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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 -
International Journal of Pharmaceutics Jun 2024In this study, once-daily extended-release tablets with dual-phase release of oseltamivir phosphate were developed for the treatment of influenza. The goal was to...
In this study, once-daily extended-release tablets with dual-phase release of oseltamivir phosphate were developed for the treatment of influenza. The goal was to improve patient adherence and offer more therapeutic choices. The tablets were manufactured using wet granulation, bilayer tablet compression, and enteric membrane-controlled coating processes. Various polymers, such as hydroxypropyl methylcellulose (HPMC K100MCR, K15MCR, K4MCR, K100LV), enteric polymers (HPMC AS-LF, Eudragit L100-55) and membrane-controlled polymers (OPADRY® CA), were used either individually or in combination with other common excipients. The formulations include enteric-coated extended-release tablet (F1), hydrophilic matrix extended-release tablet (F2), semipermeable membrane-controlled release tablet (F3) and a combination extended-release tablet containing both enteric and hydrophilic matrix (F4). The in vitro drug release profile of each formulation was fitted to the first-order model, and the Ritger-Peppas model suggested that Fickian diffusion was the primary mechanism for drug release. Comparative bioequivalence studies with Tamiflu® (oseltamivir phosphate) capsules revealed that formulations F1, F2, and F3 did not achieve bioequivalence. However, under fed conditions, formulation F4 achieved bioequivalence with a relative bioavailability of 95.30% (90% CI, 88.83%-102.15%). This suggests that the formulation F4 tablet could potentially be a new treatment option for patients with influenza.
PubMed: 38914352
DOI: 10.1016/j.ijpharm.2024.124364 -
American Journal of Obstetrics and... Jan 2012Given the lack of data regarding the use of oseltamivir (Tamiflu) during pregnancy, we aimed to evaluate the placental transfer of oseltamivir phosphate and its active...
OBJECTIVE
Given the lack of data regarding the use of oseltamivir (Tamiflu) during pregnancy, we aimed to evaluate the placental transfer of oseltamivir phosphate and its active metabolite oseltamivir carboxylate, using the perfused placental cotyledon model.
STUDY DESIGN
Cotyledons were coperfused with oseltamivir phosphate and oseltamivir carboxylate using the maximal concentrations described with a 75 mg, twice-daily oral dose. Main transfer parameters such as fetal transfer rate (FTR) and clearance index (CI) were assessed.
RESULTS
Five placentas were coperfused with oseltamivir phosphate and oseltamivir carboxylate. The median FTR of oseltamivir phosphate was 8.5% (range, 5.0-11.6%) and the median CI was 0.3 (range, 0.2-0.6). Regarding oseltamivir carboxylate transplacental transfer, the median FTR was 6.6% (range, 3.9-9.7%), whereas the median CI was 0.2 (range, 0.2-0.5).
CONCLUSION
A transplacental transfer of oseltamivir phosphate and its metabolite oseltamivir carboxylate was detected and might have clinical relevance. Clinicians should be encouraged to report oseltamivir treatment outcomes during pregnancy.
Topics: Antiviral Agents; Female; Fetus; Humans; Maternal-Fetal Exchange; Oseltamivir; Placenta; Pregnancy; Prodrugs
PubMed: 21958869
DOI: 10.1016/j.ajog.2011.07.023 -
Analytical and Bioanalytical Chemistry May 2016A simple, precise, and rapid method to simultaneously determine the levels of oseltamivir (OS) and oseltamivir carboxylate (OSC) in human plasma was developed....
A simple, precise, and rapid method to simultaneously determine the levels of oseltamivir (OS) and oseltamivir carboxylate (OSC) in human plasma was developed. Additionally, the stability of both substances in plasma was investigated under different conditions. The method involved protein precipitation (0.01 % HCl in acetonitrile), and then the supernatant was injected into the high-performance liquid chromatography (HPLC)-MS/MS. The chromatographic separation was achieved on a YMC-Triart C18 (100 × 2.0 mm, 5 μm) column using acetonitrile/water (30:70, v/v) containing 0.1 % formic acid as the mobile phase. Sample volume was 5 μl. The linearity of the method was established in the concentration range of 0.5-100 ng/mL for OS and 1.0-1000 ng/mL for OSC. The intra-day precision and accuracy for oseltamivir were 1.5-8.9 and 94.4-101.0 %, respectively. For oseltamivir carboxylate, the intra-day precision and accuracy were 3.2-12.7 and 92.8-108.8 %, respectively, whereas the inter-day precision and accuracy were 5.5-11.5 and 94.6-104.0 % for oseltamivir and 4.7-11.5 and 99.9-103.9 % for oseltamivir carboxylate, respectively. The application of this method was demonstrated by a bioequivalence study in 28 healthy humans with 75 mg oseltamivir phosphate capsules (Tamiflu®). Sodium fluoride (2.4 mg/mL) with potassium oxalate (3 mg/mL) was used as anticoagulant within sampling of trial. The assay reproducibility was established by reanalysis of 80 incurred samples.
