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BACKGROUND: Immune checkpoint inhibitors (ICIs) have become standard-of-care at different stage disease in non-small cell lung cancer (NSCLC). Based on the increasing characterization of molecular aberrations and oncogenic drivers in NSCLC, it is expected that more and more patients will benefit from orally small targeted therapies in NSCLC. However, their concomitant or sequential use is associated with an increased risk of a various toxicity pattern. METHODS: Relevant publications were included if they reported data on the question of toxicities associated with sequential or combined use of ICIs and small targeted therapies used in NSCLC treatment. MEDLINE, Google Scholar, and the Cochrane Library were searched for the following request, from database inception until June 2023. RESULTS: This review highlighted a various pattern of toxicities (i.e., interstitial lung disease, hepatitis, dermatoses) in the context of both sequential and concomitant administration of ICIs and small targeted therapies. Such toxicities seem rather a "drug-effect" than a "class-effect" and some of these toxicities are more specific of a small targeted therapy. This review highlights on the impact of treatment sequence administration and emphasis for physicians to be particularly careful whether small targeted therapy is administered within one to three months after last ICIs injection. CONCLUSION: Physicians have to be aware of severe toxicities in case of both concomitant or sequential ICIs/small targeted therapies administration in NSCLC. Further studies are needed to better understand the mechanisms underlying these toxicities in order to prevent them and to refine ICIs and small targeted therapy sequencing strategy.

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The goal of the treatment for Alzheimer's dementia (AD) is the cure of dementia. A literature review revealed 18 major elements causing AD and 29 separate medications that address them. For any individual with AD, one is unlikely to discern which major causal elements produced dementia. Thus, for personalized, precision medicine, all causal elements must be treated so that each individual patient will have her or his causal elements addressed. Twenty-nine drugs cannot concomitantly be administered, so triple combinations of drugs taken from that list are suggested, and each triple combination can be administered sequentially, in any order. Ten combinations given over 13 weeks require 2.5 years, or if given over 26 weeks, they require 5.0 years. Such sequential treatment addresses all 18 elements and should cure dementia. In addition, any comorbid risk factors for AD whose first presence or worsening was within ±1 year of when AD first appeared should receive appropriate, standard treatment together with the sequential combinations. The article outlines a randomized clinical trial that is necessary to assess the safety and efficacy of the proposed treatments; it includes a triple-drug Rx for equipoise. Clinical trials should have durations of both 2.5 and 5.0 years unless the data safety monitoring board (DSMB) determines earlier success or futility since it is uncertain whether three or six months of treatment will be curative in humans, although studies in animals suggest that the briefer duration of treatment might be effective and restore defective neural tracts.

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Background: Based on previous research, both dapagliflozin (DAPA) and sacubitril-valsartan (S/V) improve the prognosis of patients with heart failure (HF). Our study aims to investigate whether the early initiation of DAPA or the combination of DAPA with S/V in different orders would exert a greater protective effect on heart function than that of S/V alone in post-myocardial infarction HF (post-MI HF). Methods: Rats were randomized into six groups: (A) Sham; (B) MI; (C) MI + S/V (1st d); (D) MI + DAPA (1st d); (E) MI + S/V (1st d) + DAPA (14th d); (F) MI + DAPA (1st d) + S/V (14th d). The MI model was established in rats via surgical ligation of the left anterior descending coronary artery. Histology, Western blotting, RNA-seq, and other approaches were used to explore the optimal treatment to preserve the heart function in post-MI HF. A daily dose of 1 mg/kg DAPA and 68 mg/kg S/V was administered. Results: The results of our study revealed that DAPA or S/V substantially improved the cardiac structure and function. DAPA and S/V monotherapy resulted in comparable reduction in infarct size, fibrosis, myocardium hypertrophy, and apoptosis. The administration of DAPA followed by S/V results in a superior improvement in heart function in rats with post-MI HF than those in other treatment groups. The administration of DAPA following S/V did not result in any additional improvement in heart function as compared to S/V monotherapy in rats with post-MI HF. Our findings further suggest that the combination of DAPA and S/V should not be administered within 3 days after acute myocardial infarction (AMI), as it resulted in a considerable increase in mortality. Our RNA-Seq data revealed that DAPA treatment after AMI altered the expression of genes related to myocardial mitochondrial biogenesis and oxidative phosphorylation. Conclusions: Our study revealed no notable difference in the cardioprotective effects of singular DAPA or S/V in rats with post-MI HF. Based on our preclinical investigation, the most effective treatment strategy for post-MI HF is the administration of DAPA during the 2 weeks, followed by the addition of S/V to DAPA later. Conversely, adopting a therapeutic scheme whereby S/V was administered first, followed by later addition of DAPA, failed to further improve the cardiac function compared to S/V monotherapy.

