Neonicotinoid Residues in Fruits and Vegetables: An Integrated Dietary Exposure Assessment Approach.

Neonicotinoids have become the most widely used insecticides in the world since introduced in the mid 1990s, yet the extent of human exposure and health impacts is not fully understood. In this study, the residues were analyzed of seven neonicotinoids in fruit and vegetable samples collected from two cross-sectional studies: the U.S. Congressional Cafeteria study (USCC) and the Hangzhou China (HZC) study. We then employed a relative potency factor method to integrate all neonicotinoids in each food sample using the respective reference dose values as the basis for summation. The findings were compared with data published by the U.S. Department of Agriculture Pesticide Data Program (USDA/PDP). Imidacloprid and thiamethoxam were the most commonly detected neonicotinoids in fruits and vegetables with 66 and 51% detection in the HZC study and 52 and 53% detection in the USCC study, respectively. The overall frequency of detection for neonicotinoids in the USDA/PDP samples was much lower than those reported here for the USCC or HZC studies, with imidacloprid being the most frequently detected neonicotinoid at 7.3%. The high frequencies of neonicotinoid detection in fruits and vegetables in the USCC and HZC studies give us a snapshot of the ubiquity of neonicotinoid use in global agriculture and make it clear that neonicotinoids have become part of the dietary staple, with possible health implications for individuals.

Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations.

Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.

Design of potent and selective inhibitors to overcome clinical anaplastic lymphoma kinase mutations resistant to crizotinib.

Crizotinib (1), an anaplastic lymphoma kinase (ALK) receptor tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration in 2011, is efficacious in ALK and ROS positive patients. Under pressure of crizotinib treatment, point mutations arise in the kinase domain of ALK, resulting in resistance and progressive disease. The successful application of both structure-based and lipophilic-efficiency-focused drug design resulted in aminopyridine 8e, which was potent across a broad panel of engineered ALK mutant cell lines and showed suitable preclinical pharmacokinetics and robust tumor growth inhibition in a crizotinib-resistant cell line (H3122-L1196M).

Screening for multiple weight loss and related drugs in dietary supplement materials by flow injection tandem mass spectrometry and their confirmation by liquid chromatography tandem mass spectrometry.

A new method has been developed using flow injection tandem mass spectrometry to semi-quantitatively screen for weight loss drugs, including sibutramine, N-desmethylsibutramine, N-didesmethylsibutramine, and phenolphthalein in dietary supplements. Positive identification of these drugs in samples was further confirmed and quantified by liquid chromatography tandem mass spectrometry. The degradation products of sibutramine were observed and identified by LC-MS/MS which include N-desmethylsibutramine, N-didesmethylsibutramine, N-formyldesmethylsibutramine, and N-formyldidesmethylsibutramine.

Structural modifications of a 3-methoxy-2-aminopyridine compound to reduce potential for mutagenicity and time-dependent drug-drug interaction.

(S)-1-((4-(3-(6-Amino-5-methoxypyridin-3-yl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-ol, 1, was recently identified as a potent inhibitor of the oncogenic kinase bRAF. Compounds containing 3-methoxy-2-aminopyridine, as in 1, comprised a promising lead series because of their high ligand efficiency and excellent ADME profile. However, following metabolic oxidation, compounds in this series also demonstrated two significant safety risks: mutagenic potential and time-dependent drug-drug interaction (TDI). Metabolite identification studies revealed formation of a reactive metabolite. We hypothesized that minimizing or blocking the formation of such a metabolite would mitigate the safety liabilities. Our investigation demonstrated that structural modifications which either reduced the electron density of the 3-methoxy-2-aminopyridine ring or blocked the reactive site following metabolic oxidation were successful in reducing TDI and AMES mutagenicity.

Epithelial tissue hyperplasia induced by the RAF inhibitor PF-04880594 is attenuated by a clinically well-tolerated dose of the MEK inhibitor PD-0325901.

