Therapeutic drug monitoring of imipenem/cilastatin and meropenem in critically ill adult patients.

OBJECTIVES: To investigate the factors influencing imipenem/cilastatin (IMI) and meropenem (MEM) concentrations in critically ill adult patients and the role of these concentrations in the clinical outcome. METHODS: Plasma trough concentrations of IMI and MEM were detected by high-performance liquid chromatography. A target value of 100%-time above MIC was used for the drugs. RESULTS: A total of 186 patients were included, with 87 receiving IMI and 99 receiving MEM. The percentages of patients reaching the target IMI and MEM concentrations were 44.8% and 38.4%, respectively. The proportions of patients infected with drug-resistant bacteria were 57.5% and 69.7% in the IMI group and MEM group, respectively. In the multivariate analysis, the risk factors for an IMI concentration that did not reach the target were infection with drug-resistant bacteria, and those for MEM were infection with drug-resistant bacteria, estimated glomerular filtration rate, and diabetes mellitus. A total of 47.1% of patients had good outcomes in the IMI cohort, and 38.1% of patients had good outcomes in the MEM cohort. The duration of mechanical ventilation and IMI concentration were associated with ICU stay in patients in the IMI cohort, while MEM concentration and severe pneumonia affected the clinical outcome of patients in the MEM cohort. CONCLUSION: Infection with drug-resistant bacteria is an important factor influencing whether IMI and MEM concentrations reach the target. Furthermore, IMI and MEM concentrations are associated with the clinical outcome, and elevated doses of IMI and MEM should be given to patients who are infected with drug-resistant bacteria.

Correlations among the plasma concentrations of first-line anti-tuberculosis drugs and the physiological parameters influencing concentrations.

Background: The plasma concentrations of the four most commonly used first-line anti-tuberculosis (TB) drugs, isoniazid (INH), rifampicin (RMP), ethambutol (EMB), and pyrazinamide (PZA), are often not within the therapeutic range. Insufficient drug exposure could lead to drug resistance and treatment failure, while excessive drug levels may lead to adverse reactions. The purpose of this study was to identify the physiological parameters influencing anti-TB drug concentrations. Methods: A retrospective cohort study was conducted. The 2-h plasma concentrations of the four drugs were measured by using the high-performance liquid chromatography-tandem mass spectrometry method. Results: A total of 317 patients were included in the study. The proportions of patients with INH, RMP, EMB, and PZA concentrations within the therapeutic range were 24.3%, 31.5%, 27.8%, and 18.6%, respectively. There were positive associations between the concentrations of INH and PZA and RMP and EMB, but negative associations were observed between the concentrations of INH and RMP, INH and EMB, RMP and PZA, and EMB and PZA. In the multivariate analysis, the influencing factors of the INH concentration were the PZA concentration, total bile acid (TBA), serum potassium, dose, direct bilirubin, prealbumin (PA), and albumin; those of the RMP concentration were PZA and EMB concentrations, weight, α-l-fucosidase (AFU), drinking, and dose; those of the EMB concentration were the RMP and PZA concentrations, creatinine, TBA and indirect bilirubin; and those of the PZA concentration were INH, RMP and EMB concentrations, sex, weight, uric acid and drinking. Conclusion: The complex correlations between the concentrations of the four first-line anti-TB drugs lead to a major challenge in dose adjustment to maintain all drugs within the therapeutic window. Levels of TBA, PA, AFU, and serum potassium should also be considered when adjusting the dose of the four drugs.

Cyclic RGD-Functionalized pH/ROS Dual-Responsive Nanoparticle for Targeted Breast Cancer Therapy.

