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Ribavirin Abstracts



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image Ribavirin enhances the efficacy but not the adverse effects of interferon in chronic hepatitis C. Meta-analysis of individual patient data from European centers
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Interferon-ribavirin combination therapy for chronic hepatitis C

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Antiviral therapy of hepatitis C

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Treatment of chronic hepatitis C: Another therapeutic option

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Long-term efficacy of ribavirin plus interferon alfa in the treatment of chronic hepatitis C

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Therapy of hepatitis C

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Combination antiviral therapy for respiratory virus infections

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Inhibitors of infectious pancreatic necrosis virus (IPNV) replication

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The effects of ribavirin on the GTP level and the VIP receptor dynamic of human IGR39 cells

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Treatment with ribavirin in 4 patients with chronic hepatitic C refractory to alpha interferon

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Beneficial effect of ribavirin on hepatitis C-associated cryoglobulinemia after liver transplantation

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Perspectives for the chemotherapy of respiratory syncytial virus (RSV) infections

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Liver transplantation

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Synergistic anti-influenza virus A (H1N1) activities of PM-523 (polyoxometalate) and ribavirin in vitro and in vivo

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Inhibition of coxsackievirus B3 carrier state infection of cultured human myocardial fibroblasts by ribavirin and human natural interferon-a

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Antiviral efficacy and toxicity of ribavirin and foscarnet each given alone or in combination in the murine AIDS model

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Management of viral infections in bone marrow transplant recipients

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Inhibitory effects of recombinant manganese superoxide dismutase on influenza virus infections in mice

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Effective ribavirin concentration in hamster brains for antiviral chemotherapy for subacute sclerosing panencephalitis

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Influenza in the elderly


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Ribavirin enhances the efficacy but not the adverse effects of interferon in chronic hepatitis C. Meta-analysis of individual patient data from European centers

Journal of Hepatology (Denmark), 1997, 26/5 (961-966)

Background/Aims: This study aimed to obtain a more precise estimation of the efficacy and tolerability of interferon-ribavirin combination therapy for chronic hepatitis C. Methods: A meta-analysis was carried out of individual patient data comprising about 90% of the published experience with combination therapy. The study was set in four European university- affiliated liver referral centers. A total of 186 individuals with chronic hepatitis C who had participated in three randomized controlled trials and one open study were selected for the study. Fifty-one had received ribavirin monotherapy (1000-1200 mg/day), 37 interferon monotherapy (3 MU 3x/week) and 78 interferon-ribavirin combination therapy (dosage as for monotherapy) for 6 months. Twenty patients served as controls. Follow-up after therapy was 6 months. Data analysis was by the multivariate logistical regression method. Results: The primary outcome measure for efficacy was the percentage with a sustained response (ALT normalization and HCV RNA negativity 6 months after therapy). The sustained response rate was significantly higher for interferon-ribavirin combination therapy than for interferon or ribavirin monotherapy (odds ratio IFN-Riba vs IFN=9.8, 95% CI 1.9-50). The estimated probability of sustained response following interferon-ribavirin combination therapy was 51% for patients without previous IFN therapy, 52% for patients with previous IFN therapy and response-relapse, and 16% for previous IFN non-responders. No serious adverse events were observed and less than 10% withdrew. Conclusions: The efficacy of interferon-ribavirin therapy appears to be enhanced two- to threefold over interferon monotherapy in all major subgroups of chronic hepatitis C patients tested. In view of its acceptable toxicity profile, interferon-ribavirin combination therapy is a candidate for the new standard therapy for chronic hepatitis C.



Interferon-ribavirin combination therapy for chronic hepatitis C

Digestive Diseases and Sciences (USA), 1996, 41/12 SUPPL. (131S-134S)

