pyrimidinones and Severe-Acute-Respiratory-Syndrome

Inhibition of viral assembly (protease inhibitors) and of fusion of viral and target membranes (fusion inhibitors) are general approaches to antiviral treatment, not specific for HIV. Nonetheless, the agents that induce these phenomena are most often specific for a given virus or virus family. Drugs developed for HIV treatment were reevaluated for use against severe acute respiratory syndrome-coronavirus (SARS-CoV) during and after the epidemic in 2003, in view of the absence of any other available treatment. Of the protease and entry inhibitors approved for treating HIV-infected patients, none was effective against SARS-CoV, although in vitro activity against this virus was reported for the protease inhibitor lopinavir/ritonavir, in results that have not been confirmed in the most recent studies. The epidemiologic methods used to assess this drug's efficacy are not robust. Preliminary results for SARS treatment with protease and entry inhibitors, although at early stages of development, are promising.

Topics: Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Clinical Trials as Topic; Cohort Studies; Drug Therapy, Combination; HIV Infections; Humans; Lopinavir; Protease Inhibitors; Pyrimidinones; Ribavirin; Ritonavir; Severe Acute Respiratory Syndrome; Severe acute respiratory syndrome-related coronavirus; Viral Fusion Proteins

Severe acute respiratory syndrome (SARS) is a newly emerged infectious disease with a significant morbidity and mortality. The major clinical features include persistent fever, chills/rigor, myalgia, malaise, dry cough, headache and dyspnoea. Respiratory failure is the major complication of SARS and approximately 20% of patients may progress to acute respiratory distress syndrome requiring invasive mechanical ventilatory support. However, the severity is much milder in infected young children. Treatment of SARS was empirical in 2003 due to our limited understanding of this new disease. Protease inhibitors (lopinavir/ritonavir) in combination with ribavirin may play a role as antiviral therapy in the early phase, whereas the role of IFN and systemic steroid in preventing immune-mediated lung injury deserves further investigation. Knowledge of the genomic sequence of the SARS coronavirus has facilitated the development of rapid diagnostic tests. In addition, other antiviral treatment, RNA interference, monoclonal antibody, synthetic peptides, and vaccines are being developed. This paper provides a review of the epidemiology, clinical features and possible treatment strategies of SARS.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Antiviral Agents; Humans; Interferons; Lopinavir; Protease Inhibitors; Pyrimidinones; Ribavirin; Ritonavir; Severe Acute Respiratory Syndrome; Severe acute respiratory syndrome-related coronavirus; Viral Vaccines

The pharmacotherapy for severe acute respiratory syndrome (SARS) is controversial and largely anecdotal. Most patients with suspected SARS should initially be treated with potent antibiotics before proceeding to 'anti-SARS' therapy. There is a spectrum of severity and rate of progression in SARS, and the stages of viral replication, inflammatory pneumonitis and residual pulmonary fibrosis are clinically non-distinct. Although now considered lacking in efficacy, ribavirin was used extensively in Hong Kong for treatment of SARS. Retrospective data suggest that the use of Kaletra (ritonavir and lopinavir), an anti-protease, could reduce mortality and improve outcomes, although the adverse reactions are also worrisome. Anecdotal experience strongly supports the use of steroid, at least in a subset of SARS patients, particularly with 'critical SARS' who display continued clinical instability or deterioration and progressive radiographic or HRCT deterioration. A retrospective study carried out of 72 probable SARS patients has shown that cases who received pulse methylprendisolone did not differ in cumulative steroid dosage or adverse reactions, although the former patients had less oxygen requirement, better radiographic outcome, and less likelihood of requiring rescue pulse steroid therapy than their counterparts. Nevertheless, lower dosage of steroid as initial therapy in SARS had also been associated with good clinical outcomes. Poor responders to initial therapy might benefit from rescue steroid therapy or intravenous Pentaglobin. Other drug treatments had also been tried in desperate patients, including the use of convalescence serum and plasmapheresis. Secondary infections could be troublesome, particular for patients with prolonged hospitalization and mechanical ventilation.

