] A review of antiviral therapies in the treatment of cytomegalovirusDERMATOLOGIC THERAPY, Issue 3 2000Adrienne M. Hinkle ABSTRACT: Cytomegalovirus (CMV) is a member of the herpesvirus family that is very prevalent world wide based on serologic testing. In immunocompromised persons CMV produces high rates of morbidity and mortality. Congenital CMV is the leading infectious cause of fetal abnormalities in the United States. Infection of human immunodeficiency virus (HIV) seropositive persons or transplant patients with CMV can produce retinitis, encephalitis, pneumonitis, hepatitis, gastrointestinal ulcerations, and cutaneous lesions. Three intravenous therapies are available for CMV infections: ganciclovir; foscarnet and cidofovir. Most recently a fourth antiviral agent was approved for intravitreal injection. This drug, fomivirsen, is the first antisense oligonucleotide available for therapeutic use. A number of other antiviral drugs and vaccines are currently under study. [source] Infantile spasms and cytomegalovirus infection: antiviral and antiepileptic treatmentDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 9 2007Dorota Dunin-Wasowicz MD PhD From 1 January 1995 to 31 December 2004, 22 patients (13 males, nine females; age range 2-12mo) with infantile spasms and cytomegalovirus (CMV) infection were treated with intravenous ganciclovir (GCV) and antiepileptic drugs. GCV was given for 3 to 12 weeks with a 1-month interval (one, two, or three courses). Epileptic spasms occurred before (group A: eight patients), simultaneously (group B: eight patients), and after (group C: six patients) a diagnosis of human CMV (HCMV) infection and antiviral treatment. In 11 patients, DNA HCMV was found in cerebrospinal fluid by nested-polymerase chain reaction method (neuroinfection). All infants excreted CMV in urine. DNA HCMV and specific immunoglobulin M and immunoglobulin G antibodies were present in blood. Ten patients, including four with neuroinfection, have been seizure-free for at least the past 18 months. In two patients with neuroinfection, vigabatrin monotherapy was withdrawn after a 2 year 6 month seizure-free period. Eighteen patients required antiepileptic drugs polytherapy, four of whom required additional adrenocorticotropic hormone (ACTH). Six patients on polytherapy were seizure-free on follow-up, two of whom were treated with ACTH, but no patient with hypsarrhythmia who required ACTH treatment was seizure-free on follow-up. In five patients, psychomotor development was normal, 16 had tetraplegia (Gross Motor Function Classification System [GMFCS] Level V), and one had diplegia (GMFCS Level III). Early antiviral and antiepileptic therapy could result in the long-term cessation of seizures. [source] A case of immune recovery vitritis induced by donor leukocyte infusion for the treatment of cytomegalovirus retinitisEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 4 2005Manabu Kawakami Abstract:, Donor leukocyte infusion (DLI) has been successfully used for some life-threatening viral infections after stem cell transplantation (SCT). We describe here the first case of DLI treatment for cytomegalovirus (CMV) retinitis. A 49-year-old female patient with AML, M1 underwent SCT with a reduced-intensity conditioning regimen from HLA-haploidentical son. On day +140, the patient developed CMV retinitis of her left eye despite the continuing antiviral therapy. DLI at a dose of 1 × 105 CD3+ cells/kg was added to ganciclovir and foscarnet therapy. Eighteen days after the DLI, the funduscopic findings revealed improvement of the retinitis and the development of vitreous inflammation. Simultaneously, the number of CD4+ cells in the peripheral blood rapidly increased. Thus, we consider it likely that DLI induced a local immune response against CMV antigens, which resulted in the immune recovery vitritis. This case suggested the potentiality of DLI for the treatment of CMV retinitis. [source] Does cytomegalovirus play a causative role in the development of various inflammatory diseases and cancer?JOURNAL OF INTERNAL MEDICINE, Issue 3 2006C. SÖDERBERG-NAUCLÉR Abstract. Human cytomegalovirus (HCMV) is a herpes virus that infects and is carried by 70,100% of the world's population. During its evolution, this virus has developed mechanisms that allow it to survive in an immunocompetent host. For many years, HCMV was not considered to be a major human pathogen, as it appeared to cause only rare cases of HCMV inclusion disease in neonates. However, HCMV is poorly adapted for survival in the immunosuppressed host