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Science Advances Jun 2023Viral infections continue to threaten human health. It remains a major challenge to efficiently inhibit viral infection while avoiding secondary injury. Here, we...
Viral infections continue to threaten human health. It remains a major challenge to efficiently inhibit viral infection while avoiding secondary injury. Here, we designed a multifunctional nanoplatform (termed as ODCM), prepared by oseltamivir phosphate (OP)-loaded polydopamine (PDA) nanoparticles camouflaged by the macrophage cell membrane (CM). OP can be efficiently loaded onto the PDA nanoparticles through the π-π stacking and hydrogen bonding interactions with a high drug-loading rate of 37.6%. In particular, the biomimetic nanoparticles can accumulate actively in the damaged lung model of viral infection. At the infection site, PDA nanoparticles can consume excess reactive oxygen species and be simultaneously oxidized and degraded to achieve controlled release of OP. This system exhibits enhanced delivery efficiency, inflammatory storm suppression, and viral replication inhibition. Therefore, the system exerts outstanding therapeutic effects while improving pulmonary edema and protecting lung injury in a mouse model of influenza A virus infection.
Topics: Humans; Animals; Mice; Antiviral Agents; Nanomedicine; Oseltamivir; Indoles
PubMed: 37315148
DOI: 10.1126/sciadv.adf4098 -
Viruses May 2023Although the prevalence of polymerase acidic (PA)/I38T strains of influenza virus with reduced susceptibility to baloxavir acid is low, there is a possibility of...
Although the prevalence of polymerase acidic (PA)/I38T strains of influenza virus with reduced susceptibility to baloxavir acid is low, there is a possibility of emergence under selective pressure. Furthermore, the virus may be transmitted between humans. We investigated the in vivo efficacy of baloxavir acid and oseltamivir phosphate against influenza A subtypes H1N1, H1N1pdm09, and H3N2, with PA/I38T substitution, at doses simulating human plasma concentrations. A pharmacokinetic/pharmacodynamic analysis was performed to strengthen the validity of the findings and the applicability in a clinical setting. Although the antiviral effect of baloxavir acid was attenuated in mice infected with PA/I38T-substituted viral strains compared with the wild type (WT), baloxavir acid significantly reduced virus titers at higher-but clinically relevant-doses. The virus titer reduction with baloxavir acid (30 mg/kg subcutaneous single dose) was comparable to that of oseltamivir phosphate (5 mg/kg orally twice daily) against H1N1 and H1N1pdm09 PA/I38T strains in mice, as well as the H3N2 PA/I38T strain in hamsters. Baloxavir acid demonstrated an antiviral effect against PA/I38T-substituted strains, at day 6, with no further viral rebound. In conclusion, baloxavir acid demonstrated dose-dependent antiviral effects comparable to that of oseltamivir phosphate, even though the degree of lung virus titer reduction was diminished in animal models infected with PA/I38T-substituted strains.
Topics: Humans; Animals; Mice; Antiviral Agents; Oseltamivir; Influenza A virus; Oxazines; Pyridines; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H1N1 Subtype; Thiepins; Drug Resistance, Viral; Influenza, Human; Nucleotidyltransferases; Phosphates
PubMed: 37243240
DOI: 10.3390/v15051154 -
BioRxiv : the Preprint Server For... May 2024Hearing loss affects up to 10% of all people worldwide, but currently there is only one FDA-approved drug for its prevention in a subgroup of cisplatin-treated pediatric...
Hearing loss affects up to 10% of all people worldwide, but currently there is only one FDA-approved drug for its prevention in a subgroup of cisplatin-treated pediatric patients. Here, we performed an unbiased screen of 1,300 FDA-approved drugs for protection against cisplatin-induced cell death in an inner ear cell line, and identified oseltamivir phosphate (brand name Tamiflu), a common influenza antiviral drug, as a top candidate. Oseltamivir phosphate was found to be otoprotective by oral delivery in multiple established cisplatin and noise exposure mouse models. The drug conferred permanent hearing protection of 15-25 dB SPL for both female and male mice. Oseltamivir treatment reduced in mice outer hair cells death after cisplatin treatment and mitigated cochlear synaptopathy after noise exposure. A potential binding protein, ERK1/2, associated with inflammation, was shown to be activated with cisplatin treatment and reduced by oseltamivir cotreatment in cochlear explants. Importantly, the number of infiltrating immune cells to the cochleae in mice post noise exposure, were significantly reduced with oseltamivir treatment, suggesting an anti-inflammatory mechanism of action. Our results support oseltamivir, a widespread drug for influenza with low side effects, as a promising otoprotective therapeutic candidate in both cisplatin chemotherapy and traumatic noise exposure.
