Impact of individualized pharmaceutical care on efficacy and safety of opioid-tolerant outpatients with cancer pain: a multicenter randomized controlled trial.

Background: Managing cancer pain is a growing challenge. Individualized pharmaceutical care is particularly important for opioid-tolerant outpatients due to variation in terms of their knowledge about pain, treatment adherence, and risk of experiencing inadequate analgesia and severe adverse events. This study aimed to determine the influence of individualized pharmaceutical care on outcomes in opioid-tolerant outpatients with cancer pain. Methods: A multicenter, open-label, randomized, controlled study was carried out. Opioid-tolerant outpatients experiencing chronic cancer pain and receiving sustained-release opioids were randomly assigned to the intervention group and the control group with a 1:1 ratio. The intervention group received individualized pharmaceutical care, while the control group received conventional care during 4-week period. The primary endpoint was medication adherence on the intention-to-treat (ITT) population. Secondary outcomes included the patients' knowledge of cancer pain and pain medications, pain score, frequency of breakthrough pain, quality of life (QoL) which were assessed on the ITT population. Adverse events were evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) version 4.0 on the per-protocol (PP) population. Results: A total of 118 patients were enrolled, and 102 patients (51 in each group) completed the 30-day follow-up from six oncology centers in China. The proportion of patients adhering to opioid medication increased to similar levels in the two groups during the 4 weeks (P=0.149). The intervention group had a significantly lower pain score at 4 weeks compared to the control group (P=0.015), and the proportion of participants without breakthrough pain was significantly higher at 4 weeks than at baseline in the intervention group (P=0.029), but not in the control group (P=0.322). The two groups did not differ significantly in terms of QoL or adverse events. Conclusions: Our results suggest that individualized pharmaceutical care can markedly reduce patient-related problems and significantly improve pain control in opioid-tolerant outpatients. These findings validate the recommendations to include clinical pharmacists in the management of cancer pain. Trial Registration: ClinicalTrials.gov identifier: NCT03439904.

Pharmacist-Led Management Improves Treatment Adherence and Quality of Life in Opioid-Tolerant Patients With Cancer Pain: A Randomized Controlled Trial.

INTRODUCTION: Opioid-tolerant patients are more likely to deviate from recommended treatments and to experience inadequate analgesia than opioid-naive ones. The aim of this study was to examine whether pharmacist-led management could help improve treatment adherence and quality of life. METHODS: Eligible patients were randomized in a 1:1 ratio to control group and intervention group. The control group received routine education and support, while the intervention group received additional individualized pharmacist-led care. The primary endpoint was treatment adherence in the per-protocol analysis, as evaluated by blinded assessors. An interim analysis was planned when 30% patients completed the study. Alpha was divided into the interim analysis (0.015) and the final analysis (0.035). RESULTS: In the interim analysis (97 and 87 patients in the control and intervention groups, respectively), the primary endpoint was met. Pharmacist-led intervention significantly increased treatment adherence (93.3 vs. 79.8%; OR: 2.25; 95% CI 1.02, 4.94; P = 0.013), quality of life (0.81 ± 0.17 vs. 0.72 ± 0.25; P = 0.008), and reporting of adverse events (82.7 vs. 61.9%; OR: 1.88; 95% CI 1.16, 3.07; P = 0.004). The two groups did not differ in pain control rate (66.7 vs. 57.1%; OR: 1.25; 95% CI 0.87, 1.78; P = 0.218), breakthrough pain-free rate (66.7 vs. 61.9%; OR: 1.12; 95% CI 0.78, 1.59; P = 0.532) and pain score (1.97 ± 1.04 vs. 2.15 ± 1.24; P = 0.522). CONCLUSIONS: Pharmacist-led management improved treatment adherence, quality of life, and the reporting of adverse events in opioid-tolerant patients with cancer pain. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03455023.

Determination of Afatinib in Human Plasma by 2-Dimensional Liquid Chromatography.