Breast cancer is the most common malignant tumor in women and is a big challenge to clinical treatment due to the high morbidity and mortality. The pH/ROS dual-responsive nanoplatforms may be an effective way to significantly improve the therapeutic efficacy of breast cancer. Herein, we report a docetaxel (DTX)-loaded pH/ROS-responsive NP that could achieve active targeting of cancer cells and selective and complete drug release for effective drug delivery. The pH/ROS-responsive NPs were fabricated using nanocarriers that consist of an ROS-responsive moiety (4-hydroxymethylphenylboronic acid pinacol ester, HPAP), cinnamaldehyde (CA, an aldehyde organic compound with anticancer activities) and cyclodextrin (α-CD). The NPs were loaded with DTX, modified with a tumor-penetration peptide (circular RGD, cRGD) and named DTX/RGD NPs. The cRGD could promote DTX/RGD NPs penetration into deep tumor tissue and specifically target cancer cells. After internalization by cancer cells through receptor-mediated endocytosis, the pH-responsive acetal was cleaved to release CA in the lysosomal acidic environment. Meanwhile, the high ROS in tumor cells induced the disassembly of NPs with complete release of DTX. In vitro cellular assays verified that DTX/RGD NPs could be effectively internalized by 4T1 cells, obviously inducing apoptosis, blocking the cell cycle of 4T1 cells and consequently, killing tumor cells. In vivo animal experiments demonstrated that the NPs could target to the tumor sites and significantly inhibit the tumor growth in 4T1 breast cancer mice. Both in vitro and in vivo investigations demonstrated that DTX/RGD NPs could significantly improve the antitumor effect compared to free DTX. Thus, the DTX/RGD NPs provide a promising strategy for enhancing drug delivery and cancer therapy.

Association of burnout with depression in pharmacists: A network analysis.

Background: Burnout and depression have overlapping symptoms, but the extent of overlap remains unclear, and the complex relationship between burnout and depression in pharmacists is rarely explored. Methods: We investigated burnout and depression in 1,322 frontline pharmacists, and explored the complex relationship between burnout and depression in those pharmacists using network analysis. Results: Network analysis showed that there were 5 communities. A partial overlap was found between burnout and depressive symptoms in pharmacists. The nodes MBI-6 (I have become more callous toward work since I took this job), D18 (My life is meaningless), and D10 (I get tired for no reason) had the highest expected influence value. D1 (I feel down-hearted and blue) and D14 (I have no hope for the future) were bridge symptoms connected with emotional exhaustion and reduced professional efficacy, respectively. Conclusion: A partial overlap exists between burnout and depressive symptoms in pharmacists, mainly in the connection between the emotional exhaustion and reduced professional efficacy and the depressive symptoms. Potential core targets identified in this study may inform future prevention and intervention.

The expression and significance of efferocytosis and immune checkpoint related molecules in pancancer samples and the correlation of their expression with anticancer drug sensitivity.

Background: The efferocytosis-related molecules have been considered to be correlated with the resistance to cancer chemotherapy. The aim of this study was to investigate the expression and significance of efferocytosis-related molecules in cancers and the correlation of their expression with anticancer drug sensitivity, and provide new potential targets and treatment options for cancers. Methods: We investigated the differential expression of 15 efferocytosis-related molecules (Axl, Tyro3, MerTK, CX3CL1, Tim-4, BAI1, Stab2, Gas6, IDO1, Rac1, MFGE8, ICAM-1, CD47, CD31, and PD-L1) and other 12 common immune checkpoint-related molecules in tumor and normal tissues, the correlation between their expression and various clinicopathological features in 16 types of cancers using publicly available pancancer datasets in The Cancer Genome Atlas. We also analyzed the correlation of the expression of efferocytosis and immune checkpoint related molecules with 126 types of anticancer drugs sensitivity using drug-RNA-seq data. Results: There is a panel of circulating molecules among the 27 molecules. Based on the results of differential expression and correlation with various clinicopathological features of efferocytosis-related molecules in cancers, we identified new potential therapeutic targets for anticancer therapy, such as Axl for kidney renal clear cell carcinoma, Tyro3 for liver hepatocellular carcinoma, and IDO1 for renal papillary cell carcinoma. Except for BAI1, CD31, and MerTK, the enhanced expressions of Axl, Tyro3, Gas6, MFGE8, Stab2, Tim-4, CX3CL1, IDO1, Rac1, and PD-L1 were associated with decreased sensitivity of the cancer cells to many anti-cancer drugs; however, for other common immune checkpoint-related molecules, only enhanced expressions of PD-1, CD28, CTLA4, and HVEM were associated with decreased sensitivity of the cancer cells to a few drugs. Conclusion: The efferocytosis-related molecules were significantly associated with clinical outcomes in many types of cancers and played important roles in resistance to chemotherapy. Combination therapy targeting efferocytosis-related molecules and other immune checkpoint-related molecules is necessary to reduce resistance to chemotherapy.

