Trends and prescribing patterns of oral anti-neoplastic drugs: a retrospective longitudinal study.

Background: Cancer as a global public health problem, imposes a heavy disease burden. With the rapid development of oral anti-neoplastic drugs, there has been a paradigm shift in the treatment of cancer from intravenous to oral administration. Objective: This study was conducted to investigate the trends and prescribing patterns of oral anti-neoplastic drugs in an academic tertiary hospital in China. Methods: A single-center and retrospective analysis was performed based on the prescriptions of outpatients treated with oral anti-neoplastic drugs from 2017 to 2022. Yearly prescriptions and expenditure were calculated according to their pharmacological classes, and trends were further analyzed. Defined daily doses (DDDs) and defined daily cost (DDC) of oral targeted anti-neoplastic drugs were also determined. Results: Both the number of prescriptions and expenditure of oral anti-neoplastic drugs increased progressively. There was a significant upward trend in the number and proportion of prescriptions for the older adult group, male group, and patients with gynecologic/genitourinary and respiratory cancer. Hormonal therapy agents accounted for the highest proportion of prescriptions, and letrozole was initially the most frequently prescribed drug. The number of DDDs of total oral targeted anti-neoplastic drugs showed a continuously ascending trend, primarily driven by the usage of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and BCR-ABL TKIs. Conclusion: The prescriptions and expenditure of oral anti-neoplastic drugs, and the number of DDDs of oral targeted anti-neoplastic drugs all showed a progressively ascending trend. Further studies are needed to evaluate the long-term health and financial outcomes, and the factors influencing these prescribing patterns.

Genome-wide analysis of R2R3-MYB genes in cultivated peanut (Arachis hypogaea L.): Gene duplications, functional conservation, and diversification.

The cultivated Peanut (Arachis hypogaea L.), an important oilseed and edible legume, are widely grown worldwide. The R2R3-MYB transcription factor, one of the largest gene families in plants, is involved in various plant developmental processes and responds to multiple stresses. In this study we identified 196 typical R2R3-MYB genes in the genome of cultivated peanut. Comparative phylogenetic analysis with Arabidopsis divided them into 48 subgroups. The motif composition and gene structure independently supported the subgroup delineation. Collinearity analysis indicated polyploidization, tandem, and segmental duplication were the main driver of the R2R3-MYB gene amplification in peanut. Homologous gene pairs between the two subgroups showed tissue specific biased expression. In addition, a total of 90 R2R3-MYB genes showed significant differential expression levels in response to waterlogging stress. Furthermore, we identified an SNP located in the third exon region of AdMYB03-18 (AhMYB033) by association analysis, and the three haplotypes of the SNP were significantly correlated with total branch number (TBN), pod length (PL) and root-shoot ratio (RS ratio), respectively, revealing the potential function of AdMYB03-18 (AhMYB033) in improving peanut yield. Together, these studies provide evidence for functional diversity in the R2R3-MYB genes and will contribute to understanding the function of R2R3-MYB genes in peanut.

Adverse drug reactions and correlations with drug-drug interactions: A retrospective study of reports from 2011 to 2020.

Introduction: Adverse drug reactions (ADRs) represent a public health problem worldwide that deserves attention due to the impact on mortality, morbidity, and healthcare costs. Drug-drug interactions (DDIs) are an important contributor to ADRs. Most of the studies focused only on potential DDIs (pDDIs), while the detailed data are limited regarding the ADRs associated with actual DDIs. Methods: This retrospective study evaluated ADRs reported between 2011 and 2020 in a tertiary hospital. The causality and severity of ADRs were evaluated through the Naranjo Algorithm and Hartwig's scale, respectively. Preventability classification was based on the modified Schoumock and Thornton scale. For ADRs with at least two suspected drugs, pDDIs were identified according to the Lexi-Interact. We further checked whether the ADR description in the reports corresponded to the clinical consequences of the pDDIs. Results: A total of 1,803 ADRs were reported, of which 36.77% ADRs were classified as mild, 43.26% as moderate, and 19.97% as severe. The assessment of causality showed that the distributions of definite, probable, and possible categories were 0.33%, 58.68%, and 40.99%, respectively. A total of 53.97% of ADRs were identified as preventable ADRs, while 46.03% were recognized as unpreventable. The severity of ADRs was significantly correlated with age, the number of suspected drugs and preventability. Antimicrobial agents were the most common implicated pharmacological group, and the most frequently affected system was the gastrointestinal system. Considering individual drugs, aspirin was the most frequently reported drug. Among 573 ADRs with at least two suspected drugs, 105 ADRs were caused by actual DDIs, of which only 59 and 6 ADRs were caused by actual DDIs in category D and X, respectively. The most frequent drugs involved in actual DDIs of category D were aspirin and heparin, with the majority of ADRs being gastrointestinal bleeding. Conclusion: This study analyzed the pattern of ADRs in detail and obtained clinical evidence about ADRs associated with actual DDIs. These findings may be useful to compare patterns between different centers and to design preventive strategies for ADRs. Continuous education and training should be provided for physicians regarding the knowledge and recognition of ADRs associated with DDIs.

