Safety analysis of Oseltamivir and Baloxavir Marboxil after market approval: a pharmacovigilance study based on the FDA adverse event reporting system.

BACKGROUND AND OBJECTIVES: Amidst limited influenza treatment options, evaluating the safety of Oseltamivir and Baloxavir Marboxil is crucial, particularly given their comparable efficacy. This study investigates post-market safety profiles, exploring adverse events (AEs) and their drug associations to provide essential clinical references. METHODS: A meticulous analysis of FDA Adverse Event Reporting System (FAERS) data spanning the first quarter of 2004 to the fourth quarter of 2022 was conducted. Using data mining techniques like reporting odds ratio (ROR), proportional reporting ratio, Bayesian Confidence Propagation Neural Network, and Multiple Gamma Poisson Shrinkage, AEs related to Oseltamivir and Baloxavir Marboxil were examined. Venn analysis compared and selected specific AEs associated with each drug. RESULTS: Incorporating 15,104 Oseltamivir cases and 1,594 Baloxavir Marboxil cases, Wain analysis unveiled 21 common AEs across neurological, psychiatric, gastrointestinal, dermatological, respiratory, and infectious domains. Oseltamivir exhibited 221 significantly specific AEs, including appendicolith [ROR (95% CI), 459.53 (340.88 ∼ 619.47)], acne infantile [ROR (95% CI, 368.65 (118.89 ∼ 1143.09)], acute macular neuroretinopathy [ROR (95% CI), 294.92 (97.88 ∼ 888.64)], proctitis [ROR (95% CI), 245.74 (101.47 ∼ 595.31)], and Purpura senile [ROR (95% CI), 154.02 (81.96 ∼ 289.43)]. designated adverse events (DMEs) associated with Oseltamivir included fulminant hepatitis [ROR (95% CI), 12.12 (8.30-17.72), n=27], ventricular fibrillation [ROR (95% CI), 7.68 (6.01-9.83), n=64], toxic epidermal necrolysis [ROR (95% CI), 7.21 (5.74-9.05), n=75]. Baloxavir Marboxil exhibited 34 specific AEs, including Melaena [ROR (95% CI), 21.34 (14.15-32.18), n = 23], cystitis haemorrhagic [ROR (95% CI), 20.22 (7.57-54.00), n = 4], ileus paralytic [ROR (95% CI), 18.57 (5.98-57.71), n = 3], and haemorrhagic diathesis [ROR (95% CI), 16.86 (5.43-52.40)), n = 3]. DMEs associated with Baloxavir Marboxil included rhabdomyolysis [ROR (95% CI), 15.50 (10.53 ∼ 22.80), n = 26]. CONCLUSION: Monitoring fulminant hepatitis during Oseltamivir treatment, especially in patients with liver-related diseases, is crucial. Oseltamivir's potential to induce abnormal behavior, especially in adolescents, necessitates special attention. Baloxavir Marboxil, with lower hepatic toxicity, emerges as a potential alternative for patients with liver diseases. During Baloxavir Marboxil treatment, focused attention on the occurrence of rhabdomyolysis is advised, necessitating timely monitoring of relevant indicators for those with clinical manifestations. The comprehensive data aims to provide valuable insights for clinicians and healthcare practitioners, facilitating an understanding of the safety profiles of these influenza treatments in real-world scenarios.

Genomic Analysis of Influenza A and B Viruses Carrying Baloxavir Resistance-Associated Substitutions Serially Passaged in Human Epithelial Cells.

Baloxavir marboxil (baloxavir) is an FDA-approved inhibitor of the influenza virus polymerase acidic (PA) protein. Here, we used next-generation sequencing to compare the genomic mutational profiles of IAV H1N1 and H3N2, and IBV wild type (WT) and mutants (MUT) viruses carrying baloxavir resistance-associated substitutions (H1N1-PA I38L, I38T, and E199D; H3N2-PA I38T; and IBV-PA I38T) during passaging in normal human bronchial epithelial (NHBE) cells. We determined the ratio of nonsynonymous to synonymous nucleotide mutations (dN/dS) and identified the location and type of amino acid (AA) substitutions that occurred at a frequency of ≥30%. We observed that IAV H1N1 WT and MUT viruses remained relatively stable during passaging. While the mutational profiles for IAV H1N1 I38L, I38T, and E199D, and IBV I38T MUTs were relatively similar after each passage compared to the respective WTs, the mutational profile of the IAV H3N2 I38T MUT was significantly different for most genes compared to H3N2 WT. Our work provides insight into how baloxavir resistance-associated substitutions may impact influenza virus evolution in natural settings. Further characterization of the potentially adaptive mutations identified in this study is needed.