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OBJECTIVE: An open-label study was conducted to compare the safety and immunogenicity of a sequential administration of 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) between an interval of 0.5 (0.5-y) and 1 year (1.0-y) in adults aged ≥ 65 years. METHODS: Pneumococcal vaccine-naïve adults aged ≥ 65 years (n = 129) received a sequential administration with an interval of 0.5-y or 1.0-y or received a single administration of PPSV23 (single PPSV23). We evaluated the immunogenicity before and 1 month after each vaccination and at 0.5-y intervals for 2 years. The primary endpoint was the increase in geometric mean fold rises (GMFRs) of immunoglobulin G (IgG) or opsonophagocytic activity (OPA) for eight common serotypes one month after one dose of PPSV23. The secondary endpoint was the safety profile for one dose of PPSV23. RESULTS: One month after administration of PPSV23, the GMFRs of IgG considerably increased for five of eight serotypes in the 1.0-y interval group, whereas the GMFRs of IgG considerably increased for two serotypes in the 0.5-y interval group. Furthermore, GMFRs of OPA markedly increased for all eight serotypes in the 1.0-y interval group, while GMFRs of OPA markedly increased for four serotypes in the 0.5-y interval group. At 2 years after initial vaccination, GMFRs of IgG or OPA were higher for all serotypes, except for serotype 3, than those in the single PPSV23 group irrespective of intervals. No significant difference was found in the frequencies of local reactions of all grades between the two intervals. CONCLUSIONS: The 1.0-y interval provided better booster effects induced by PPSV23 than those of the 0.5-y interval in a sequential administration in pneumococcal vaccine-naïve adults aged ≥ 65 years. No difference was found in the safety profile between both intervals.

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Flavonoid 7-O-glucosides exhibit various biological activities; however, some are not abundant in nature. Therefore, a method to produce flavonoid 7-O-glucosides was investigated. Escherichia coli expressing tobacco-derived glucosyltransferase (Ec-NtGT2) converted several flavonoids (apigenin, luteolin, quercetin, kaempferol, and naringenin) to their 7-O-glucosides with conversion rates of 67-98%. In scaled-up production, Ec-NtGT2 yielded 24 mg/L of apigenin 7-O-glucoside, 41 mg/L of luteolin 7-O-glucoside, 118 mg/L of quercetin 7-O-glucoside, 40 mg/L of kaempferol 7-O-glucoside, and 75 mg/L of naringenin 7-O-glucoside through sequential administration of substrates in 4-9 h. The conversion rates of apigenin, luteolin, quercetin, kaempferol, and naringenin were 97%, 72%, 77%, 98%, and 96%, respectively. These results indicated that Ec-NtGT2 is a simple and efficient bioconversion system for the production of flavonoid 7-O-glucosides.

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In most countries worldwide, pneumococcal conjugate vaccines have been included in the infant immunization program, resulting in a significant reduction in the burden of pneumococcal disease in children and adults. Shifting serotype distribution due to the indirect effect of infant vaccination with the 13-valent pneumococcal conjugate vaccine (PCV13) may continue to increase the gap between 23-valent pneumococcal polysaccharide vaccine (PPSV23) and PCV13 serotype coverage for older adults in the coming years. This clinical study (V110-029; NCT02225587) evaluated the safety and immunogenicity of sequential administration of PCV13 followed approximately 8 weeks later, or approximately 26 weeks later, by PPSV23 in healthy adults ≥50 years of age. Both dosing intervals were generally well tolerated as measured by the nature, frequency, and intensity of reported adverse events (AEs) in both vaccination groups. Serotype-specific opsonophagocytic activity (OPA) geometric mean titers (GMTs) measured 30 days following receipt of PPSV23 in either group and at Week 30 were generally comparable between the 2 groups for 6 serotypes unique to PPSV23 and 12 serotypes shared between PCV13 and PPSV23, regardless of the interval between receipt of PCV13 and PPSV23. In addition, administration of PPSV23 given either 8 weeks or 26 weeks following PCV13 did not negatively impact immune responses induced by PCV13. Furthermore, administration of PPSV23 given either 8 weeks or 26 weeks after PCV13 elicited serotype-specific OPA GMTs to serotypes unique to PPSV23, which could provide earlier protection against pneumococcal disease caused by these serotypes in comparison with the current Advisory Committee on Immunization Practices recommended interval of at least 12 months.

