Thematic Analysis of Alzheimer's Medication Management Discussion in a Non-Moderated Online Forum.

BACKGROUND: Managing medications for Alzheimer's disease and related dementias is challenging for caregivers. Information about caregivers' strategies to manage these challenges is needed to inform intervention development. OBJECTIVE: This study aimed to understand caregivers' medication management experiences by analyzing online community discussions. METHODS: Posts were extracted from the ALZConnected® Forum using keywords "medication" and "drug" via web scraping. The researchers applied thematic analysis. RESULTS: Four major themes emerged: (1) role transition of medication management responsibilities, (2) caregivers' uncertainty about medication purpose and values, (3) conflicts between the care recipients and caregivers, and (4) difficulty accessing and affording medications. CONCLUSIONS: The experiences shared on a non-moderated, unstructured online forum indicate that medication management is challenging and overwhelming for caregivers of people living with Alzheimer's disease and related dementias. Since this is a progressive disease with various stages and changing needs, caregivers' strategies vary and are often limited by available resources and support. Health care providers should offer training and support for caregivers to navigate the transfer of medication management responsibilities and changing care needs as the disease progresses.

Role of Insulin Resistance in Patients of Acne Vulgaris and Hirsutism in the Western Part of India- A Cross-Sectional Study.

Background: Despite being common and easy to treat conditions, acne and hirsutism may have a striking consequence on one's perception of self. Though understanding the pathogenesis of acne and hirsutism has undergone a major paradigm shift, one of them being insulin resistance (IR), extensive research is still underway. The purpose of the study is to establish causal relationship linking IR with acne vulgaris and hirsutism, as well as to assess severity of the two with increasing IR. Materials and Methods: A cross-sectional observational study was conducted in the dermatology department. Patient's detailed clinical history and necessary parameters like height, weight, body mass index (BMI), etc., were recorded in predefined proforma, noting signs and symptoms of underlying IR, along with acne severity calculated by global acne grading system (GAGS) and hirsutism severity by modified Ferriman Gallwey score (mFG), then analyzing using Pearson's correlation test to establish correlation between IR and acne with/without hirsutism and hirsutism alone. Results: A total of 349 patients included in our study were divided into three groups, (i) Acne-only (N = 308) group showed statistically significant correlation of IR with acne severity (P < 0.0001) and recurrence (P < 0.0001). (ii) In hirsutism-only (N = 24) group, homeostatic model assessment for insulin resistance (HOMA-IR) was strongly associated with modified Ferriman-Gallwey score and recurrence suggesting raised insulin resistance with increased severity of hirsutism (P < 0.0001) and recurrence (P < 0.007). (iii) In acne + hirsutism (N = 17) group, raised BMI was found to be positively associated with IR but not with severity of both conditions. Conclusion: IR has emerged as an important contributory, if not, causative event in pathogenesis of severe, resistant acne, and hirsutism. These conditions have great deal of impact on the psychological health of those affected necessitating different approach to manage such cases.

Examining the Delivery of a Tailored Chinese Mind-Body Exercise to Low-Income Community-Dwelling Older Latino Individuals for Healthy Aging: Feasibility and Acceptability Study.