Lenthionine, a Key Flavor Substance in Lentinula edodes, Is Regulated by Cysteine under Drought Stress.

Due to its unique flavor profile, Lentinula edodes has become one of the most popular edible mushrooms in the world, but the regulatory mechanism of its flavor substances has not been revealed. To study the mechanism that regulates the anabolic metabolism of the important flavor substance lenthionine (LT), the effect of cysteine (Cys) synthesized by the cystathionine-γ-lyase (CSE-1) gene participating in the regulation of LT metabolism under drought stress was analyzed. Our results showed that drought stress promoted the accumulation of LT, and the key genes GTT and LECSL were activated. Furthermore, drought stress promoted the accumulation of intracellular Cys and activated the key gene for Cys synthesis, CSE-1. Both inhibition of the CSE enzyme activity by inhibitors and silencing of the CSE-1 gene under drought stress significantly reduced the intracellular contents of Cys and LT, but the inhibition of LT synthesis disappeared after the exogenous addition of Cys. These results indicate that LT synthesis in L. edodes under drought stress is dependent on Cys. In summary, the mechanism of the regulation of flavor substances in edible mushrooms by the environment was revealed for the first time.

Comprehensive Evaluation of Biological Effects of Pentathiepins on Various Human Cancer Cell Lines and Insights into Their Mode of Action.

Pentathiepins are polysulfur-containing compounds that exert antiproliferative and cytotoxic activity in cancer cells, induce oxidative stress and apoptosis, and inhibit glutathione peroxidase (GPx1). This renders them promising candidates for anticancer drug development. However, the biological effects and how they intertwine have not yet been systematically assessed in diverse cancer cell lines. In this study, six novel pentathiepins were synthesized to suit particular requirements such as fluorescent properties or improved water solubility. Structural elucidation by X-ray crystallography was successful for three derivatives. All six underwent extensive biological evaluation in 14 human cancer cell lines. These studies included investigating the inhibition of GPx1 and cell proliferation, cytotoxicity, and the induction of ROS and DNA strand breaks. Furthermore, selected hallmarks of apoptosis and the impact on cell cycle progression were studied. All six pentathiepins exerted high cytotoxic and antiproliferative activity, while five also strongly inhibited GPx1. There is a clear connection between the potential to provoke oxidative stress and damage to DNA in the form of single- and double-strand breaks. Additionally, these studies support apoptosis but not ferroptosis as the mechanism of cell death in some of the cell lines. As the various pentathiepins give rise to different biological responses, modulation of the biological effects depends on the distinct chemical structures fused to the sulfur ring. This may allow for an optimization of the anticancer activity of pentathiepins in the future.

Successful treatment with baloxavir marboxil of a patient with peramivir-resistant influenza A/H3N2 with a dual E119D/R292K substitution after allogeneic hematopoietic cell transplantation: a case report.