Topics: Algorithms; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antiviral Agents; Drug Combinations; Humans; Lopinavir; Pyrimidinones; Ribavirin; Ritonavir; Severe Acute Respiratory Syndrome

The clinical response of patients with severe acute respiratory syndrome (SARS) to a combination of lopinavir/ritonavir and ribavirin was examined after establishing the in vitro antiviral susceptibility of the SARS associated coronavirus to a panel of antiviral agents.. The in vitro susceptibility of the prototype of SARS associated coronavirus to a panel of nucleoside analogues and protease inhibitors currently licensed for clinical use was studied. Forty one patients with SARS followed for 3 weeks were treated with a combination of lopinavir/ritonavir and ribavirin. The clinical progress and virological outcomes were monitored and compared with 111 patients treated with ribavirin only who served as historical controls.. In vitro antiviral activity against SARS associated coronavirus was demonstrated for lopinavir and ribavirin at concentrations of 4 micro g/ml and 50 micro g/ml, respectively, only at 48 hours. The adverse clinical outcome (ARDS or death) was significantly lower in the treatment group than in the historical controls (2.4% v 28.8%, p<0.001) at day 21 after the onset of symptoms. The adverse outcome remained significantly lower in the treatment group than in the controls-both those diagnosed early (p<0.001) and those diagnosed later in the course of the epidemic (p = 0.002)-but there was no significant difference in adverse outcome rates between the two time periods (p = 0.548). No time related difference in outcome was observed in the control groups. A reduction in steroid usage and nosocomial infections was seen in patients initially treated with lopinavir/ritonavir, and these patients had a decreasing viral load and rising peripheral lymphocyte count. Multivariate analysis showed that age, hepatitis B carrier status, and lack of treatment with this antiviral combination were independent predictors of an adverse outcome. Lopinavir/ritonavir treatment was associated with a better outcome even when adjusted for baseline lactate dehydrogenase level.. The apparent favourable clinical response with lopinavir/ritonavir and ribavirin supports further randomised placebo controlled trials in patients with SARS.

Topics: Adult; Aged; Cross Infection; Disease Progression; Drug Therapy, Combination; Female; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Odds Ratio; Pyrimidinones; Ritonavir; Severe Acute Respiratory Syndrome; Steroids; Treatment Outcome; Viral Load

The severe acute respiratory syndrome (SARS) pandemic caught the world by surprise in 2003 and spread rapidly within a relatively short period of time. Hence, randomised placebo-controlled clinical trials on the treatment of SARS were not possible. Our understanding was obtained from observational, cohort studies, case series and reports. Nevertheless, such information is useful in providing clinical management guidelines and directing future research in case SARS recurs. Early in the pandemic, a combination of ribavirin and corticosteroids was adopted as the standard treatment in Hong Kong, Canada and elsewhere because of the apparent good results of the first few patients. Subsequent reports showed that ribavirin was associated with a high rate of toxicity and lacked in vitro antiviral effect on SARS-coronavirus (SAR-CoV). The timing and dosage regimens of steroid in the treatment of SARS are controversial. Pulse methylprednisolone 250 to 500 mg/day for 3 to 6 days has been reported to have some efficacy in a subset of patients with "critical SARS", i.e., critically ill SARS patients with deteriorating radiographic consolidation, increasing oxygen requirement with PaO2 <10 kPa or SpO2 <90% on air, and respiratory distress (rate of 30/min). Prolonged therapy with high-dose steroids, in the absence of an effective antimicrobial agent, could predispose patients to complications such as disseminated fungal infection, and avascular necrosis. Kaletra (400 mg ritonavir and 100 mg lopinavir), a protease inhibitor used in the treatment of human immunodeficiency virus infection, may be considered for early treatment of SARS patients, preferably in a randomised double-blind placebo-controlled clinical trial setting. Interferon (IFN) is not recommended as standard therapy in SARS. However, there are enough data on in vitro activity of IFN preparations and a few clinical studies for these products to support a controlled trial if SARS recurs. Many other experimental treatments have been tried in an uncontrolled manner, and they should not be recommended as standard therapy.