Meta-analysis of the associations of IMPDH and UGT1A9 polymorphisms with rejection in kidney transplant recipients taking mycophenolic acid.

PURPOSE: To investigate the associations of IMPDH and UGT1A9 polymorphisms with rejection in kidney transplant recipients taking mycophenolic acid (MPA). METHODS: PubMed, Web of Science, Embase, Cochrane Library, Wanfang Data, and the China Academic Journal Network Publishing Database were systematically searched for studies investigating the associations of IMPDH1, IMPDH2, and UGT1A9 polymorphisms with rejection in kidney transplant recipients taking MPA. Associations were evaluated by pooled odds ratios (ORs) and effect sizes (ESs) with 95% confidence intervals (CIs). RESULTS: Twelve studies were included in the analysis, including a total of 2342 kidney transplant recipients. The results showed that compared with the TC + CC variant genotypes, the TT genotype of IMPDH2 3757 T > C was significantly associated with a higher risk of rejection (ES = 1.60, 95% CI = 1.07-2.40, P = 0.021), while there was no significant association of the IMPDH2 3757 T > C polymorphism with acute rejection within 1 year in kidney transplant recipients (OR = 1.49, 95% CI = 0.79-2.80, P = 0.217; ES = 1.44, 95% CI = 0.88-2.36, P = 0.142). The GG genotypes of IMPDH1 125G > A and IMPDH1 106G > A were significantly associated with a higher risk of rejection (ES = 1.91, 95% CI = 1.11-3.28, P = 0.019) and acute rejection within 1 year (ES = 2.12, 95% CI = 1.45-3.10, P < 0.001) than the variant genotypes GA + AA. The TT genotype of UGT1A9 275 T > A showed a decreased risk of rejection compared with the variant genotypes TA + AA (ES = 0.44, 95% CI = 0.23-0.84, P = 0.013). CONCLUSIONS: IMPDH1, IMPDH2, and UGT1A9 polymorphisms were associated with rejection in kidney transplant recipients, and the genetic backgrounds of patients should be considered when using MPA.

Meta-Analysis of ABCG2 and ABCB1 Polymorphisms With Sunitinib-Induced Toxicity and Efficacy in Renal Cell Carcinoma.

Background: ABCG2 and ABCB1 are genes related to the pharmacokinetics of sunitinib and have been associated with its toxicity and efficacy. However, the results have been controversial. This study aimed to evaluate the associations of ABCG2 and ABCB1 polymorphisms with sunitinib-induced toxicity and efficacy in renal cell carcinoma (RCC) by meta-analysis. Methods: PubMed, EMBASE, Cochrane Library, and Web of Science were systematically searched for studies investigating the associations of the ABCG2 rs2231142 polymorphism with sunitinib-induced toxicity and the associations of the ABCB1 rs1128503 and ABCB1 rs2032582 polymorphisms with sunitinib-induced toxicity and clinical outcomes. The associations were evaluated by effect size (ES) with 95% confidence intervals (CIs). Results: Eight and five studies were included in the toxicity and efficacy analysis, respectively, including a total of 1081 RCC patients. The ABCG2 rs2231142 A allele was associated with an increased risk of sunitinib-induced thrombocytopenia and hand-foot syndrome (HFS) in Asians (ES = 1.65, 95% CI = 1.15-2.36, p = 0.006; ES = 1.52, 95% CI = 1.02-2.27, p = 0.041). However, the ABCG2 rs2231142 polymorphism was not associated with sunitinib-induced hypertension or neutropenia (ES = 1.09, 95% CI = 0.69-1.73, p = 0.701; ES = 0.87, 95% CI = 0.57-1.31, p = 0.501). Compared with the C allele, the ABCB1 rs1128503 T allele was associated with a decreased risk of sunitinib-induced hypertension but worse progression-free survival (PFS) (ES = 0.44, 95% CI = 0.26-0.77, p = 0.004; ES = 1.36, 95% CI = 1.07-1.73, p = 0.011). There was no significant association between the T allele or C allele of ABCB1 rs1128503 and overall survival (OS) (ES = 0.82, 95% CI = 0.61-1.10, p = 0.184). The ABCB1 rs2032582 T allele was associated with worse PFS than the other alleles (ES = 1.46, 95% CI = 1.14-1.87, p = 0.003), while there was no significant association between the T allele or other alleles and sunitinib-induced hypertension, HFS, or OS (ES = 0.77, 95% CI = 0.46-1.29, p = 0.326; ES = 1.02, 95% CI = 0.65-1.62, p = 0.919; ES = 1.32, 95% CI = 0.85-2.05, p = 0.215). Conclusion: The results indicate that the ABCG2 rs2231142 polymorphism may serve as a predictor of sunitinib-induced thrombocytopenia and HFS in Asians, while the ABCB1 rs1128503 polymorphism may serve as a predictor of sunitinib-induced hypertension, and both the ABCB1 rs1128503 and rs2032582 polymorphisms may serve as predictors of PFS in RCC. These results suggest a possible application of individualized use of sunitinib according to the genetic background of patients.