and has emerged as an important human pathogen in AIDS patients and in patients undergoing immunosuppressive therapy following organ or bone marrow transplantation. HCMV-mediated disease in such patients has highlighted the possible role of this virus in the development of other diseases, in particular inflammatory diseases such as vascular diseases, autoimmune diseases and, more recently, with certain forms of cancers. Current research is focused on determining whether HCMV plays a causative role in these diseases or is merely an epiphenomenon of inflammation. Inflammation plays a central role in the pathogenesis of HCMV. This virus has developed a number of mechanisms that enable it to hide from the cells of the immune system and, at the same time, reactivation of a latent infection requires immune activation. Numerous products of the HCMV genome are devoted to control central functions of the innate and adaptive immune responses. By influencing the regulation of various cellular processes including the cell cycle, apoptosis and migration as well as tumour invasiveness and angiogenesis, HCMV may participate in disease development. Thus, the various drugs now available for treatment of HCMV disease (e.g. ganciclovir, acyclovir and foscarnet), may also prove to be useful in the treatment of other, more widespread diseases. [source] Synthesis of the stable isotope labeled antiviral nucleoside analog [8- 13C,7,9- 15N2]-ganciclovirJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 13 2006Naiyu Zheng Abstract Ganciclovir, a nucleoside analog of 2,-deoxyguanosine, is a drug used in suicide gene therapy for the treatment of mesothelioma. We required a stable isotope analog of ganciclovir for use in pharmacokinetic studies in order to monitor the systemic exposure of patients to the drug. Therefore, a facile and efficient synthesis of [8- 13C,7,9- 15N2]-ganciclovir, was devised. The synthesis was achieved in 4 steps with 25% total yield using commercially-available [8- 13C,7,9- 15N2]-guanine, without the need for purification of intermediates. The key step of the synthesis involved the coupling of [8- 13C,7,9- 15N2]-guanine with 3-propionyloxy-2-propionyloxy-methoxypropyl propionate. The latter was synthesized from a commercially available dichlorohydrin. Each step of the reaction could be easily monitored by liquid chromatography,mass spectrometry. The structure of the labeled ganciclovir was confirmed using 1H, 13C, and 15N nuclear magnetic resonance spectroscopy. Copyright © 2006 John Wiley & Sons, Ltd. [source] Water diffusion in a rat glioma during ganciclovir-thymidine kinase gene therapy-induced programmed cell death in vivo: Correlation with cell densityJOURNAL OF MAGNETIC RESONANCE IMAGING, Issue 4 2004Piia K. Valonen MSc Abstract Purpose To study the characteristics of diffusion magnetic resonance imaging (MRI) contrast in a rat brain BT4C glioma during progression of ganciclovir (GCV)-thymidine kinase gene therapy-induced programmed cell death (PCD) in vivo. Materials and Methods The trace of the diffusion tensor (Dav = 1/3Trace ), T2, and spin density were determined by MRI and the apparent diffusion coefficient (ADC) of water by diffusion nuclear MR (NMR) spectroscopy using largely varying b values and diffusion times (tD) at 4.7 T. Cell count and apoptotic cells were quantified by histological means. Results Decline in cell count was strongly associated with increase in both Dav and T2. Spin density ratio between tumor and contralateral parietal cortex increased with a very similar time course as Dav and T2, indicating net water gain into the eradicating tumor. Diffusion spectroscopy showed a nonmonoexponential signal decay at all tD values ranging from 14,192 msec. During PCD, the ADC of the component yielding fast diffusion coefficient (D1), as acquired with tD , 47 msec, increased with kinetics similar to those of Dav (tD = 4.8 msec). The fractional size of D1 increased by 10% to 15% throughout the entire tD range. Apparent water residence time of the slow diffusion component, D2, shortened from a value of 38.3 ± 1.7 msec on day 0 to 33.4 ± 0.5 msec by day 8. Conclusion The present results show that reduced cell density and increased water content, leading to altered water microenvironment, are associated with increased water diffusion coefficient in eradicating gliomas as a result of PCD. J. Magn. Reson. Imaging 2004;19:389,396. © 2004 Wiley-Liss, Inc. [source] HHV-6 and HHV-7 antigenemia related to CMV infection after liver transplantationJOURNAL OF MEDICAL VIROLOGY, Issue 6 2006Maiju Härmä