Topics: Antiviral Agents; Chromatography, High Pressure Liquid; Humans; In Vitro Techniques; Limit of Detection; Oseltamivir; Reproducibility of Results; Tandem Mass Spectrometry; Therapeutic Equivalency
PubMed: 27002612
DOI: 10.1007/s00216-016-9483-2 -
Pediatrics International : Official... Aug 2005
Topics: Acetamides; Antiviral Agents; Humans; Infant; Influenza, Human; Oseltamivir
PubMed: 16091087
DOI: 10.1111/j.1442-200x.2005.02088.x -
American Journal of Obstetrics and... Jun 2011Women in the postpartum period are at high risk for complications from influenza. Pharmacokinetic data of oseltamivir phosphate in postpartum women, however, are lacking.
OBJECTIVE
Women in the postpartum period are at high risk for complications from influenza. Pharmacokinetic data of oseltamivir phosphate in postpartum women, however, are lacking.
STUDY DESIGN
Seven healthy patients within 48 hours of delivery were recruited. Each woman received 75 mg of oseltamivir phosphate. Plasma and breast milk samples were obtained at times 0, 0.5, 1, 2, 4, 8, 12, and 24 hours after the first dose. The samples were analyzed for oseltamivir and oseltamivir carboxylate levels. Using a noncompartmental model, area under the curve (AUC), maximum concentration (C(max)), time to maximum concentration, and half-life were estimated.
RESULTS
Oseltamivir phosphate and oseltamivir carboxylate were found in breast milk, although later and in lower levels than that found in plasma. The C(max) and AUC 0-24 was higher for the active metabolite than for the prodrug in both plasma and breast milk.
CONCLUSION
Oseltamivir carboxylate was present in breast milk but in concentrations significantly lower than considered therapeutic in infants.
Topics: Antiviral Agents; Female; Humans; Milk, Human; Oseltamivir; Postpartum Period; Young Adult
PubMed: 21457910
DOI: 10.1016/j.ajog.2011.01.056 -
Drug Development and Industrial Pharmacy Apr 2022Oseltamivir phosphate is used to treat influenza. For registration of a generic product, bioequivalence studies are crucial, however, studies can sometimes replace the...
Oseltamivir phosphate is used to treat influenza. For registration of a generic product, bioequivalence studies are crucial, however, studies can sometimes replace the conventional human pharmacokinetic. To assess whether the dissolution profile is comparable with the release, physiologically based pharmacokinetic absorption models (PBPK) are being used. The aim of the study was to develop a generic capsule of oseltamivir phosphate 30 mg with process understanding and control, development of PBPK model and comparison of virtual bioequivalence study (VBE) to the real bioequivalence study that was also performed. For that, 30 mg capsules were prepared by wet granulation according to 2 full factorial design. The biobatch was prepared with the selected process and a batch was made with the API from the second manufacture. Both manufactures presented polymorph A and the second manufacture showed higher particle size. Product batches produced without adding water during granulation showed higher dissolution. The addition of water associated with higher conical mill speed, lowered the average weight of the capsules. The biobatch dissolution was similar to Tamiflu; also, they were bioequivalent. The crossover VBE between the biobatch and Tamiflu corroborated with the real bioequivalence study. The same result was found for the batch with higher particle size. PBPK model showed that computer simulations can help pharmaceutical companies to replace studies.
Topics: Capsules; Drug Development; Humans; Models, Biological; Oseltamivir; Phosphates; Therapeutic Equivalency; Water
PubMed: 35876070
DOI: 10.1080/03639045.2022.2102647 -
OncoTargets and Therapy 2014Resistance to drug therapy, along with high rates of metastasis, contributes to the low survival rate in patients diagnosed with pancreatic cancer. An alternate...
