Psoriatic arthritis risk in psoriasis patients prescribed acitretin versus disease-modifying antirheumatic drugs: a nationwide cohort study.

OBJECTIVES: To compare the risk of psoriatic arthritis (PsA) in psoriasis (PsO) patients treated with acitretin vs disease-modifying antirheumatic drugs (DMARDs). METHODS: This retrospective study used Taiwan's National Health Insurance Research Database from 1997 to 2013. Adult PsO patients without PsA prescribed acitretin or DMARDs for ≥30 days within a year were assigned to the acitretin cohort or DMARDs cohort, respectively. Patients in the acitretin cohort prescribed DMARDs for >7 days, or in the DMARDs cohort prescribed acitretin for >7 days, were excluded. Cumulative incidence of PsA were determined within both cohorts using the Kaplan-Meier method. The hazard ratio (HR) comparing acitretin to DMARDs was calculated with Cox regression models, adjusting for demographic and clinical covariates including the use of non-steroidal anti-inflammatory drugs (NSAIDs) and comorbidities. RESULTS: The study included 1,948 patients in each cohort. The 5-year cumulative incidence of PsA in the acitretin cohort was lower than that in the reference cohort (7.52% vs 9.93%; P=0.005), with a more pronounced difference in the subpopulation receiving NSAIDs treatment. However, in subpopulations without NSAIDs treatment, the 5-year cumulative incidence of PsA in the acitretin cohort was comparable to the DMARDs cohort (5.26% vs 6.98%; P = 0.106). Acitretin was not associated with PsA development in PsO (HR 0.83, 95% confidence interval 0.65-1.05). This risk remained consistent regardless of adjustments for NSAID treatment and comorbidities. Other independent risk factors for PsA included female and NSAIDs treatment. CONCLUSION: Compared with DMARDs, acitretin was not associated with increased PsA risk in PsO patients.

Risk of Psychiatric Disorders in Patients with Psoriasis Prescribed Acitretin versus Disease-Modifying Antirheumatic Drugs: A Nationwide Matched Cohort Study.

BACKGROUND: Acitretin has been linked to the development of psychiatric disturbance. OBJECTIVES: The aim of this study was to assess the psychiatric hazards in patients with psoriasis prescribed acitretin compared with those prescribed disease-modifying antirheumatic drugs (DMARDs). METHODS: This is a nationwide matched cohort study. From Taiwan's National Health Insurance Research Database, adult patients with psoriasis between 1997 and 2013 were screened. Patients prescribed acitretin for at least 30 days per year on average (acitretin cohort) were matched 1:2 with those prescribed DMARDs for at least 30 days per year on average (reference cohort), by means of age, gender, and psoriasis duration. Patients prescribed medication of the corresponding cohort for more than 7 days during the observation period were excluded. Cumulative incidences of psychiatric disorders in both cohorts were plotted with the Kaplan-Meier method. The modified Cox regression models were constructed to estimate hazard ratios (HRs). RESULTS: In total, 1,152 and 2,304 patients in the acitretin and the reference cohorts, respectively, were included. The 4-year cumulative incidence of overall psychiatric disorders (19.62% vs. 12.06%; p < 0.001), mood disorders (12.81% vs. 7.67%; p < 0.001), and psychosis (7.21% vs. 4.63%; p < 0.001) in the acitretin cohort was significantly higher than that in the reference cohort. Acitretin was independently associated with psychiatric disorders (HR 1.51, 95% confidence interval [CI] 1.23-1.85). The risk is more accentuated in the subgroups of comorbid chronic liver disease (HR 2.60, 95% CI: 1.56-4.33) or psoriatic arthritis (HR 3.23, 95% CI: 1.75-5.97). Other independent risk factors included insomnia, acute coronary syndrome, females, and age. CONCLUSIONS: Compared with DMARDs, acitretin was associated with higher hazards of psychiatric disorders among psoriasis patients.

Impact of medication therapy management (MTM) service model on multi-morbidity (MMD) patients with hypertension: a pilot RCT.

