Insight into autophagy in platinum resistance of cancer.

Platinum drugs, as a class of widely used chemotherapy agents, frequently appear in the treatment of cancer at different phrases. However, platinum resistance is the major bottleneck of platinum drugs for exerting anti-tumor effect. At present, the mechanism of platinum resistance has been thoroughly explored in terms of drug delivery methods, DNA damage repair function, etc., but it has not yet been translated into an effective weapon for reversing platinum resistance. Recently, autophagy has been proved to be closely related to platinum resistance, and the involved molecular mechanism may provide a new perspective on platinum resistance. The aim of this review is to sort out the studies related to autophagy and platinum resistance, and to focus on summarizing the relevant molecular mechanisms, so as to provide clues for future studies related to autophagy and platinum resistance.

Establishing and evaluating physician-pharmacist collaborative clinics to manage patients with type 2 diabetes in primary hospitals in Hunan province: study protocol of a multi-site randomized controlled trial in the era of COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has exerted an unprecedented and universal impact on global health system, resulting in noticeable challenges in traditional chronic disease care, of which diabetes was reported to be most influenced by the reduction in healthcare resources in the pandemic. China has the world's largest diabetes population, and current diabetes management in China is unsatisfactory, particularly in rural areas. Studies in developed countries have demonstrated that physician-pharmacist collaborative clinics are efficient and cost-effective for diabetes management, but little is known if this mode could be adapted in primary hospitals in China. The aim of this proposed study is to develop and evaluate physician-pharmacist collaborative clinics to manage type 2 diabetes mellitus (T2DM) in primary hospitals in Hunan province. METHODS: A multi-site randomized controlled trial will be conducted to evaluate the effectiveness and cost-effectiveness of the physician-pharmacist collaborative clinics compared with usual care for Chinese patients with T2DM. Six primary hospitals will participate in the study, which will recruit 600 eligible patients. Patients in the intervention group will receive services from both physicians and pharmacists in the collaborative clinics, while the control group will receive usual care from physicians. Patients will be followed up at the 3rd, 6th, 9th and 12th month. Comparison between the two groups will be conducted by assessing the clinical parameters, process indicators and costs on diabetes. A satisfaction survey will also be carried out at the end of the study. DISCUSSION: If effective, the physician-pharmacist collaborative clinics can be adapted and used in primary hospitals of China to improve glycemic control, enhance medication adherence, decrease incidence of complications and reduce patients' dependence on physicians. Findings from the present study are meaningful for developing evidence-based diabetes care policy in rural China, especially in the COVID-19 pandemic era. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000031839 , Registered 12 April 2020.

Population Pharmacokinetics of Polymyxin B and Dosage Optimization in Renal Transplant Patients.

Currently, polymyxin B has been widely used in the treatment of multidrug-resistant Gram-negative pathogen infections. Due to the limited pharmacokinetic/pharmacodynamic data, the optimal dosage regimen for the recently proposed therapeutic target of the area under the concentration-time curve over 24 h in steady state divided by the minimum inhibitory concentration 50-100 mg⋅h/L has not yet been established. Moreover, most studies have focused on critically ill patients, yet there have been no studies in the field of renal transplantation. To optimize the dosage strategy and reduce the risk of toxicity, a population pharmacokinetics model of polymyxin B with the Phoenix NLME program was developed in our study. A total of 151 plasma samples from 50 patients were collected in the present study. Polymyxin B plasma concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. A one-compartment model adequately described the data, and the clearance and volume of distribution were 1.18 L/h and 12.09 L, respectively. A larger creatinine clearance was associated with increased clearance of polymyxin B (p < 0.01). Monte Carlo simulation showed that a regimen of a 75 mg loading dose with a 50 mg maintenance dose was a better option to achieve an optimal therapeutic effect (minimum inhibitory concentration ≤1 mg/L) and to reduce the incidence of side effects for patients with renal impairments. The developed model suggested that dosing adjustment should be based on renal function in renal transplant patients.

The Impact of a Training Program on Clinical Pharmacists on Pharmacy Clinical Services in a Tertiary Hospital in Hunan China.