Identification, expression, and association analysis of calcineurin B-like protein-interacting protein kinase genes in peanut.

Plants usually respond to the external environment by initiating a series of signal transduction processes mediated by protein kinases, especially calcineurin B-like protein-interacting protein kinases (CIPKs). In this study, 54 CIPKs were identified in the peanut genome, of which 26 were from cultivated species (named AhCIPKs) and 28 from two diploid progenitors (Arachis duranensis-AdCIPKs and Arachis ipaensis-AiCIPKs). Evolution analysis revealed that the 54 CIPKs were composed of two different evolutionary branches. The CIPK members were unevenly distributed at different chromosomes. Synteny analysis strongly indicated that whole-genome duplication (allopolyploidization) contributed to the expansion of CIPK. Comparative genomics analysis showed that there was only one common collinear CIPK pairs among peanut, Arabidopsis, rice, grape, and soybean. The prediction results of cis-acting elements showed that AhCIPKs, AdCIPKs, and AiCIPKs contained different proportions of transcription factor binding motifs involved in regulating plant growth, abiotic stress, plant hormones, and light response elements. Spatial expression profiles revealed that almost all AhCIPKs had tissue-specific expression patterns. Furthermore, association analysis identified one polymorphic site in AdCIPK12 (AhCIPK11), which was significantly associated with pod length, seed length, hundred seed weight, and shoot root ratio. Our results provide valuable information of CIPKs in peanut and facilitate better understanding of their biological functions.

Global Survey, Expressions and Association Analysis of CBLL Genes in Peanut.

Cystathionine γ-synthase (CGS), methionine γ-lyase (MGL), cystathionine ß-lyase (CBL) and cystathionine γ-lyase (CGL) share the Cys_Met_Meta_PP domain and play important roles in plant stress response and development. In this study, we defined the genes containing the Cys_Met_Meta_PP domain (PF01053.20) as CBL-like genes (CBLL). Twenty-nine CBLL genes were identified in the peanut genome, including 12 from cultivated peanut and 17 from wild species. These genes were distributed unevenly at the ends of different chromosomes. Evolution, gene structure, and motif analysis revealed that CBLL proteins were composed of five different evolutionary branches. Chromosome distribution pattern and synteny analysis strongly indicated that whole-genome duplication (allopolyploidization) contributed to the expansion of CBLL genes. Comparative genomics analysis showed that there were three common collinear CBLL gene pairs among peanut, Arabidopsis, grape, and soybean, but no collinear CBLL gene pairs between peanut and rice. The prediction results of cis-acting elements showed that AhCBLLs, AdCBLLs, and AiCBLLs contained different proportions of plant growth, abiotic stress, plant hormones, and light response elements. Spatial expression profiles revealed that almost all AhCBLLs had significantly higher expression in pods and seeds. All AhCBLLs could respond to heat stress, and some of them could be rapidly induced by cold, salt, submergence, heat and drought stress. Furthermore, one polymorphic site in AiCBLL7 was identified by association analysis which was closely associated with pod length (PL), pod width (PW), hundred pod weight (HPW) and hundred seed weight (HSW). The results of this study provide a foundation for further research on the function of the CBLL gene family in peanut.

High-Risk Perioperative Medications in the Chinese Elderly Population.

