Small Molecular Inhibitors That Target ATM for Drug Discovery: Current Research and Potential Prospective.

The protein kinase ataxia telangiectasia mutated (ATM) is a constituent of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, exerting a pivotal influence on diverse cellular processes, notably the signaling of double-strand DNA breaks (DSB) and stress response. The dysregulation of ATM is implicated in the pathogenesis of cancer and other diseases such as neurodegeneration. Hence, ATM is deemed a promising candidate for potential therapeutic interventions across a spectrum of diseases. Presently, while ATM small molecule inhibitors are not commercially available, various selective inhibitors have progressed to the clinical research phase. Specifically, AZD1390, WSD0628, SYH2051, and ZN-B-2262 are under investigation in clinical studies pertaining to glioblastoma multiforme and advanced solid tumors, respectively. In this Perspective, we encapsulate the structure, biological functions, and disease relevance of ATM. Subsequently, we concentrate on the design concepts and structure-activity relationships (SAR) of ATM inhibitors, delineating potential avenues for the development of more efficacious ATM-targeted inhibitors.

Similar cities, but diverse carbon controls: Inspiration from the Yangtze River Delta megacity cluster in China.

Addressing global uneven urban development and the urgent need to reduce carbon emissions (CE), this study presents a new method for calculating urban socioeconomic development indexes using a variety of data sources. Using the Yangtze River Delta as an example, we categorize urban areas into core, transitional, and peripheral cities. With the help of extended Kaya-index decomposition models, we evaluate the effects of regional industrial growth, consumer markets, and spatial expansion on urban CE. The research explores differences in CE drivers across and within these city categories. Our findings reveal that in core cities, 31.5 % of CE is due to the industrial structure and 14.9 % due to population density. In transitional cities, CE increases by 60.22 % primarily due to industrial structure and consumer consumption. Peripheral cities, on the other hand, have a complex set of causes for CE, with per capita living, spatial expansion, population size, urbanization, and consumption limitation contributing to 91.97 %, 10.73 %, 14.2 %, 9.34 %, and 24.92 % of CE respectively. Varied factors influence CE intensity differences within each city group. Cleaner production technologies and potential carbon reductions in consumption and industry are identified as key strategies for compensating CE reduction. We propose the adoption of carbon function zoning in urban clusters to leverage the role of carbon function in each area. Territorial spatial planning should ensure a balanced layout of production, living, and ecological functions. Residents' consumption, being the key factor driving CE, must transition toward green, low-carbon consumption, reinforced by societal norms and responsibilities. This research provides valuable theoretical and practical insights into urban classification and CE reduction strategies.

Practical Guidance for the Management of Adverse Events in Patients with KRASG12C-Mutated Non-Small Cell Lung Cancer Receiving Adagrasib.

Adagrasib (MRTX849) is a KRASG12C inhibitor with favorable properties, including long half-life (23 h), dose-dependent pharmacokinetics, and central nervous system (CNS) penetration. As of September 1, 2022, a total of 853 patients with KRASG12C-mutated solid tumors, including patients with CNS metastases, had received adagrasib (monotherapy or in combination). Adagrasib-related treatment-related adverse events (TRAEs) are generally mild to moderate in severity, start early in treatment, resolve quickly with appropriate intervention, and result in a low rate of treatment discontinuation. Common TRAEs seen in clinical trials included gastrointestinal-related toxicities (diarrhea, nausea, and vomiting); hepatic toxicities (increased alanine aminotransferase/aspartate aminotransferase) and fatigue, which can be managed through dose modifications, dietary modifications, concomitant medications (such as anti-diarrheals and anti-emetics/anti-nauseants) and the monitoring of liver enzymes and electrolytes. To manage common TRAEs effectively, it is imperative that clinicians are informed, and patients are fully counseled on management recommendations at treatment initiation. In this review, we provide practical guidance on the management of adagrasib TRAEs and discuss some best practices for patient and caregiver counseling to facilitate optimal outcomes for patients. Safety and tolerability data from the phase II cohort of the KRYSTAL-1 study will be reviewed and presented with practical management recommendations based on our experience as clinical investigators.

Retinoic acid induced 16 deficiency exacerbates high-fat diet-induced steatohepatitis in mice.