Following preliminary reports of small studies that suggested a clinically important enhanced benefit from combination therapy with interferon-alpha (IFN) and ribavirin over IFN monotherapy in chronic hepatitis C, a meta-analysis of data from these studies was performed to estimate the efficacy and tolerability of combination therapy in chronic hepatitis C. Records were obtained from 59 patients who had received combination therapy with IFN 3 MU three times weekly and ribavirin 1000-1200 mg daily for six months and were followed for six months after stopping combination therapy. Outcome measures included the percentage of patients showing ALT normalization and HCV-RNA negativity six months after therapy (sustained response) and the percentage of patients stopping therapy because of side effects. Sustained response was observed in 21% of IFN nonresponders and in 60% of patients who had relapsed after IFN. For naive patients, the estimated sustained response rate was 52%; the observed response rate was 46%. No serious adverse effects were noted; less than 10% of patients discontinued study medication. This meta-analysis of IFN-ribavirin combination therapy for chronic hepatitis C suggests that combination therapy results in a two- to threefold greater efficacy than IFN monotherapy, whereas side effects are similar to IFN monotherapy, with the exception of ribavirin-induced anemia. Interferon-ribavirin combination therapy might become the next step in antiviral therapy for chronic hepatitis C.



Antiviral therapy of hepatitis C

Scandinavian Journal of Gastroenterology, Supplement (Norway), 1997, 32/223 (46-49)

Background: Chronic hepatitis C can be treated with interferon therapy, but persistent viral clearance is achieved only in 20% of patients. Which patients have a high chance of viral clearance and what other treatmentmight enhance the effectivity of interferon therapy are reviewed.

Methods: Data from published randomized trials on interferon mono-therapy, ribavirin mono-therapy and combination therapy of interferon-ribavirin and interferon-ursodeoxycholic acid are analysed separately and in a meta-analysis of individual data.

Results: Interferon mono-therapy leads to viral clearance in only 10% of patients with genotype 1 and in less than 10% in cirrhosis; patients with plasma HCV RNA detectable at 4 weeks of therapy have only 2% chance of viral clearance. Prolongation of therapy reduces relapse in treatment responders. Interferon-ribavirin combination therapy appears to enhance the efficacy 2-3 fold without increasing toxicity.

Conclusions: The benefit-risk/cost ratio of interferon mono-therapy can be improved by selection of patients, monitoring plasma HCV RNA at 4 weeks, and prolonging therapy to 12 months in responders with genotype 1. Interferon-ribavirin combination is promising for its enhanced efficacy.



Treatment of chronic hepatitis C: Another therapeutic option

Nephrology Dialysis Transplantation (United Kingdom), 1996, 11/SUPPL. 4 (62-64)

Ribavirin is a nucleoside analogue with antiviral activity against a number of DNA and RNA viruses. That molecule is administered per os and its most frequent adverse effect is haemolysis, moderate in most cases. Used alone, ribavirin normalized liver enzyme concentrations in 45% of patients while viraemia is not significantly modified. Histological improvement is observed in responder patients. The most interesting results have been obtained by associating ribavirin with interferon. In patients who have never been treated, a six-month course of ribavirin-interferon association produced a lasting and total response in 47% of patients versus 25% in patients treated with interferon alone. In relapsers, this bi-therapy produced total and prolonged response in more than 40% of cases and in 20% of non-responder patients. Lastly, that association appears promising in treating hepatitis C reinfection after liver transplantation.



Long-term efficacy of ribavirin plus interferon alfa in the treatment of chronic hepatitis C

Gastroenterology (USA), 1996, 111/5 (1307-1312)

Background and Aims: Sustained response to interferon treatment for chronic hepatitis C is unsatisfactory. This study examined whether combining interferon alfa with ribavirin induces a better sustained efficacy than interferon alone in the treatment of chronic hepatitis C. Methods: Sixty noncirrhotic patients with chronic hepatitis C were randomly assigned to three groups. Group 1 received 1200 mg oral ribavirin daily plus 3 million units of recombinant interferon alfa 2a thrice weekly for 24 weeks, group 2 received the same dose of interferon alfa 2a alone for 24 weeks, and group 3 received no treatment. The patients were then followed up for an additional 96 weeks. Results: At the end of treatment, a complete response (normal serum alanine aminotransferase level and undetectable serum hepatitis C virus RNA) was achieved in 16 of the 21 patients in group 1 (76%), as compared with 6 of 19 in group 2 (32%) and none in group 3. At 96 weeks after the end of treatment, patients in group 1 sustained a higher complete response rate than patients in group 2 (43% vs. 6%). Conclusions: Combined treatment with ribavirin and interferon alfa 2a for 24 weeks is more effective than interferon alfa 2a alone for the treatment of chronic hepatitis C. The biochemical and virological responses were sustained in about one half of the treated patients for at least 2 years after cessation of the therapy.