BACKGROUND: Inappropriate perioperative medications among elderly patients increase the risk of adverse events and undermine surgical outcomes. This study aimed to assess the prevalence of high-risk medications in elderly surgical patients and verify the effectiveness of a new-developed high-risk perioperative medications (HRPOMs) list for the elderly. METHODS: A cross-sectional, single-center study was conducted at Jinshan Hospital of Fudan University. A total of 810 elderly surgical patients were included in the study. The HRPOMs list was applied to patients' data to identify the HRPOMs including chronic medications and medications related to surgery. RESULTS: A total of 2113 HRPOMs were identified in 810 patients who fulfilled the inclusion criteria. Of these, 1067 (50.5%) involved medications related to surgery, and 982 (46.5%) involved chronic medications. The prevalence of HRPOM exposure, which was defined as at least one HRPOM was 76.3%. Patients that were 70 years or older (adjusted odds ratio [AOR] =2.118, 95% confidence interval [CI], 1.420~3.159), hospitalized over two weeks (AOR =4.192, 95% CI, 1.493~11.771), with more than 2 distinct diagnoses (AOR =3.407, 95% CI, 2.224~5.220) and with 16 or more medications during hospitalization were more likely to be exposed to HRPOMs. Patients who underwent surgeries of Grade IV were at 1.73 increased odds of HRPOM exposure compared with those who received surgeries of Grade III or lower (P=0.071). CONCLUSION: HRPOMs are more common in patients of 70 years or older, with 3 or more distinct diagnoses, with 16 or more medications and hospitalized for 15 days or longer. Our study showed the validity of the HRPOMs list in the perioperative medication review for the elderly and may induce further research to reveal the impact of HRPOMs upon the surgical outcomes of the elderly.

A Negative Feedback Loop Between NAMPT and TGF-ß Signaling Pathway in Colorectal Cancer Cells.

BACKGROUND: Nicotinamide phosphoribosyltransferase (NAMPT) and the transforming growth factor-ß (TGF-ß) signaling pathway play important roles in colorectal tumorigenesis and progress. However, the underlying regulatory mechanisms between NAMPT and TGF-ß signaling in colorectal cancer (CRC) remain poorly understood. METHODS: Public data were extracted from the Oncomine database and the PrognoScan database to investigate the mRNA expression and the prognostic value of NAMPT, respectively, in CRC. Western blot tests were performed to detect Smad2, Smad3, p-Smad2, p-Smad3, Smad4 expression in CRC cells transfected with human NAMPT-siRNA or NAMPT-overexpressing plasmid. TGF-ß1 concentrations in culture supernatants were assayed using ELISA kits. The effect of TGF-ß1 on NAMPT expression was evaluated by quantitative real-time PCR and Western blot. The dual-luciferase reporter assay was employed to confirm the binding of miR-1-3p to NAMPT 3'-UTR. Subsequently, NAMPT levels in HCT116 cells transfected with the mimics and inhibitors of miR-1-3p were detected by quantitative real-time PCR and Western blot. RESULTS: NAMPT was overexpressed in human CRC and was correlated with short overall survival. NAMPT increased the protein expression levels of components in the TGF-ß signaling pathway including Smad2, Smad3, and Smad4. Moreover, NAMPT promoted TGF-ß1 secretion. Intriguingly, the TGF-ß1 treatment down-regulated NAMPT expression at mRNA and protein levels in CRC cells which were partly through the up-regulation of miR-1-3p that directly bound to the NAMPT 3'-UTR. These outcomes demonstrated that NAMPT was a downstream target of miR-1-3p and there was a negative association between NAMPT and miR-1-3p in CRC. CONCLUSION: There is a negative feedback loop between NAMPT and the TGF-ß signaling pathway in CRC cells, providing new insight into the mechanism underlying the regulatory pathways in CRC.

Prevalence of potential drug-drug interactions in outpatients of a general hospital in China: a retrospective investigation.