BACKGROUND: Older Latino individuals are disproportionally affected by various chronic conditions including impairments in physical and cognitive functions, which are essential for healthy aging and independent living. OBJECTIVE: This study aimed to evaluate the feasibility and acceptability of FITxOlder, a 12-week mind-body exercise program, in community-dwelling low-income, predominantly older Latino individuals, and assess its preliminary effects on health parameters relevant to healthy aging and independent living. METHODS: This 12-week, single-arm, stage 1B feasibility study had a pre- and poststudy design. A total of 13 older adults (mean age 76.4, SD 7.9 years; 11/13, 85% Latino) of a congregate meal program in a senior center were enrolled. FITxOlder was a tailored Chinese mind-body exercise program using Five Animal Frolics led by a bilingual community health worker (CHW) participating twice a week at the senior center and facilitated by mobile health technology for practice at home, with incrementally increasing goals moving from once a week to at least 3 times a week. The feasibility and acceptability of the study were examined using both quantitative and qualitative data. Healthy aging-related outcomes (eg, physical and cognitive function) were assessed using paired 2-tailed t tests. Qualitative interview data were analyzed using thematic analysis. RESULTS: The attendance rate for the 24 exercise sessions was high (22.7/24, 95%), ranging from 93% (1.8/2) to 97% (1.9/2) over the 12 weeks. Participants were compliant with the incremental weekly exercise goals, with 69.2% (9/13) and 75.0% (9/12) meeting the home and program goals in the last 4 weeks, respectively. Approximately 83% (10/12) to 92% (11/12) of the participants provided favorable feedback on survey questions regarding the study and program implementation, such as program content and support, delivery by the CHW, enjoyment and appeal of the Five Animal Frolics, study burden and incentives, and safety concerns. The qualitative interview data revealed that FITxOlder was well accepted; participants reported enjoyment and health benefits and the desire to continue to practice and share it with others. The 5-time sit-to-stand test (mean change at posttest assessment=-1.62; P<.001; Cohen d=0.97) and 12-Item Short Form Health Survey physical component scores (mean change at post intervention=5.71; P=.01; Cohen d=0.88) exhibited changes with large effect sizes from baseline to 12 weeks; the other parameters showed small or medium effect sizes. CONCLUSIONS: The research findings indicated that the CHW-led and mobile health-facilitated Chinese qigong exercise program is feasible and acceptable among low-income Latino older adults. The trending health benefits of the 12-week FITxOlder program suggest it is promising to promote physical activity engagement in underserved older populations to improve health outcomes for healthy aging and independent living. Future research with larger samples and longer interventions is warranted to assess the health benefits and suitability of FITxOlder.

Full Code to Do-Not-Resuscitate: Culturally Adapted Palliative Care Consultations and Code Status Change Among Seriously Ill Hispanic Patients.

BACKGROUND: Palliative care and hospice services are disproportionately underutilized by ethnic minority patients. Addressing barriers to utilization of these services is critical to reducing disparities. The purpose of this study was to assess the impact of a culturally adapted palliative care consultation service for Hispanics on end-of-life decisions, specifically likelihood of changing from full code to do-not-resuscitate (DNR) status during index admission for serious illness. METHODS: A cross-sectional study design was applied to data extracted from electronic health records (EHR) of patients seen by a Geriatric Palliative Care service during inpatient stays between 2018 and 2019. The majority of referrals came from critical care sites. Culturally adapted palliative care consultations using the SPIKES tool featured a Spanish-speaking team member leading discussions, involvement of multiple and key family members, and a chaplain who is a Catholic Priest. RESULTS: The analytic sample included 351 patients who were, on average, 72 years old. 54.42% were female, 59.54% were Hispanic, and of Hispanic patients, 47.37% spoke primarily Spanish. Culturally adapted consults resulted in higher rates of conversion to DNR status in palliative cases of the target population. Both primary language and ethnicity were associated with likelihood of change from full code to DNR status, such that Spanish speakers and those of Hispanic ethnicity were more likely to switch to DNR than non-Hispanics and English-Speakers. CONCLUSION: This study illustrates how culturally adapted palliative care consultations can help reduce barriers and improve end-of-life decision-making, and can be applied with similar populations of seriously ill Hispanic patients.

Engagement with a diverse Stakeholder Advisory Council for research in dementia care.