Non-alcoholic fatty liver disease (NAFLD) associated with obesity may progress to non-alcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma (HCC). Retinoic acid induced 16 (RAI16) plays an important role in cell apoptosis and is also a potential marker for HCC. Here we aimed to test the effect of RAI16 deficiency on liver pathology in high-fat diet (HFD) fed mice. Wild type (WT) and RAI16 knockout (RAI16-/-) C57BL/6 mice were fed with HFD or chow for up to 12 months. With consumption of HFD diet, RAI16-/- mice on HFD developed much more excess fatty liver within 4 months than WT mice on HFD. The expressions of fatty acid synthesis associated molecules Ppar-γ, Srebp-1c and Fas were further increased in RAI16-/- mice compared with WT mice on HFD. Macrophage infiltration related molecules Mcp-1 and F4/80 and pro-inflammatory factor Lcn2 were significantly increased in RAI16-/- mice compared with WT mice on HFD. Conclusively, RAI16 deficiency exacerbated HFD-induced liver injury, associated with increased inflammation. These findings indicate that RAI16 plays an important role in HFD-induced liver pathology and might be considered as a target for treatment of NAFLD. SIGNIFICANCE: 1. RAI16-/- mice on HFD developed much more excess fatty liver. 2. RAI16-/- mice showed more macrophage infiltration and proinflammation.

Identification of retinoid acid induced 16 as a novel androgen receptor target in prostate cancer cells.

BACKGROUND: Retinoid acid induced 16 (RAI16) was reported to enhance tumorigenesis in hepatocellular carcinoma (HCC). The androgen receptor (AR) is a nuclear hormone receptor that functions as a critical oncogene in several cancer progressions. However, whether RAI16 is a candidate AR target gene that may involve in prostate cancer progression was unclear. MATERIALS & METHODS: RAI16 expression was detected in prostate cancer cells with or without the AR agonist R1881 treatment by quantitative RT-PCR and Western blot. Direct AR binding to the RAI16 promoter was tested using AR chromatin immunoprecipitation (ChIP) and luciferase assay. Cell viability and colony formation assays in response to R1881 were analyzed in cells with RAI16 knockdown by specific siRNA. RESULTS: The expression of RAI16 was high in LNCaP(AI), LNCaP(AD), C4-2 expressing AR, but low in Du145 and Pc-3 cells without AR expressing. In addition, the expression of RAI16 could be induced by 10 nM R1881 treatment LNCaP(AD) and C4-2 cells, but inhibited by AR specific siRNA treatment. Furthermore, AR binds directly to ARE3 (-2003~-1982bp) of RAI16 promoter region by ChIP and luciferase assay. RAI16 knockdown inhibited the enhancement of cell viability and colony formation of AR stimulation. CONCLUSIONS: We demonstrate for the first time that RAI16 is a direct target gene of AR. RAI16 may involved in cell growth of prostate cancer cells in response to AR signaling.

Retinoid acid induced 16 deficiency aggravates colitis and colitis-associated tumorigenesis in mice.

Inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC) is a serious health issue, but etiopathological factors remain unclear. Although some studies reported the roles of Retinoid acid induced 16 (RAI16) in the tumorigenesis of hepatocellular carcinoma and PKA signaling, the roles of RAI16 in IBD and CRC are undressed. RAI16-/- mice were generated and the roles of RAI16 were addressed in dextran sodium sulfate (DSS) or azoxymethane (AOM)-DSS induced IBD or CAC mouse models, respectively. At first, RAI16-/- mice were viable, fertile with no apparent defects. Then, it was found that RAI16-/- mice were more susceptibility to colitis induced by DSS than wild type (WT) littermates, which was evaluated by disease activity index and histological score. Furthermore, the expressions of tissues repair associated molecules Cox2, Ereg and MMP-10 were significantly decreased in RAI16-/- colon under DSS treatment. Gut barrier related genes including antimicrobial peptides Reg3b and Reg3g and intestinal mucus genes Muc4, Muc6 and Muc20 were reduced in RAI16-/- colon. These findings indicated that RAI16 may function to affect genes involved in intestinal barrier function and immunoprotective inflammation. Accordingly, RAI16-/- mice displayed significantly increased tumor burden compared with WT mice assessed in CAC model induced by AOM/DSS. Much more Ki67 + nuclei were observed in RAI16-/- tumors suggesting RAI16 to be critical in colonic cell proliferation during tumorigenesis. Conclusively, we demonstrate the roles of RAI16 in colonic inflammation and inflammation-associated tumorigenesis by using a novel RAI16-/- mouse model for the first time.