PubMed: 38765999
DOI: 10.1101/2024.05.06.592815 -
Frontiers in Oncology 2024Mounting evidence has revealed the anti-cancer activity of various anti-viral drugs. Oseltamivir phosphate (OP), namely Tamiflu, is routinely used to combat influenza...
PURPOSE
Mounting evidence has revealed the anti-cancer activity of various anti-viral drugs. Oseltamivir phosphate (OP), namely Tamiflu, is routinely used to combat influenza infections. Although evidence has indicated the anti-cancer effects of OP and , little information is known about the effect of OP use on cancers in humans.
METHODS
A nationwide population-based cohort study involving 13,977,101 cases with 284,733 receiving OP was performed to examine the association between OP use and cancers using the National Health Insurance Research Database in Taiwan between 2009 and 2018.
RESULTS
The cohort study found that OP users showed a significantly lower incidence of lung cancer, colon cancer, liver, and intrahepatic bile duct cancer, oral cancer, pancreas cancer, esophagus cancer, stomach cancer, and prostate cancer. Additionally, OP users exhibited a lower risk of cancer-related mortality (adjusted HR=0.779; 95% confidence interval [CI] 0.743-0.817; p<0.001) and a reduced risk of developing liver cancer (adjusted HR=0.895; 95% CI 0.824-0.972; p=0.008), esophagus cancer (adjusted HR=0.646; 95% CI 0.522-0.799; p<0.001) and oral cancer (adjusted HR=0.587; 95% CI 0.346-0.995; p=0.048). Notably, OP users had a significant reduction in liver cancer occurrence over a 10-year period follow-up and a lower cancer stage at liver cancer diagnosis.
CONCLUSION
These findings first suggest the beneficial effects and therapeutic potential of OP use for certain cancers, especially liver cancer.
PubMed: 38469236
DOI: 10.3389/fonc.2024.1329986 -
PLoS Neglected Tropical Diseases Jan 2022Thrombocytopenia, bleeding and plasma leakage are major complications of dengue. Activation of endogenous sialidases with desialylation of platelets and endothelial... (Randomized Controlled Trial)
Randomized Controlled Trial
Effect of oseltamivir phosphate versus placebo on platelet recovery and plasma leakage in adults with dengue and thrombocytopenia; a phase 2, multicenter, double-blind, randomized trial.
BACKGROUND
Thrombocytopenia, bleeding and plasma leakage are major complications of dengue. Activation of endogenous sialidases with desialylation of platelets and endothelial cells may underlie these complications. We aimed to assess the effects of the neuraminidase inhibitor oseltamivir on platelet recovery and plasma leakage in dengue.
METHODS
We performed a phase 2, double-blind, multicenter, randomized trial in adult dengue patients with thrombocytopenia (<70,000/μl) and a duration of illness ≤ 6 days. Oseltamivir phosphate 75mg BID or placebo were given for a maximum of five days. Primary outcomes were the time to platelet recovery (≥ 100,000/μl) or discharge from hospital and the course of measures of plasma leakage.
RESULTS
A total of 70 patients were enrolled; the primary outcome could be assessed in 64 patients (31 oseltamivir; 33 placebo). Time to platelet count ≥100,000/μl (n = 55) or discharge (n = 9) were similar in the oseltamivir and placebo group (3.0 days [95% confidence interval, 2.7 to 3.3] vs. 2.9 days [2.5 to 3.3], P = 0.055). The kinetics of platelet count and parameters of plasma leakage (gall bladder thickness, hematocrit, plasma albumin, syndecan-1) were also similar between the groups.
DISCUSSION
In this trial, adjunctive therapy with oseltamivir phosphate had no effect on platelet recovery or plasma leakage parameters.
TRIAL REGISTRATION
ISRCTN35227717.
Topics: Adolescent; Adult; Antiviral Agents; Blood Platelets; Dengue; Double-Blind Method; Female; Humans; Male; Oseltamivir; Young Adult
PubMed: 34995275
DOI: 10.1371/journal.pntd.0010051 -
BMC Pharmacology & Toxicology Feb 2023The study was aimed at evaluating the bioequivalence and safety of oseltamivir phosphate for suspension, provided by Shenzhen Beimei Pharmaceutical Co. Ltd. and... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
The study was aimed at evaluating the bioequivalence and safety of oseltamivir phosphate for suspension, provided by Shenzhen Beimei Pharmaceutical Co. Ltd. and manufactured by Hetero Labs Limited, and the reference product TAMIFLU® in healthy Chinese subjects.
METHODS
A single-dose, randomized, two-phase, self-crossed model was adopted. Among 80 healthy subjects, 40 subjects in the fasting group and 40 subjects in the fed group. Subjects in the fasting group were randomized into two sequences according to the proportion of 1:1, each given 75 mg/12.5 mL of Oseltamivir Phosphate for Suspension or TAMIFLU®, and cross-administered after 7 days. Postprandial group is the same as fasting group.