BACKGROUND: The inclusion of stakeholders throughout the research process has been gaining recognition as an approach that can improve the quality and impact of research. Stakeholder engagement for dementia care research has been identified as a national priority, though evaluation of engagement strategies and their impact has been limited. In dementia care research, stakeholders can include individuals living with dementia, family care partners, and health and social care professionals in dementia care. A Stakeholder Advisory Council (SAC) was established to identify priorities for dementia care research that are most important to stakeholders. Strategies to build capacity for research and facilitate engagement among the SAC were used to identify the research priorities. This study describes the experiences of SAC members engaged in the research process. METHODS: To evaluate stakeholder engagement, semi-structured interviews were conducted with members of the SAC to understand their experiences and perspectives on the strategies used to facilitate engagement and build capacity for research. Interviews were recorded, transcribed, and thematically analyzed using a mixed inductive and deductive approach. Findings were presented to members of the SAC to determine whether they felt their perspectives and experiences were accurately represented. Final domains and themes presented here were approved by the SAC. RESULTS: Interviews (N = 11) were conducted with members of the SAC representing each stakeholder group; persons living with dementia (n = 2); family care partners (n = 4), and health and social care professionals in dementia care (n = 5). Ten themes were categorized into four overarching domains: accessibility, council infrastructure, values and environment, and benefits of involvement. CONCLUSIONS: Findings from this qualitative study are a resource for researchers seeking to collaborate with diverse stakeholder groups to represent their perspectives in research, including individuals living with dementia. The domains and themes identified here support the inclusion of diverse stakeholders in the research process, centering engagement and capacity building strategies around individuals living with dementia.

Involving stakeholders in research about dementia care is recognized as an important approach to develop findings that are relevant to individuals living with dementia, family care partners, and health and social professionals in dementia care. Still, this approach is not often used and there is a need for more information about how researchers can engage stakeholders in the research process and the impact of engagement from the perspectives of stakeholders. In this paper, we describe how a mixed group of stakeholders was engaged for a project to identify priorities for dementia care research and their perspectives of the experience.A Stakeholder Advisory Council (SAC) worked together to develop their skills in research and connected with their communities to determine what is most important to be studied in the field of dementia care research. To understand the perspectives of the stakeholders involved in this project, we conducted individual interviews with members of the SAC.This study will help researchers understand how they can collaborate with stakeholders in dementia care and the benefits of including individuals living with dementia, family care partners, and professional stakeholders in the research process.

Engaging multi-stakeholder perspectives to identify dementia care research priorities.

OBJECTIVES: The purpose of this study was to partner with stakeholders to identify gaps in care for persons living with dementia and their family caregivers and from this list, identify priorities for dementia care research. METHODS: Using a community-engaged research approach, a Stakeholder Advisory Council (SAC) consisting of diverse membership including persons living with dementia and family caregivers was convened. Through our work with the SAC, along with input from the wider network through a symposium, webinars, and an online learning community, gaps in dementia care and a list of topics for dementia care research was generated. This list was reduced to 46 topics for dementia care research and sent to stakeholders (persons living with dementia, family caregivers, and health/social care professionals in dementia care) to be prioritized by rating each of the 46 topics as "Not so important," "Important," or "Very important." Priorities for dementia care were summarized by frequencies and proportions. RESULTS: A total of 186 participants completed the survey from August through October 2020, including 23 (12.4%) persons living with dementia, 101 (54.3%) family caregivers, and 62 (33.3%) health/social care professionals. Consistent across stakeholder groups was the focus on research on how best to support families following a diagnosis of dementia. Among persons living with dementia, research focused on support for continuing to live in their own homes was ranked as the highest priority, rated by 91.3% as "Very Important". High priority research areas for family caregivers included interventions to slow cognitive decline (76.3%) as well as non-pharmacological approaches to manage behavioral symptoms (74.7%). The highest priority research topics for health/social care professionals were focused on the diagnosis including benefits of an early diagnosis (71.4%), how best to deliver the diagnosis (70.9%), and supports needed following a diagnosis (78.6%). CONCLUSIONS: This project draws on the strengths of its multi-stakeholder perspective to support patient-centered outcomes research. Findings are intended to inform those who conduct research and those who fund research about which research topics stakeholders believe are most important and thus have greatest potential to improve the quality of life among people living with dementia and their families.

Higher levels of physical activity buffered the negative effect of pain severity on physical frailty in older Latinx adults.