Health Care Utilization and Costs Associated with Nausea and Vomiting in Patients Receiving Oral Immediate-Release Opioids for Outpatient Acute Pain Management.

INTRODUCTION: Nausea and vomiting (NV) are common side effects of opioid use and limiting factors in pain management. This study sought to quantify the frequency of antiemetic prescribing and the impact of NV on health care resource utilization and costs in outpatients prescribed opioids for acute pain. The perspective was that of a commercial health plan. METHODS: Medical and pharmacy claims from IMS PharMetrics Plus were used to identify patients initiating opioid therapy with a prescription for an oxycodone-, hydrocodone- or codeine-containing immediate-release product for acute use (≤15-day supply) between October 1, 2013 and September 30, 2014. Patients with a medical claim for NV (International Classification of Diseases, Ninth Revision, Clinical Modification codes 787.0x), with or without an antiemetic prescription fill, were compared with patients with no NV claim or antiemetic prescription fill to assess differences in all-cause health care utilization and costs over 1 month. Propensity score matching (PSM) was used to adjust for between-group differences in baseline patient characteristics. RESULTS: The co-prescribing of opioids with antiemetic agents was 10.2%. After PSM (n = 45,790 per group), patients with NV claims had significantly more hospitalizations (11.5% vs 4.2%), emergency department visits (65.0% vs 12.1%), and physician office visits (85.2% vs 64.5%) compared with patients with no NV claims (all P < 0.0001). Mean total health care costs were higher among patients with a NV claim versus those without evidence of the side effect ($6290 vs $2309; P < 0.0001). Among patients with a recent hospitalization, patients with NV claims had higher rates of 30-day rehospitalization than those with no NV claims (24.4% vs 3.0%; P < 0.0001). CONCLUSIONS: Among outpatients prescribed opioids for management of acute pain, co-prescribing with antiemetics was low, and the economic burden associated with NV was high. Efforts to prevent NV in patients receiving opioid therapy may improve patient outcomes and provide cost savings to the health care system. FUNDING: Daiichi Sankyo, Inc.

Treatment Patterns Associated with ACR-Recommended Medications in the Management of Fibromyalgia in the United States.

BACKGROUND: Fibromyalgia (FM) affects up to 6% of U.S. adults, resulting in a significant burden on the health care system and poor quality of life for patients. Duloxetine, pregabalin, and milnacipran are approved for management of FM; however, consensus is lacking regarding optimal therapy. Patients with FM taking approved medications often do not experience meaningful symptom relief, and many experience intolerable adverse events. OBJECTIVE: To assess treatment patterns associated with available and commonly used medications for the management of FM using U.S. health insurance claims. METHODS: This retrospective analysis used the MarketScan claims database to identify adults with a first diagnosis of FM (ICD-9-CM code 729.1) between 2009 and 2011 with continuous health plan enrollment for 12 months pre- and post-index. Medications of interest were pregabalin, gabapentin, duloxetine, milnacipran, cyclobenzaprine, and tramadol. These are 6 of the 8 medications recommended by the American College of Rheumatology (ACR) for treating FM; the other 2 (amitriptyline and venlafaxine) were only included in some initial assessments. The Charlson Comorbidity Index (CCI) was used to assess overall comorbidity burden. Endpoints included proportion of patients treated within 1 year after first diagnosis; initial treatment pattern; adherence over the first-year follow-up period for the medications of interest; and discontinuation, switching, and combination therapy patterns among pain medications of interest at different time points. Proportion of days covered (PDC; defined as number of days in the period when the patient had drug supply divided by the number of days in the period) was used to define adherence, which was categorized as low (PDC < 50%), medium (PDC 50% to < 80%), or high (PDC ≥ 80%). The time to discontinuation (defined as the first drug supply gap ≥ 90 days) was estimated using Kaplan-Meier analysis. RESULTS: Overall, 240,144 patients met the inclusion criteria. Patients were predominantly women (68%), had preferred provider organization insurance coverage (68%), and had a CCI score < 1 at baseline (69%). Only 31% (n = 74,738) initiated a treatment with a prescription medication listed in the ACR guidelines, and many patients received less than the recommended dose. Most (n = 70,919) patients initially received monotherapy with one of the 8 prescription medications. Of those who started with ≥ 2 medications (n = 3,819), cyclobenzaprine plus tramadol was the most frequent combination. Adherence was suboptimal for all 6 medications of interest. Duloxetine had the highest mean PDC (59%); for all other agents, mean PDC was < 50%. With the exception of duloxetine, discontinuation rates at 6 months were > 50% for all agents. Alterations in therapy were common. Among patients who discontinued their initial treatment of duloxetine, pregabalin, or milnacipran, approximately one-third had switched treatments within 90 days after their first prescription. For those who maintained their initial treatment agent, approximately 50% of patients added a second pain medication within 1 year of treatment initiation. CONCLUSIONS: The evidence suggests that patients with FM often do not receive 1 of the prescription medications recommended by ACR guidelines, and those who do are commonly prescribed lower-than-recommended doses, potentially resulting in poor effectiveness and tolerability. Discontinuation, switching, and addition of new pain medications are common, which may indicate low levels of satisfaction with initial treatment. New therapies with improved effectiveness and better tolerability are urgently needed for patients with FM.

