Rauvolfia vomitoria is widely distributed in the tropical regions of Africa and Asia, and has been used in traditional folk medicine in China. Indole alkaloids were found to be major bioactive components, while the effects of diabetes mellitus on the pharmacokinetic parameters of the components have not been reflected in vivo. In this study, an efficient and sensitive liquid chromatography–tandem mass spectrometry method was developed and validated for the simultaneous determination of five ingredients of R. vomitoria in rats. Detection was implemented in multiple‐reaction‐monitoring mode with an electrospray positive‐ionization source. Validation parameters were all in accordance with the current criterion. The established method was effectively employed to compare the pharmacokinetic behaviors of five alkaloids (reserpine, yohimbine, ajmaline, ajmalicine, and serpentine) between normal and type 2 diabetic rats. The single‐dose pharmacokinetic parameters of the five alkaloids were determined in normal and diabetic rats after oral administration of 100 and 200 mg/kg body weight. The results indicated that diabetes mellitus significantly altered the pharmacokinetic characteristics of yohimbine, ajmaline, and ajmalicine after oral administration in rats. This is an attempt to provide some evidence for clinicians that may serve as a guide for the use of antidiabetic medicine in clinical practice.
BackgroundThere is no standard treatment for stage III lung cancer due to its low surgical resection rate, and improving PFS and survival of patients with III NSCLC has become an urgent challenge in clinical treatment. For EGFR mutation-positive patients, targeted therapy has the remarkable feature of high efficiency and low toxicity compared with first-line standard chemotherapy, and targeted neoadjuvant therapy needs to be further explored.MethodWe report 3 diagnosed cases of locally advanced unresectable NSCLC with EGFR-sensitive mutations who first received 1–2 cycles of preoperative chemotherapy neoadjuvant therapy and were treated with 110 mg daily of 3rd-generation EGFR-TKI aumolertinib instead because of poor efficacy or safety intolerance.ResultAfter 2 cycles of aumolertinib treatment, all 3 patients achieved symptomatic remission and significant tumor size reduction and achieved downstaging to allow surgical treatment. No additional operative difficulties were added during the surgery. They continued to receive adjuvant therapy with the original dose of aumolertinib after surgical treatment, and no evidence of tumor recurrence was found until the most recent imaging examination. In addition, the course of neoadjuvant and adjuvant therapy was free of serious adverse effects.ConclusionPerioperative treatment of these three cases of locally advanced unresectable NSCLC with EGFR-sensitive mutations with the third-generation EGFR-TKI aumolertinib showed significant efficacy and excellent safety and may be a new option for targeted therapy in the perioperative period.
Background: Naphthoquine (NQ) is a suitable partner anti-malarial for the artemisinin-based combination therapy (ACT), which is recommended to be taken orally as a single-dose regimen. The metabolism of NQ was mainly mediated by CYP2D6, which is well-known to show gender-specific differences in its expression. In spite of its clinical use, there is limited information on the pharmacokinetics of NQ, and no data are available for females. In this study, the effect of gender on the pharmacokinetics and antiplasmodial efficacy of NQ in rodents was evaluated. The underlying factors leading to the potential gender difference, i.e., plasma protein binding and metabolic clearance, were also evaluated. Methods: The pharmacokinetic profiles of NQ were investigated in healthy male or female rats after a single oral administration of NQ. The antiplasmodial efficacy of NQ was studied in male or female mice infected with Plasmodium yoelii. The recrudescence and survival time of infected mice were also recorded after drug treatment. Plasma protein binding of NQ was determined in pooled plasma collected from male or female mice, rat or human. In vitro metabolism experiments were performed in the liver microsomes of male or female mice, rat or human. Results: The results showed that the gender of rats did not affect NQ exposure (AUC 0-t and C max) significantly (P > 0.05). However, a significant (P < 0.05) longer t 1/2 was found for NQ in male rats (192.1 ± 47.7), compared with female rats (143.9 ± 27.1). Slightly higher but not significant (P > 0.05) antiplasmodial activity was found for NQ in male mice (ED 90 , 1.10 mg/kg) infected with P. yoelii, compared with female mice (ED 90 , 1.67 mg/kg). The binding rates of NQ to plasma protein were similar in males and females. There was no metabolic difference for NQ in male and female mice, rat or human liver microsomes. Conclusions: These results indicated that the pharmacokinetic profiles of NQ were similar between male and female rats, except for a longer t 1/2 in male rats. The difference was not associated with plasma protein binding or hepatic metabolic clearance. Equivalent antiplasmodial activity was found for NQ in male and female mice infected with P. yoelii. This study will be helpful for the rational design of clinical trials for NQ.