Background Potential drug-drug interactions are important factors resulting in adverse drug reactions or therapeutic failure. Therefore, potential drug-drug interactions need to be identified to prevent the related risk and improve drug safety. Objective This study was designed to determine the prevalence of potential drug-drug interactions and investigate the association of potential drug-drug interactions with characteristics in outpatient prescriptions. Setting A large-scale general university hospital in Jinshan District of Shanghai, China. Method The retrospective study was conducted on data obtained from prescriptions containing two or more drugs, written for outpatients older than 18 years. They were screened for potential drug-drug interactions using Lexi-Interact in UpToDate, Stockley's Drug Interactions and Medicine Specification in the order of priority. Main outcome measure Drug-drug interactions with C, D, X risk rating and clinical parameters recorded at the prescriptions. Results 16,120 prescriptions were screened for the presence of potential drug-drug interactions and 4882 (30.29%) prescriptions containing 6667 potential drug-drug interactions were identified. Among 6667 potential drug-drug interactions, 90.81% (6054/6667), 8.49% (566/6667), 0.70% (47/6667) potential drug-drug interactions belonged to the risk category of C, D and X, respectively. Male, old age and polypharmacy increased the likelihood of potential drug-drug interactions. The most frequently prescribed drugs responsible for potential drug-drug interactions included pioglitazone, dihydrocodeine, thalidomide, sotalol, amiodarone and amlodipine. The predominant potential adverse outcome of potential drug-drug interactions was the increased central nervous system suppression function with the mechanism of reinforced pharmacological effects. Conclusion This study showed that potentially significant drug-drug interactions in outpatients were prevalent in real-world practice. Considering the risk of potential clinical consequences related to potential drug-drug interactions, it is necessary to implement the computerized surveillance and warning systems with drug-drug interactions databases as well as develop the clinical guidelines regarding the widespread potential drug-drug interactions.

Time trends analysis of statin prescription prevalence, therapy initiation, dose intensity, and utilization from the hospital information system of Jinshan Hospital, Shanghai (2012-2018).

BACKGROUND: Statin remains a mainstay in the prevention and treatment of cardiovascular diseases. Statin utilization has evolved over time in many countries, but data on this topic from China are quite limited. This study aimed to investigate the changing trends of statins prescription, as well as detail the statin utilization through a successive longitudinal study. METHODS: The prescription database was established based on electronic health records retrieved from the hospital information system of Jinshan Hospital, Fudan University from January 2012 to December 2018 in Shanghai, China. The prescription rates and proportions of different statin types and doses among all patients were examined. Sub-analyses were performed when stratifying the patients by age, gender, dose intensity, and preventative intervention. RESULTS: During the study period, a total of 51,083 patients, who were prescribed for statins, were included in this study (mean [SD] age, 59.78 [±13.16] years; 53.60% male, n = 27, 378). The overall statins prescription rate in which patients increased from 2012 (1.24, 95% CI: 1.21-1.27%) to 2018 (3.16, 95% CI: 3.11-3.20%), P < 0.001. Over 90% of patients were given a moderate dose of statins. Patients with a history of coronary and cerebrovascular events (over 32%) were more likely to be prescribed with statins for preventative intervention. Furthermore, our study has witnessed a significant rise in statin therapy in primary and secondary prevention. CONCLUSIONS: In conclusion, statins were frequently prescribed and steadily increased over time in our study period. There were also changes in statin drug choices and dosages. A coordinated effort among the patient, clinical pharmacist, stakeholders and health system is still needed to improve statin utilization in clinical practice in the future.

Genome-wide identification, expression, and association analysis of the monosaccharide transporter (MST) gene family in peanut (Arachis hypogaea L.).

In this study, we reported the genome-wide analysis of the whole sugar transporter gene family of a legume species, peanut (Arachis hypogaea L.), including the chromosome locations, gene structures, phylogeny, expression patterns, as well as comparative genomic analysis with Arabidopsis, rice, grape, and soybean. A total of 76 AhMST genes (AhMST1-76) were identified from the peanut genome and located unevenly in 20 chromosomes. Phylogeny analysis indicated that the AhMSTs can be divided into eight groups including two undefined peanut-specific groups. Transcriptional profiles revealed that many AhMST genes showed tissue-specific expression, the majority of the AhMST genes mainly expressed in sink organs and floral organ of peanut. Chromosome distribution pattern and synteny analysis strongly indicated that genome-wide segmental and tandem duplication contributed to the expansion of peanut MST genes. Four common orthologs (AhMST9, AhMST13, AhMST40, and AhMST43) between peanut and the other four species were identified by comparative genomic analysis, which might play important roles in maintaining the growth and development of plant. Furthermore, four polymorphic sites in AhMST11, AhMST13, and AhMST60 were significantly correlated with hundred pod weight (HPW) and hundred seed weight (HSW) by association analysis. In a word, these results will provide new insights for understanding the functions of AhMST family members to sugar transporting and the potential for yield improvement in peanut.

Clostridium difficile-associated diarrhea following the therapy with antibiotic and proton pump inhibitors in a 77-year-old man with several comorbidities: A case report.