Therapy of hepatitis C

Ospedale Maggiore (Italy), 1997, 91/2 (112-130)

Hepatitis C affects about 200 million people worldwide. Hepatitis C Virus (HCV) infection usually causes chronic hepatitis, that is followed by liver cirrhosis in about 20-50% of cases. Moreover, the chronic liver disease due to HCV infection is a major risk factor for hepatocellular carcinoma. This impressive scenario urgently calls for effective antiviral treatments. Interferon-alpha (alpha-IFN) causes complete sustained remission of hepatitis in about 25% of patients. The chance of response in the single case largely depends on variables related to the virus, to the treatment schedule and to the patient. Among the factors predictive of response to treatment, the following are discussed: virus genotype, heterogeneity of the virus genome, pretreatment serum HCV-RNA titre, HCV viremia during and at the end of treatment, treatment schedule, stage of chronic liver disease, duration of hepatitis, anti-IFN antibodies, serum ferritin concentration and liver iron stores and, finally, gamma-glutamyltranspeptidase. Retreatment of non- sustained responsive cases with alpha-IFN is possible but sustained remission of hepatitis is obtained in few patients. Sometimes it is difficult to decide whether treatment is to be given or not, because the patient has normal transaminase levels in spite of ongoing HCV viremia, or is an alcoholic, or has coexisting infection with hepatitis B virus, hepatitis delta virus or human immunodeficiency virus, shows some evidence of autoimmunity or, finally, has end stage renal failure. Quite often alpha-IFN therapy causes side effects that, in rare occasions, are life-threatening. Ribavirin, to be used either alone or in combination with alpha-IFN, is emerging as an effective therapy. Other therapies, like ursodeoxycholic acid or phlebotomy are still of unproven value.



Combination antiviral therapy for respiratory virus infections

Antiviral Research (Netherlands), 1996, 29/1 (45-48)

A limited number of antiviral drug combinations have been shown to have enhanced activity for important human respiratory viruses. Rimantadine or amantadine combined with ribavirin shows increased antiviral effects in vitro and in experimental animal models. This combination warrants testing in human influenza. Immunoglobulin containing neutralizing anti-RSV antibody combined with ribavirin shows enhanced antiviral effects in experimental animal infections and provides clinical benefit in severe RSV infections of transplant patients. Generally, more effective treatments for acute respiratory viral infections will likely involve combinations of both antivirals and agents that modulate host inflammatory responses to infection.



Inhibitors of infectious pancreatic necrosis virus (IPNV) replication

Antiviral Research (Netherlands), 1996, 29/2-3 (309-312)

In attempts to detect inhibitors of infectious pancreatic necrosis virus (IPNV) replication, we have evaluated, by an IPNV plaque inhibition assay, a group of compounds that have broad spectrum antiviral activity for both single- and double-stranded RNA viruses. The inosine monophosphate dehydrogenase (IMP dehydrogenase) inhibitors 1-beta-D-ribofuranosyl-1,2,4-t riazole-3-carboxamide (ribavirin) and 5-ethynyl-1-beta-D-ribofuranosylimida zole-4-carboxamide (EICAR), and orotidine monophosphate decarboxylase (OMP decarboxylase) inhibitor 4-hydroxy-3-beta-D-ribofuranosylpyrazole-5-carboxa mide (pyrazofurin), were found to inhibit IPNV replication. For EICAR and pyrazofurin the concentrations that inhibited the IPNV plaque formation by 50% (EC50) were 0.01 microg/ml and 0.5 microg/ml, respectively. The cytotoxic concentrations required to reduce cell viability by 50% (CC50) were 50 microg/ml and 100 microg/ml, respectively, and the concentrations that reduced (methyl-3H) thymidine incorporation by 50% (IC50) were 0.5-1 and 50 microg/ml. Thus, for both compounds the IPNV-inhibitory concentration was 50-100 times lower than the concentration that affected DNA synthesis in growing cells. EICAR and pyrazofurin seem to be good candidates for further evaluation in an in vivo model of IPNV infection.