BACKGROUND
Resistance to drug therapy, along with high rates of metastasis, contributes to the low survival rate in patients diagnosed with pancreatic cancer. An alternate treatment for human pancreatic cancer involving targeting of Neu1 sialidase with oseltamivir phosphate (Tamiflu®) was investigated in human pancreatic cancer (PANC1) cells with acquired resistance to cisplatin and gemcitabine. Its efficacy in overcoming the intrinsic resistance of the cell to chemotherapeutics and metastasis was evaluated.
METHODS
Microscopic imaging, immunocytochemistry, immunohistochemistry, and WST-1 cell viability assays were used to evaluate cell survival, morphologic changes, and expression levels of E-cadherin, N-cadherin, and VE-cadherin before and after treatment with oseltamivir phosphate in PANC1 cells with established resistance to cisplatin, gemcitabine, or a combination of the two agents, and in archived paraffin-embedded PANC1 tumors grown in RAGxCγ double mutant mice.
RESULTS
Oseltamivir phosphate overcame the chemoresistance of PANC1 to cisplatin and gemcitabine alone or in combination in a dose-dependent manner, and disabled the cancer cell survival mechanism(s). Oseltamivir phosphate also reversed the epithelial-mesenchymal transition characteristic of the phenotypic E-cadherin to N-cadherin changes associated with resistance to drug therapy. Low-dose oseltamivir phosphate alone or in combination with gemcitabine in heterotopic xenografts of PANC1 tumors growing in RAGxCγ double mutant mice did not prevent metastatic spread to the liver and lung.
CONCLUSION
Therapeutic targeting of Neu1 sialidase with oseltamivir phosphate at the growth factor receptor level disables the intrinsic signaling platform for cancer cell survival in human pancreatic cancer with acquired chemoresistance. These findings provide evidence for oseltamivir phosphate (Tamiflu) as a potential therapeutic agent for pancreatic cancer resistant to drug therapy.
PubMed: 24470763
DOI: 10.2147/OTT.S55344 -
American Journal of Obstetrics and... Jun 2011The purpose of this study was to determine pharmacokinetic parameters for oseltamivir in all trimesters of pregnancy. Thirty pregnant women, 10 per trimester, who were...
The purpose of this study was to determine pharmacokinetic parameters for oseltamivir in all trimesters of pregnancy. Thirty pregnant women, 10 per trimester, who were receiving oseltamivir phosphate (75 mg) were recruited to study first-dose pharmacokinetics. Plasma samples were obtained at 0, 0.5, 1, 2, 4, 8, and 12 hours after the first dose. Samples were analyzed for oseltamivir and oseltamivir carboxylate levels. With the use of a noncompartmental model, we estimated the area-under-the-curve, maximum concentration, time-to-maximum concentration, and half-life. There were no significant differences in the pharmacokinetics of oseltamivir by trimester, except for an increased half-life in the first trimester for oseltamivir phosphate and an increased maximum concentration in the third trimester for oseltamivir carboxylate. The levels of oseltamivir carboxylate that were observed were within the range that was needed to achieve inhibitory concentrations at 50% for pandemic H1N1. The pharmacokinetics of oseltamivir does not change significantly according to trimester of pregnancy.
Topics: Adolescent; Adult; Antiviral Agents; Area Under Curve; Female; Half-Life; Humans; Influenza A Virus, H1N1 Subtype; Influenza A virus; Influenza B virus; Influenza, Human; Maximum Allowable Concentration; Oseltamivir; Pandemics; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Trimesters; Time Factors; Young Adult
PubMed: 21492824
DOI: 10.1016/j.ajog.2011.03.005 -
The Journal of Organic Chemistry Oct 2012Oseltamivir phosphate (Tamiflu) has been synthesized from cis-2,3-bis(hydroxymethyl)aziridine. After protection of the cis-2,3-bis(hydroxymethyl)aziridine with a Boc...
Oseltamivir phosphate (Tamiflu) has been synthesized from cis-2,3-bis(hydroxymethyl)aziridine. After protection of the cis-2,3-bis(hydroxymethyl)aziridine with a Boc group, desymmetrization provided a chiral aziridine, which was a key intermediate to install the required stereogenic center containing a nitrogen atom. Allylation and ring closing metathesis are the key reactions to obtain the cyclic product that was successfully converted to the desired oseltamivir phosphate.
Topics: Alkylation; Aziridines; Catalysis; Cyclization; Molecular Structure; Oseltamivir; Stereoisomerism
PubMed: 22970883
DOI: 10.1021/jo3015853