A novel class of heat shock protein 90 (Hsp90) inhibitors was developed from an unbiased screen to identify protein targets for a diverse compound library. These indol-4-one and indazol-4-one derived 2-aminobenzamides showed strong binding affinity to Hsp90, and optimized analogues exhibited nanomolar antiproliferative activity across multiple cancer cell lines. Heat shock protein 70 (Hsp70) induction and specific client protein degradation in cells on treatment with the inhibitors supported Hsp90 inhibition as the mechanism of action. Computational chemistry and X-ray crystallographic analysis of selected member compounds clearly defined the protein-inhibitor interaction and assisted the design of analogues. 4-[6,6-Dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(trans-4-hydroxycyclohexyl)amino]benzamide (SNX-2112, 9) was identified as highly selective and potent (IC(50) Her2 = 11 nM, HT-29 = 3 nM); its prodrug amino-acetic acid 4-[2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-phenylamino]-cyclohexyl ester methanesulfonate (SNX-5422, 10) was orally bioavailable and efficacious in a broad range of xenograft tumor models (e.g. 67% growth delay in a HT-29 model) and is now in multiple phase I clinical trials.

A chemoproteomics-based drug discovery strategy is presented that utilizes a highly parallel screening platform, encompassing more than 1000 targets, with a focused chemical library prior to target selection. This chemoproteomics-based process enables a data-driven selection of both the biological target and chemical hit after the screen is complete. The methodology has been exemplified for the purine binding proteome (proteins utilizing ATP, NAD, FAD). Screening of an 8000 member library yielded over 1500 unique protein-ligand interactions, which included novel hits for the oncology target Hsp90. The approach, which also provides broad target selectivity information, was used to drive the identification of a potent and orally active Hsp90 inhibitor, SNX-5422, which is currently in phase 1 clinical studies.

The impact of a publication in a particular medical area is reflected by the number of times the article is included as a citation. It is not known, however, which articles are cited the most in primary care journals. In our study, we aimed to identify the 100 most cited articles in primary care medicine and analyze their characteristics.We searched the Science Citation Index Expanded for articles published in 18 primary care journals using the subject category “Primary health care.” We identified 100 articles in primary health care that were the most cited. We analyzed the characteristics of these articles using the title, number of citations, citation density, year of publication, journal source, decade published, country of origin, institution, author names, and type of article.The 100 articles that were cited the most were published between the years 1977 and 2009. The 1990s decade was the most productive decade. The number of citations ranged from 117 to 775. The articles were published in 9 journals and the journal with the largest number of most cited articles (n = 33) was the Journal of Family Practice. This was followed by the British Journal of General Practice (n = 17) and the journal Family Practice (n = 16). The United States was the most productive country (n = 59); the United Kingdom was next (n = 25) and this was followed by Canada (n = 5) and The Netherlands (n = 5). The most popular article type was a review article and this was followed by a qualitative study and then methodological study.Our study provides insight into the historical development of primary care studies, based on citations, and provides the foundation for further investigations.

Purpose: To evaluate the incidence and risk of tremor in patients treated with valproic aid (VPA) monotherapy.Methods: We searched the PubMed, Embase, and Cochrane Library databases to gather relevant data on tremor in patients taking VPA and other drugs and performed a meta-analysis using Stata15.1 software.Results: Twenty-nine randomized controlled trials (RCTs) met the inclusion criteria and were included in the meta-analysis. The overall incidence of tremor in patients receiving VPA therapy was 14% [OR = 0.14, 95% CI (0.10–0.17)]. The pooled estimate risk of tremor showed a significant difference between patients treated with VPA and all other drugs [OR = 5.40, 95% CI (3.22–9.08)], other antiepileptic drugs (AEDs) [OR = 5.78, 95% CI (3.18–10.50)], and other non-AEDs [OR = 4.77, 95% CI (1.55–14.72)]. Both a dose of <1,500 mg/d of VPA [included 500 mg/d: OR = 3.57, 95% CI (1.24–10.26), 500–999 mg/d: OR = 3.99, 95% CI (1.95–8.20), 1,000–1,499 mg/d: OR = 8.82, 95% CI (3.25–23.94)] and a VPA treatment duration of <12 m [included ≤ 3 months: OR = 3.06, 95% CI (1.16–8.09), 3–6 months: OR = 16.98, 95% CI (9.14–31.57), and 6–12 months: OR = 4.15, 95% CI (2.74–6.29)] led to a higher risk of tremor than did other drugs, as did higher doses and longer treatment times.Conclusion: Compared with other drugs, VPA led to a higher risk of tremor, and the level of risk was associated with the dose and duration of treatment.