Suboptimal Treatment of Diabetic Peripheral Neuropathic Pain in the United States.

OBJECTIVE: Approximately one third of patients with diabetic peripheral neuropathy (DPN) also experience neuropathic pain, resulting in a significant health care burden, and reduced quality of life. Pregabalin, duloxetine, and tapentadol extended-release are approved for treating diabetic peripheral neuropathic pain (DPNP), but many other medications are commonly used "off-label" with various degrees of success. We examined US health insurance claims to determine the current DPNP treatment patterns. METHODS: This retrospective analysis used the MarketScan claims database to identify adults with continuous health plan enrollment for 12 months pre- and postindex who were initially diagnosed with DPN between 2006 and 2011 and were provided a prescription for a medication reported to be beneficial for treating DPNP (anticonvulsants, antidepressants, opioids, or topical agents). We evaluated the frequency and types of medication dispensed within 1 year after first diagnosis, treatment adherence, and patterns of treatment alteration. RESULTS: Overall, 12,074 patients met inclusion criteria, with 66.6% initiating an anticonvulsant (gabapentin 45.0%; pregabalin 21.6%), and 5.2% initiating duloxetine. Patients commonly received less than the recommended dose of prescribed medication, and adherence was suboptimal for all treatments. It is estimated that up to 50% of patients discontinued their initial treatment within 3 months of initiation. CONCLUSIONS: Newly diagnosed patients with DPNP are most commonly prescribed anticonvulsants. Many patients receive lower than recommended dosages, potentially resulting in poor outcomes. Initial treatments are frequently discontinued, indicating low levels of satisfaction and/or poor tolerability. New therapies with improved efficacy and better tolerability are urgently needed for DPNP.

Colesevelam in the treatment of hypercholesterolemia and hyperglycemia: a retrospective analysis from an ambulatory care medical network.

OBJECTIVE: To examine outcomes associated with colesevelam treatment among patients with hypercholesterolemia in real-world clinical practice. METHODS: This analysis was conducted as a retrospective, observational cohort study in an ambulatory-care medical network in Northern California. Patients with orders for colesevelam were identified in the electronic health record between January 2004 and December 2011. The date of the first order during the study period was designated the index date. Patients were evaluated for the following eligibility criteria: a diagnosis of hypercholesterolemia, ≥18 years of age at index date, baseline laboratory values ≤3 months before the index date, ≥12 months of treatment and follow-up, and no prior orders for colesevelam ≤12 months before the index date. Patients who were pregnant during the study period were excluded. Changes in LDL-C and percentage of patients at LDL-C goal were examined. Among patients with diabetes mellitus (DM), changes in glycated hemoglobin (HBA1C) and percentage of patients at HBA1C goal were also examined. RESULTS: Overall, 468 and 181 patients with hypercholesterolemia met the predefined inclusion criteria with treatment and follow-up through 12 and 24 months, respectively. LDL-C decreased significantly from baseline by a mean of 11.4 mg/dL and 15.7 mg/dL (P < 0.0001, for each) at 12 and 24 months, respectively, and the percentages of patients at LDL-C goal increased by 13.9% and 21.0%. Among patients with DM and a baseline HBA1C ≥8%, 113 and 39 had treatment and follow-up through 12 and 24 months, respectively. HBA1C decreased significantly by a mean of 0.72% (P = 0.0001) and 0.75% (P = 0.010) and 11.5% and 12.8% were at HBA1C goal at 12 and 24 months, respectively. This study is limited by its retrospective and observational study design. CONCLUSIONS: Colesevelam treatment in a real-world setting was associated with improvements in LDL-C and HBA1C through 24 months of follow-up.