This cross-sectional study examined whether and to what extent physical activity (PA) mediated the effect of chronic pain on physical frailty in a sample of predominantly older Latinx adults. Study participants were 118 community-dwelling older adults in southwest United States. Physical frailty was measured by a summary score of physical function tests. Pain severity and pain interference were measured by the Brief Pain Inventory. PA levels were defined as meeting the PA recommendation by 7-day accelerometry. Pain outcomes and PA were associated with physical frailty, respectively. Hierarchical regression analysis revealed that PA mediated the relationship between pain severity and physical frailty. However, no mediation effect of PA was found in the relationship between pain interference and physical frailty scores. Higher levels of PA buffered the negative effect of pain severity on physical frailty. Future studies should pay attention to PA promotion to prevent the negative consequences of frailty in older minority adults.

The relationship between perceived support and depression in spousal care partners: a dyadic approach.

OBJECTIVES: Caregiving within a spousal partnership marks a novel relationship stage for couples. Caregiving introduces new stressors and affects couples' ability to cope, and potentially alters perceptions of emotional support. Prior research on older married couples illustrates how perceived support not only affects an individual's mental health, but also that of their partner. To date, the dyadic relationship between emotional support and mental health is largely unexamined among caregiving partners, where support expectations may differ. METHOD: Actor partner interdependence models using linear mixed modeling were applied to data from spouses where one partner received caregiving within the 2014 and 2016 waves of the Health and Retirement Study. We examined the cross-sectional and lagged associations between perceived emotional support and strain from a spouse on actor and partner depression scores, as well as whether one was the caregiver or the care recipient moderated associations. RESULTS: More positive perceptions of support were associated with lower depression scores for oneself (b= -0.55, p < 0.001) and one's partner (b= -0.24, p < 0.001). Actor effects-how one's own perceptions of support associate with one's own depressive symptomology-were stronger for care recipients than for caregivers (b= -0.83, p < 0.001 v. b= -0.26, p < 0.05). Higher perceptions of strain were also associated with higher depression scores for oneself (b = 0.57, p < 0.001) and one's partner (b = 0.39, p < 0.001), associations that remained even in lagged models. CONCLUSIONS: The observation of both actor and partner effects in this study suggests opportunities to improve care recipient outcomes through intervention with caregivers or both members of the care dyad.

The effects of yoga on physical functioning and health related quality of life in older adults: a systematic review and meta-analysis.

OBJECTIVE: The goal was to review systematically the comparative effectiveness of yoga, compared with other exercise interventions, for older adults as shown on measures of health and physical functioning. DESIGN: This was a systematic review with both narrative synthesis and meta-analysis. DATA SOURCES: Searches were conducted in MEDLINE®/PUBMED, PSYCINFO, CINAHL, Web of Science, and SCOPUS; bibliographies of selected articles; and one systematic review on the effects of yoga on cardiovascular disease. METHODS: Original studies from 1950 to November 2010 were sought, evaluating the effects of yoga on older adults. The search was restricted to randomized controlled trials of yoga in subjects ≥age 60, and published in English. Data were extracted and evaluated regarding setting, population size and characteristics, intervention type and duration, comparison group, outcome assessment, data analysis, follow-up, key results, and the quality of each study according to specific predetermined criteria. RESULTS: The search yielded 18 eligible studies (N=649). The studies reported on older adults across a range of settings, intervention intensity, and outcome measures. The majority of the studies had<35 participants (range 9-77). Quantitative and qualitative synthesis of the studies suggested that the benefits of yoga may exceed those of conventional exercise interventions for self-rated health status, aerobic fitness, and strength. However, the effect sizes were modest, and the evidence was mixed for yoga's effect on depression, sleep, and bone-mineral density. Studies did not find an effect on cognition. CONCLUSIONS: Small studies with mixed methodological quality suggested that yoga may be superior to conventional physical-activity interventions in elderly people. The precision of the estimates remains low. Larger studies are necessary to define better the intersection of populations, settings, and interventions in which yoga is most beneficial.