BACKGROUND: Prior to 2015, clinical consultation was the only clinical service provided by clinical pharmacists in Changsha Second Hospital. Between 2015 and 2017, a train-the-trainer program was implemented to train clinical pharmacists to provide pharmaceutical care and to conduct clinical research. The objective of the study is to examine the impact on the clinical services provided by pharmacists after the implementation of the train-the-trainer program. PATIENTS AND METHODS: Between 2004 and 2014, all completed clinical consultation activities were tallied and summarized. The results from the tallied consultation activities were used as a baseline for clinical activities provided by pharmacists prior to the training. A structured training program was implemented between 2015 and 2017 to train clinical pharmacists to provide pharmaceutical care. After the implementation of the training program was completed, all clinical activities provided by pharmacists between January 2017 and December 2017 were documented in the clinical workload form. The clinical activities completed by each pharmacist were tallied and summarized. RESULTS: Between 2004 and 2014, a total of 6569 (average 657 per year) pharmacy consultations were requested and completed from a total of 44 departments. In 2017, a total of 15,078 hrs of clinical activities were logged. The pharmacists completed 3481 consultations in 2017 (an increase of 430%), averaging 316 consultations for each pharmacist and 271.8 hr per pharmacist. Over 2000 hrs (of the 15,078 hrs) were spent on direct patient care by the pharmacists. CONCLUSION: This study shows that there was a 430% increase in clinical pharmacy consultation services provided by the clinical pharmacists after the implementation of the training program. This is directly related to the number of well-trained pharmacists available. After the implementation of the train-the-trainer program, the range of services as well as the number of clinical services and clinical hours spent on providing pharmaceutical care have significantly increased.

Diclofenac--Acetaminophen Combination Induced Acute Kidney Injury In Postoperative Pain Relief.

PURPOSE: The objective of this study was to determine: 1) the incidence and the risk factors of diclofenac/acetaminophen combination as a single agent induced Acute Kidney Injury (AKI) in postoperative pain relief 2) the average cost and length of hospital stay for patients in AKI group and non-AKI group. METHODS: All patients with no prior history of chronic kidney disease (CKD) and normal serum creatinine [44~130 µmol /l] who received diclofenac and acetaminophen combination as a single agent intramuscularly (IM) between January and December 2015 in The Second Xiangya Hospital, Changsha, Hunan, China were included in this retrospective own-control study. Baseline serum creatinine (SCr) and SCr during NSAID use were collected. AKI is defined as an increased of Scr over 1.5 times the baseline. Multivariate analyses were performed with a logistic regression model to assess the significant risk factors of AKI. RESULTS: A total of 821 patients were included in the study with 63 [7.7%] patients had diclofenac/acetaminophen combination single agent induced AKI. Multivariate analysis confirmed that using diclofenac/acetaminophen combination after surgeries within 24 h were significantly associated with AKI [odds ratio, OR, 2.173; 95% CI, 1.113-4.243; P=0.023]. The average cost and length of hospitalization in AKI group was 1.87 times [p=0.000] and 1.2 times [p=0.043] comparison than non-AKI group, respectively. CONCLUSIONS: The incidence of diclofenac/acetaminophen combination single agent induced AKI in postoperative pain relief was 7.7%. Patients with hypertension or liver cirrhosis was more likely to develop AKI and using diclofenac/acetaminophen combination after surgeries within 24 h was significant risk factors for AKI. AKI prolonged the cost and length of hospitalization. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Association Between Vancomycin Blood Brain Barrier Penetration and Clinical Response in Postsurgical Meningitis.

PURPOSE: This study investigated the association between vancomycin blood brain barrier penetration and clinical response in patients with postsurgical meningitis. METHODS: Adult patients with postsurgical meningitis were recruited. Eligible patients received vancomycin 500 mg every 6 h for at least 5 days. On day 3 or 4, cerebrospinal fluid (CSF) and simultaneous serum samples were obtained to determine CSF minimum concentrations (Cmin), serum Cmin and CSF to serum Cmin ratio. RESULTS: Twenty-two patients (14 men and 8 women; mean age of 52.6± 12.1 years) were recruited. The vancomycin Cmin was 3.63 ± 1.64 mg/L in CSF and 13.38 ± 5.36 mg/L in serum, with the CSF to serum Cmin ratio of 0.291 ± 0.118. The Cmin in serum and in CSF showed a significant correlation (p=0.005, r =0.575). The vancomycin CSF Cmin had a significant correlation with the decline of white blood cell counts (WBCs) in CSF (p=0.003, r =0.609). CSF Cmin, serum Cmin and CSF to serum Cmin ratio all showed no significant correlation with clinical response (p=0.335, 0.100, 0.679, respectively). CONCLUSIONS: There was a positive correlation between serum Cmin and CSF Cmin. However, only CSF Cmin is positively correlated with WBCs improvement in CSF. All other parameters such as serum Cmin, CSF Cmin and CSF to serum Cmin ratio had no correlation with clinical response. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Meta-analysis of polymorphism rs6311 and rs6313 in the 5-HT2AR gene and schizophrenia.

