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Nicotinamide phosphoribosyltransferase (NAMPT) is a promising anticancer target. Using high throughput screening system targeting NAMPT, we obtained a potent NAMPT inhibitor MS0 (China Patent ZL201110447488.9) with excellent in vitro activity (IC50 = 9.87 ± 1.15nM) and anti-proliferative activity against multiple human cancer cell lines including stem-like cancer cells. Structure-activity relationship studies yielded several highly effective analogues. These inhibitors specifically bound NAMPT, rather than downstream NMNAT. We provided the first chemical case using cellular thermal shift assay to explain the difference between in vitro and cellular activity; MS7 showed best in vitro activity (IC50 = 0.93 ± 0.29 nM) but worst cellular activity due to poor target engagement in living cells. Site-directed mutagenesis studies identified important residues for NAMPT catalytic activity and inhibitor binding. The present findings contribute to deep understanding the action mode of NAMPT inhibitors and future development of NAMPT inhibitors as anticancer agents.

Colorectal cancer (CRC) is the third most common cancer disease. Here we examined Nampt expression in patients with CRC and the effect of Nampt on cell viability in CRC cells. Nampt protein was overexpressed in colorectal adenoma as well as colorectal carcinoma. The immunoreactive staining of Nampt was negative in the adjacent normal colorectal tissue, weak in colorectal adenoma, and strong in colorectal carcinoma, which may represent tumor progression. Further evaluation of clinical data showed that Nampt expression was not correlated with the clinicopathological characteristics of CRC. Additionally, our in vitro studies demonstrated that Nampt promotes CRC cell viability, whereas the Nampt inhibitor FK866 suppressed CRC cell viability, which was in concordance with the previous studies in other cancer cells. Treatment with Nampt-siRNA reduced the Nampt protein expression resulting in the inhibition of the cell viability of HCT116 and Caco2. Thus, the involvement of Nampt in cell growth indicates that Nampt may play an important role in colorectal tumorigenesis. As a consequence, our results suggest that Nampt may be considered as a progression marker of colorectal tumor and a potentially therapeutic target for the treatment of CRC.

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.

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.

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. Subanalyses 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.

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.

Background: Nicotinamide phosphoribosyltransferase (NAMPT) and the transforming growth factor-β (TGF-β) signaling pathway play important roles in colorectal tumorigenesis and progress. However, the underlying regulatory mechanisms between NAMPT and TGF-β 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-β1 concentrations in culture supernatants were assayed using ELISA kits. The effect of TGF-β1 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 3ʹ-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-β signaling pathway including Smad2, Smad3, and Smad4. Moreover, NAMPT promoted TGF-β1 secretion. Intriguingly, the TGF-β1 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 3ʹ-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-β signaling pathway in CRC cells, providing new insight into the mechanism underlying the regulatory pathways in CRC.