Cultural Considerations: Pharmacological and Nonpharmacological Means for Improving Blood Pressure Control among Hispanic Patients.

Cardiovascular disease is a leading cause of morbidity and mortality in the United States, and its prevention and treatment remain a priority for the medical community. Ethnic variations account for some differences in the prevalence of hypertension and blood pressure (BP) control rates among Hispanics, indicating the need for culturally appropriate management models. Aggressive treatment strategies are key to achieving optimal BP control in high-risk Hispanic patients. Hypertension in this ethnic group continues to be a major health concern. Of note, when provided access to comprehensive care, Hispanics demonstrate similar response rates to treatment as the majority of non-Hispanic whites. This highlights the importance of effective, culturally responsive hypertension management among high-risk Hispanic patients for achieving observable, positive health outcomes.

Transitional care of the long-term care patient.

This article reviews the literature on transitional care to and from the LTC environment, highlighting strategies to improve the quality of care transitions. Several factors are vital in the improvement of systems of care dealing with transitions. Key factors include communication with and among health care providers, effective medication reconciliation, advanced discharge planning, and timely use of palliative care.

The Chronic Care Model and Exercise Discussions during Primary Care Diabetes Encounters.

BACKGROUND: discussing self-care activities like exercise is challenging with the many competing demands during primary care encounters. Our objective was to study the relationship between the Chronic Care Model (CCM) score in the clinic and time spent by the physicians discussing exercise during encounters with diabetic patients. METHODS: consecutive patients with diabetes across 20 primary care clinics in South Texas were included. Time spent discussing exercise was determined using the Davis Observation Code on audio recordings of the visits. Clinicians completed the Assessment of Chronic Illness Care survey, a validated measure of the extent to which care delivered is consistent with the CCM. Data were analyzed using hierarchical linear models. RESULTS: a total of 162 transcribed recordings were analyzed. Age, the number of problems addressed, stage of change (SOC), and overall length of the visit were associated with time spent discussing exercise. There was a significant relationship between clinic CCM score and time spent by physicians advising about exercise, independent of SOC for exercise (P < .01). Also, a discussion about exercise was more likely to occur with patients who were in the contemplation SOC for exercise. CONCLUSIONS: discussions of exercise may be 18 to 33 seconds longer in clinics with full implementation of the CCM compared with those with basic implementation. Facilitating more complete CCM implementation in clinics with a basic level of CCM that serve a population of patients who are sedentary may realize the most benefit.

Picoplatin overcomes resistance to cell toxicity in small-cell lung cancer cells previously treated with cisplatin and carboplatin.

PURPOSE: Picoplatin is a new generation platinum designed to overcome platinum resistance. The goal of this study was to assess picoplatin anti-tumor activity and measure various cellular parameters in small-cell lung cancer (SCLC) cells resistant to cell killing by cisplatin and carboplatin. METHODS: We developed several platinum-resistant SCLC cell lines to evaluate picoplatin activity and drug resistance mechanisms in vitro. Drug cytotoxicity was measured by MTS assay. Total cellular platinum accumulation was measured by inductively coupled plasma mass spectrometry (ICP-MS). Whole genome gene expression profiling was carried out by microarray analysis. RESULTS: Picoplatin retained significant cytotoxic activity in platinum-resistant SCLC lines compared to cisplatin and carboplatin. Cellular picoplatin accumulation in platinum-resistant and parental cells was high relative to levels of cellular platinum found in the same cell lines after cisplatin or carboplatin treatment. Gene expression analyses revealed substantial differences in gene expression and highlighted specific annotation clusters in carboplatin-resistant cells. In addition, a similar gene expression pattern was observed in picoplatin-treated carboplatin-resistant and parental cells. CONCLUSIONS: Our study demonstrates that picoplatin can overcome carboplatin and cisplatin resistance. The results suggest decreased platinum accumulation as a potential mechanism of platinum resistance in SCLC cells, provide candidate markers (e.g. several genes in the Hox, glutathione biosynthetic process, and MAGE families) that may serve as signatures for platinum resistance, support distinct effects of picoplatin on SCLC cells compared to other platinums, and provide a rationale to develop picoplatin for the treatment of recurrent SCLC following initial therapy with cisplatin or carboplatin.