Topics: Adrenal Cortex Hormones; Antiviral Agents; Clinical Competence; Disease Outbreaks; Global Health; Humans; Immunoglobulins; Immunologic Factors; Interferons; Lopinavir; Practice Guidelines as Topic; Protease Inhibitors; Pyrimidinones; Ribavirin; Severe Acute Respiratory Syndrome; Severe acute respiratory syndrome-related coronavirus

Liver impairment is commonly reported in up to 60% of patients who suffer from severe acute respiratory syndrome (SARS). Here we report the clinical course and liver pathology in three SARS patients with liver impairment. Three patients who fulfilled the World Health Organization case definition of probable SARS and developed marked elevation of alanine aminotransferase were included. Percutaneous liver biopsies were performed. Liver specimens were examined by light and electron microscopy, and immunohistochemistry. Reverse-transcriptase polymerase chain reaction (RT-PCR) using enhanced real-time PCR was applied to look for evidence of SARS-associated coronavirus infection. Marked accumulation of cells in mitosis was observed in two patients and apoptosis was observed in all three patients. Other common pathologic features included ballooning of hepatocytes and mild to moderate lobular lymphocytic infiltration. No eosinophilic infiltration, granuloma, cholestasis, fibrosis, or fibrin deposition was noted. Immunohistochemical studies revealed 0.5% to 11.4% of nuclei were positive for proliferative antigen Ki-67. RT-PCR showed evidence of SARS-associated coronavirus in the liver tissues, but not in the sera of all 3 patients. However, electron microscopy could not identify viral particles. No giant mitochondria, micro- or macro-vesicular steatosis was observed. In conclusion, hepatic impairment in patients with SARS is due to SARS-associated coronavirus infection of the liver. The prominence of mitotic activity of hepatocytes is unique and may be due to a hyperproliferative state with or without disruption of cell cycle by the coronavirus. With better knowledge of pathogenesis, specific therapy may be targeted to reduce viral replication and modify the disease course.

Topics: Adult; Anti-Inflammatory Agents; Apoptosis; Biopsy; Coronavirus; DNA, Viral; Drug Combinations; Female; Hepatitis, Viral, Human; HIV Protease Inhibitors; Humans; Liver; Lopinavir; Methylprednisolone; Middle Aged; Mitosis; Pyrimidinones; Ritonavir; Severe Acute Respiratory Syndrome

We observed that 0 of 19 patients with human immunodeficiency virus type 1 (HIV-1) infection, including those with acquired immunodeficiency syndrome (AIDS), who were hospitalized together and who had close contact with 95 patients with severe acute respiratory syndrome (SARS) on the same hospital floor contracted SARS, whereas 6 of 28 medical workers who served on this floor contracted SARS while caring for these patients. Our investigation found that most of the patients with HIV-1/AIDS were receiving treatment of highly active antiretroviral therapy (HAART) during hospitalization. Coincidentally, a research group from Hong Kong recently reported that patients with SARS who received treatment with the anti-HIV-1 drug lopinavir-ritonavir experienced significantly better clinical outcomes than did those who did not receive lopinavir-ritonavir. On the basis of these observations and studies, we propose that HAART should be considered for patients with SARS and their close contacts when the SARS epidemic reemerges.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; HIV Protease Inhibitors; Hong Kong; Humans; Infectious Disease Transmission, Patient-to-Professional; Lopinavir; Pyrimidinones; Ritonavir; Severe Acute Respiratory Syndrome

The SARS-associated coronavirus (SARS-CoV) main proteinase is a key enzyme in viral polyprotein processing. To allow structure-based design of drugs directed at SARS-CoV main proteinase, we predicted its binding pockets and affinities with existing HIV, psychotic and parasite drugs (lopinavir, ritonavir, niclosamide and promazine), which show signs of inhibiting the replication of SARS-CoV. Our results suggest that these drugs and another two HIV inhibitors (PNU and UC2) could be used as templates for designing SARS-CoV proteinase inhibitors.