Abstract Background Betaherpesviruses human herpesvirus-6 and -7 (HHV-6, HHV-7), which are closely related to cytomegalovirus (CMV), have been reported in transplant patients. In this retrospective study, we investigated the occurrence of HHV-6 and HHV-7 antigenemia in relation to symptomatic CMV infection after liver transplantation. Methods: Sample material from 64 adult liver transplant recipients was included in the study. The patients were monitored weekly for CMV, HHV-6, and HHV-7. CMV infections were diagnosed by pp65-antigenemia and viral cultures. Concomitantly HHV-6 and HHV-7 antigens were demonstrated in peripheral blood mononuclear cells by monoclonal antibodies against both variants A and B and immunoperoxidase staining. Altogether 540 post-transplant blood specimens were analyzed. Results: Nineteen patients (30%) developed symptomatic CMV pp65 antigenemia during the first 3 months (mean 33 days, range 5,62 days) post-transplantation and were treated with intravenous ganciclovir. Concurrent HHV-6 antigenemia was detected in 16/19 (median 9 days, range 6,24 days) and HHV-7 antigenemia 15/19 patients (median 17 days, range 5,58 days) after transplantation. HHV-6 appeared before CMV in most cases (12/16), HHV-7 usually together with CMV. In those cases that HHV-6 preceded CMV antigenemia, it also was a possible cause of graft dysfunction. HHV-7 and CMV were so closely overlapping, that no symptoms could solely be linked with HHV-7. Conclusion: HHV-6 and HHV-7 antigenemia usually occurred together with symptomatic CMV infection after liver transplantation. HHV-6 preceded CMV, but HHV-7 appeared together with CMV. Further investigation of the clinical significance of HHV-6 and HHV-7 antigenemia in organ transplant patients is necessary. J. Med. Virol. 78:800,805, 2006. © 2006 Wiley-Liss, Inc. [source] Kinetics of host immune responses and cytomegalovirus resistance in a liver transplant patientLIVER TRANSPLANTATION, Issue 10 2009Kirsten Schaffer Among solid organ transplant (SOT) recipients, donor-seropositive/recipient-seronegative (D+/R,) cytomegalovirus (CMV) status is associated with the highest risk of ganciclovir-resistant CMV disease, which has been reported for patients receiving oral ganciclovir but not valganciclovir prophylaxis. We report a case of CMV breakthrough infection in a D+/R, liver transplant patient while he was receiving oral valganciclovir. Forty samples collected over 6 months were analyzed for the CMV viral load, lymphocyte counts, cytokine levels, and lymphocyte differentiation status. Genotypic resistance testing of the viral UL97 gene was performed when the patient failed to respond. CMV viremia occurred on day 50 post-transplant, and 5 samples taken between days 50 and 85 showed the wild-type UL97 genotype. The appearance of deletion 594-595 was observed from day 114 post-transplant. Viral loads declined when foscarnet was commenced and remained below 10,000 copies/mL when the lymphocyte count was greater than 1000/,L (P = 0.02). T cell responses revealed significant expansion of CD8+ terminal effector memory cells. CD4+ cells were largely populations of naïve and central memory cells. Circulating interleukin 10 (IL-10) levels correlated with the viral load (P < 0.0001). Seroconversion occurred on day 230. The CMV viral load in combination with lymphocyte counts and IL-10 may be a predictive marker for the risk of development of resistant CMV disease in D+/R, SOT patients. Liver Transpl 15:1199,1203, 2009. © 2009 AASLD. [source] Treatment of recurrent hepatitis B infection in liver transplant recipientsLIVER TRANSPLANTATION, Issue 10B 2002Norah A. Terrault MD 1Therapeutic decisions are guided by a patient's clinical status (severity of disease and presence of comorbidities) and previous drug-exposure history. 2Lamivudine is safe and effective in liver transplant recipients with recurrent hepatitis B virus (HBV) infection caused by wild-type virus or failure of hepatitis B immunoglobulin therapy. Lamivudine resistance, developing in approximately 25% after 12 months of therapy, is its main limitation. 3Famciclovir is safe in liver transplant recipients; however, virological and clinical responses are less consistent than with lamivudine. Thus, lamivudine is favored over famciclovir as first-line therapy in transplant recipients with no previous exposure to nucleoside analogues. 4Although limited in availability, adefovir dipivoxil appears safe and effective in treating liver transplant recipients with lamivudine-resistant HBV disease. Close monitoring of renal function is recommended, with dose adjustment in patients with reduced creatinine clearances. 