The effects of ribavirin on the GTP level and the VIP receptor dynamic of human IGR39 cells

Journal of Receptor and Signal Transduction Research (USA), 1996, 16/1-2 (39-58)

GTP is one of the major cellular molecules involved in fundamental functions of cell life. Ribavirin, an antiviral and antitumoral agent, the primary site of action of which is the IMP deshydrogenase, was used in order to depress the intracellular GTP level. Consequential effects were tested on the property and dynamic of the VIP receptor on human melanoma IGR 39 cells. A concentration of 100 microM of Ribavirin reduced the intracellular GTP level by more than 60% and induced a reversible growth arrest. Nevertheless this drug displayed no effect on: i) the VIP binding parameters (K(d) and B(max)) of both high and low affinity receptors; ii) the cycling of the VIP receptor; iii) the basal and VIP-stimulated cAMP production and iv) the subcellular GTP distribution. We show that Ribavirin, in the range of concentrations used, is very efficient to inhibit GTP synthesis in the human melanoma cell line IGR 39 and its growth, without affecting VIP receptor functions.



Treatment with ribavirin in 4 patients with chronic hepatitic C refractory to alpha interferon

Gastroenterologia y Hepatologia (Spain), 1996, 19/5 (243-246)

Four patients with chronic hepatitis C who did not respond to treatment with alpha interferon were treated with oral ribavirin at a dosis of 1.000-1.200 mg/day for 6 months. A marked, although transitory, decrease was observed in the transaminase values which returned to pre-treatment values on termination of the same. Normal transaminase values were only obtained at some point in the treatment in two patients. Ribavirin was well tolerated with very slight anemia being detected in all the cases. These results, which are superposable to those of other authors who have studied the effects of this antiviral agent in chronic hepatitis C, suggest that ribavirin may play a role in the treatment of this disease. Given the existing data, this role would be one of a drug associated with interferon with which it may have a synergic action rather than as a monotherapy.



Beneficial effect of ribavirin on hepatitis C-associated cryoglobulinemia after liver transplantation

Liver Transplantation and Surgery (USA), 1996, 2/4 (263-268)

Mixed cryoglobulinemia is a well-known complication after hepatitis C virus (HCV) infection. We report five cases in which cryoglobulinemia appeared or grossly exacerbated following orthotopic liver transplantation (OLT). Cryoglobulinemia and the associated clinical symptoms resolved or improved in two patients treated with ribavirin after liver transplantation, while plasmapheresis was ineffective in another patient. The mechanism involved in induction of cryoglobulinemia after liver transplantation is unknown. However, the effect of antiviral therapy observed in these patients suggests a correlation between cryoglobulinemia, HCV replication, and possibly hepatocellular disease activity. A larger-scale study is warranted to test the effect of ribavirin on post-OLT HCV-associated cryoglobulinemia.



Perspectives for the chemotherapy of respiratory syncytial virus (RSV) infections

International Journal of Antimicrobial Agents (Netherlands), 1996, 7/3 (193-202)

Respiratory syncytial virus (RSV) is the major respiratory pathogen in infants and young children. Ribavirin is the only antiviral agent approved for the treatment of RSV infections, but its efficacy has remained controversial. In the past few years several compounds have been described that in vitro exhibit marked activity against RSV at a 50% effective concentration that is significantly lower, and with a selectivity index that is significantly higher, than that of ribavirin. Among the most potent and selective RSV inhibitors are various polyanionic substances (polysulfates, polysulfonates and polyoxometalates), EICAR (an IMP dehydrogenase inhibitor), pyrazofurin (an OMP decarboxylase inhibitor) and cyclopentenylcytosine (Ce-Cyd, a CTP synthetase inhibitor). These compounds should be further explored for their therapeutic potential in the treatment of RSV infections, following systemic or, preferably, topical administration (i.e. as an aerosol), as topical application may better mimic the potency and selectivity exhibited in vitro by these compounds.