BACKGROUND: Extended use of oseltamivir in an immunocompromised host could reportedly induce neuraminidase gene mutation possibly leading to oseltamivir-resistant influenza A/H3N2 virus. To our knowledge, no report is available on the clinical course of a severely immunocompromised patient with a dual E119D/R292K neuraminidase mutated-influenza A/H3N2 during the administration of peramivir. CASE PRESENTATION: A 49-year-old male patient was admitted for second allogeneic hematopoietic cell transplantation for active acute leukemia. The patient received 5 mg prednisolone and 75 mg cyclosporine and had severe lymphopenia (70/µL). At the time of hospitalization, the patient was diagnosed with upper tract influenza A virus infection, and oseltamivir treatment was initiated immediately. However, the patient was intolerant to oseltamivir. The following day, treatment was changed to peramivir. Despite a total period of neuraminidase-inhibitor administration of 16 days, the symptoms and viral shedding continued. Changing to baloxavir marboxil resolved the symptoms, and the influenza diagnostic test became negative. Subsequently, sequence analysis of the nasopharyngeal specimen revealed the dual E119D/R292K neuraminidase mutant influenza A/H3N2. CONCLUSIONS: In a highly immunocompromised host, clinicians should take care when peramivir is used for extended periods to treat influenza virus A/H3N2 infection as this could potentially leading to a dual E119D/R292K substitution in neuraminidase protein. Baloxavir marboxil may be one of the agents that can be used to treat this type of mutated influenza virus infection.

7-Acylamino-3H-1,2-benzoxathiepine 2,2-dioxides as new isoform-selective carbonic anhydrase IX and XII inhibitors.

A series of 3H-1,2-benzoxathiepine 2,2-dioxides incorporating 7-acylamino moieties were obtained by an original procedure starting from 5-nitrosalicylaldehyde, which was treated with propenylsulfonyl chloride followed by Wittig reaction of the bis-olefin intermediate. The new derivatives, belonging to the homosulfocoumarin chemotype, were assayed as inhibitors of the zinc metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Four pharmacologically relevant human (h) isoforms were investigated, the cytosolic hCA I and II and the transmembrane, tumour-associated hCA IX and XII. No relevant inhibition of hCA I and II was observed, whereas some of the new derivatives were effective, low nanomolar hCA IX/XII inhibitors, making them of interest for investigations in situations in which the activity of these isoforms is overexpressed, such as hypoxic tumours, arthritis or cerebral ischaemia.

Acute ischemic colitis with hematochezia related to baloxavir marboxil treatment for influenza A.

Oseltamivir, an established oral anti-influenza medication, increases the risk of ischemic colitis. Baloxavir marboxil is a novel oral anti-influenza medication, and few studies have evaluated its potential side effects, including ischemic colitis. Moreover, as influenza A can also induce ischemic colitis, drug-induced colitis associated with anti-influenza medication is not clearly understood. In this report, we describe the case of a 62-year-old Japanese woman who developed acute ischemic colitis after taking baloxavir for influenza A. The day after taking baloxavir (day 2), the patient experienced abdominal pain, diarrhea, and nausea. On day 3, she had developed hematochezia and decided to visit our hospital. Upon presentation, inflammation of the descending and sigmoid colon was detected by abdominal echography and computed tomography. Fluid replacement therapy and dietary restrictions were initiated. On day 4, the inflammation of the descending colon and marked intestinal edema were confirmed by colonoscopy. She was clinically diagnosed with ischemic colitis, from which she recovered completely by day 9. This case suggests that patients taking baloxavir may be at risk of developing ischemic colitis with hematochezia and underscores the need to further study the induction of this condition by commonly used oral anti-influenza agents.

Antimicrobial, Cytotoxic, Anti-Inflammatory, and Antioxidant Activity of Culinary Processed Shiitake Medicinal Mushroom (Lentinus edodes, Agaricomycetes) and Its Major Sulfur Sensory-Active Compound-Lenthionine.

The antimicrobial, cytotoxic, anti-inflammatory, and antioxidant properties of aqueous extracts of raw and culinary processed shiitake mushrooms were evaluated and compared with those of lenthionine (1,2,3,5,6-penta-thiepane), the principal aroma-bearing substance of the shiitake medicinal mushroom (Lentinus edodes). Antimicrobial activity was tested using a panel of 4 strains of bacteria, 2 yeasts, and 2 fungi. Cytotoxic properties were evaluated against 3 cell lines (HepG2, HeLa, PaTu), whereas the anti-inflammatory activity of tested samples was assayed based on their ability to attenuate the secretion of the cytokine tumor necrosis factor-α. Antioxidant activity was measured using in vitro DPPH and ABTS assays. It was found that lenthionine possesses significant antimicrobial properties; it is remarkably effective in inhibiting the growth of yeasts and fungi (minimum inhibitory concentration, 2-8 µg/mL) and thus is comparable to standard antifungal agents. Lenthionine is also able to decrease significantly the production of tumor necrosis factor-a and thus could be at least partly responsible for the observed anti-inflammatory effect of shiitake. On the other hand, lenthionine does not seem to contribute significantly to the well-known anticancer and antioxidant effects of the mushroom.