5Limited data suggest that intravenous ganciclovir, tenofovir disoproxil fumarate, and interferon alfa may be useful as rescue therapies for patients with lamivudine- or famciclovir-resistant HBV disease. 6Antiviral therapy with two or more suitable agents may minimize the chance for viral resistance; therefore, future therapeutic strategies likely will use combination therapy in the long-term management of recurrent HBV disease. [source] Design of translactam HCMV protease inhibitors as potent antiviralsMEDICINAL RESEARCH REVIEWS, Issue 4 2005Alan D. Borthwick Abstract Human cytomegalovirus (HCMV) is an important pathogen for which there is a significant unmet medical need. New HCMV antivirals, active against novel molecular targets, are undoubtedly needed as the currently available drugs ganciclovir, cidofovir, and foscarnet, which are all viral DNA inhibitors, suffer from limited effectiveness, mainly due to the development of drug resistance, poor bioavailability, and toxicity. One of the newer molecular targets that has been exploited in the search for better drug candidates is HCMV protease. Our ,Ala HCMV protease (wild type variant with the internal cleavage site deleted) was cloned and expressed in E. coli. This viral enzyme was used to develop HCMV protease assays to evaluate potential inhibitors. The chirally pure (SRS)-,-methyl pyrrolidine-5,5- trans -lactam template was synthesized, which together with the natural substrate requirements of HCMV protease and detailed SAR, was used to design potent and selective mechanism based inhibitors of HCMV protease. The mechanism of action of these inhibitors of HCMV protease was investigated by ESI/MS, and the X-ray crystal structure of the HCMV protease was used to refine our selective viral enzyme inhibitors to obtain plasma stable antivirals. A novel ELISA antiviral assay was developed which, together with a cytotoxicity assay, enabled us to discover anti-HCMV drug candidates equivalent in potency to ganciclovir that had good pharmacokinetics in the dog and good brain and ocular penetration in the guinea pig. © 2005 Wiley Periodicals, Inc. Med Res Rev. [source] Prevention of CMV disease in pediatric kidney transplant recipients: Evaluation of pp67 NASBA-based pre-emptive ganciclovir therapy combined with CMV hyperimmune globulin prophylaxis in high-risk patientsPEDIATRIC TRANSPLANTATION, Issue 4 2008Edith Renoult Abstract:, A new prevention strategy for CMV infection was evaluated in our pediatric kidney transplant unit. This approach comprises a pre-emptive therapy, based upon the monitoring of CMV pp67 mRNA in whole blood by the qualitative NASBA, combined with prophylactic CMV-IG in high risk (R,/D+) children. Thirty-one kidney transplant children were followed for six months with serial measurements of CMV pp67 mRNA in the blood. The R,/D+ patients were given prophylactic CMV-IG for the first 16 wk after transplantation. I.v. ganciclovir was administered upon CMV detection by NASBA and was discontinued after two consecutive negative results. CMV infection, detected by NASBA, developed in 11 (35%) recipients: one (33%) of the R+/D, patients and 10 (72%) of the R,/D+ patients. CMV disease developed in 9.6% of the patients (3/31), exclusively in the R,/D+ group. These three patients presented concurrently with CMV viremia and disease. It is noteworthy that two of the three patients could not receive a complete course of CMV-IG, and one of the latter two subjects had been treated for acute rejection 15 days before CMV infection. Ganciclovir was given for the 11 cases of primary infection, and for three cases of relapsed CMV infection. pp67 NASBA-based pre-emptive ganciclovir therapy, combined with prophylactic CMV-IG in high-risk patients leads to a lower rate of CMV disease, as long as a complete course of CMV-IG has been administered and ganciclovir is given during the period of treatment for acute rejection in high-risk populations. [source] Characterization of Herpes Simplex Virus type 1 thymidine kinase mutants engineered for improved ganciclovir or acyclovir activityPROTEIN SCIENCE, Issue 9 2002Mark S. Kokoris Abstract Herpes Simplex Virus type 1 (HSV-1) thymidine kinase (TK) is currently the most widely used suicide agent for gene therapy of cancer. Tumor cells that express HSV-1 thymidine kinase are rendered sensitive to prodrugs due to preferential phosphorylation by this enzyme. Although ganciclovir (GCV) is the prodrug of choice for use with TK, this