BACKGROUND: This study explored the impact of MTM service on MMD patients with hypertension. METHODS: A total of 120 MMD inpatients from September to November 2019 were received and randomly divided into intervention group and control group. General services for noninfectious chronic diseases were given to the control group, while a standard MTM service was given to the intervention group. Patients' blood pressure, EQ-5D utility value, readmission rate, drug-related problems, and average daily medication therapy cost were compared between the two groups and within the groups. This was done at the initial admission phase and in the first, third, sixth, and twelfth months after discharge. RESULTS: The intervention group had significantly lower blood pressure and average daily medication therapy cost 12 months after discharge compared to the control group (systolic blood pressure: P = 0.023, diastolic blood pressure: P < 0.001, average daily medication therapy cost: P = 0.049); the number of DRPs decreased in both groups 12 months after discharge; the number of DRPs solved in the intervention group in the third, sixth and twelfth months after discharge were statistically higher compared with that in the control group (P = 0.013, P = 0.012, P = 0.001); there was no significant difference in the EQ-5D utility value and readmission rate between the two groups (P > 0.05). CONCLUSIONS: MTM implementation in MMD patients can improve health outcomes and reduce healthcare-related costs among MMD patients. TRIAL REGISTRATION: Chinese Clinical Trial Register ChiCTR2200065111, date of registration: October 28, 2022.

Association between early life laxative exposure and risk of allergic diseases A nationwide matched cohort study.

BACKGROUND: The early life microbiome can shape human immunity. Recent studies have revealed gut dysbiosis after laxative administration. OBJECTIVE: To investigate the impact of infantile laxative exposure on subsequent allergic diseases. METHODS: This nationwide matched cohort study was conducted using Taiwan's National Health Insurance Research Database for the period 1997 to 2013. A total of 32,986 patients who had complete information of maternal history and delivery modes were identified. We included 291 children having laxatives for at least 7 days within the first 6 months of life and 1164 reference children not receiving laxatives, matching by sex, propensity score, number of hospital visits, and maternal age at delivery. Demographic characteristics and maternal factors were compared, and cumulative incidences of allergic diseases were calculated. Cox proportional hazard model was used to evaluate associations. RESULTS: The 5-year cumulative incidence of allergic diseases in the laxative cohort was significantly higher than that in the reference cohort (49.81% vs 41.68%; P = .01). Early life laxative exposure (adjusted hazard ratio, 1.61; 95% confidence interval, 1.32-1.97) was independently associated with allergic disease development. Other independent risk factors included preterm, male sex, maternal allergic diseases, and prenatal laxative use. Multivariable stratified analyses verified the association between early life laxative exposure and subsequent allergic disease development in all subgroups of children, including those born to mothers without allergic diseases or prenatal laxative use. CONCLUSION: Early life laxative exposure is associated with allergic disease development.

Fracture risks in patients with atopic dermatitis: A nationwide matched cohort study.

BACKGROUND: The risk of osteoporosis has been explored in atopic dermatitis (AD). The long-term risk of fractures in patients with AD and the effects of various AD treatments on bone health remain to be elucidated. OBJECTIVE: To evaluate the long-term risk of fractures in patients with AD. METHODS: This nationwide matched cohort study was conducted using the National Health Insurance Research Database of Taiwan for the period 1997 to 2013. A total of 36,855 patients with AD and 147,420 reference subjects without AD were identified. Demographic characteristics and comorbidities were compared, and cumulative incidence of fractures was evaluated. Adjusted hazard ratios for fracture risks of AD and various AD treatments were calculated using the Cox proportional hazards model. RESULTS: A total of 1518 patients (4.12%) in the AD cohort and 5579 patients (3.78%) in the reference cohort had fractures (P = .003). The mean ages were 22.6 years in both groups. The 16-year cumulative incidence of fractures in the AD cohort (8.043%) was significantly higher than that in the reference cohort (7.366%) (P = .002). Severe AD (adjusted hazard ratio [aHR], 1.31; 95% confidence interval [CI], 1.08-1.59) was independently associated with fractures. Other independent risk factors included exposure to topical (aHR, 1.21; 95% CI, 1.05-1.39) or systemic (≥10 mg/d; aHR, 1.62; 95% CI, 1.38-1.91) corticosteroids. Use of disease-modifying antirheumatic drugs (aHR, 0.71; 95% CI, 0.53-0.90) and phototherapy (aHR, 0.73; 95% CI, 0.56-0.95) was associated with a lower risk of fractures. The results were consistent across sensitivity analyses. CONCLUSION: Patients with AD have a higher incidence of fractures. Severe AD is independently associated with fractures.