Discovery of a novel class of AKT pleckstrin homology domain inhibitors.

AKT, a phospholipid-binding serine/threonine kinase, is a key component of the phosphoinositide 3-kinase cell survival signaling pathway that is aberrantly activated in many human cancers. Many attempts have been made to inhibit AKT; however, selectivity remains to be achieved. We have developed a novel strategy to inhibit AKT by targeting the pleckstrin homology (PH) domain. Using in silico library screening and interactive molecular docking, we have identified a novel class of non-lipid-based compounds that bind selectively to the PH domain of AKT, with "in silico" calculated K(D) values ranging from 0.8 to 3.0 micromol/L. In order to determine the selectivity of these compounds for AKT, we used surface plasmon resonance to measure the binding characteristics of the compounds to the PH domains of AKT1, insulin receptor substrate-1, and 3-phosphoinositide-dependent protein kinase 1. There was excellent correlation between predicted in silico and measured in vitro K(D)s for binding to the PH domain of AKT, which were in the range 0.4 to 3.6 micromol/L. Some of the compounds exhibited PH domain-binding selectivity for AKT compared with insulin receptor substrate-1 and 3-phosphoinositide-dependent protein kinase 1. The compounds also inhibited AKT in cells, induced apoptosis, and inhibited cancer cell proliferation. In vivo, the lead compound failed to achieve the blood concentrations required to inhibit AKT in cells, most likely due to rapid metabolism and elimination, and did not show antitumor activity. These results show that these compounds are the first small molecules selectively targeting the PH domain of AKT.

Platinum (II) complexes with stereochemically-defined thiepane dioxide diamine ligands as anticancer drugs.

Platinum (II) complexes are accredited with biological activities. New complexes with thiepane dioxide diamine as ligands, characterized by defined stereochemical features, a flexible 7-membered thiepane moiety and by C2 symmetry, were prepared. The complexes, related to the diamino cyclohexane family of platinum complexes, were soluble in dimethyl sulfoxide with the solvent substituting one chloride ion. These positively-charged complexes were tested against a human carcinoma cell line A431 and its cisplatin-resistant counterpart A431/Pt and were found to show: i) capability in bypassing cisplatin-resistance; ii) cytotoxicity comparable to that of oxaliplatin; iii) lower activity than cisplatin. In both cells lines, [PtCl(DACH)(DMSO)]+ was more cytotoxic than oxaliplatin. The best activity was shown by the platinum complexes with ligands which presented C2 symmetry.

Mini-laparotomy for repair of infrarenal abdominal aortic aneurysm.

AIM: In this study, we evaluated the surgical results of minimal incision aortic surgery (MIAS) compared with the transabdominal approach (TPA) and the retroperitoneal approach (RPA) to repair non-ruptured infrarenal abdominal aortic aneurysm (AAA). METHODS: Three different surgical techniques were studied prospectively in 72 consecutive patients with non-ruptured infrarenal AAA. These patients were randomized into 3 groups of 24 patients each. Group I comprised of patients who underwent MIAS repair. They were compared with group II patients, who underwent the traditionally long midline TPA, and group III patients, who underwent the left RPA to repair non-ruptured infrarenal AAA. All surgery was performed between January 2000 and December 2004. Demographic characteristics, including age, sex, body weight, aneurysm size, previous abdominal operations and comorbid factors of the three groups studied, were compared using the Fischer's exact test. Parameters including operative time, intraoperative fluid administration, and transfusion requirements were compared using the 2-tailed Student t test. Length of stay in the Intensive Care Unit (ICU), time to resumption of regular dietary feeding, and hospital length of stay were recorded and compared using the Wilcox rank sum test. The incidence of 30 day postoperative complications and mortality were compared between the three groups. All 72 patients who entered this study had informed consent. RESULTS: There was no significant difference between group I (MIAS), group II (TPA), and group III (RPA) with regard to age, sex distribution, aneurysm size, or body weight. There was male sex prevalence in all three groups. Surgical exposure of the common femoral arteries was more commonly required in group III (RPA) than in the other groups. Although the length of incision tended to be longer in group III (RPA) than in group II (TPA) and I (MIAS), there was no significant difference in intraoperative time, or aortic cross-clamped time among the three groups. There was a significant difference in the need for intraoperative fluid, the most being in group II (TPA) and the least in group I (MIAS). There was significantly less blood loss in group I (MIAS), as compared with the other 2 groups, but intraoperative blood transfusion for all groups was not significantly different. ICU stay, return to general dietary feeding, and hospital length of stay for group I (MIAS) and III (RPA) were significantly lower than in group II (TPA), which had a higher incidence of postoperative ileus. CONCLUSIONS: MIAS is as safe as retroperitoneal repair and standard transabdominal repair in the treatment of non-ruptured infrarenal AAA, and also more costefficient than retroperitoneal and standard transabdominal repair.