Real-world utilization patterns and outcomes of colesevelam hcl in the ge electronic medical record.

BACKGROUND: In randomized controlled trials (RCTs), colesevelam HCI, added to other anti-diabetic therapy, reduced hemoglobin A1C by approximately 0.3% to 0.4% over 16- to 26-weeks compared with an increase of approximately 0.1% to 0.2% for placebo, for a placebo-adjusted treatment effect of approximately 0.5%. Evidence on real-world effectiveness is unknown. This retrospective cohort study examined A1C changes following colesevelam HCL initiation in patients with diabetes, regardless of concomitant anti-diabetic medication use. METHODS: 2000-2011 GE Centricity electronic medical records data were used to identify patients with type 2 diabetes mellitus (T2DM) aged 18 or older initiating colesevelam HCL. The sample was further restricted to uncontrolled patients with database activity ≥ 395 days before and after colesevelam HCL initiation, A1C > 7% during 90 days prior to starting colesevelam HCL, without prior use of bile acid sequestrants, and with at least one A1C result between 42 to 210 days after initiation. Three overlapping time intervals were created for A1C measurement, including 16-weeks, 26-weeks, and 52-weeks following therapy initiation. The last observed A1C lab measurement during each interval was used to define change from baseline. Mean change in A1C was examined using paired t-tests. Sensitivity analyses considered only patients who remained on colesevelam HCL through each respective measurement period, as well as the effect of concomitant diabetes medications. RESULTS: Of 1,709,393 patients in the GE database with T2DM, 1,747 met inclusion criteria. The cohort was 58% female, 38% age ≥ 65, and the majority was white. For the 16-week endpoint (N = 1,385), A1C dropped from a mean of 8.22% to 7.75% (mean change -0.47%; P < 0.0001). For the 26- and 52-week endpoints (N = 1,747), A1C dropped from a mean of 8.25% to 7.81% (mean change -0.44%; P < 0.0001) and 8.25% to 7.79% (mean change -0.46%; P < 0.0001), respectively. Sensitivity analyses showed that A1C reductions were of similar direction and magnitude for patients who remained on treatment, and for the subgroups of patients stratified by receipt of concomitant T2DM treatments. CONCLUSIONS: The 0.44% to 0.47% A1C reduction observed in this study was similar to the reduction observed in RCTs, supporting the real-world effectiveness of colesevelam HCL in reducing A1C.

Lower risk of major cardiovascular events associated with adherence to colesevelam HCI.

STUDY OBJECTIVE: To examine the relationship between adherence to colesevelam and the risk of major cardiovascular events (acute myocardial infarction [AMI] and stroke) among patients newly treated with colesevelam. DESIGN: Retrospective cohort study using administrative claims data. DATA SOURCE: MarketScan commercial and Medicare databases (2005-2011). PATIENTS: A total of 42,549 adults with hyperlipidemia and/or type 2 diabetes mellitus who newly started colesevelam between January 1, 2005, and September 30, 2011, and who had continuous enrollment in employer-sponsored commercial health insurance or Medicare supplemental benefit plans for at least 6 months before and 12 months after the date of colesevelam initiation. MEASUREMENTS AND MAIN RESULTS: Adherence was measured as the proportion of days covered (PDC) by prescription claims for colesevelam during the 1-year period after the drug initiation date. Patients were assigned to one of three adherence cohorts: adherent, PDC of 0.8 or more; partially adherent,PDC of 0.5-0.8; or nonadherent, PDC of less than 0.5. The primary outcome was time to the first hospitalization with a primary diagnosis for AMI or stroke during the follow-up period. Association of colesevelam adherence with the primary outcome was examined by multivariate Cox regression models, adjusting for demographics, comorbidity, and concomitant drugs. A sensitivity analysis between propensity score-matched cohorts was conducted to compare the outcome between adherent and nonadherent groups. Of the 42,549 patients included in the analysis, 7968 (18.7%) were adherent, 6197 (14.6%) were partially adherent, and 28,384 (66.7%) were nonadherent. Compared with nonadherent patients, adherent patients were older, more likely to be male and from the Northeast or North Central regions of the United States, and had more cardiovascular risk factors and concomitant drugs. Controlling for patient demographic and clinical characteristics, adherent patients were about 43% less likely to experience an AMI or stroke hospitalization during the follow-up period compared with nonadherent patients (hazard ratio 0.57, 95% confidence interval[CI] 0.44-0.73, p<0.0001). Results of the sensitivity analysis using propensity score matching techniques were consistent. CONCLUSION: Adherence to colesevelam was associated with lower risk of major cardiovascular events (AMI and stroke) among patients with hyperlipidemia and/or type 2 diabetes. Research to assess interventions to improve adherence to colesevelam and subsequently to evaluate the effects of these interventions on cardiovascular outcomes is warranted.