RESULTS
The T of TAMIFLU® and Oseltamivir Phosphate for Suspension in the fasting group were 1.50 h and 1.25 h, which in the fed group were both 1.25 h. Geometrically adjusted mean ratios of the PK parameters of Oseltamivir Phosphate for Suspension along with TAMIFLU® under fasting and postprandial conditions were in the range of 80.00-125.00% at the 90% confidence interval (CI). The 90% CI of C, AUC, AUC for fasting group and postprandial group were (92.39,106.50), (94.26,100.67), (94.32,100.89) and (93.61,105.83),(95.64,100.19),(96.06,102.66). Among the subjects on medication, a total of 18 subjects reported 27 adverse events, all of which were treatment-emergent adverse events (TEAEs), six of these TEAEs were rated as grade 2 in severity and the rest were as grade 1. The number of TEAEs in the test product and the reference product were 14,13 respectively.
CONCLUSION
Two Oseltamivir phosphate for suspensions are safe and bioequivalent.
Topics: Humans; Oseltamivir; Therapeutic Equivalency; Suspensions; Cross-Over Studies; Area Under Curve; Fasting; Healthy Volunteers; Phosphates; Tablets
PubMed: 36810140
DOI: 10.1186/s40360-023-00646-1 -
Journal of Pharmaceutical Health Care... 2020Baloxavir marboxil (baloxavir) is a new anti-influenza virus agent that is comparable to oseltamivir phosphate (oseltamivir). Since the efficacy of baloxavir in...
BACKGROUND
Baloxavir marboxil (baloxavir) is a new anti-influenza virus agent that is comparable to oseltamivir phosphate (oseltamivir). Since the efficacy of baloxavir in preventing household transmission of influenza is not well established, we compared the secondary household influenza virus transmission rates between patients on baloxavir vs oseltamivir.
METHODS
Between October 2018 and March 2019, we enrolled index patients (diagnosed with influenza and treated with baloxavir or oseltamivir) and household members. The secondary attack rate of household members was compared between index patients treated with baloxavir vs oseltamivir. Risk factors of household transmission were determined using multivariate logistic analyses.
RESULTS
In total, 169 index patients with influenza type A were enrolled. The median age was 27.0 (interquartile range; 11-57) years. The number of index patients treated with baloxavir and oseltamivir was 49 and 120, respectively. The secondary attack rate was 9.0% (95% confidence interval [CI]: 4.6-15.6) in the baloxavir group and 13.5% (95% CI: 9.8-17.9) in the oseltamivir group. In the multivariate analysis, independent risk factors were 0-6 years of age (odds ratio [OR] 2.78, 95% CI: 1.33-5.82, < 0.01) and not being on baloxavir treatment. (OR: 0.63, 95% CI: 0.30-1.32, = 0.22).
CONCLUSION
The household secondary attack rate of influenza was comparable in patients treated with baloxavir vs oseltamivir. Therefore, baloxavir can be used as an alternative therapy to oseltamivir in reducing household transmission of influenza.
TRIAL REGISTRATION
Patients in this study were retrospectively registered. https://www.tosei.or.jp/clinical/pdf/2_influenza.pdf.
PubMed: 33014405
DOI: 10.1186/s40780-020-00178-4 -
Beni-Suef University Journal of Basic... 2022Tamiflu/oseltamivir phosphate (OP), an anti-influenza drug, has a highly doubted safety especially after many cases of abnormal behaviour and deaths reported after being...
BACKGROUND
Tamiflu/oseltamivir phosphate (OP), an anti-influenza drug, has a highly doubted safety especially after many cases of abnormal behaviour and deaths reported after being used. Such controversy was also locally and globally generated, especially after being heavily used in COVID-19 treatment protocol. This study was designed to evaluate the effect of three different doses of OP on the liver and kidneys of male adult albino rats through histological approaches, measuring their DNA integrity and biochemical analyses. Different doses of Tamiflu applied to humans were converted to rats, then observed their effects on the liver and kidneys. Rats were divided into four groups. G1: considered as control group. The rest of the three treated groups were received the same calculated dose of Tamiflu (6.75 mg/kg b.w.) in three different durations. G2, G3 and G4 represented the animals orally received OP, in which the rats received OP twice for 5 consecutive days, once for 10 and 45 days, respectively.
RESULTS
Our data showed numerous deleterious necrotic and fibrotic histopathological changes in the liver, and kidneys; as well as necrotic DNA smears, by using electrophoresis, in OP-treated rats of G2 and G4. In addition, OP significantly increased the serum cellular hepatic/renal toxicity markers (ALT, AST, ALP, GGT, indirect bilirubin, urea, creatinine, uric acid, & Na). Also, it showed a reduction in the levels of serum total protein, albumin and K ions in rats of G2 and G4 compared with G1. In G3, OP treatment did not significantly alter hepatic/renal histological, DNA integrity and biochemical analyses in rats.