INTRODUCTION: A simple, sensitive, rapid, and practical 2-dimensional liquid chromatography (2D-LC) method was developed and validated for the quantification of a 500-µL afatinib sample extracted from human plasma. METHODS: The plasma samples were pretreated with acetonitrile for protein precipitation. The mobile phase consisted of a first-dimensional mobile phase (acetonitrile, methanol, and 25 mmol/L ammonium phosphate in a ratio of 25:25:50, V/V/V) and a second-dimensional mobile phase (acetonitrile and 10 mmol/L ammonium phosphate in a ratio of 25:75, V/V). The average recovery of the plasma samples was stable and reproducible (98.56%-100.02%). RESULTS: The analyte was sufficiently stable for handling and analysis. The calibration curve was linear, ranging from 10.93 to 277.25 ng/mL with regression equation y = 804.60 x - 4,169.87 (R2 = 0.999). The relative standard deviations for accuracy and precision studies were within ±2.30% and <3.41%, respectively (intra- and interday). Finally, the validated method was successfully employed to determine the drug levels in plasma from the patients treated with afatinib. In clinical assessment, the patients with gastric cancer were orally administered with 30 or 40 mg per day of afatinib, which resulted in large plasma concentrations, ranging from 5.52 to 45.16 ng/mL. CONCLUSION: The results indicated that this method was useful for the therapeutic drug monitoring of afatinib and suitable for the assessment of the risks and benefits of chemotherapy in patients with non-small cell lung cancer.

A novel use for an old drug: resistance reversal in Candida albicans by combining dihydroartemisinin with fluconazole.

Aim: To investigate the effects of dihydroartemisinin combined with fluconazole against C. albicans in vitro and to explore the underlying mechanisms. Materials & methods: Checkerboard microdilution assay and time-kill curve method were employed to evaluate the static and dynamic antifungal effects against C. albicans. Reactive oxygen species (ROS) was measured by a fluorescent probe. Results: Combination of dihydroartemisinin and fluconazole exerted potent synergy against planktonic cells and biofilms of fluconazole-resistant C. albicans, with the fractional inhibitory concentration index values less than 0.07. A potent fungistatic activity of this drug combination could still be observed after 18 h. The accumulation of ROS induced by the drug combination might contribute to the synergy. Conclusion: Dihydroartemisinin reversed the resistance of C. albicans to fluconazole.

Lay abstract Patients with weakened immune system often suffer from C. albicans infections. C. albicans is a common fungus. Fluconazole is a widely used antifungal drug owing to its low price and few side effects. Unfortunately, fluconazole is gradually losing its effect against C. albicans due to the constantly emerging resistance in C. albicans. Interestingly, in this study a combined use of fluconazole and an old antimalarial agent restored the effect of fluconazole against resistant C. albicans. The antimalarial drug we used is dihydroartemisinin, with low price, high safety and multiple biological activities, which originates from a traditional Chinese medicine. Our study also presented that this drug combination generated abundant reactive oxygen, which might account for the effect. The drug combination would be expected to be used for treating C. albicans infections.

Reversal of azole resistance in Candida albicans by oridonin.

OBJECTIVES: Candida albicans is a yeast that causes fungal infections with high mortality and is typically resistant to azole drugs. To overcome this resistance, we explored the combined use of oridonin (ORI) and three azole drugs, namely fluconazole (FLC), itraconazole (ITR) and voriconazole (VOR). Azole-resistant C. albicans strains were obtained from cancer patients and the reversal of drug resistance in these strains was investigated. METHODS: The synergistic antifungal activity of ORI and azole drugs was measured by checkerboard microdilution and time-kill assays. The resistance reversal mechanisms, namely inhibition of drug efflux and induction of apoptosis, were investigated by flow cytometry. Expression levels of the efflux pump-related genesCDR1 and CDR2 were assessed by RT-qPCR. RESULTS: The efflux pump inhibition assay with ORI showed that the minimum inhibitory concentrations (MICs) of FLC (128-fold), ITR (64-fold) and VOR (250-fold) decreased significantly. Upregulation of genes encodingCDR1 and CDR2 was confirmed in the resistant strain. The sensitising effect of ORI on FLC in the treatment of C. albicans also included the promotion of apoptosis. CONCLUSION: We demonstrated that combining azoles with ORI exerted potent synergism and that ORI could promote sensitisation to azoles in azole-resistantC. albicans. The discovery that ORI can effectively inhibit drug efflux and promote apoptosis may provide new insights and therapeutic strategies to overcome increasing azole resistance in C. albicans.