Comparative effectiveness analysis of amlodipine/renin-angiotensin system blocker combinations.

A comparative effectiveness analysis of antihypertensive therapy amlodipine (AML) and angiotensin receptor blocker (ARB) fixed- and loose-dose combinations (FDCs and LDCs) in achieving blood pressure (BP) reduction and Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) goal attainment was made using retrospective electronic medical record (EMR) data. Treatment goal rates ranged from 35.0% for LDC AML/losartan to 45.7% for FDC AML/olmesartan (OM). FDC AML/OM achieved significantly greater reductions in systolic BP than FDC AML/benazepril (BEN), FDC AML/valsartan (VAL), and LDC AML/ARBs, respectively, and significantly greater reductions in diastolic BP than FDC AML/VAL and LDC therapy, respectively. Compared with patients treated with AML/OM, patients prescribed AML/VAL and LDC AML/ARB were significantly less likely to attain JNC 7 BP goal. Among subpopulations, AML/OM yielded higher rates of goal attainment among both African Americans and obese/overweight patients relative to AML/VAL and combined LDCs. Switchers from monotherapy with AML, OM, or VAL to AML/OM were significantly more likely to attain JNC 7 goals than those switching to AML/VAL or AML/BEN.

Blood pressure outcomes in patients receiving angiotensin II receptor blockers in primary care: a comparative effectiveness analysis from electronic medical record data.

The authors examined the comparative effectiveness of 4 angiotensin receptor blockers (ARBs) in patients with hypertension using a large electronic medical record database. Analysis of covariance and logistic multivariate regression models were used to estimate the blood pressure (BP) outcomes of 73,012 patients during 13 months of treatment with olmesartan, losartan, valsartan, and irbesartan. Results were adjusted by baseline BP, starting dose, year, age, sex, race, body mass index, comorbid conditions, and concomitant medications of patients. All ARBs led to sustained reductions in BP, but with significant differences in the magnitude of BP reduction. Raw mean systolic BP/diastolic BP reductions with losartan, valsartan, irbesartan, and olmesartan were 9.3/4.9 mm Hg, 10.4/5.6 mm Hg, 10.1/5.3 mm Hg, and 12.4/6.8 mm Hg, respectively. Adjusting for all covariates, the overall BP reductions with olmesartan were 1.88/0.86 mm Hg, 1.21/0.52 mm Hg, and 0.89/0.51 mm Hg greater than for losartan, valsartan, and irbesartan, respectively, and mean differences were higher for monotherapy: 2.43/1.16 mm Hg; 2.18/0.93 mm Hg; 1.44/0.91 mm Hg, respectively (all P values <.0001). Adjusted odds ratios of the JNC 7 goal attainment for losartan, valsartan, and irbesartan compared with olmesartan were 0.76, 0.86, and 0.91 (P<.05). Differences were also found in subpopulations: African Americans, diabetics, and obese/overweight patients but not all of these reached statistical significance. A broad choice of ARBs may be required to get patients to treatment goals.

A titrate-to-goal study of switching patients uncontrolled on antihypertensive monotherapy to fixed-dose combinations of amlodipine and olmesartan medoxomil ± hydrochlorothiazide.