Background: Hepatocellular damage has been reported for the antimalarial piperaquine (PQ) in the clinic after cumulative doses. Objectives: The role of metabolism in PQ toxicity was evaluated, and the mechanism mediating PQ hepatotoxicity was investigated. Method: The toxicity of PQ and its major metabolite (PQ N-oxide; M1) in mice was evaluated in terms of serum biochemical parameters. The role of metabolism in PQ toxicity was investigated in mice pretreated with an inhibitor of CYP450 (ABT) and/or FMO enzyme (MMI). The dose-dependent pharmacokinetics of PQ and M1 were studied in mice. Histopathological examination was performed to reveal the mechanism mediating PQ hepatotoxicity. Results: Serum biochemical levels (ALT and BUN) increased significantly (P < 0.05) in mice after three-day oral doses of PQ (> 200 mg/kg/day), indicating hepatotoxicity and nephrotoxicity of PQ at a high dose. Weaker toxicity was observed for M1. Pretreatment with ABT and/or MMI did not increase PQ toxicity. PQ and M1 showed linear pharmacokinetics in mice after a single oral dose, and multiple oral doses led to their cumulative exposures. Histopathological examination showed that a high dose of PQ (> 200 mg/kg/day for three days) could induce hepatocyte apoptosis. The mRNA levels of targets in NF-κB and p53 pathways could be up-regulated by 2-30-fold in mice by PQ or M1. Conclusions: PQ metabolism led to detoxification of PQ, but there was a low possibility of altered toxicity induced by metabolism inhibition. The hepatotoxicity of PQ and its N-oxidation metabolite was partly mediated by NF-κB inflammatory pathway and p53 apoptosis pathway.
Background: As parasite resistance to the main artemisinin drugs has emerged in Southern Asia, the traditional herb Artemisia annua L. (AAL), from which artemisinin (QHS) is isolated, was found to overcome resistance to QHS. However, the component and metabolite profiles of AAL remain unclear. Objectives: In this study, component profiling of marker compounds in AAL (amorphane sesquiterpene lactones and flavonoids) was performed, and their subsequent metabolism was investigated in rats. Methods: For efficient component classification and structural characterization, an improved liquid chromatography tandem high-resolution mass spectrometry (HRMS)-based analytical strategy was applied, i.e., background subtraction (BS) followed by ring-double-bond (RDB) filter in tandem with repeated BS processing. Structures of detected components/metabolites were characterized based on integrated information, including their HRMSn patterns, RDB values, the established component/metabolite network, the biosynthesis pathways of AAL, and/or NMR data. Results: A total of 38 amorphane sesquiterpene lactones and 35 flavonoids were found in AAL as prototype compounds, among which 26 components were previously undescribed. Major compounds were identified by comparing with reference standards. Among 73 AAL prototypes administered, 38 were absorbed in the circulation as the prototype. Moreover, 20 metabolites of amorphane sesquiterpene lactones and 10 metabolites of flavonoids were detected in rats. The major metabolic pathways included oxidation, methylation, glucuronidation, and sulfation. Conclusion: The component and metabolite network were established for marker components in AAL, which will be valuable to understand the synergistic antimalarial potency of QHS in A. annua L. The analytical strategy can also be applied to other herbal medicines.