Antipsychotic-induced dyslipidemia could increase the risk of cardiovascular diseases. This is a meta-analysis of randomized double-blind placebo-controlled trials to examine the efficacy and safety of adjunctive metformin for dyslipidemia induced by antipsychotics in schizophrenia. The standardized mean differences (SMDs) and risk ratios (RRs) with their 95% confidence intervals (CIs) were calculated using the random-effects model with the RevMan 5.3 version software. The primary outcome was the change of serum lipid level. Twelve studies with 1215 schizophrenia patients (592 in metformin group and 623 in placebo group) were included and analyzed. Adjunctive metformin was significantly superior to placebo with regards to low density lipoprotein cholesterol (LDL-C) [SMD: −0.37 (95%CI:−0.69, −0.05), P = 0.02; I 2 = 78%], total cholesterol [SMD: −0.47 (95%CI:−0.66, −0.29), P < 0.00001; I 2 = 49%], triglyceride [SMD: −0.33 (95%CI:−0.45, −0.20), P < 0.00001; I 2 = 0%], and high density lipoprotein cholesterol [SMD: 0.29 (95% CI:0.02, 0.57), P = 0.03; I 2 = 69%]. The superiority of metformin in improving LDL-C level disappeared in a sensitivity analysis and 80% (8/10) of subgroup analyses. Metformin was significantly superior to placebo with regards to decrease in body weight, body mass index, glycated hemoglobin A1c, fasting insulin, and homeostasis model assessment-insulin resistance (P = 0.002-0.01), but not regarding changes in waist circumference, waist-to-hip rate, leptin, fasting glucose, and blood pressure (P = 0.07-0.33). The rates of discontinuation due to any reason [RR: 0.97 (95%CI: 0.66, 1.43), P = 0.89; I 2 = 0%] was similar between the two groups. Adjunctive metformin could be useful to improve total cholesterol and triglyceride levels, but it was not effective in improving LDL-C level in schizophrenia.

BackgroundHyperprolactinaemia is a common antipsychotic (AP)-induced adverse effect, particularly in female patients.AimsThis meta-analysis examined the efficacy and safety of adjunctive aripiprazole in preventing AP-related hyperprolactinaemia in patients with first-episode schizophrenia.MethodsPubMed, PsycINFO, EMBASE, Cochrane Library, WanFang and China Journal Net databases were searched to identify eligible randomised controlled trials (RCTs). Primary outcomes were the reductions of serum prolactin level and prolactin-related symptoms. Data were independently extracted by two reviewers and analysed using RevMan (V.5.3). Weighted/standardised mean differences (WMDs/SMDs)±95% CIs were reported.ResultsIn the five RCTs (n=400), the adjunctive aripiprazole (n=197) and the control groups (n=203) with a mean of 11.2 weeks of treatment duration were compared. The aripiprazole group had a significantly lower endpoint serum prolactin level in all patients (five RCTs, n=385; WMD: −50.43 ng/mL (95% CI: −75.05 to −25.81), p<0.00001; I2=99%), female patients (two RCTs, n=186; WMD: −22.58 ng/mL (95% CI: −25.67 to −19.49), p<0.00001; I2=0%) and male patients (two RCTs, n=127; WMD: −68.80 ng/mL (95% CI: −100.11 to −37.49), p<0.0001). In the sensitivity analysis for the endpoint serum prolactin level in all patients, the findings remained significant (p<0.00001; I2=96%). The aripiprazole group was superior to the control group in improving negative symptoms as assessed by the Positive and Negative Syndrome Scale (three RCTs, n=213; SMD: −0.51 (95% CI: −0.79 to −0.24), p=0.0002; I2=0%). Adverse effects and discontinuation rates were similar between the two groups.ConclusionsAdjunctive aripiprazole appears to be associated with reduced AP-induced hyperprolactinaemia and improved prolactin-related symptoms in first-episode schizophrenia. Further studies with large sample sizes are needed to confirm these findings.

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ObjectiveFluorodeoxyglucose Positron emission tomography/computerized tomography (FDG PET/CT) has become popular for diagnosing periprosthetic joint infections (PJI). However, the diagnostic accuracy for this technique has varied from report to report. This meta-analysis was performed to assess the accuracy of FDG PET/CT for PJI diagnosis.Material and MethodsWe conducted a systematic search of online academic databases for all studies reporting the diagnostic accuracy of FDG PET/CT for PJI. Meta-analysis was performed using STATA software.Results23 studies, containing data on 1,437 patients, met inclusion criteria. Pooled sensitivity and specificity of FDG PET/CT for diagnosing PJI were 85% (95% CI, 76%, 91%) and 86% (95% CI, 78%, 91%), respectively with an AUC of 0.92. LRP was 6.1 (95% CI, 3.8, 9.7) and LRN was 0.17 (0.11, 0.28), indicating that FDG PET/CT cannot be used for confirmation or exclusion of PJI. There was significant inter-study heterogeneity, but no significant publication bias was noted.ConclusionsOur study found that FDG PET/CT has an important role as a diagnostic tool for PJI with high sensitivity and specificity. Further studies exploring its accuracy in different PJI locations remain necessary.