PND-1186 FAK inhibitor selectively promotes tumor cell apoptosis in three-dimensional environments.

Tumor cells can grow in an anchorage-independent manner. This is mediated in part through survival signals that bypass normal growth restraints controlled by integrin cell surface receptors. Focal adhesion kinase (FAK) is a cytoplasmic protein-tyrosine kinase that associates with integrins and modulates various cellular processes including growth, survival, and migration. As increased FAK expression and tyrosine phosphorylation are associated with tumor progression, inhibitors of FAK are being tested for anti-tumor effects. Here, we analyze PND-1186, a substituted pyridine reversible inhibitor of FAK activity with a 50% inhibitory concentration (IC50) of 1.5 nM in vitro. PND-1186 has an IC50 of ~100 nM in breast carcinoma cells as determined by anti-phospho-specific immunoblotting to FAK Tyr-397. PND-1186 did not alter c­Src or p130Cas tyrosine phosphorylation in adherent cells, yet functioned to restrain cell movement. Notably, 1.0 µM PND-1186 (>5-fold above IC50) had limited effects on cell proliferation. However, under non-adherent conditions as spheroids and as colonies in soft agar, 0.1 µM PND-1186 blocked FAK and p130Cas tyrosine phosphorylation, promoted caspase-3 activation, and triggered cell apoptosis. PND-1186 inhibited 4T1 breast carcinoma subcutaneous tumor growth correlated with elevated tumor cell apoptosis and caspase 3 activation. Addition of PND-1186 to the drinking water of mice was well tolerated and inhibited ascites- and peritoneal membrane-associated ovarian carcinoma tumor growth associated with the inhibition of FAK Tyr-397 phosphorylation. Our results with low-level PND-1186 treatment support the conclusion that FAK activity selectively promotes tumor cell survival in three-dimensional environments.

Oral delivery of PND-1186 FAK inhibitor decreases tumor growth and spontaneous breast to lung metastasis in pre-clinical models.

Tumor metastasis is a leading cause of cancer-related death. Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase recruited to integrin-mediated matrix attachment sites where FAK activity is implicated in the control of cell survival, migration, and invasion. Although genetic studies support the importance of FAK activity in promoting tumor progression, it remains unclear whether pharmacological FAK inhibition prevents tumor metastasis. Here, we show that the FAK inhibitor PND-1186 blocks FAK Tyr-397 phosphorylation in vivo and exhibits anti-tumor efficacy in orthotopic breast carcinoma mouse tumor models. PND-1186 (100 mg/kg intraperitoneal, i.p.) showed promising pharmacokinetics (PK) and inhibited tumor FAK Tyr-397 phosphorylation for 12 hours. Oral administration of 150 mg/kg PND-1186 gave a more sustained PK profile verses i.p., and when given twice daily, PND-1186 significantly inhibited sygeneic murine 4T1 orthotopic breast carcinoma tumor growth and spontaneous metastasis to lungs. Moreover, low-level 0.5 mg/ml PND-1186 ad libitum administration in drinking water prevented oncogenic KRAS- and BRAF-stimulated MDA-MB-231 breast carcinoma tumor growth and metastasis with inhibition of tumoral FAK and p130Cas phosphorylation. Although PND-1186 was not cytotoxic to cells in adherent culture, tumors from animals receiving PND-1186 exhibited increased TUNEL staining, decreased leukocyte infiltrate and reduced tumor-associated splenomegaly. In vitro, PND-1186 reduced tumor necrosis factor-a triggered interleukin-6 cytokine expression, indicating that FAK inhibition may impact tumor progression via effects on both tumor and stromal cells. As oral administration of PND-1186 also decreased experimental tumor metastasis, PND-1186 may therefore be useful clinically to curb breast tumor progression.