In the prospective, open-label, titrate-to-goal Blood Pressure Control in All Subgroups With Hypertension (BP-CRUSH) study, 999 patients with hypertension uncontrolled on monotherapy (mean age, 55.6 ± 11.4 years; baseline blood pressure [BP], 153.7 ± 9.2/91.9 ± 8.6 mm Hg) were switched to fixed-dose amlodipine/olmesartan medoxomil (AML/OM) 5/20 mg. Patients were uptitrated every 4 weeks to AML/OM 5/40 mg and 10/40 mg to achieve BP < 120/70 mm Hg. Patients were subsequently uptitrated every 4 weeks to AML/OM+hydrochlorothiazide (HCTZ) 10/40+12.5 mg and 10/40+25 mg to achieve BP <125/75 mm Hg. The primary end point, the cumulative percentage of patients achieving seated systolic BP < 140 mm Hg (< 130 mm Hg for patients with diabetes) by week 12, was 75.8%. The mean (± standard error) BP changes from baseline during the titration periods ranged from -14.2±0.4 mm Hg/-7.7 ± 0.3 mm Hg for AML/OM 5/20 mg to -25.1 ± 0.7 mm Hg/-13.7 ± 0.4 mm Hg for AML/OM+HCTZ 10/40+25 mg. By week 20, the cumulative BP threshold of <140/90 mm Hg was achieved by 90.3% of patients. An ambulatory BP monitoring substudy (n=243) showed that 24-hour efficacy was maintained. Treatment-emergent adverse events (TEAEs), mostly mild to moderate in severity, occurred in 529 patients (53.0%). Drug-related TEAEs occurred in 255 patients (25.5%). This well-tolerated, treat-to-goal algorithm enabled a large proportion of patients with uncontrolled hypertension on monotherapy to safely achieve BP control on single-pill AML/OM combination therapy or triple therapy with the addition of HCTZ. .

Management of hypertension in patients with diabetes using an amlodipine-, olmesartan medoxomil-, and hydrochlorothiazide-based titration regimen.

The safety and efficacy of an amlodipine/olmesartan medoxomil (OM)-based titration regimen was assessed in patients with type 2 diabetes mellitus and hypertension. After a 2- to 3-week placebo run-in period, 207 patients received amlodipine 5 mg and were uptitrated to amlodipine/OM 5/20, 5/40, and 10/40 mg and then amlodipine/OM 10/40 mg plus hydrochlorothiazide 12.5 and 25 mg in a step-wise manner at 3-week intervals if the seated blood pressure (BP) remained ≥120/70 mm Hg. The primary end point was the change from baseline in the mean 24-hour ambulatory systolic BP after 12 weeks of treatment. The baseline mean ± SD seated cuff systolic/diastolic BP was 158.8 ± 13.1/89.1 ± 10.1 mm Hg and the mean ± SD 24-hour ambulatory systolic/diastolic BP was 144.4 ± 11.7/81.6 ± 9.8 mm Hg. At week 12, the change from baseline in the mean ± SEM 24-hour ambulatory systolic/diastolic BP was -19.9 ± 0.8/-11.2 ± 0.5 mm Hg (p<0.0001 vs baseline), and 70% of patients had achieved a 24-hour ambulatory BP target of <130/80 mm Hg. At the end of 18 weeks of active treatment in patients uptitrated to amlodipine/OM 10/40 mg plus hydrochlorothiazide 25 mg, the change from baseline in the mean ± SEM seated BP was -28.0 ± 1.5/-13.7 ± 1.0 mm Hg (p<0.0001 vs baseline), with 62% of patients reaching the guideline-recommended seated BP goal of <130/80 mm Hg. Drug-related treatment-emergent adverse events occurred in 19.3% of patients. The most frequent events were peripheral edema (6%), dizziness (3%), and hypotension (2%). In conclusion, this amlodipine/OM-based titration regimen was well tolerated and effectively lowered BP throughout the 24-hour dosing interval in patients with hypertension and type 2 diabetes.

Comparison of the effects of omapatrilat and lisinopril on circulating neurohormones and cytokines in patients with chronic heart failure.

Angiotensin-converting enzyme (ACE) inhibitors exert their effects by modulating the neurohumoral milieu. Vasopeptidase inhibitors (VPI) are ACE and neutral endopeptidase inhibitors and may increase natriuretic peptides, bradykinin, and perhaps endothelin-1 in patients with congestive heart failure. Patients (n = 107) with ischemic or dilated cardiomyopathy, New York Heart Association functional class II to III, with left ventricular ejection fraction <40%, and on ACE inhibitor therapy were randomized to either the VPI omapatrilat 40 mg/day or the ACE inhibitor lisinopril 20 mg/day. Trough levels of neurohormones (24 hours after dosing) were assessed at baseline, and at 12 and 24 weeks of follow-up. C-terminal atrial natriuretic peptide (C-ANP) levels decreased with lisinopril (p = 0.035), but not with omapatrilat. In contrast, N-terminal ANP levels did not change, and brain natriuretic peptide (BNP) levels tended to decrease similarly in both groups. Endothelin-1 levels increased in both groups, the increase reaching statistical significance with omapatrilat (p = 0.008). Levels of the proinflammatory cytokine interleukin-6 tended to decrease, and the anti-inflammatory cytokine interleukin-10 increased in both groups, with statistical significance only for interleukin-10 with omapatrilat therapy. Neither agent changed catecholamines or angiotensin II. Thus, even at trough levels, omapatrilat potentiates C-ANP more than lisinopril. Potentially important effects of omapatrilat on endothelin-1 and anti-inflammatory cytokines were identified, providing potential explanations for differences in clinical outcome.