approach is limited in part by the toxicity of this prodrug. From a random mutagenesis library, seven thymidine kinase variants containing multiple amino acid substitutions were identified on the basis of activity towards ganciclovir and acyclovir based on negative selection in Escherichia coli. Using a novel affinity chromatography column, three mutant enzymes and the wild-type TK were purified to homogeneity and their kinetic parameters for thymidine, ganciclovir, and acyclovir determined. With ganciclovir as the substrate, one mutant (mutant SR39) demonstrated a 14-fold decrease in Km compared to the wild-type enzyme. The most dramatic change is displayed by mutant SR26, with a 124-fold decrease in Km with acyclovir as the substrate. Such new "prodrug kinases" could provide benefit to ablative gene therapy by now making it feasible to use the relatively nontoxic acyclovir at nanomolar concentrations or ganciclovir at lower, less immunosuppressive doses. [source] Retroviral vector-producing mesenchymal stem cells for targeted suicide cancer gene therapyTHE JOURNAL OF GENE MEDICINE, Issue 5 2009Ryosuke Uchibori Abstract Background Mesenchymal stem cells (MSCs) are a promising vehicle for targeted cancer gene therapy because of their potential of tumor tropism. For efficient therapeutic application, we developed retroviral vector-producing MSCs that enhance tumor transduction via progeny vector production. Methods Rat bone marrow-derived MSCs were nucleofected with the proviral plasmids (vesicular stomatitis virus-G protein-pseudotyped retroviral vector components) (VP-MSCs) or pLTR plasmid alone (non-VP-MSCs). The luciferase-based in vivo imaging system was used to assess gene expression periodically. To evaluate the anticancer effects, we administered MSCs expressing herpes simplex virus-thymidine kinase (HSV- tk) into the left ventricular cavity of nude mice engrafted with 9L glioma cells subcutaneously. Results In vivo imaging revealed that administration of luciferase-expressing non-VP-MSCs enhanced the bioluminescence signal at the inoculation sites of 9L cells, whereas no accumulation was observed in mice at the site of the control Rat-1 fibroblasts. Compared to non-VP-MSCs, the administration of VP-MSCs resulted in significant augmentation of the signal with an increase in transgene copy number. Immunohistochemical analysis showed marked luciferase expression at the tumor periphery in mice injected with VP-MSCs, whereas little expression was detected in those injected with non-VP-MSCs. Under the continuous infusion of ganciclovir, systemic administration of VP-MSCs expressing HSV- tk suppressed tumor growth more effectively than non-VP-MSC administration, whereas no anticancer effect was observed without ganciclovir treatment. Furthermore, VP-MSC administration caused no transgene transduction in the normal tissues and organs. Conclusions VP-MSCs accumulated at the site of tumors after intravascular injection in tumor-bearing mice, followed by in situ gene transfer to tumors without transduction of normal organs. When applied to the HSV- tk/ganciclovir suicide gene therapy, more efficient tumor growth suppression was observed using VP-MSCs compared to non-VP-MSCs. This VP-MSC-based system has great potential for improved cancer gene therapy. Copyright © 2009 John Wiley & Sons, Ltd. [source] VP22-mediated intercellular transport correlates with enhanced biological activity of MybEngrailed but not (HSV-I) thymidine kinase fusion proteins in primary vascular cells following non-viral transfectionTHE JOURNAL OF GENE MEDICINE, Issue 3 2005Paul J. Sheridan Background The intercellular transport properties of the herpes simplex virus (HSV) protein VP22 have been harnessed to enhance the effectiveness of viral gene transfer. We investigated the intercellular transport and biological effects of VP22 fused with the dominant negative c-Myb chimera, MybEngrailed (MybEn) and HSV-I thymidine kinase (TK), in primary vascular smooth muscle cells (VSMC) following non-viral transfection. Materials and methods Porcine VSMC transfected with plasmids encoding MybEn, TK and their respective N- and C-terminal VP22 fusion proteins were assayed for the extent and distribution of transgene expression (by immunohistochemistry), culture growth and apoptosis. Results The N-terminal MybEn fusion with VP22 (MybEnVP22) and both TK fusions, but not VP22MybEn, exhibited intercellular spread from primary transfected to up to 200 surrounding cells. pMybEnVP22 -transfected cultures exhibited growth inhibition and apoptosis rates that were 