The epidemiology of pediatric psoriasis: A nationwide cohort study in Taiwan.

Psoriasis can affect individuals of all age groups. While the epidemiology of psoriasis in adults has been extensively studied, there is limited research specifically investigating pediatric cases. This study aimed to investigate the prevalence and incidence of skin psoriasis (PsO) and psoriatic arthritis (PsA) among pediatric patients in Taiwan. A nationwide cohort of 17 535 patients with psoriatic diseases under the age of 18 was enrolled from the National Health Insurance Research Database for the period 2000-2013, including 16 129 PsO patients and 2022 PsA patients. The age- and sex-standardized prevalence and incidence of pediatric PsO and PsA were calculated. The 2007 yearly reports of age- and sex-specific distribution of the general population was adopted as a standard. The results showed that between 2000 and 2013, the prevalence for pediatric PsO increased from 0.03% to 0.07%, and from 0.003% to 0.014% for pediatric PsA. During the same period, the incidence slightly decreased from 19.81 to 17.55 per 100 000 for pediatric PsO but increased from 1.02 to 5.06 per 100 000 for pediatric PsA. Adolescents (12 to <18 years) had higher prevalence and incidence rates of PsO and PsA than children (aged ≤ 12 years), with no sex difference observed in either age group. PsA preceding PsO was more common among children than adolescents (27.07% vs. 13.46%). This study provides important insights into the prevalence and incidence of psoriatic diseases in the pediatric population. Further research is needed to identify risk factors for pediatric psoriasis and to investigate its long-term health outcomes.

Early-Life Antibiotic Exposure Associated With Varicella Occurrence and Breakthrough Infections: Evidence From Nationwide Pre-Vaccination and Post-Vaccination Cohorts.

Background: Antibiotic-driven dysbiosis may impair immune function and reduce vaccine-induced antibody titers. Objectives: This study aims to investigate the impacts of early-life antibiotic exposure on subsequent varicella and breakthrough infections. Methods: This is a nationwide matched cohort study. From Taiwan's National Health Insurance Research Database, we initially enrolled 187,921 children born from 1997 to 2010. Since 2003, the Taiwan government has implemented a one-dose universal varicella vaccination program for children aged 1 year. We identified 82,716 children born during the period 1997 to 2003 (pre-vaccination era) and 48,254 children born from July 1, 2004, to 2009 (vaccination era). In the pre-vaccination era, 4,246 children exposed to antibiotics for at least 7 days within the first 2 years of life (Unvaccinated A-cohort) were compared with reference children not exposed to antibiotics (Unvaccinated R-cohort), with 1:1 matching for gender, propensity score, and non-antibiotic microbiota-altering medications. Using the same process, 9,531 children in the Vaccinated A-cohort and Vaccinated R-cohort were enrolled from the vaccination era and compared. The primary outcome was varicella. In each era, demographic characteristics were compared, and cumulative incidences of varicella were calculated. Cox proportional hazards model was used to examine associations. Results: In the pre-vaccination era, the 5-year cumulative incidence of varicella in the Unvaccinated A-cohort (23.45%, 95% CI 22.20% to 24.70%) was significantly higher than in the Unvaccinated R-cohort (16.72%, 95% CI 15.62% to 17.82%) (p<.001). In the vaccination era, a significantly higher 5-year cumulative incidence of varicella was observed in the Vaccinated A-cohort (1.63%, 95% 1.32% to 1.93%) than in the Vaccinated R-cohort (1.19%, 95% CI 0.90% to 0.45%) (p=0.006). On multivariate analyses, early-life antibiotic exposure was an independent risk factor for varicella occurrence in the pre-vaccination (adjusted hazard ratio [aHR] 1.92, 95% CI 1.74 to 2.12) and vaccination eras (aHR 1.66, 95% CI 1.24 to 2.23). The use of penicillins, cephalosporins, macrolides, or sulfonamides in infancy was all positively associated with childhood varicella regardless of vaccine administration. Conclusions: Antibiotic exposure in early life is associated with varicella occurrence and breakthrough infections.