Chebulanin exerts its anti-inflammatory and anti-arthritic effects via inhibiting NF-κB and MAPK activation in collagen-induced arthritis mice.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by synovial inflammation and progressive joint destruction. Chebulanin is a natural polyphenol acid isolated from the traditional Tibetan medicine Terminalia chebula Retz that has previously been reported to possess anti-inflammatory properties. The present study aimed to investigate the anti-inflammatory and anti-arthritic effects of chebulanin and explore its underlying mechanisms in vivo and in vitro using a collagen-induced arthritis (CIA) mouse model and lipopolysaccharide (LPS) stimulated RAW264.7 cell inflammation model. Arthritis severity scores were assessed twice weekly; the levels of cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in serum were detected using enzyme-linked immunosorbent assay kits; histopathological assessment was performed using micro computed tomography and hematoxylin and eosin staining. Activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways were assessed using western blotting. The inhibition of translocation of cytosolic p38 and p65 into the nucleus was observed using immunofluorescence staining and western blotting in vitro. Chebulanin significantly suppressed the progression and development of RA in CIA mice by decreasing the arthritis severity scores, attenuating paw swelling and joint destruction, and reducing the levels of IL-6 and TNF-α significantly (p < 0.05). Furthermore, chebulanin reduced the levels of excised phosphorylated (p)-p38, phosphorylated-c-JUN N-terminal kinase (p-JNK), p-p65 and phosphorylated NF-κB inhibitor alpha (p-IκBα) in CIA mice, but did not affect the level of phosphorylated extracellular-signal-regulated kinase (ERK). In addition, chebulanin could inhibit the nuclear translocation of p38 and p65 in LPS-stimulated macrophages in dose-dependent manner. In conclusion, this study demonstrated that chebulanin exerts anti-inflammatory and anti-arthritic effects by inhibiting the activation of NF-κB and MAPK signaling pathways.

Scorpion primer PCR analysis for genotyping of allele variants of thiopurine s­methyltransferase*3.

Thiopurine S-methyltransferase (TPMT) plays an important role in the metabolism of thiopurines. Mutations in the TPMT gene can affect drug activity, which may have adverse effects in humans. Thus, genotyping can help elucidate genetic determinants of drug response to thiopurines and optimize the selection of drug therapies for individual patients, effectively avoiding palindromia during maintenance treatment caused by insufficient dosing and the serious side effects caused by excessive doses. The current available detection methods used for TPMT*3B and TPMT*3C are complex, costly and time­consuming. Therefore, innovative detection methods for TPMT genotyping are urgently required. The aim of the present study was to establish and optimize a simple, specific and timesaving TPMT genotyping method. Using the principles of Web­based Allele­Specific PCR and competitive real­time fluorescent allele­specific PCR (CRAS­PCR), two pairs of Scorpion primers were designed for the detection of TPMT*3B and *3C, respectively, and a mutation in TPMT*3A was inferred based on data from TPMT*3B and *3C. In total, 226 samples from volunteers living in Chongqing were used for CRAS­PCR to detect TPMT*3 mutations. Results showed that nine (3.98%) were mutant (MT) heterozygotes and none were MT homozygotes for TPMT*3C, and no TPMT*3A and TPMT*3B mutations were found. Three TPMT*3C MT heterozygotes were randomly selected for DNA sequencing, and CRAS­PCR results were consistent with the sequencing results. In conclusion, in order to improve simplicity, specificity and efficiency, the present study established and optimized CRAS­PCR assays for commonly found mutant alleles of TPMT*3A (G460A and A719G), TPMT*3B (G460A), and TPMT*3C (A719G).