10.6 ± 3.6 and 3.2 ± 1.0 fold higher than in pMybEn -transfected cultures; pVP22MybEn -transfected cultures showed no difference in these parameters. pTK -transfected cultures underwent 60,70% cell death in the presence of ganciclovir despite <2% primary transfection, which was not increased in cultures transfected with plasmids encoding VP22-TK fusions. Conclusions The close correlation between immunocytochemical and biological assays suggests that intercellular transport is crucial to the enhanced biological activity of the MybEnVP22 fusion. The ,intrinsic' bystander activity of TK was 4-fold greater than was ,engineered' by VP22 fusion, probably reflecting the abundance of gap junctions between VSMC. VP22 fusion may enhance the efficiency of non-viral gene delivery when combined with the appropriate therapeutic transgene, target tissue and transfection method. Copyright © 2004 John Wiley & Sons, Ltd. [source] Cytotoxicity and antiangiogenesis by fibroblast growth factor 2,targeted Ad-TK cancer gene therapy,THE LARYNGOSCOPE, Issue 4 2009Koichiro Saito MD Abstract Objectives: Human head and neck squamous cell carcinoma (HNSCC) in addition to lung, skin, ovarian, and other cancers overexpress fibroblast growth factor (FGF) receptors on both individual tumor cells and endothelial cells within the tumor microenvironment. The purpose of this study was to investigate whether FGF2-targeted gene therapy could redirect adenoviral vectors encoding the herpes simplex virus thymidine kinase gene (Ad-TK) to FGF receptors on tumor and endothelial cells with the intent of improving both the efficiency of transgene expression and the antitumor response. Study Design and Methods: An Ad-TK vector consisting of a conjugate of FGF2 linked to a Fab, fragment against the adenoviral knob region was directly delivered to human HNSCC xenograft tumors in nude mice, which were subsequently dosed with ganciclovir. Tumor specimens were assessed for herpes simplex virus thymidine kinase (HSV- tk) transgene mRNA expression, FGF1/2 receptor expression, terminal deoxynucleotidyl transferase biotin,deoxy uridine triphosphate nick end labeling assay for apoptosis, CD31 immunohistochemistry to estimate tumor microvessel density, and tumor volume change. Results: FGF2-retargeted Ad-TK gene therapy demonstrated significant increases in both HSV- tk mRNA expression and cellular apoptosis levels, and a significant decrease in tumor volume size compared with all other groups. Furthermore, microvessel density was significantly lower in the FGF2-retargeted Ad-TK group, indicating a strong antiangiogenesis effect. Conclusions: These data suggest that FGF2-retargeted Ad-TK produces a combination of expected direct antitumor cytotoxicity and a newly reported antiangiogenesis effect that could prove promising as a novel therapeutic approach in the treatment of FGF receptor,expressing cancers. Laryngoscope, 2009 [source] Clinical Predictors of Relapse after Treatment of Primary Gastrointestinal Cytomegalovirus Disease in Solid Organ Transplant RecipientsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2010A. J. Eid Primary gastrointestinal cytomegalovirus (CMV) disease after solid organ transplantation (SOT) is difficult to treat and may relapse. Herein, we reviewed the clinical records of CMV D+/R, SOT recipients with biopsy-proven gastrointestinal CMV disease to determine predictors of relapse. The population consisted of 26 kidney (13 [50%]), liver (10 [38%]) and heart (3 [12%]) transplant recipients who developed gastrointestinal CMV disease at a median of 54 (interquartile range [IQR]: 40,70) days after stopping antiviral prophylaxis. Except for one patient, all received induction intravenous ganciclovir (mean ± SD, 33.8 ± 19.3 days) followed by valganciclovir (27.5 ± 13.3 days) in 18 patients. Ten patients further received valganciclovir maintenance therapy (41.6 ± 28.6 days). The median times to CMV PCR negativity in blood was 22.5 days (IQR: 16.5,30.7) and to normal endoscopic findings was 27.0 days (IQR: 21.0,33.5). CMV relapse, which occurred in seven (27%) patients, was significantly associated with extensive disease (p = 0.03). CMV seroconversion, viral load, treatment duration, maintenance therapy and endoscopic findings at the end of therapy were not significantly associated with CMV relapse. In conclusion, an extensive involvement of the gastrointestinal tract was significantly associated with CMV relapse. However, endoscopic evidence of resolution of gastrointestinal disease did not necessarily translate into a lower risk of CMV