2,3-Dihydro-dithiin and -dithiepine-1,1,4,4-tetroxides: small molecule non-peptide antagonists of the human galanin hGAL-1 receptor.

The neuropeptide galanin modulates several physiological functions such as cognition, learning, feeding behavior, and depression, probably via the galanin 1 receptor (GAL-R1). Using an HTS assay based on 125I-human galanin binding to the human galanin-1 receptor (hGAL-R1), we discovered a series of 1,4-dithiin and dithiipine-1,1,4,4-tetroxides that exhibited binding affinity IC50's to hGAL-R1 ranging from 190 to 2700 nM. Two of the dithiepin analogues, 7 and 23, behaved pharmacologically as hGAL-R1 antagonists in secondary assays involving adenylate cyclase activity and GTP binding to G-proteins. Analogues 7 and 23 were also active in functional assays involving galanin, reversing the inhibitory effect of galanin on acetylcholine (ACh) release in rat brain hippocampal slices and electrically-stimulated guinea pig ileum twitch.

Structure activity analysis of the formation of DNA damage induced in human tumor cells by the cyclodisone class of anti-tumor agent.

1,5,2,4-dioxadithiocane-2,2,4,4-tetraoxide (compound II) and 1,5,2,4-dioxadithionane-2,2,4,4-tetraoxide (compound III) are two structural analogues of the anticancer agent cyclodisone. Compound III was found to be more toxic to human colon carcinoma cells of the Mer- phenotype (BE) than the Mer+ phenotype (HT-29). In contrast, compound II showed little preferential toxicity with both cell lines being equally sensitive to this agent. DNA interstrand crosslinks were induced in the sensitive cell line by compound III but only at concentrations which were extremely cytotoxic. No DNA interstrand crosslinks were detected in the resistant cell line by compound III nor in either cell line by compound II. Total crosslinks which reflects both DNA interstrand and DNA-protein crosslinks, were observed in both cell lines after exposure to each agent although the kinetics of formation and repair of these lesions differed between both the compounds and each cell line. DNA strand breaks were also induced in both cell lines by each compound and were found to be totally 'protein associated' with compound III and to a lesser extend with compound II. The mechanism of action of this class of compound is thus different from other bifunctional alkylating agents and has still to be identified.

Inhibition of cellular esterases by the antitumour imidazotetrazines mitozolomide and temozolomide: demonstration by flow cytometry and conventional spectrofluorimetry.