Reduced risk of skin cancer and internal malignancies in vitiligo patients: a retrospective population-based cohort study in Taiwan.

The relationship between cancer and vitiligo has been explored but with inconsistent results. To examine the long-term cancer risk in vitiligo patients, we conducted a retrospective nationwide cohort study. From the National Health Insurance Research Database of Taiwan, a total of 13,824 vitiligo patients were identified and matched with 55,296 reference subjects without vitiligo by age, gender, and propensity score estimated by major comorbidities from 1997 to 2013. Demographic characteristics and comorbidities were compared between these two groups. Incidence rate ratios and hazard ratios (HRs) were calculated to examine cancer risks. The 16-year incidence rates of overall cancers were 621.06 (566.56-675.55) and 726.99 (697.24-756.74) per 100,000 person-years in the vitiligo and reference groups. Patients with vitiligo showed a significantly decreased risk of overall cancers [adjusted HR, 0.85; 95% confidence interval (CI), 0.77 to 0.93, p < 0.001] compared with reference subjects without vitiligo after adjusting for age, sex, comorbidities, and treatments. The risks of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) were significantly reduced (adjusted HR 0.21, 95% CI 0.11-0.38, p < 0.001), as well as internal malignancies (adjusted HR 0.89, 95% CI 0.81-0.99, p = 0.026). The results were consistent across different subgroups of patients, including male gender, ages more than 40 years, and those receiving long-term systemic disease-modifying antirheumatic drugs and phototherapies. Information related to phenotype, disease duration, vitiligo lesion sites, family history of vitiligo or cancer, occupation, and personal lifestyle was not included in the database. Vitiligo is associated with reduced risks of BCC and SCC, as well as internal malignancies.

Atopic dermatitis does not increase the risk of inflammatory bowel disease: A nationwide cohort study.

Coexistence of inflammatory bowel disease (IBD) in atopic dermatitis (AD) patients has been reported. The long-term risk of IBD in AD patients remains unclear. Our aim for the study is to examine the long-term risk of IBD in AD patients. This is a nationwide cohort study. From the National Health Insurance Research Database of Taiwan (1997-2013), a total of 36 400 AD patients were identified and matched with 364 000 reference subjects without AD by age, sex and number of hospital visits. Demographic characteristics and comorbidities were compared. Cox proportional hazards regression analysis was conducted to examine the risk of IBD. The 16-year cumulative incidences of IBD were 0.047% (95% confidence interval [CI], 0.040-0.054) and 0.047% (95% CI, 0.025-0.096) in non-AD and AD cohorts, respectively (P = 0.973). There were 17 cases of IBD (0.05%), including 10 ulcerative colitis and seven Crohn's disease, among AD patients compared with 169 IBD cases (0.05%) among controls (P > 0.999). Infections (adjusted hazard ratio [HR], 2.71; 95% CI, 1.96-3.95; P < 0.001) and age (adjusted HR, 1.03; 95% CI, 1.02-1.03; P < 0.001) were independently associated with IBD, after adjusting for major comorbidities and conducting multivariate analyses. AD was not associated with IBD development. In conclusion, AD is not independently associated with IBD development.

A New Infrared Heat Treatment on Hot Forging 7075 Aluminum Alloy: Microstructure and Mechanical Properties.

When hot forging 7075 aluminum alloy, as a military material durable enough for most of its applications, it needs to be heat-treated to ensure the target material property achieves the application requirements. However, the material properties change because of heat throughout usage. In this study, a new approach was devised to heat treat the alloy to prevent material property changes. The study further clarified the effect of rapid heat treatment on the high-temperature resistance of a hot forging 7075 aluminum alloy. Infrared (IR) heat treatment was used as a rapid heating technique to effectively replace the conventional resistance heat (RH) treatment method. Our experimental result showed that IR heat treatment resulted in better age hardening at the initial aging stage, where its tensile strength and elongation appeared like that of a resistance heat treatment. More so, based on hardness and tensile test results, the IR-heated treatment process inhibited the phase transformation of precipitations at a higher temperature, improving high-temperature softening resistance and enhancing the thermal stability of the hot forging 7075 aluminum alloy.