Comparison of cryptococcal meningitis in HIV-negative patients with and without lung infections.

OBJECTIVE: To investigate the clinical features and outcomes of cryptococcal meningitis (CM) in HIV-negative patients with and without lung infections. METHODS: We retrospectively reviewed the medical records of HIV-negative patients with CM admitted to two university hospitals in Southwest China over the past 5 years. RESULTS: Seventy-one patients were included, of whom 35 (49.3%) had lung disease. Compared with patients without lung infection, CM patients with lung infection tended to be male and younger (≤30 years), experienced more fever, less vomiting and fewer central nervous system symptoms; more often had low white blood cell (WBC) counts (<20 × 106/L), and fewer often had ethmoid sinusitis, maxillary sinusitis, paranasal sinusitis, and otitis media. Cryptococcus neoformans isolates from these patients were sensitive to itraconazole, voriconazole, fluconazole, and amphotericin B but resistant to flucytosine. CM patients with lung infection had higher mortality at discharge compared with patients without lung infection (8.6% vs. 0%). Multivariable analyses showed that a WBC count <20 × 106/L was significantly associated with poor treatment outcome (odds ratio 0.01, 95% confidence interval 0-0.83). CONCLUSION: HIV-negative CM patients with lung infections tended to be male and younger. Fever, fewer central nervous system symptoms, and WBC counts <20 × 106/L were characteristic of this patient group.

Meta-analysis of the associations of CYP2B6-516G>T polymorphisms with efavirenz-induced central nervous system side effects and virological outcome in HIV-infected adults.

Clinical data on the relationships of cytochrome P450 (CYP2) B6 516G>T polymorphisms with efavirenz-induced central nervous system (CNS) side effects and virological response in HIV-infected adults are controversial. We sought to analyze the associations by meta-analysis. To identify eligible studies, we systematically searched PubMed, Embase, ScienceDirect, and Web of Science. The strength of the associations was measured by odds ratio (OR) and effect size (ES) with 95% confidence interval (CI). Seventeen studies comprising a total of 3598 HIV-infected adults were included. The results showed that the CYP2B6-516 GG genotype was significantly associated with a decreased risk of efavirenz-induced CNS side effects compared with the GT and TT genotypes (GG + GT vs. TT: OR = 0.60, 95% CI = 0.41-0.87, P = 0.006; GG vs. GT + TT: OR = 0.68, 95% CI = 0.51-0.91, P = 0.008; GG vs. GT: OR = 0.70, 95% CI = 0.51-0.94, P = 0.018), and there was no significant association between the genetic variants GT and TT (GT vs. TT: OR = 0.82, 95% CI = 0.54-1.26, P = 0.372). However, there was no significant association between CYP2B6-516 GG and GT + TT genotypes in virological response (GT + TT vs. GG: ES = 1.06, 95% CI = 0.95-1.18, P = 0.321; OR = 1.01, 95% CI = 0.65-1.58, P = 0.963). Taken together, our results demonstrated that compared with the normal efavirenz clearance genotype CYP2B6-516 GG, the slow and very slow efavirenz clearance genotypes GT and TT were significantly associated with an increased risk of efavirenz-induced CNS side effects but not an increased virological response. To promote the tolerance of efavirenz, it is better to adjust the dosage of efavirenz according to the polymorphisms of CYP2B6-516 in HIV-infected adults.