Background: Piperaquine (PQ) and its pharmacologically active metabolite PQ N-oxide (PM1) can be metabolically interconverted via hepatic cytochrome P450 and FMO enzymes. background: Piperaquine (PQ) and its pharmacologically active metabolite PQ N-oxide (PM1) can be metabolically interconverted via hepatic cytochrome P450 and FMOs enzymes. Objectives: The reductive metabolism of PM1 and its further N-oxidation metabolite (PM2) by intestinal microflora was evaluated, and its role in PQ elimination was also investigated. objective: The reductive metabolism of PM1 and its further N-oxidation metabolite (PM2) by intestinal microflora was evaluated, and its role in PQ elimination was also investigated. Method: The hepatic and microbial reduction metabolism of PM1 and PM2 was studied in vitro. The reaction phenotyping experiments were performed using correlation analysis, selective chemical inhibition, and human recombinant CYP/FMO enzymes. The role of microbial reduction metabolism in PQ elimination was evaluated in mice pretreated with antibiotics. The effect of the reduction of metabolism on PQ exposures in humans was predicted using a physiologically-based pharmacokinetic (PBPK) model. method: The hepatic and microbial reduction metabolism of PM1 and PM2 was studied in vitro. The reaction phenotyping experiments were performed using correlation analysis, selective chemical inhibition, and/or human recombinant CYP/FMO enzymes. The role of microbial reduction metabolism in PQ elimination was investigated in mice pretreated with antibiotics. The effect of the reduction metabolism on PQ exposures in humans was predicted using a physiologically-based pharmacokinetic (PBPK) model. Results: Both hepatic P450/FMOs enzymes and microbial nitroreductases (NTRs) contributed to the reduction metabolism of two PQ N-oxide metabolites. In vitro physiologic and enzyme kinetic studies of both N-oxides showed a comparable intrinsic clearance by the liver and intestinal microflora. Pretreatment with antibiotics did not lead to a significant (P > 0.05) change in PQ pharmacokinetics in mice after an oral dose. The predicted pharmacokinetic profiles of PQ in humans did not show an effect of metabolic recycling. result: Both hepatic P450/FMOs enzymes and microbial nitroreductases (NTRs) contributed to the reduction metabolism of two PQ N-oxide metabolites. In vitro physiologic and enzyme kinetic studies of both N-oxides showed a comparable intrinsic clearance by the liver and intestinal microflora. Pretreatment with antibiotics did not lead to a significant (P > 0.05) change in PQ pharmacokinetics in mice after a single oral dose. The predicted pharmacokinetic profiles of PQ in humans did not show an effect of metabolic recycling. Conclusions: Microbial NTRs and hepatic P450/FMO enzymes contributed to the reduction metabolism of PQ N-oxide metabolites. The reduction in metabolism by intestinal microflora did not affect PQ clearance, and the medical warning in patients with NTRs-related disease (e.g., hyperlipidemia) will not be clinically meaningful. other: None
Background: Fixed-dose combination of artemisinin and naphthoquine (NQ) is a new artemisinin-based combination therapy for the treatment of uncomplicated Plasmodium falciparum. NQ absorption has been reported to be affected by food in human. Objectives: The effect of gastric pH on NQ pharmacokinetics and antiplasmodial activity was investigated. Method: The pharmacokinetic profiles of NQ were studied in healthy rodents after an oral dose of NQ with or without gastric pH modulators, i.e., pentagastrin (stimulator) and famotidine (suppressant). The effect of gastric pH on NQ exposures in human was predicted using a physiologically-based pharmacokinetic (PBPK) model. The effect of gastric pH on the antiplasmodial activity of NQ was evaluated in mice infected with Plasmodium yoelii. Results: Neither pentagastrin nor famotidine affected NQ absorption (AUC0-t and Cmax) significantly (P > 0.05) in rodents. The predicted PK profiles of NQ in human did not show an effect of gastric pH. Compared to pure NQ (ED90, 1.2 mg/kg), the combination with pentagastrin showed non-significantly (< 1.5-fold) higher antimalarial potency (ED90, 1.1 mg/kg). Correspondingly, elevation of gastric pH (up to pH 5) by famotidine treatment resulted in a relatively weaker antimalarial potency for NQ (ED90, 1.4 mg/kg). Such a difference is within the acceptable range of variability in NQ pharmacokinetics and antiplasmodial activity. Conclusions: Although food was found to significantly impact on NQ pharmacokinetics, other factors except for gastric pH should account for the result, and the warning of careful use of NQ in patients with acid-related disease is not expected to be clinical meaningful.
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