Impact of interactive situated and simulated teaching program on novice nursing practitioners' clinical competence, confidence, and stress.

BACKGROUND: Novice nursing practitioners (NNPs) often struggle to make the transition to fully competent professionals. We sought to determine the impact of an interactive, situated learning workshop on a participant's clinical competence. OBJECTIVES: This work aimed to improve the clinical competence, promote the self-confidence, and reduce the number of work-related stressors of NNPs. METHODS: We randomly allocated 31 newly graduated NNPs into interactive situated and simulated teaching (ISST) and non-ISST groups, which were perceived as the homogeneity of the 2 groups based upon no significant difference at age, education level and work units. The ISST program comprised six follow-up interactive face-to-face support sessions over a three-month period following the standard orientation training course. We assessed the participants' competency, stress, and confidence levels in professional competence before and at the end of the study. RESULTS: At the end of the three-month study period, the ISST group demonstrated superior nursing competency (p=0.001), as well as reported lower stress levels (p=0.011), and increased confidence in professional competence (p=0.026) as compared with those in the control group. A multiple regression analysis revealed that clinical nursing competence was positively correlated with the use of ISST (p=0.02) and negatively correlated with stress (p=0.03). CONCLUSIONS: The ISST program for NNPs significantly improved their clinical competence. It may be helpful to ensure that new trainees have access to training programs that can facilitate their acclimation to their new working environments at the beginning of their careers.

Dual mechanisms regulate the nucleocytoplasmic localization of human DDX6.

DDX6 is a conserved DEAD-box protein (DBP) that plays central roles in cytoplasmic RNA regulation, including processing body (P-body) assembly, mRNA decapping, and translational repression. Beyond its cytoplasmic functions, DDX6 may also have nuclear functions because its orthologues are known to localize to nuclei in several biological contexts. However, it is unclear whether DDX6 is generally present in human cell nuclei, and the molecular mechanism underlying DDX6 subcellular distribution remains elusive. In this study, we showed that DDX6 is commonly present in the nuclei of human-derived cells. Our structural and molecular analyses deviate from the current model that the shuttling of DDX6 is directly mediated by the canonical nuclear localization signal (NLS) and nuclear export signal (NES), which are recognized and transported by Importin-α/ß and CRM1, respectively. Instead, we show that DDX6 can be transported by 4E-T in a piggyback manner. Furthermore, we provide evidence for a novel nuclear targeting mechanism in which DDX6 enters the newly formed nuclei by "hitch-hiking" on mitotic chromosomes with its C-terminal domain during M phase progression. Together, our results indicate that the nucleocytoplasmic localization of DDX6 is regulated by these dual mechanisms.