Vasopeptidase inhibition with omapatrilat in chronic heart failure: acute and long-term hemodynamic and neurohumoral effects.

OBJECTIVES: We investigated the acute and long-term hemodynamic and neurohumoral effects of the vasopeptidase inhibitor omapatrilat in human heart failure. BACKGROUND: Angiotensin-converting enzyme (ACE) inhibition constitutes a major advance in the treatment of chronic heart failure (CHF). Simultaneous inhibition of both neutral endopeptidase and ACE with omapatrilat may represent a new treatment strategy in CHF. METHODS: Three hundred and sixty-nine patients with symptomatic heart failure were randomized to double-blind treatment with omapatrilat (first 190 patients: 2.5 mg, 5 mg or 10 mg; last 179 patients: 2.5 mg, 20 mg or 40 mg once daily) for 12 weeks. RESULTS: Acutely, the 10 mg, 20 mg and 40 mg doses of omapatrilat produced greater reductions in pulmonary capillary wedge pressure (PCWP), systolic blood pressure (SBP) and systemic vascular resistance compared with 2.5 mg. Higher doses were associated with greater increases in vasodilator and natriuretic peptides, in addition to ACE inhibition. After 12 weeks, omapatrilat 20 mg and 40 mg showed greater falls from baseline in PCWP (40 mg: 0 h to 12 h average change -7.3 +/- 0.8 mm Hg) and SBP (40 mg: -11.7 +/- 1.7 mm Hg) than 2.5 mg (both p < 0.01 vs. 2.5 mg). The incidence of adverse experiences and patient withdrawal were similar in all groups. CONCLUSIONS: In CHF, the acute hemodynamic benefit seen with higher doses of omapatrilat was associated with increases in plasma vasodilator and natriuretic peptide levels in addition to ACE inhibition. After 12 weeks, the hemodynamic benefit was maintained. Omapatrilat may be a promising new agent in CHF.

Omapatrilat reduces pulse pressure and proximal aortic stiffness in patients with systolic hypertension: results of the conduit hemodynamics of omapatrilat international research study.

BACKGROUND: Increased pulse pressure, an indicator of conduit vessel stiffness, is a strong independent predictor of cardiovascular events in hypertensive cohorts, which suggests that reduction of conduit vessel stiffness may be desirable in hypertension. METHODS AND RESULTS: We assessed changes in pulse pressure and conduit vessel stiffness in a 12-week double-blind, randomized clinical trial that compared monotherapy with the ACE inhibitor enalapril 40 mg daily (n=87) versus the vasopeptidase (dual ACE and neutral endopeptidase) inhibitor omapatrilat 80 mg daily (n=80) in patients with systolic hypertension. Patients were withdrawn from antihypertensive medications 1 to 2 weeks before enrollment, and systolic pressure was confirmed to be > or =160 mm Hg. With the use of calibrated tonometry and pulsed Doppler, pulsatile hemodynamics were assessed before randomization and at 12 weeks. Characteristic impedance (Z(c)), a direct measure of the stiffness of the central aorta, was calculated from the ratio of changes in carotid pressure and aortic flow in early systole. Omapatrilat compared with enalapril produced greater reductions in peripheral (-8.2+/-12.2 versus -4.0+/-12.2 mm Hg, P<0.05) and central (-10.2+/-16.2 versus -3.2+/-16.9 mm Hg, P<0.01) pulse pressures and Z(c) (237+/-83 to 208+/-70 versus 225+/-87 to 231+/-94 dyne x s/cm(5), P<0.001); the latter remained significant (P<0.05) after adjusting for change in mean pressure. CONCLUSIONS: Greater reductions in pulse pressure and Z(c) in hypertensive subjects treated with omapatrilat compared with enalapril suggest that aortic stiffness is maintained by specific, partially reversible mechanisms and underscore a potential role for pharmacological modulation of natriuretic peptides in the treatment of hypertension.