Antiviral Agent Oseltamivir Research Articles

Oseltamivir and S-Adenosyl-L-Methionine Combination as Effective Therapeutic Strategy for Suppression of Oxidative Damage in Lung Caused by Influenza Virus Infection in Mice.

The pathogenesis of influenza infection is associated with two general processes in the body: (a) lung damage based on virus replication; (b) overproduction of free radicals, antioxidant deficiency, and development of oxidative stress. To attack these aspects of flu pathogenesis, we explored the combined effect of the antiviral agent oseltamivir, and s-adenosyl-l-methionine (SAM) as a precursor of the endogenous antioxidant glutathione, in mice infected with influenza virus. After inoculation of albino mice with 10 MLD50 of influenza virus A/Aichi/2/68 (H3N2), oseltamivir was applied twice a day, for five days post-infection in doses of 1.25 and 2.5 mg/kg. SAM was administered once a day for 10 days, starting 5 days before infection in doses of 50, 100 and 150 mg/kg. Monotherapy with SAM did not influence the markers of oxidative stress in the lung. Combination of SAM 50 mg/kg and oseltamivir 2.5 mg/kg affected best the virological parameters - viral titer, protection index, and mean survival time, as well as the biochemical markers of oxidative stress. Combining of SAM and oseltamivir in a dose of 1/4 of optimal therapeutic could be considered as a perspective therapy of influenza viral infection.

The Role of Extracellular Histones in Influenza Virus Pathogenesis

Although exaggerated host immune responses have been implicated in influenza-induced lung pathogenesis, the etiologic factors that contribute to these events are not completely understood. We previously demonstrated that neutrophil extracellular traps exacerbate pulmonary injury during influenza pneumonia. Histones are the major protein components of neutrophil extracellular traps and are known to have cytotoxic effects. Here, we examined the role of extracellular histones in lung pathogenesis during influenza. Mice infected with influenza virus displayed high accumulation of extracellular histones, with widespread pulmonary microvascular thrombosis. Occluded pulmonary blood vessels with vascular thrombi often exhibited endothelial necrosis surrounded by hemorrhagic effusions and pulmonary edema. Histones released during influenza induced cytotoxicity and showed strong binding to platelets within thrombi in infected mouse lungs. Nasal wash samples from influenza-infected patients also showed increased accumulation of extracellular histones, suggesting a possible clinical relevance of elevated histones in pulmonary injury. Although histones inhibited influenza growth invitro, invivo treatment with histones did not yield antiviral effects and instead exacerbated lung pathology. Blocking with antihistone antibodies caused a marked decrease in lung pathology in lethal influenza-challenged mice and improved protection when administered in combination with the antiviral agent oseltamivir. These findings support the pathogenic effects of extracellular histones in that pulmonary injury during influenza was exacerbated. Targeting histones provides a novel therapeutic approach to influenza pneumonia.

Rapamycin adjuvant therapy did not improve the outcome of severe influenza virus infection in an experimental mouse model system

Abstract The host immune system responds to influenza virus infection for eradication of the virus but the immune response associated inflammation causes tissue injury and damage to the host as well. Severe influenza with morbidity and mortality is commonly believed to be the result of overwhelming immune response. In addition to antiviral agent, adjuvant therapy with immune modulating agent is a reasonable approach for severe influenza and has been reported to be effective in clinical series. As the immunity is also critical for virus eradication and recovery, we investigated to try to define the appropriate window for immune modulation in our murine animal model of influenza virus infection. Rapamycin treatment in a wide dose range did not alter the clinical course of severe influenza. In combination with antiviral agent Oseltamivir, rapamycin failed to offer additional benefit beyond treatment with Oseltamivir alone. Oseltamivir barely rescued the mice from severe influenza if the treatment was delayed until 48 hours after infection. Rapamycin did not provide salvage effect in this scenario. In fact, rapamycin suppressed influenza antigen specific CD4+ T cell response and impaired the virus eradication capacity. The virus burden in the lung increased with intense neutrophil infiltration and hyaline deposition in the alveoli. In conclusion, rapamycin cannot be relied upon as a salvage measure in severe influenza with progressive illness under treatment with Oseltamivir. T cell immunity is suppressed but other arms of immunity are recruited with undesirable effect on the disease outcome.

Eichhornia crassipes: An advantageous source of shikimic acid

The water hyacinth (Eichhornia crassipes (Mart.) Solms, Pontederiaceae) is considered as one of the most productive plants on earth, and an aquatic weed, which causes serious environmental problems. In this study, this species is presented as an alternative of a renewable source of shikimic acid. Although this acid is an important intermediate in the biosynthesis of aromatic compounds in plants and microorganisms, its occurrence is described for the first time in a species of the Pontederiaceae family. Shikimic acid is the lead compound for the production of the antiviral agent oseltamivir phosphate (Tamiflu®). Semi-quantitative analyses of the plant extracts by HPLC-PDA showed that the aerial parts of E. crassipes contain higher shikimic acid concentration (0.03%-2.70% w/w) than the roots (0.05%-0.90% w/w), and that methanol is a better solvent than water for shikimic acid extraction.

A Short Overview on the Medicinal Chemistry of (—)-Shikimic Acid

Shikimic acid, a natural compound is a key intermediate in the biosynthesis of amino acids. Consequently, this derivative is widely present in many plants and has interesting biological properties. But besides the pharmacological relevance of shikimic acid itself, it is also an intermediate in the synthesis of many drugs, being the most relevant the antiviral agent oseltamivir (Tamiflu™). Here we present a short overview on recent natural, biotechnological and synthetical sources of shikimic acid, togheter with pharmacological applications of this compound and a selection of derivatives, including oseltamivir (Tamiflu™).