A comparative proteomic study of secretomes in kaempferitrin-treated CTX TNA2 astrocytic cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Kaempferitrin is extracted in significantly high quantities from the leaves of Cinnamomum osmophloeum (C.O) and Bauhinia forficata, and are used as an antidiabetic herbal remedy in China and Brazil. Commercial product using dry Cinnamomum osmophloeum leaves has been sold locally in Taiwan. Oral administration of kaempferitrin reduced blood sugar in diabetic rats. AIM OF THE STUDY: Though previously demonstrated to activate the classical insulin signaling pathways, a mechanism for kaempferitrin is still not fully understood. Also, studies on kaempferitrin on immune related cells have been inconclusive, and people consuming extract containing kaempferitrin often happen to be at high risk of diabetes and neurodegenerative diseases. Therefore, for kaempferitrin to be used every day, a comprehensive study is needed. MATERIALS AND METHODS: Astrocytic cell line was used as a model to test the differentially regulated secretomes, to test kaempferitrin effect on CNS glia, on pro-inflammatory cytokines, and to test how different the mechanism of kaempferitrin is from that of insulin. CTX TNA2 astrocytic cells were differentially treated with and without 10 µM kaempferitrin for 24 h, and the conditioned medium was collected. For the proteomic study, protein in conditioned medium was trypsin digested, and resulting peptides in kaempferitrin/non-treated sample pair were differentially dimethyl labeled. The labeled peptides were further fractionated by StageTip-based strong-exchange method before LC-MS/MS analyses. Levels of interesting proteins were verified using Western or Eliza. C.O. leaf crude extract treated samples were included for a comparison of effects of purified kaempferitrin vs. kaempferitrin containing crude extract. RESULTS AND CONCLUSIONS: Data were obtained via ProteomeXchange with identifier PXD002814. It was found that no pro-inflammatory cytokines or inhibitory ECM were elevated upon treatment of kaempferitrin or a crude extract of C.O. leaves. This suggests that prolonged use of kaempferitrin containing herbs may not increase pro-inflammatory reaction. LDL-R trafficking between the cell membrane and the extracellular niche was regulated by kaempferitrin toward reduced secretion. Our proteomic study also demonstrated that molecules related to plasma membrane recycling were regulated by kaempferitrin. Our discoveries provide evidence that link kaempferitrin regulation for LDL-R and membrane recycling to the blood lipid regulation by the C.O. leaves extract. However, these proteins were differently regulated when cells were treated with crude extract. This demonstrates that the molecular interactions within crude extract of herbs are complex and may not act similar to the compound purified from the crude extract.

BPR0L075, a novel synthetic indole compound with antimitotic activity in human cancer cells, exerts effective antitumoral activity in vivo.

BPR0L075 is a novel synthetic compound discovered through research to identify new microtubule inhibitors. BPR0L075 inhibits tubulin polymerization through binding to the colchicine-binding site of tubulin. Cytotoxic activity of BPR0L075 in a variety of human tumor cell lines has been ascertained, with IC(50) values in single-digit nanomolar ranges. As determined by flow cytometry, human cervical carcinoma KB cells are arrested in G(2)-M phases in a time-dependent manner before cell death occurs. Terminal deoxynucleotidyl transferase-mediated nick end labeling assay indicates that cell death proceeds through an apoptotic pathway. Additional studies indicate that the effect of BPR0L075 on cell cycle arrest is associated with an increase in cyclin B1 levels and a mobility shift of Cdc2 and Cdc25C. The changes in Cdc2 and Cdc25C coincide with the appearance of phosphoepitopes recognized by a marker of mitosis, MPM-2. Furthermore, phosphorylated forms of Bcl-2, perturbed mitochondrial membrane potential, and activation of the caspase-3 cascade may be involved in BPR0L075-induced apoptosis. Notably, several KB-derived multidrug-resistant cell lines overexpressing P-gp170/MDR and MRP are resistant to vincristine, paclitaxel, and colchicine but not to BPR0L075. Moreover, BPR0L075 shows potent activity against the growth of xenograft tumors of the gastric carcinoma MKN-45, human cervical carcinoma KB, and KB-derived P-gp170/MDR-overexpressing KB-VIN10 cells at i.v. doses of 50 mg/kg in nude mice. These findings indicate BPR0L075 is a promising anticancer compound with antimitotic activity that has potential for management of various malignancies, particularly for patients with drug resistance.

[Supercritical fluid extraction of paeonol from Liuwei Dihuang pill].

OBJECTIVE: To study the method of extraction of active ingredient from complex Chinese patent medicine. METHOD: Supercritical fluid extraction (SFE) has been used to extract paeonol from Liuwei Dihuang pill and HPLC was used to analyze the extracts. RESULT: The methanol modified supercritical CO2 (0.4 mL x min(-1)) can effectively extract paeonol from Liuwei Dihuang pill. CONCLUSION: SFE-HPLC method of off-line for analysis of extract was simple, quick and accurate.

Incidental Finding of Urinary Bladder Retention on the 99mTc-Labeled Red Blood Cells Subcutaneous Radionuclide Venography.