BACKGROUND: rs6311 and rs6313 polymorphism of 5-hydroxytryptamine 2A receptor has been widely studied regarding association with susceptibility to schizophrenia, but the results remained inconsistent. AIMS: This study aimed to assess the association between rs6311 and rs6313 polymorphism and schizophrenia using a meta-analysis. METHODS: Pubmed, Web of Science, and Embase databases were searched for all articles linking rs6311 and rs6313 polymorphism and schizophrenia. All studies which met the inclusion and exclusion criteria were included in this meta-analysis. Pooled odds ratio and 95% confidence intervals were used to evaluate the association between rs6311 and rs6313 polymorphism and schizophrenia risk. Sub-group analysis was also performed by different ethnic studies (Asian and Caucasian) and different minor allelic studies (rs6311: minor allele = A and minor allele = G; rs6313: minor allele = T and minor allele = C). RESULTS: Forty articles, including 50 case-control studies, were included in this meta-analysis. Specifically, 12 studies with 4100 cases and 4541 controls involved rs6311, 38 studies with 8960 cases and 9729 controls involved rs6313. The results showed that rs6311 and rs6313 were not associated with schizophrenia. Moreover, no associations were found between rs6311 and schizophrenia in different sub-groups, rs6313 was found to associated with schizophrenia among studies in which C is the minor allele. CONCLUSIONS: This meta-analysis indicates that rs6311 and rs6313 polymorphisms of 5-HT2AR are not associated with schizophrenia. However, the rs6313 polymorphism is associated with schizophrenia in studies in which the minor allele is C.

Effect of the novel antipsychotic drug perospirone on P-glycoprotein function and expression in Caco-2 cells.

OBJECTIVE: Perospirone (PER) is a novel atypical antipsychotic drug for the treatment of schizophrenia and other psychotic disorders. The multidrug resistance transporter, P-glycoprotein (Pgp), is involved in the efflux transport of several antipsychotics across the blood-brain barrier (BBB). The aim of the present study was to evaluate the modulating effect of PER on both Pgp activity and expression in Caco-2 cell monolayers. METHODS: The effects of PER were analyzed by means of rhodamine 123 (Rhd 123) assays, and those of Pgp expression were analyzed by flow cytometry and reverse transcriptase-PCR. RESULTS: Perospirone at concentrations of 0.01-30 microM, which were found to be non-cytotoxic towards the Caco-2 cells, was observed to inhibit Pgp-mediated efflux transport of Rhd 123 in the cells as well as to down-regulate the cellular Pgp protein and MDR1 mRNA levels in a concentration-dependent manner. In the rhodamine accumulation assays, 30 microM PER produced a 429% increase of the cellular Rhd 123 concentration, which exceeded the inhibitory effect of the well-known Pgp inhibitor verapamil. CONCLUSION: Our findings provide experimental evidence that PER is an inhibitor of Pgp which interferes directly and indirectly with the function of Pgp.

Ultra-performance liquid chromatography-tandem mass spectrometry for the determination of atypical antipsychotics and some metabolites in in vitro samples.

The ultra-performance liquid chromatography-electrospray tandem mass spectrometry (UPLC-ESI-MS/MS) method has been developed to perform the determination of quetiapine, perospirone, aripiprazole and quetiapine sulfoxide in in vitro samples in less than 3 min. The UPLC separation was carried out using an Acquity UPLC BEH C18 column (100 mm x 2.1mm i.d., 1.7 microm particle size) that provided high efficiency and resolution in combination with high linear velocities. The UPLC system was coupled to a Waters Micromass Quattro Premier XE tandem quadrupole mass spectrometer. This system permits high-speed data acquisition without peak intensity degradation, and produces sharp and narrow chromatographic peaks (w(h) about 2.5s) of compounds. The determination was performed in multiple reaction monitoring (MRM) mode. The quantification parameters of the developed method were established, obtaining instrumental LODs lower than 0.005 microg/l and a repeatability at a low concentration level lower than 10% CV (n=10). Finally, the method was successfully applied to the analysis of atypical antipsychotics and some metabolites in in vitro samples.

[Ovicidal activity of nine essential oils against Chrysomya megacephara in bacon and kipper].

To exploit safe ovicides against the flies that attack bacon and kipper, the ovicidal activity of 9 plant essential oils was investigated by a modified egg-dipping method. The results indicated that the essential oils from Cinnamomun cassia, Eugenia caryophyllata and Illicum verum had higher ovicidal activity, with their LC50 values being 0.428, 1.605 and 2.489 mg x ml(-1), respectively. Through GC/MS analysis, a total of 22 components were identified from C. cassia oil, among which, cinamaldehyde was the most predominant one, accounting for 92.33% of the total. The LC50 of synthesized cinamaldehyde (97.33%) was 0.281 mg x ml(-1), being a little higher than the LC50 of C. cassia oil, suggesting that cinamaldehyde was the main ovicidal component of C. cassia oil and could replace the latter as an ovicide against harmful flies.