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Combined administration of drugs can improve efficacy and reduce toxicity; therefore, this combination approach has become a routine method in cancer therapy. The main combination regimens are sequential, mixed (also termed "cocktail"), and co-loaded; however, other combinations, such as administration of synergistic drugs and the use of formulations with different mechanisms of action, may exert better therapeutic effects. Tumor-associated macrophages (TAMs) play functional roles throughout tumor progression and exhibit characteristic phenotypic plasticity. Sialic acid (SA)-modified epirubicin liposomes (S-E-L) and SA-modified zoledronate liposomes (S-Z-L) administered separately kill TAMs, reverse their phenotype, and achieve antitumor effects. In this study, we examined the effects of a two-treatment combination for drug delivery, using sequential, mixed, and co-loaded drug delivery. We found that therapeutic effects differed between administration methods: mixed administration of S-E-L and S-Z-L, co-loaded administration of SA-modified liposomes (S-ZE-C), and sequential administration of S-E-L injected 24 h after S-Z-L did not inhibit tumor growth; however, sequential administration of S-Z-L injected 24 h after S-E-L resulted in no tumor growth, no toxicity to noncancerous tissue, and no death of mice, and exhibited 25% tumor shedding. Thus, our results thus encourage the further development of combined therapies for nanomedicines based on the mechanisms investigated here.

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BACKGROUND: The combination of ketoconazole and dexamethasone acetate is one of the commonly used treatments in dermatology regiment for skin inflammation accompanied by fungal infections. This interaction of ketoconazole and dexamethasone may make the drug much effective, decrease the adverse reaction or toxic effects. At present, there was no information about the interaction of these two external drugs. Therefore, it was necessary to build a model to measure the levels and evaluate the interaction of ketoconazole and dexamethasone acetate in skin cells. METHODS: In our study, the determination methodology of ketoconazole and dexamethasone acetate in human keratinocyte (HaCaT cells) was established and the interaction of these two drugs in cells was explored. HaCaT cells were cultured in medium containing ketoconazole, then they were sequentially cultured with or without dexamethasone acetate treatment for another 1, 2, 4, 8 and 12 h. The samples were then harvested and the concentrations were quantified by enhanced BCA (the bicinchoninic acid) protein assay. Furthermore, the analytes in the cell suspension were also prepared and analyzed by LC-MS method. RESULTS: As a result, ketoconazole and dexamethasone acetate were detected at the concentration range of 0.02 to 5 µg/mL and 0.2 to 100 µg/mL, respectively. The RSD (relative standard deviation) and RE (relative error) of precision and accuracy of the two analytes in the cell suspension were all less than 15 %. The matrix effect values variations were all less than 15%. The results showed that there was no significant difference in the concentration of ketoconazole with or without dexamethasone acetate treatment within 12 h. CONCLUSIONS: A simple, sensitive and rapid LC-MS method which could quantify these two analytes in cells simultaneously was developed for the first time. The results of the concentration changes meant that no interaction occurred when dexamethasone sequentially administrated for 12 h after ketoconazole treatment. This method was successfully applied to establish the cell pharmacokinetics methodology and preliminary studied the metabolism of drug-drug interaction of ketoconazole and dexamethasone acetate.

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Although no nebulized, dual mechanism, long-acting bronchodilator is currently marketed, with the approval of once-daily long-acting muscarinic antagonist (LAMA) revefenacinefenacin, it is theoretically possible to deliver a LAMA and long-acting beta2-agonist via standard jet nebulizer. The primary and secondary objectives of our study were to characterize the safety profile of revefenacin administered sequentially before or in combination with formoterol, via standard jet nebulizer in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). In this randomized, double-blind, 42-day trial (NCT03573817), patients received revenacin 175 µg (n=63) or placebo (n=59), followed by formoterol 20 µg in the morning and formoterol alone in the evening formoterol 21 days via standard jet nebulizer (sequential administration). For another 21 days, revefenacin/placebo and formoterol, were administered as mixed solutions via single nebulization in the morning (combined administration), and formoterol alone in the evening. The adverse events' (AEs) incidence was higher in the placebo + formoterol arms (11%-12%) than in the revefenacin + formoterol arms (5%-8%). The most common AEs were worsening/exacerbation of COPD, cough, and dizziness. There were no serious AEs or deaths reported in any arm. The least squares mean in trough forced expiratory volume in 1 second (FEV1) versus baseline was higher in the revefenacin + formoterol arms (116-157 mL) than in the placebo + formoterol arms (35-53 mL). Revefenacin had a safety profile similar to formoterol alone when delivered sequentially or combined. Trough FEV1 was similar when revefenacin was delivered sequentially or combined with formoterol, with revefenacin providing an additional 81-104 mL improvements over formoterol alone.