Liver transplantation

Ospedale Maggiore (Italy), 1997, 91/2 (174-182)

The level of success that we confidently expect in liver transplantation today directly results from several factors including surgical technique, the scientific use of immunosuppressive drugs and most importantly patient selection. The goal of an accurate selection is to recognize those patients that will benefit the most from the surgical procedure. This approach is crucial if we consider the limited availability of suitable donors. In general terms a patient with chronic liver disease and a Child Pugh score between 9 and 10 is considered suitable for grafting. Recent studies have shown that liver transplantation can be cost effective and lead to complete social and working rehabilitation provided that the 'timing' for the procedure is not inappropriately delayed. Medium term survival rates after liver transplantation (at 5 years) range between 60 and 80%. Disease recurrence greatly affects the morbidity and mortality after grafting. In patients transplanted for hepatitis B, active vital replication at the time of operation represents the strongest predictor of recurrence although the recent availability of antiviral nucleosids has provided effective prophylactic and therapeutic options. Recurrence of HCV infection is almost universal after transplantation but only 50% of the patients develop histologic hepatitis. The combination therapy with interferon and ribavirin has proved beneficial in modifying the natural history of recurrent disease. If untreated, recurrent hepatitis C can progress to cirrhosis in up to 15% of the patients. Lastly, the strict selection of patients undergoing liver transplantation on account of hepatocellular carcinoma has been associated with favourable results not different from those obtained with other indications.



Synergistic anti-influenza virus A (H1N1) activities of PM-523 (polyoxometalate) and ribavirin in vitro and in vivo

Antimicrobial Agents and Chemotherapy (USA), 1997, 41/7 (1423-1427)

A Kegin-type polyoxometalate, PM-523, in combination with ribavirin, was tested for its therapeutic effectiveness against influenza virus (FluV) A (H1N1) infection in tissue culture and in mice. PM-523 {(PriNH3)6H (PTi2W10O38(O2)2) . H2O, where Pri is isopropanol} and ribavirin individually inhibited FluV A-induced cytopathic effects in Madin-Darby canine kidney (MDCK) cells at median effective concentrations (EC50s) of 30 and 34 microM, respectively, and at 70% effective concentrations (EC70s) of 48 and 72 microM, respectively. On the other hand, a combination of PM-523 and ribavirin at a ratio of 1:16 exhibited lower EC50s and EC70s than each compound used singly, and combination indices were less than 1. A wide range of combinations of PM-523 and ribavirin at ratios of from 1:128 to 1:1 exhibited additive or synergistic anti-FluV effects in MDCK cells. When these compounds were tested for their anti-FluV A activities in vivo by aerosol exposure of mice which had been infected with a lethal dose of FluV A by an intranasal route, a 1:16 combination of PM-523 and ribavirin was found to have a significantly better therapeutic effect than a single dose of either compound used singly with respect to both the survival rate of the mice and the virus titer in the lungs of the infected mice. PM-523 was effective for the treatment of experimental FluV infection, and in combination with ribavirin, PM-523 exhibited enhanced anti-FluV effects in vitro and in vivo compared with the effect of PM-523 alone.



Inhibition of coxsackievirus B3 carrier state infection of cultured human myocardial fibroblasts by ribavirin and human natural interferon-a

Antiviral Research (Netherlands), 1997, 34/3 (101-111)

As enterovirus infections of the heart cause myocarditis and eventually congestive heart failure, the antiviral activity of ribavirin was studied in coxsackie virus B3 (CVB3)-infected carrier cultures of human myocardial fibroblasts. Cultures were infected 7 days before application of ribavirin and effects were evaluated over a period of 16 days by plaque assays and in situ hybridization. Compared to the low antiviral activity in HeLa cells, ribavirin was highly active in reducing infectious virus yields in human myocardial fibroblasts, for example, to 2.0 x 103 pfu/ml with 25 microg/ml and to 1.3 x 102 pfu/ml with 50 microg/ml (4.3 x 104 pfu/ml in infected controls). Moreover, 100 microg ribavirin/ml completely suppressed infectious virus progeny in two of three cultures, and reduced the number of infected cells from 14.3 to 0.3% as determined by in situ hybridization, whereas up to 3200 microg ribavirin/ml did not result in a significant cytotoxic effect. Interaction with interferon-alpha (IFN-alpha) was additive to slightly synergistic in reducing the number of infected cells and virus yields. In conclusion, our results suggest a cell-specific high activity of ribavirin in human myocardial fibroblasts and indicate the importance of using organ-specific cells for testing antiviral agents in myocarditis. Furthermore, the usefulness of in situ hybridization for determining the long term effects of antivirals in carrier state cell cultures was demonstrated.