We present a case with swelling of the lower extremities, shortness of breath, and hyponatremia. (99m)Tc-labeled red blood cells subcutaneous radionuclide venography was performed to rule out deep vein thrombosis. Disturbed iliac venous flow and a photopenic lesion were noted in the lower abdomen on the planar imaging. SPECT/CT imaging revealed a hypodense lesion in the lower abdomen. Distended urinary bladder and retention were impressed. After approximately 4000 mL of urine was drained, symptoms were dramatically relieved, and improvement of hyponatremia was also observed.

Synthesis and structure-activity relationship of 2-aminobenzophenone derivatives as antimitotic agents.

A new type of inhibitor of tubulin polymerization was discovered on the basis of the combretastatin molecular skeleton. The lead compounds in this series, compounds 6 and 7, strongly inhibited tubulin polymerization in vitro and significantly arrested cells at the G(2)/M phase. Compounds 6 and 7 yielded 50- to 100-fold lower IC(50) values than did combretastatin A-4 against Colo 205, NUGC3, and HA22T human cancer cell lines as well as similar or greater growth inhibitory activities than did combretastain A-4 against DLD-1, HR, MCF-7, DU145, HONE-1, and MES-SA/DX5 human cancer cell lines. Structure-activity relationship information revealed that introduction of an amino group at the ortho position of the benzophenone ring plays an integral role for increased growth inhibition.

Concise synthesis and structure-activity relationships of combretastatin A-4 analogues, 1-aroylindoles and 3-aroylindoles, as novel classes of potent antitubulin agents.

The synthesis and study of the structure-activity relationships of two new classes of synthetic antitubulin compounds based on 1-aroylindole and 3-aroylindole skeletons are described. Lead compounds 3, 10, and 14 displayed potent cytotoxicities with IC50 = 0.9-26 nM against human NUGC3 stomach, MKN45 stomach, MESSA uterine, A549 lung, and MCF-7 breast carcinoma cell lines. The inhibition of proliferation correlated with in vitro polymerization inhibitory activities. Structure-activity relationships revealed that 6-methoxy substitution of 3-aroylindoles and 5-methoxy substitution of 1-aroylindoles contribute to a significant extent for maximal activity by mimicking the para substitution of the methoxy group to the carbonyl group in the case of aminobenzophenones. Addition of a methyl group at the C-2 position on the indole ring exerts an increased potency. The 3,4,5-trimethoxybenzoyl moiety was necessary for better activity but not essential and can be replaced by 3,5-dimethoxybenzoyl and 3,4,5-trimethoxybenzyl moieties. We conclude that 1- and 3-aroylindoles constitute an interesting new class of antitubulin agents with the potential to be clinically developed for cancer treatment.

Design, synthesis, and structure-activity relationship of pyridyl imidazolidinones: a novel class of potent and selective human enterovirus 71 inhibitors.

When skeletons of Win compounds were used as templates, computer-assisted drug design led to the identification of a novel series of imidazolidinone derivatives with significant antiviral activity against enterovirus 71 (EV 71), the infection of which had resulted in about 80 fatalities during the 1998 epidemic outbreak in Taiwan. In addition to inhibiting all the genotypes (A, B, and C) of EV 71 in the submicromolar to low micromolar range, compounds 1 and 8 were extensively evaluated against a variety of viruses, showing potent activity against coxsackievirus A9 (IC(50) = 0.47-0.55 microM) and coxsackievirus A24 (IC(50) = 0.47-0.55 microM) as well as moderate activity against enterovirus 68 (IC(50) = 2.13 microM) and echovirus 9 (IC(50) = 2.6 microM). Our SAR studies revealed that imidazolidinone analogues with an aryl substituent at the para position of the phenoxyl ring, such as compounds 20, 21, 27, 57, 58, and 61, in general exhibited the highest activity against EV 71. Among them, compound 20 and its corresponding hydrochloride salt 57, in terms of potency and selectivity index, appear to be the most promising candidates in this series for further development of anti-EV-71 agents. Preliminary results of the study on the mode of action by a time-course experiment suggest that test compounds 1 and 8 can effectively inhibit the virus replication at the early stages, referring to virus attachment or uncoating. This indicates that the surface protein may be the target for this type of compounds.