Discovery of 5-substituted 2-amino-4-chloro-8-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7,8-dihydropteridin-6(5H)-ones as potent and selective Hsp90 inhibitors.

A new series of compounds, 5-substituted 2-amino-4-chloro-8-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7,8-dihydropteridin-6(5H)-ones, have been designed and identified as potent and selective inhibitors of Hsp90. These compounds demonstrated nanomolar potency toward both Hsp90-regulated Her2 degradation and the growth of a panel of human tumor cell lines in cell-based assays. High selectivity of these compounds toward Hsp90 was evident given that they did not inhibit a panel of 34 kinases at 10microM. The structure-activity relationship (SAR) of this series is reported here.

Potent and selective inhibitors of the Met [hepatocyte growth factor/scatter factor (HGF/SF) receptor] tyrosine kinase block HGF/SF-induced tumor cell growth and invasion.

The hepatocyte growth factor/scatter factor (HGF/SF) receptor, Met, mediates various cellular responses on activation with its ligand, including proliferation, survival, motility, invasion, and tubular morphogenesis. Met expression is frequently up-regulated in sarcomas and carcinomas. Experimental evidence suggests that Met activation correlates with poor clinical outcome and the likelihood of metastasis. Therefore, inhibitors of Met tyrosine kinase may be useful for the treatment of a wide variety of cancers that have spread from the primary site. We have discovered potent and selective pyrrole-indolinone Met kinase inhibitors and characterized them for their ability to inhibit HGF/SF-induced cellular responses in vitro. These compounds inhibit HGF/SF-induced receptor phosphorylation in a dose-dependent manner. They also inhibit the HGF/SF-induced motility and invasion of epithelial and carcinoma cells. Therefore, these compounds represent a class of prototype small molecules that selectively inhibit the Met kinase and could lead to identification of compounds with potential therapeutic utility in treatment of cancers.

A selective and oral small molecule inhibitor of vascular epithelial growth factor receptor (VEGFR)-2 and VEGFR-1 inhibits neovascularization and vascular permeability.

Vascular endothelial growth factor (VEGF) is a key driver of the neovascularization and vascular permeability that leads to the loss of visual acuity in diabetic retinopathy and neovascular age-related macular degeneration. Our aim was to identify an orally active, selective small molecule kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-2 with activity against both VEGF-induced angiogenesis and vascular permeability. We used a biochemical assay to identify 3-[5-methyl-2- (2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrol-3-yl]-proprionic acid (SU10944), a pyrrole indolinone, which is a potent ATP-competitive inhibitor of VEGFR-2 (Ki of 21 +/- 5 nM). In cellular assays, SU10944 inhibited VEGF-induced receptor autophosphorylation (IC50 of 227 +/- 80 nM) as well as downstream signaling (IC50 of 102 +/- 27 nM). In biochemical assays, SU10944 exhibits potent inhibitory activity against VEGFR-1; weak activity against other related subgroup members, including stem cell factor receptor (SCFR), platelet-derived growth factor receptor beta (PDGFRbeta), and fibroblast growth factor receptor-1 (FGFR-1); and no detectable activity against other protein tyrosine kinases such as epidermal growth factor receptor (EGFR), Src, and hepatocyte growth factor receptor. In cellular assays, the selectivity for SU10944 to inhibit VEGFR is maintained compared with other tyrosine kinases (IC50 for SCFR of 1.6 +/- 0.3 microM, for PDGFRbeta of 30.6 +/- 13.3 microM, for FGFR-1 of >50 microM, and for EGFR of >50 microM). Upon oral administration, SU10944 gave a clear dose response in the corneal micropocket model with an ED50 value for inhibition of neovascularization of approximately 30 mg/kg and a maximum inhibition of 95% at 300 mg/kg. Similarly, upon oral administration in the Miles assay, SU10944 potently inhibited VEGF-induced vascular permeability. Our data indicate that small molecule inhibitors of VEGFR signaling have the potential to ameliorate VEGF-induced neovascularization as well as vascular permeability.