CONCLUSIONS
The therapeutic and long-term prophylactic doses of OP most likely cause structural and functional hepato- and nephrotoxicity in experimentally subjected rats. So, caution must be taken during Tamiflu treatment, and not used for long durations and/or with repetitive doses (time- and/or accumulative-dose-dependent); especially with patients suffer from liver and/or kidney dysfunction, while the short-term prophylactic dose of OP appears to be relatively safe and could be explored for oral medications.
PubMed: 35097134
DOI: 10.1186/s43088-021-00189-6 -
Journal of Advanced Pharmaceutical... 2022Oseltamivir is an antiviral neuraminidase inhibitor used for the treatment and prophylaxis of influenza infection with viruses A and B. The mechanism of oseltamivir...
Innovated formulation of oseltamivir powder for suspension with stability study after reconstitution using a developed ion-pair reversed phase high-performance liquid chromatography method.
Oseltamivir is an antiviral neuraminidase inhibitor used for the treatment and prophylaxis of influenza infection with viruses A and B. The mechanism of oseltamivir antiviral activity is by inhibiting the activity of the viral neuraminidase enzyme present on the surface of the virus, which stops viral replication and infectivity. Oral suspensions of oseltamivir phosphate are dispensed orally capsules and suspension. However, the use of oral suspension for pediatric administration is preferable and is prepared as a powder for suspension. The reconstituted suspension degrades rapidly within a few days. The objective of this work is to establish a stable formulation of oseltamivir phosphate as a suspension and to assure the stability conditions for prolonged use after reconstitution in aqueous form. In addition, this required formulation should maintain a high rate of dissolution, which subsequently leads to higher bioavailability. In this study, oseltamivir forms an inclusion complex with the natural and safe polymer hydroxypropyl beta-cyclodextrin, which resembles a host because its structural cavity carries the oseltamivir molecule in the aqueous preparation and provides a protective property against environmental challengers. In addition, a high-performance liquid chromatography (HPLC) stability-indicating method of analysis has been developed using an ion-pair reversed-phase HPLC technique that is validated for precision, accuracy, reproducibility, and specificity for the determination of oseltamivir in suspension. The results of this work show the relatively long shelf life of the reconstituted oseltamivir oral powder for suspension in the new pediatric formulation, and the developed HPLC method was precisely suitable for stability study.
PubMed: 35935702
DOI: 10.4103/japtr.japtr_33_22 -
Translational Pediatrics Jun 2022Qinxiang Qingjie (QXQJ), an oral solution containing various Chinese herbs, is indicated for pediatric upper respiratory tract infections. The treatment of influenza...
BACKGROUND
Qinxiang Qingjie (QXQJ), an oral solution containing various Chinese herbs, is indicated for pediatric upper respiratory tract infections. The treatment of influenza also shows potential advantages in shortening the duration of illness and improving symptoms. However, there is still a lack of high-quality clinical evidence to support this. The trial was to explore the efficacy and safety of QXQJ for treating pediatric influenza and provide an evidence-based basis for expanding its applicability.
METHODS
A randomized, double-blind, double-dummy, positive-controlled, multicenter clinical trial was conducted in 14 hospitals in China. Children aged 1-13 years with influenza and "exterior and interior heat syndromes" as defined by traditional Chinese medicine (TCM) were randomly assigned to two groups with 1:1 radio. Children in the test group received QXQJ oral solution and oseltamivir simulant, while the control group received oseltamivir phosphate granules and QXQJ simulant. The duration of treatment was five days, followed by a two-day follow-up period. The primary endpoint was the clinical recovery time. Secondary endpoints included the time to defervescence, incidences of complications and severe or critical influenza, negative conversion rate, improvement of TCM syndromes, and safety profiles of the therapeutics, which mainly contained the adverse clinical events and adverse drug reactions.
RESULTS
A total of 231 children were randomized to either the QXQJ (n=117) or oseltamivir (n=114) group. The FAS and PPS results showed that both groups experienced a median clinical recovery time of three days (P>0.05). The median time to defervescence of both groups were 36 hours in FAS and PPS (P>0.05), and two groups did not differ in terms of the other secondary endpoints (P>0.05). 14 patients (12.39%) in the QXQJ group and 14 patients (12.50%) in the oseltamivir group reported at least one adverse event, respectively. One serious adverse event occurred in the QXQJ group. There was no significant difference in the incidence of adverse events or adverse drug reactions between the groups.
CONCLUSIONS
The efficacy of QXQJ oral solution was comparable to that of oseltamivir for treating influenza in children, with an acceptable safety profile.
TRIAL REGISTRATION
Chinese Clinical Trial Registry ChiCTR1900021060.
PubMed: 35800262
DOI: 10.21037/tp-22-201