RATIONALE: Clostridium difficile-associated diarrhea (CDAD) remains a persistent challenge, with substantially increased incidence and severity. The rising burden of CDAD requires urgent identification of preventable risk factors. PATIENTS CONCERNS: A 77-year-old man with the symptoms of abdominal pain and watery diarrhea was readmitted to the hospital, who received cephalosporins and proton pump inhibitors (PPIs) during the initial hospitalization for 12 days until discharge. Antibiotic-associated diarrhea was seriously suspected. And the stool sample was immediately sent for inspection for C difficile. He had a history of chronic bronchitis, coronary heart disease, and osteonecrosis. DIAGNOSIS: CDAD, renal insufficiency INTERVENTIONS:: Oral vancomycin was administered for 14 days. OUTCOMES: On the third day after readmission, the stool sample turned out to be positive for both C difficile toxin and its antigen. After 10-day treatment with vancomycin, diarrhea symptoms disappeared and his stools became normal. LESSONS: In elderly patients with multiple comorbidities, PPIs must be administered cautiously to minimize the risk for adverse effects including CDAD. It is important to identify the preventable risk factors of CDAD for clinicians and pharmacists. Oral vancomycin therapy seems to be effective in CDAD.

Reversal of multidrug resistance in human lung cancer cells by delivery of 3-octadecylcarbamoylacrylic acid-cisplatin-based liposomes.

Liposome-based drug delivery system would be an innovative and promising candidate to circumvent multidrug resistance (MDR) of cisplatin (CDDP). However, the reversal efficacy of liposomal CDDP was severely impaired by weak cellular uptake and insufficient intracellular drug release. In this study, 3-octadecylcarbamoylacrylic acid-CDDP nanocomplex (OMI-CDDP-N)-based liposomes (OCP-L) with high cellular uptake and sufficient intracellular drug release were designed to circumvent MDR of lung cancer. OMI-CDDP-N was synthesized through a pH-sensitive monocarboxylato and an O→Pt coordinate bond, which is more efficient than CDDP. Also, OCP-L incorporated with OMI-CDDP-N could induce effective cellular uptake, enhanced nuclear distribution, and optimal cellular uptake kinetics. In particular, OCP-L presented superior effects on enhancing cell apoptosis and in vitro cytotoxicity in CDDP-resistant human lung cancer (A549/CDDP) cells. The mechanisms of MDR reversal in A549/CDDP cells by OCP-L could attribute to organic cation transporter 2 restoration, ATPase copper-transporting beta polypeptide suppression, hypoxia-inducible factor 1 α-subunit depletion, and phosphatidylinositol 3-kinase/Akt pathway inhibition. These results demonstrated that OCP-L may provide an effective delivery of CDDP to resistant cells to circumvent MDR and enhance the therapeutic index of the chemotherapy.

3-octadecylcarbamoylacrylic acid-cisplatin nanocomplexes for the development of novel liposome formulation.

It was the first time that 3-octadecylcarbamoylacrylicacid-cisplatin nanocomplexes (OMI-CDDP-N) were synthesized via monocarboxylato and O→Pt coordination. The nanocomplexes exhibited lower IC50 values compared with cisplatin (CDDP) in vitro, and enhanced antitumor efficacy in murine liver cancer (H22) in vivo. However, the toxicity of the nanocomplexes was more severe than CDDP. OMI-CDDP-N-based liposome (OCP-L) was prepared in order to maintain the efficacy and reduce the toxicity of OMI-CDDP-N. Here, a series of parameters were investigated to optimize liposome formulation. The optimal formulation was CDDP/phospholipids/cholesterol (1/10/0.7 wt.%), with distilled water as hydration medium and an encapsulation efficiency of 94.2 ± 2.1%. In vitro cytotoxicity studies revealed that OCP-L and OMI-CDDP-N exhibited a lower IC50 compared with commercial cisplatin injection (CDDP-S) in a variety of human cancer cells. In H22-implanted mice, OCP-L showed a significantly higher antitumor activity than OMI-CDDP-N or CDDP-S at a dose of 5 mg/kg (p < 0.01). Moreover, OCP-L exceeded the size cutoff for kidney clearance, hence it bypassed the nephrotoxicity of CDDP which is a major curse of CDDP in the clinic. These results suggested that the unique OMI-CDDP-N-entrapped liposome can overcome the disadvantages associated with conventional CDDP therapy and provide a higher safety profile.