Antiviral efficacy and toxicity of ribavirin and foscarnet each given alone or in combination in the murine AIDS model

Toxicology and Applied Pharmacology (USA), 1997, 143/1 (140-151)

The antiviral efficacy and toxicity of ribavirin, foscarnet (PFA), and combinations of both drugs at two different doses have been evaluated in the murine AIDS (MAIDS) model. Our results clearly demonstrated that infected mice treated with ribavirin at 100 mg/ kg/day were protected against splenomegaly, lymphadenopathy, and hypergammaglobulinemia whereas PFA alone at 180 or 360 mg/kg/day did not afford any protection. Treatment with drug combinations showed protective effects similar to those observed with ribavirin alone. Hyperplasia and deorganization of the lymphoid architecture-were noted in spleen and lymph nodes of infected mice compared to those of the uninfected group. However, treatment with ribavirin restored the lymphoid tissue architecture and reduced the emergence of germinal centers. Electron microscopic examination of renal cortex of animals treated with PFA at 360 mg/kg/day revealed clear mitochondrial necrosis bursting of mitochondria) of the distal tubules and vacuolization of the proximal tubules which was more striking with combination therapy. Regarding hematotoxicity, PFA did not cause significant hematotoxicity at both doses, whereas ribavirin was hematotoxic at both doses (50 and 100 mg/kg/day), this toxicity being more evident at the higher dose. In conclusion, treatment with ribavirin showed clear efficacy against MAIDS whereas PFA had no efficacy. Furthermore, ribavirin treatment caused hematoxicity and PFA treatment resulted in nephrotoxicity.



Management of viral infections in bone marrow transplant recipients

Clinical Immunotherapeutics (New Zealand), 1996, 6/5 (352-382)

Following bone marrow transplantation (BMT), patients are at risk of viral infections because of prolonged and often profound immunosuppression. Specific viral pathogens that have been identified include members of the Herpesvirus family such as herpes simplex virus (HSV), cytomegalovirus (CMV), varicella zoster virus (VZV), Epstein-Barr virus (EBV), human herpes virus-6 (HHV-6) and adenovirus, as well as respiratory viruses including respiratory syncytial virus (RSV), influenza and parainfluenza. Infections caused by HSV occur most commonly during the pre-engraftment period following BMT. Both intravenous and oral aciclovir (acyclovir) have been effective in the treatment of mucocutaneous HSV infections following BMT. Additionally, prevention strategies using oral or intravenous aciclovir have been effective in decreasing the occurrence of HSV infection following BMT. Resistance of HSV strains to aciclovir is documented, although relatively infrequently. Foscarnet is a therapeutic alternative in patients with aciclovir-resistant HSV infections. CMV-associated infections, particularly CMV interstitial pneumonia (CMV-IP), remain a major cause of mortality following allogeneic BMT. Recipients of allogeneic BMT are more likely to develop significant CMV disease than those receiving autologous grafts. Ganciclovir plus intravenous immunoglobulin has substantially decreased the mortality associated with CMV-IP, although other, more effective strategies are still needed. Aciclovir, foscarnet and ganciclovir have been used to prevent infection and disease in patients who are seropositive or have seropositive donors. Ganciclovir given pre-emptively to patients with CMV infection has significantly decreased the incidence of disease and mortality following BMT. VZV infections occur 5 to 12 months after BMT, when immune reconstitution is still ongoing. Most VZV infections respond to high-dosage intravenous aciclovir. Until further data are available, oral antiviral agents should be used with caution. Prevention strategies are not required, as most patients respond to aciclovir therapy and suffer minimal morbidity from VZV infections. EBV infections may be asymptomatic, but have also been associated with serious complications including post-transplant lymphoproliferative disorders. Antiviral therapies have often been ineffective, but strategies involving adoptive transfer of donor leukocytes with function immunologic activity appear promising. The clinical significance of post-BMT HHV-6 infection remains to be determined. As the role of HHV-6 following BMT is unknown, treatment and prevention strategies are lacking. Reactivation of adenovirus infections typically occur 2 to 3 months following BMT. Infected BMT recipients infrequently develop disseminated infection, although, in those with disseminated infection mortality rates approach 50%. Adenovirus infections have also been associated with late onset haemorrhagic cystitis. No antiviral agents has been consistently effective against adenovirus. Respiratory viruses including RSV, influenza and parainfluenza can cause symptomatic infection following BMT and often occur in conjunction with community outbreaks. Early initiation of aerosolised ribavirin may be of benefit. Influenza vaccines are often ineffective in preventing infection when given early after BMT or in patients with graft-versus-host disease.