relapse. [source] A Multicenter Study of Valganciclovir Prophylaxis up to Day 120 in CMV-Seropositive Lung Transplant RecipientsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2009V. Monforte Seventy-six cytomegalovirus (CMV)-seropositive lung transplant recipients receiving valganciclovir (900 mg/day) for CMV prophylaxis were compared with a group of 87 patients receiving oral ganciclovir (3000 mg/day). Prophylaxis was administered to day 120 post-transplantation and follow-up was 1 year. In addition, a study was conducted on risk factors for CMV infection/disease. CMV disease incidence was 7.9% and 16.1% for valganciclovir and oral ganciclovir, respectively (p = 0.11). Patients receiving valganciclovir had fewer viral syndromes (2.6% vs. 11.5%, p < 0.05), a similar rate of tissue-invasive disease (5.2% vs. 4.6%, p = ns), longer time-to-onset of CMV infection/disease (197.5 vs. 155.2 days, p < 0.05), and a lower probability of infection/disease while on prophylaxis (1.3% vs. 12.6%, p < 0.01). Nonetheless, leukopenia incidence was higher with valganciclovir (15.8% vs. 2.3%, p < 0.01), as was the need for treatment withdrawal due to adverse effects (11.8% vs. 1.1%, p < 0.01). CMV infection was similar in both groups (32.9% vs. 34.5%). Induction therapy with basiliximab and glucocorticosteroid treatment were independent risk factors for developing CMV infection/disease. In conclusion, valganciclovir prophylaxis results in a low incidence of CMV disease in lung transplant recipients and appears more effective than oral ganciclovir. Despite the comparatively higher incidence of adverse events with valganciclovir, the drug can be considered safe for prophylaxis. [source] Long-Term Outcomes of CMV Disease Treatment with Valganciclovir Versus IV Ganciclovir in Solid Organ Transplant RecipientsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2009A. Åsberg Though an important cause of morbidity and mortality in solid organ transplantation (SOT), the long-term outcomes of cytomegalovirus (CMV) disease treatment have not been well studied. In a randomized trial, 321 SOT recipients with CMV disease were followed 1 year after treatment with either twice daily intravenous ganciclovir or oral valganciclovir (for 21 days) followed by once daily valganciclovir until day 49 in all patients. Clinical and viral eradication of CMV disease was similar between groups. Clinical recurrence beyond day 49 was found in 15.1% and virological recurrence in 30.0%, no difference between groups (p > 0.77). In a multivariable logistic regression analysis, the only independent predictor for recurrence was failure to eradicate DNAemia by day 21 (clinical: OR 3.9 [1.3,11.3], p = 0.012; virological: OR 5.6 [2.5,12.6], p < 0.0001). Eight patients developed ganciclovir resistance, with no difference between groups (p = 0.62). Twenty patients (valganciclovir: 11, ganciclovir: 9, p = 0.82) died, 12 due to infections, two involving CMV disease. There were no differences in long-term outcomes between treatment arms, further supporting the use of oral valganciclovir for treatment of CMV disease. Persistent DNAemia at day 21, CMV IgG serostatus and development of resistance may be relevant factors for further individualization of treatment. [source] Imaging-guided convection-enhanced delivery and gene therapy of glioblastomaANNALS OF NEUROLOGY, Issue 4 2003Juergen Voges MD In a prospective phase I/II clinical study, we treated eight patients suffering from recurrent glioblastoma multiform with stereotactically guided intratumoral convection-enhanced delivery of an HSV-1- tk gene,bearing liposomal vector and systemic ganciclovir. Noninvasive identification of target tissue together with assessment of vector-distribution volume and the effects of gene therapy were achieved using magnetic resonance imaging and positron emission tomography. The treatment was tolerated well without major side effects. In two of eight patients, we observed a greater than 50% reduction of tumor volume and in six of eight patients focal treatment effects. Intracerebral infusion of contrast medium before vector application displayed substantial inhomogeneity of tissue staining indicating the need of test infusions to monitor the mechanical distribution of vectors. Visualization of therapeutic effects on tumor metabolism and documentation of gene expression using positron emission tomography indicated that molecular imaging technology appears to be essential for the further development of biological treatment strategies. [source] | |||||||||||||||||||||||||||||||||||||