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Objectives: The optimal combination of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and chemotherapy has helped to improve therapeutic effects in non-small-cell lung cancer (NSCLC). This study aimed to explore the progression free survival (PFS) of patients after sequential administration of TKI and pemetrexed chemotherapy. Methods: This study retrospectively screened treatment-naive advanced NSCLC patients harbouring EGFR mutations who were prescribed a TKI and salvaged with pemetrexed chemotherapy or vice versa. The total, initial and salvage PFS were collected. Results: The total PFS including both the initial and salvage PFS was 18.0 mon (95% CI: 14.1­21.9 mon), which was not influenced by the sequence of administration (TKI first: 18.0 mon, 95% CI: 15.8­20.2 mon, pemetrexed first: 16.1 mon, 95% CI: 9.1­23.1 mon, HR 0.92, P=0.748). A longer PFS was achieved for TKI over chemotherapy in both the initial (10.6 and 5.9 mon, HR 2.62, P=0.001) and salvage therapy (12.0 and 6.0 mon, HR 1.29, P=0.001). TKI remained effective either before (10.6 mon) or after (12.0 mon) chemotherapy (HR 0.96, P=0.853). The same trend was observed for chemotherapy (5.9 and 6.0 mon for initial and salvage therapy, respectively, HR 0.82, P=0.417). Conclusions: The sequential administration of TKI and pemetrexed chemotherapy achieved a long PFS and was a suitable treatment for advanced NSCLC.

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Aims: The management of myocardial ischemia has been challenged by reperfusion injury. Reactive oxygen species (ROS) production is the critical cause of reperfusion injury, but antioxidant treatment failed to gain satisfactory effects. We hypothesized that improvement of redox homeostasis by preconditioning regulation should potentiate the ability of antioxidants to protect the heart from reperfusion injury. Results: By phenotype-based screening, we identified that dihydrotanshinone I (DT) and protocatechuic aldehyde (PCA) potently protected cardiomyocytes through preconditioning regulation and antioxidant activity, respectively. DT induced transient ROS generation via reversible inhibition of mitochondrial respiratory complex I and thereby stabilizing HIF-1α, while PCA elevated the levels of reduced glutathione (GSH) by providing reducing equivalents to scavenge ROS. HIF-1α, stabilized by DT, transcriptionally upregulated Nrf2 and thereby activated antioxidant enzymes, potentiating PCA to protect cardiomyocytes from reperfusion injury by strengthening intrinsic ROS scavenging capacity. In rat ischemia/reperfusion (I/R) model, sequential administration of DT and PCA, but not in reverse, additively protected the heart from I/R injury, manifested by reduced infarct size and improved cardiac function. These results were further supported by sequential administration of metformin and vitamin E in the rat and porcine I/R models. Innovation and Conclusion: Our work demonstrates that preconditioning regulation of redox state is essential for antioxidants to protect the heart from I/R injury, providing a new direction for the treatment of myocardial injury.