Differences in terms of presentation and outcomes between patients with lung cancer as opposed to other solid organ cancer after infection with SARS-CoV-2: protocol for a systematic review.

INTRODUCTION: Scholars believe that COVID-19 can be particularly lethal for patients with cancer. Some studies found that COVID-19 appears to be more lethal in patients with lung cancer than in other cancer patients. In order to take appropriate measures to balance a delay in lung cancer treatment against the risk for a potential COVID-19 exposure, we first need to know whether patients with lung cancer have special risks. We aim to conduct a systematic review and meta-analysis to examine differences in terms of presentation and outcomes between patients with lung cancer as opposed to other solid organ cancer after infection with SARS-CoV-2. METHODS AND ANALYSIS: A comprehensive search of published original research studies will be performed in Embase, MEDLINE, Web of Science, WangFangData, CQVIP, COMPENDEX and CNKI. The medRxiv preprint server will also be searched for applicable studies (grey literature). Original research studies will be included if they include patients with: (A) laboratory-confirmed SARS-CoV-2 infection and (B) confirmed solid cancer, and (C) measurable clinical presentation or outcome, such as mortality rate, intensive care unit admission rate, incidence of pneumonia. One author will conduct the electronic database searches, two authors will independently screen studies, two will extract data and two will assess study quality. If I² exceeds 60% for the pooled analysis, we will explore sources of heterogeneity in subgroups of studies. We will use fixed-effect, random-effects or mixed-effects models to estimate the relative risk or OR. If the data reporting allows, a subgroup analysis between non-small cell lung cancer and small cell lung cancer patients will be performed. ETHICS AND DISSEMINATION: The proposed study will not collect individual-level data and, therefore, does not require ethical approval. We will submit our findings to a peer-reviewed scientific journal and will disseminate results through presentations at international scientific conferences. PROSPERO REGISTRATION NUMBER: CRD42020190118.

Validated LC-MS/MS method of Sphingosine 1-phosphate quantification in human serum for evaluation of response to radiotherapy in lung cancer.

BACKGROUND: Sphingosine 1-phosphate (S1P), a bioactive lipid, has been shown to mediate cancer processes. Therefore, accurate qualitative and quantitative determination is essential. The current assay method is still cumbersome to be of practical use worldwide and the aim of this study was therefore to develop a fast, accurate, precise and efficient LC-MS/MS method for targeted analyses of S1P in serum samples. METHODS: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is an established method used for monitoring and analyzing S1P levels in serum. We determined the level of serum S1P in 256 patients with lung cancer and 36 healthy donors, and used Spearman';s rank correlation analysis to evaluate the difference in serum S1P levels between radiotherapy and nonradiotherapy patients. RESULTS: Standard curves were linear over ranges of 25-600 ng/mL for S1P with correlation coefficient (r2 ) greater than 0.9996. The lower limit of quantifications (LLOQs) was 25 ng/mL. The intra- and interbatch precisions and accuracy was less than 10% for S1P. The recoveries of the method were found to be 80%-98%. Serum S1P levels in healthy donors were different from those in patients (P < 0.001). Of 256 lung cancer patients, 124 (48.4%) received radiotherapy and were identified to have concomitant low serum S1P levels (222.13 ± 48.63), whereas 132 (51.6%) who had not received radiotherapy were identified to have high levels (315.16 ± 51.06). The serum S1P levels were therefore associated with radiotherapy (Spearman's Rho = -0.653, P < 0.001). CONCLUSIONS: Our results indicated that this new LC-MS/MS method is rapid, sensitive, specific and reliable for the quantification of S1P levels in serum samples. The level of S1P in serum samples of patients with lung cancer who received radiotherapy was significantly lower than that in patients who did not receive radiotherapy. KEY POINTS: An improved method was established to quantify S1P levels in human serum by LC-MS/MS, which enabled the change in serum S1P levels in lung cancer patients to be monitored, in combination with radiotherapy, and their clinical significance to be analyzed.