Inhibitory effects of recombinant manganese superoxide dismutase on influenza virus infections in mice

Antimicrobial Agents and Chemotherapy (USA), 1996, 40/11 (2626-2631)

The oxygen free-radical scavenger recombinant human manganese superoxide dismutase (MnSOD) was studied for its effects on influenza virus infections in mice when used alone and in combination with ribavirin. Mice challenged with influenza A/NWS/33 (H1N1) virus were treated parenterally in doses of 25, 50, and 100 mg/kg of body weight per day every 8 h for 5 days beginning at 48 h post-virus exposure. An increase in mean day to death, lessened decline in arterial oxygen saturation, and reduced lung consolidation and lung virus titers occurred in the treated animals. To determine the influence of viral challenge, experiments were run in which mice were infected with a 100 or 75% lethal dose of virus and were treated intravenously once daily for 5 days beginning 96 h after virus exposure. Weak inhibition of the mortality rate was seen in mice receiving the high viral challenge, whereas significant inhibition occurred in the animals infected with the lower viral challenge, indicating that MnSOD effects are virus dose dependent. To determine if treatment with small-particle aerosol would render an antiviral effect, infected mice were treated by this route for 1 h daily for 5 days beginning 72 h after virus exposure. A dose- responsive disease inhibition was seen. An infection induced by influenza B/Hong Kong/5/72 virus in mice was mildly inhibited by intravenous MnSOD treatment as seen by increased mean day to death, lessened arterial oxygen saturation decline, and lowered lung consolidation. MnSOD was well tolerated in all experiments. A combination of MnSOD and ribavirin, each administered with small-particle aerosol, resulted in a generally mild improvement of the disease induced by the influenza A virus compared with use of either material alone.



Effective ribavirin concentration in hamster brains for antiviral chemotherapy for subacute sclerosing panencephalitis

Antimicrobial Agents and Chemotherapy (USA), 1996, 40/1 (241-243)

The ribavirin concentration in hamster brains was measured by a high- performance liquid chromatography (HPLC) system and a bioassay system. When ribavirin was administered intracranially at a dosage of 10 mg/kg of body weight per day for 10 days, a dosage which results in 100% survival of hamsters infected with subacute sclerosing panencephalitis (SSPE) virus and which inhibits the replication of SSPE virus in hamster brains, the ribavirin concentration in the brains estimated by HPLC and bioassay was kept higher than 50 microg/g for 10 days. The effective concentration in vivo corresponds to the concentration at which ribavirin completely inhibits the replication of SSPE virus in vitro. The maximal tolerable ribavirin concentration for hamsters was calculated to be 150 microg/g. Although ribavirin shows toxicity to the animals at a relatively low concentration (250 to 400 microg/g), intrathecal or intraventricular administration of ribavirin should be explored for potential use in the treatment of patients with SSPE, while the ribavirin concentration in cerebrospinal fluid or brain tissue should be monitored.



Influenza in the elderly

Journal of Geriatric Drug Therapy (USA), 1995, 10/2 (5-23)

Influenza virus activity occurs every year in the United States. Infections tend to be more severe and more frequently associated with complications and mortality in older patients. Influenza is highly transmissible and has been associated with severe nosocomial outbreaks despite immunization. Influenza vaccine is effective but underutilized in high-risk persons, and is more effective in preventing sequelae of influenza than illness. Influenza A infections are preventable and treatable with amantadine and rimantadine. Antiviral prophylaxis is 70-90% effective against influenza A illness and, if initiated early, treatment shortens the duration of illness in patients with uncomplicated infections. Amantadine is more likely to produce central nervous system side effects and is more dependent on renal elimination than rimantadine, factors that may be of importance in the elderly. Emergence and transmission of drug-resistant viral variants have occurred in settings in which susceptible persons were exposed to treated ill persons. However, appropriate infection control measures can limit this problem in healthcare facilities. Antiviral agents are important adjuncts to influenza management in the elderly.


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