Topics: Anti-HIV Agents; Antiparasitic Agents; Antipsychotic Agents; Antiviral Agents; Coronavirus 3C Proteases; Cysteine Endopeptidases; Drug Design; Furans; Lopinavir; Molecular Structure; Niclosamide; Promazine; Protease Inhibitors; Protein Binding; Protein Structure, Quaternary; Pyrimidines; Pyrimidinones; Ritonavir; Severe Acute Respiratory Syndrome

Effective antiviral agents are urgently needed to combat the possible return of severe acute respiratory syndrome (SARS). Commercial antiviral agents and pure chemical compounds extracted from traditional Chinese medicinal herbs were screened against 10 clinical isolates of SARS coronavirus by neutralisation tests with confirmation by plaque reduction assays. Interferon-beta-1a, leukocytic interferon-alpha, ribavirin, lopinavir, rimantadine, baicalin and glycyrrhizin showed antiviral activity. The two interferons were only active if the cell lines were pre-incubated with the drugs 16 h before viral inoculation. Results were confirmed by plaque reduction assays. Antiviral activity varied with the use of different cell lines. Checkerboard assays for synergy were performed showing combinations of interferon beta-1a or leukocytic interferon-alpha with ribavirin are synergistic. Since the clinical and toxicity profiles of these agents are well known, they should be considered either singly or in combination for prophylaxis or treatment of SARS in randomised placebo controlled trials in future epidemics.

Topics: Adult; Antiviral Agents; Cell Line; Chlorogenic Acid; Drug Synergism; Female; Flavonoids; Glycyrrhizic Acid; Humans; Interferon beta-1a; Interferon-alpha; Interferon-beta; Lopinavir; Male; Microbial Sensitivity Tests; Middle Aged; Pyrimidinones; Ribavirin; Rimantadine; Severe Acute Respiratory Syndrome; Severe acute respiratory syndrome-related coronavirus; Viral Plaque Assay

To investigate the possible benefits and adverse effects of the addition of lopinavir/ritonavir to a standard treatment protocol for the treatment of severe acute respiratory syndrome.. Retrospective matched cohort study.. Four acute regional hospitals in Hong Kong.. Seventy-five patients with severe acute respiratory syndrome treated with lopinavir/ritonavir in addition to a standard treatment protocol adopted by the Hospital Authority were matched with controls retrieved from the Hospital Authority severe acute respiratory syndrome central database. Matching was done with respect to age, sex, the presence of co-morbidities, lactate dehydrogenase level and the use of pulse steroid therapy. The 75 patients treated with lopinavir/ritonavir were divided into two subgroups for analysis: lopinavir/ritonavir as initial treatment, and lopinavir/ritonavir as rescue therapy. These groups were compared with matched cohorts of 634 and 343 patients, respectively. Outcomes including overall death rate, oxygen desaturation, intubation rate, and use of pulse methylprednisolone were reviewed.. The addition of lopinavir/ritonavir as initial treatment was associated with a reduction in the overall death rate (2.3%) and intubation rate (0%), when compared with a matched cohort who received standard treatment (15.6% and 11.0% respectively, P<0.05) and a lower rate of use of methylprednisolone at a lower mean dose. The subgroup who had received lopinavir/ritonavir as rescue therapy, showed no difference in overall death rate and rates of oxygen desaturation and intubation compared with the matched cohort, and received a higher mean dose of methylprednisolone.. The addition of lopinavir/ritonavir to a standard treatment protocol as an initial treatment for severe acute respiratory syndrome appeared to be associated with improved clinical outcome. A randomised double-blind placebo-controlled trial is recommended during future epidemics to further evaluate this treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; Drug Therapy, Combination; Female; Hong Kong; Humans; Lopinavir; Male; Middle Aged; Poisson Distribution; Pyrimidinones; Retrospective Studies; Ritonavir; Severe Acute Respiratory Syndrome; Treatment Outcome