Expression of estrogen receptor beta and overall survival in non-small cell lung cancer patients: Protocol for a systematic review and meta-analysis of cohort studies.

BACKGROUND: Lung cancer is the leading cause of cancer-related deaths among males and the second leading cause among females worldwide. Numerous studies have linked estrogen status to lung cancer outcome. However, there are studies with conflicting results about the effect of ERß on survival of lung cancer. The aim of this meta-analysis is to evaluate the prognostic impact of estrogen receptor beta expression on survival among NSCLC patients. METHODS: We will search 15 electronic databases, including PubMed, Web of Science, EMBASE, Cochrane Library, and CNKI from inception to June 1, 2019. We will include all cohort studies comparing overall survival of NSCLC patients with high or low estrogen receptor beta expression. The database searches will be supplemented by searching through citations and references. Two reviewers will independently screen search results to identify eligible articles, complete data collection, and conduct quality assessment. All disagreements will be resolved by an independent third reviewer. Methodological quality of the included studies will be assessed using the Newcastle- Ottawa scale. Discrepancies will be resolved by consensus or by consulting a third author. Meta-analyses will be performed, and findings will be reported according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) and the meta-analysis of observational studies in epidemiology (MOOSE) guidelines. RESULTS: The results will be submitted to a peer-reviewed journal for publication. CONCLUSION: This review will provide a comprehensive evaluation of the evidence on the prognostic impact of ERß expression among NSCLC patients and will help clinicians find potential treatments based on estrogen signaling.

Recent advances in fluorescent probes for monitoring of hydrogen sulfide.

Hydrogen sulfide (H2S), known for its unpleasant rotten egg smell and its high toxicity, has recently emerged as an important mediator of human physiological and pathological processes, such as the regulation of cell growth, cardiovascular protection, the stimulation of angiogenesis, gastric mucosal injury and Alzheimer's disease. Due to its significant actions in the physiology, H2S has attracted the abundant concern of numerous researchers in the cutting edge of chemistry, biology and medicine. Recently, several fluorescent probes have been developed for detecting and elucidating the role played by H2S in biological systems. This review highlights recent advances that have been made on the mechanism and applications of fluorescent probes for the detection of H2S, demonstrating a new field in which remarkable improvements have been accomplished over the last two years.

In vitro and in vivo evaluation of riccardin D nanosuspensions with different particle size.

Riccardin D (RD) is a novel compound extracted from Chinese liverwort Marchantia polymorpha L. It exhibits various anticancer activities and can be used during lung cancer treatment. However, the compound's low solubility hinders its development. Recently nanosuspension has been developed as one of the most promising formulations for poorly water-soluble drugs. In order to understand the dissolution behavior of riccardin D in vitro and in vivo, two nanosuspensions of riccardin D with markedly different sizes were prepared. The particle size of nanosuspension A prepared by bottom-up method was 184.1±3.15 nm, while that of nanosuspension B prepared by top-down method was 815.4±9.65 nm. The main purpose of this study was to investigate the effects of particle size on pharmacokinetics and tissue distribution after intravenous administration. Riccardin D dissolving in organic solution was studied as control group. In pharmacokinetics study in Wistar rats, nanosuspension A showed properties similar to the control group, while nanosuspension B exhibited rather different properties. In tissue distribution research on Kunming strain mice, nanosuspension A had a multi-peak phenomenon because of reticulate endothelial system (RES) while nanosuspension B showed a high uptake in RES organs that passively target to the lungs. In conclusion, particle size of riccardin D nanosuspensions had obvious effects on pharmacokinetics and tissue distribution.