Carboxylesterase 1 Polymorphism Impairs Oseltamivir Bioactivation in Humans

Bioactivation of the antiviral agent oseltamivir to active oseltamivir carboxylate is catalyzed by carboxylesterase 1 (CES1). After the screening of 860 healthy Finnish volunteers for the CES1 c.428G>A (p.Gly143Glu, rs121912777) polymorphism, a pharmacokinetic study with 75 mg oseltamivir was carried out in c.428G>A carriers and noncarriers. Heterozygous c.428GA carriers (n = 9) had 18% larger values of oseltamivir area under the plasma concentration-time curve from 0 h to infinity (AUC(0-∞)) (P = 0.025) and 23% smaller carboxylate-to-oseltamivir AUC(0-∞) ratio (P = 0.006) than noncarriers (n = 12). This shows that the CES1 c.428G>A polymorphism impairs oseltamivir bioactivation in humans.

Lack of Unwanted Effects of Oseltamivir Carboxylate in Juvenile Rats after Subcutaneous Administration

Lack of Unwanted Effects of Oseltamivir Carboxylate in Juvenile Rats after Subcutaneous Administration

Influenza and Obesity: Will Vaccines and Antivirals Protect?

Influenza and Obesity: Will Vaccines and Antivirals Protect?

Removal of the antiviral agent oseltamivir and its biological activity by oxidative processes

The antiviral agent oseltamivir acid (OA, the active metabolite of Tamiflu ®) may occur at high concentrations in wastewater during pandemic influenza events. To eliminate OA and its antiviral activity from wastewater, ozonation and advanced oxidation processes were investigated. For circumneutral pH, kinetic measurements yielded second-order rate constants of 1.7 ± 0.1 × 10 5 and 4.7 ± 0.2 × 10 9 M −1 s −1 for the reaction of OA with ozone and hydroxyl radical, respectively. During the degradation of OA by both oxidants, the antiviral activity of the treated aqueous solutions was measured by inhibition of neuraminidase activity of two different viral strains. A transient, moderate (two-fold) increase in antiviral activity was observed in solutions treated up to a level of 50% OA transformation, while for higher degrees of transformation the activity corresponded to that caused exclusively by OA. OA was efficiently removed by ozonation in a wastewater treatment plant effluent, suggesting that ozonation can be applied to remove OA from wastewater.

Novel influenza A (H1N1) 2009 infection in the pediatric patients with hematologic and oncologic diseases in the Yeungnam region

PurposeNatural history and consequences of the novel 2009 influenza A H1N1 (2009 H1N1) infection in immunocompromised pediatric patients are not yet fully understood. In this study, we investigated the clinical features and outcomes of the 2009 H1N1 infection in pediatric patients with hematological and oncological diseases.MethodsWe retrospectively reviewed the medical records of 528 patients who had hematological and oncological diseases and who were treated at 7 referral centers located in the Yeungnam region. Among the 528 patients, 27 with definite diagnosis of 2009 H1N1 infection were the subjects of this study. All patients were divided into the following 3 groups: patients who were receiving chemotherapy (group 1), patients who were immunosuppressed due to a non-malignant hematological disease (group 2), and patients who were off chemotherapy and had undergone their last chemotherapy course within 2 years from the influenza A pandemic (group 3).ResultsAll 28 episodes of 2009 H1N1 infection were treated with the antiviral agent oseltamivir (Tamiflu®), and 20 episodes were treated after hospitalization. Group 1 patients had higher frequencies of lower respiratory tract infection and longer durations of fever and hospitalization as compared to those in group 2. Ultimately, all episodes resolved completely with no complications.ConclusionThese results suggest that early antiviral therapy did not influence the morbidity or mortality of pediatric patients with hematological and oncological diseases in the Yeungnam region of Korea after the 2009 H1N1 infection. However, no definite conclusions can be drawn because of the small sample size.

New aspects of the Hunsdiecker–Barton halodecarboxylation—syntheses of phospha-shikimic acid and derivatives

We report an efficient synthetic approach to phospha-isosteres of important intermediates of the shikimic acid pathway by the application of the HunsdieckerBarton halodecarboxylation to cyclohexenylcarboxylic acids. As examples, phospha-shikimic acid, its 3-dehydro derivative and the respective monomethyl esters were synthesized. The approach has proven equally useful in the synthesis of isosteres of the antiviral agent oseltamivir.

Liquidambar styraciflua: a renewable source of shikimic acid

An isolation procedure is presented that yields 2.4–3.7% w/w pure shikimic acid from the seeds of Liquidambar styraciflua (Sweetgum). Shikimic acid, the starting material in the commercial synthesis of the antiviral agent oseltamivir and an important intermediate in the biosynthesis of aromatic amino acids in plants, was found by HPLC to be abundant in the granular, aborted seeds (6.5% w/w) while present only in small amounts in the developed, fertile seeds (0.14% w/w). This extraction technique makes L. styraciflua, which is found in 40 states of the continental US, a potential renewable source of this important natural product.

Design and Evaluation of Prophylactic Interventions Using Infectious Disease Incidence Data from Close Contact Groups

Prophylaxis of contacts of infectious cases such as household members and treatment of infectious cases are methods to prevent spread of infectious diseases. We develop a method based on maximum likelihood to estimate the efficacy of such interventions and the transmission probabilities. We consider both the design with prospective follow-up of close contact groups and the design with ascertainment of close contact groups by an index case as well as randomization by groups and by individuals. We compare the designs using simulations. We estimate the efficacy of the influenza antiviral agent oseltamivir in reducing susceptibility and infectiousness in two case-ascertained household trials.