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Sequential administration of the chemotherapy regimes capecitabine and oxaliplatin (XELOX) and capecitabine and irinotecan (XELIRI) in the first- to second-line treatment setting would allow patients to be managed more easily in an outpatient unit. However, a small number of studies have raised concerns of cumulative adverse events as a consequence of the continuous use of capecitabine. To investigate this, the present study conducted a retrospective review of 81 consecutive metastatic colorectal cancer (mCRC) patients treated with the oxaliplatin, fluorouracil and leucovorin-irinotecan, fluorouracil and leucovorin (FOLFOX-FOFIRI/F-F) regimen (n=40) or the XELOX-XELIRI (X-X) regimen (n=41) in first- to second-line chemotherapy in Saitama Medical Center between 2006 and 2012. The disease control rate (DCR), the progression free survival (PFS), the overall survival (OS) and the time to failure of strategy (TFS) from first to second-line chemotherapy, as well as adverse events, were assessed and compared between patients receiving X-X or F-F. A total of 10 and 20 patients were additionally treated with bevacizumab in the F-F and X-X regimens, respectively, during first or second-line chemotherapy. There was no significant difference in DCR and the median PFS between the two regimens for first or second-line chemotherapy. There was no significant difference in the median OS and TFS between the two regimens (OS=24.5 and TFS=14 months in the F-F vs. 23.2 and 12.0 months in the X-X). Regarding adverse events, 45.0% of patients (18/40) exhibited grade 3-4 neutropenia throughout treatment with F-F. Whilst, 15.0% of patients (6/41) exhibited grade 3 hypertension throughout treatment with X-X, which was effectively controlled by a single antihypertensive drug. The results show that sequential administration of X-X is as effective and feasible as F-F treatment, while additionally reducing the frequency of infusion visits and eliminating the need for a central venous access device or home infusion pump, thereby offering a more convenient treatment option to patients with mCRC.

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PURPOSE: Tedizolid phosphate is a new antibacterial agent under investigation for the treatment of Gram-positive infections in China. This study was conducted to assess the pharmacokinetic (PK) properties, oral bioavailability, and safety of once daily tedizolid phosphate 200 mg in Chinese subjects to support its further clinical development in China. METHODS: This Phase I single-center study, conducted in 16 healthy Chinese male subjects, consisted of a single-dose administration, 1:1 randomized, two-way, intravenous (IV)/oral (PO) crossover of tedizolid phosphate 200 mg (Part 1) and, after a 7-day washout, a nonrandomized, multiple-dose, 7-day tedizolid phosphate 200 mg once daily administration (IV for 3 days, PO for 4 days; Part 2). Blood samples were collected for up to 72 hours after single dosing and for up to 2 hours on Day 3 and 72 hours on Day 7 of multiple dosing to determine PK parameters. Adverse events (AEs) were recorded throughout the entire study. FINDINGS: The Cmax and AUC of tedizolid (the active moiety of tedizolid phosphate) were 3.02 µg/mL and 30.50 µg • h/mL after single IV dosing of tedizolid phosphate, and 2.25 µg/mL and 26.10 µg • h/mL after single PO dosing, respectively, and the mean half-life was 10.1 hours for both administration routes. The oral bioavailability of tedizolid was 85.5%. PK parameters of tedizolid were similar after single and multiple dosing of tedizolid phosphate, indicating no time dependency. Only minor accumulation of tedizolid was observed after multiple dosing (expressed as accumulation ratios RAAUC: 1.18 for PO dosing, and RACmax: 1.16 and 1.05 for IV and PO dosing, respectively). Steady state of tedizolid was reached after about 3 days, and trough concentrations remained constant when switching from IV to PO dosing. Tedizolid phosphate was well tolerated with 6 subjects (37.5%) in Part 1 and 5 subjects (31.3%) in Part 2 experiencing an AE; all AEs but one were related to the study drug assessed by the investigator. All AEs were of mild intensity and had recovered or resolved by the end of the study. No serious AEs were observed, and no subjects prematurely discontinued the study due to an AE. IMPLICATIONS: The results of this Phase I study conducted in Chinese male subjects indicate that no dosage adjustment of tedizolid phosphate 200 mg would be required when switching administration routes in this population. Tedizolid phosphate was well tolerated in healthy Chinese subjects. China Food and Drug Administration clinical trial permission numbers 2014L00360 and 2014L00361.

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Tumor heterogeneity makes combination chemotherapy one of the preferred modes of treatment regimens. In this work, sequential exposure of two anticancer agents, paclitaxel (Tx) followed by topotecan (TPT), was shown to have a synergistic effect on non-small cell lung cancer (NSCLC) cell line, NCI-H460. In order to improve patient compliance, the aforementioned concept was translated into a drug delivery system comprising of poly(d,l-lactide-co-glycolide) (PLGA)-chitosan composite particles. TPT-containing chitosan micro-/nanoparticles were prepared by the facile technique of electrospraying and encapsulated within PLGA microparticles using emulsion-solvent evaporation technique for delayed release of TPT. The formulation containing Tx- and TPT-loaded composite particles demonstrated synergism when exposed to NCI-H460 cellular aggregates (tumoroids) generated in vitro. Overall, the results of this study demonstrated the potential of the formulation containing Tx and PLGA-chitosan (TPT-loaded) composite particles for the treatment of lung cancer.

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