Using flow cytometry and conventional spectrofluorimetry we have previously shown that chloroethylnitrosoureas (CNUs) can exhibit marked inhibition of cellular enzymes catalysing hydrolysis of fluorescein diacetate (FDA). More potent inhibition was seen for the carbamoylating CNUs, whereas alkylating agents were largely inactive. We now report results obtained with the developmental imidazotetrazines mitozolomide and temozolomide in comparison with BCNU, the novel alkylating agents clomesome and cyclodisone, and the active mitozolomide metabonate MCTIC. Inhibition of EMT6 mouse mammary-tumour esterases was seen for mitozolomide and temozolomide, and activity against purified porcine carboxylesterase was demonstrated. Flow cytometric analysis showed that inhibition occurred across the entire EMT6 cell population, with no evidence of a subpopulation resistant to enzyme inhibition. Inhibitory potency for the imidazotetrazines was much weaker than for BCNU. With EMT6 cells, I50 values from flow cytometry were 9.7 x 10(-3) M and 1.5 x 10(-3) M for mitozolomide and temozolomide compared with 3.7 x 10(-4) M for BCNU. These were higher than the ID50 values for in vitro antitumour activity (MTT assay), 8.5 x 10(-6) M in the case of mitozolomide and 1.2 x 10(-5) M for BCNU, but similar to that of 5.6 x 10(-4) M for the less toxic temozolomide. MCTIC and cyclodisone showed very low activity, but significant inhibition was seen for clomesome. The results are consistent with the view that the imidazotetrazines do not exhibit major carbamoylating ability, although significant effects are seen at cytotoxic concentrations of temozolomide. In addition, the potential for the generation of carbamoylating species at the enzyme active site cannot be ruled out.

Characterization of DNA damage and cytotoxicity induced in two human colon carcinoma cell lines by cyclodisone.

Cyclodisone is an active alkylating antitumor agent that is being considered for Phase 1 clinical trials in humans and is currently undergoing toxicological evaluation. Cyclodisone was found to be more toxic to human colon carcinoma cells of the Mer- phenotype (BE) than cells of the Mer+ phenotype (HT-29). DNA interstrand cross-links were observed in the sensitive cell line but only at concentrations which were extremely toxic. No DNA interstrand cross-links were observed in the resistant cell line. Total DNA cross-links, which reflect both DNA interstrand and DNA-protein cross-linking, were observed in either cell type but were greater in quantity and persisted longer in the sensitive BE cell line, when compared to those produced in the resistant HT-29 cell line. DNA strand breaks were also observed in both cell types and were found to be protein associated. The mechanism of action of cyclodisone would appear to be related to the presence of total DNA cross-links and might involve an, as yet, unidentified DNA-protein interaction.

Comparison of the in vitro cytotoxicity of cyclodisone with a series of structurally related analogues.

The in vitro cytotoxicity of a series of cyclic and linear sulfonate esters has been tested against the BE and HT-29 human colon carcinoma cell lines. Cyclodisone, a cyclic sulfonate ester, was found to be more toxic to the BE cell line when compared with the HT-29 cell line. In contrast, busulfan, a linear sulfonate ester, was equally toxic to both cell lines. Furthermore, alteration of the cyclodisone structure was found to produce marked differences in its cytotoxicity to these cell lines. These compounds would thus appear an excellent class of structures with which to produce new alkylating anti-cancer agents.

DNA reactivity and in vitro cytotoxicity of the novel antitumor agent 1,5,2,4-dioxadithiepane-2,2,4,4-tetraoxide (NSC-348948) in human embryo cells.

1,5,2,4-Dioxadithiepane-2,2,4,4-tetraoxide (cyclic-SoSo) is structurally a novel synthetic compound but may functionally act as an alkylating agent. The effects of cyclic-SoSo on DNA were studied in IMR-90 and VA-13 human embryo cells by means of DNA alkaline elution analysis. In contrast to a number of bifunctional alkylating agents, cyclic-SoSo produced no DNA-DNA interstrand cross-links in either cell line, even at concentration which produced a greater than 3 log cell kill. At equimolar concentrations cyclic-SoSo induced DNA-protein cross-links in both cell lines to a similar extent. Frank DNA breaks and alkali-labile DNA lesions were detected in both cell lines. A greater quantity of strand breaks appeared in the IMR-90 than in the VA-13 cell line after exposure to cyclic-SoSo. However, cyclic-SoSo was more cytotoxic to the VA-13 cell line in vitro than to the IMR-90 cell line. Thus cyclic-SoSo may not be a typical bifunctional alkylating agent in that its mechanism of action does not appear to involve DNA interstrand cross-linking.