Clinical trials of selective RAF inhibitors in patients with melanoma tumors harboring activated BRAFV600E have produced very promising results, and a RAF inhibitor has been approved for treatment of advanced melanoma. However, about a third of patients developed resectable skin tumors during the course of trials. This is likely related to observations that RAF inhibitors activate extracellular signal-regulated kinase (ERK) signaling, stimulate proliferation, and induce epithelial hyperplasia in preclinical models. Because these findings raise safety concerns about RAF inhibitor development, we further investigated the underlying mechanisms. We showed that the RAF inhibitor PF-04880594 induces ERK phosphorylation and RAF dimerization in those epithelial tissues that undergo hyperplasia. Hyperplasia and ERK hyperphosphorylation are prevented by treatment with the mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor PD-0325901 at exposures that extrapolate to clinically well-tolerated doses. To facilitate mechanistic and toxicologic studies, we developed a three-dimensional cell culture model of epithelial layering that recapitulated the RAF inhibitor-induced hyperplasia and reversal by MEK inhibitor in vitro. We also showed that PF-04880594 stimulates production of the inflammatory cytokine interleukin 8 in HL-60 cells, suggesting a possible mechanism for the skin flushing observed in dogs. The complete inhibition of hyperplasia by MEK inhibitor in epithelial tissues does not seem to reduce RAF inhibitor efficacy and, in fact, allows doubling of the PF-04880594 dose without toxicity usually associated with such doses. These findings indicated that combination treatment with MEK inhibitors might greatly increase the safety and therapeutic index of RAF inhibitors for the treatment of melanoma and other cancers.

2-Chloro-4-(1H-pyrazol-1-yl)-5-(trifluoro-meth-yl)pyrimidine.

The reaction of 2,4-dichloro-5-(trifluoro-meth-yl)pyrimidine with 1H-pyrazole gave two structural isomers in a 1:1 ratio that were separable by chromatography. The title compound, C(8)H(4)ClF(3)N(4), was the first product to elute and was characterized in the present study to confirm that substitution by the pyrazolyl group had occurred at position 4. The mol-ecule (with the exception of the F atoms) is essentially planar, with a mean deviation of 0.034 Šfrom the least-squares plane through all non-H and non-F atoms. The bond angles in the pyrimidine ring show a pronounced alternating pattern with three angles, including those at the two N atoms being narrower, and the remaining three wider than 120°.

Best practice implementation: lessons learned from 20 partnerships.

BACKGROUND: Partnerships can facilitate effective implementation of best practices, but literature describing effective and ineffective strategies to address barriers to implementation in partnerships is lacking. METHODS: Principal investigators (PIs) were surveyed to identify barriers to best practice implementation, rank their significance, and articulate the success and failure of solutions attempted. RESULTS: The top four categories of barriers to implementation were partnership challenges, practitioner/local organization variables, time frame challenges, and financial concerns. Ninety-eight effective and 38 ineffective solutions used to overcome these barriers were identified. The most common categories of successful solutions were flexibility of interventions to align with unique local characteristics, schedules, and budgets (36.7% of listed successful solutions); communication strategies that emphasize frequent bidirectional information exchange in person (26.5%); and thoughtful use of personnel emphasizing sites' senior leadership and centralized quality and analytic content expertise (16.3%). DISCUSSION: Despite substantial partnership diversity, consistent themes related to barriers to implementation and solutions to these barriers emerged. The successful and unsuccessful solutions provided should be proactively assessed to enhance the likelihood of future partnership success.

Effectiveness and medical costs of divalproex versus lithium in the treatment of bipolar disorder: results of a naturalistic clinical trial.

OBJECTIVE: The clinical, quality of life (QOL), and medical cost outcomes of treatment with divalproex were compared with lithium in patients with bipolar I disorder over 1 year. METHODS: In a pragmatic, randomized clinical trial, 201 adults hospitalized with bipolar I manic or mixed episodes were randomized to divalproex or lithium, in addition to usual psychiatric care, and followed for 1 year. All subsequent treatment of bipolar disorder was managed by the patient's psychiatrist. Symptoms of mania and depression were evaluated at baseline and at hospital discharge. Assessments at the start of maintenance therapy and after 1, 3, 6, 9 and 12 months included manic and depressive symptoms, disability days and QOL. Medical resource use data were also collected monthly and costs were estimated using national sources. RESULTS: Divalproex-treated patients (12%) were less likely to discontinue study medications for lack of efficacy or adverse effects than lithium-treated patients (23%). No statistically significant differences between the treatment groups were observed over the 1-year maintenance phase for clinical symptoms, QOL outcomes, or disability days. Mean estimated total medical costs were USD 28,911 for the divalproex group compared with USD 30,666 for the lithium treatment group. Patients continuing mood stabilizer therapy at 3 months had slightly better health outcomes and substantially lower total medical costs than those who discontinued therapy ( USD 10,091 versus USD 34,432, respectively). CONCLUSIONS: Divalproex maintenance treatment for bipolar disorder resulted in comparable medical costs, clinical and QOL outcomes compared with lithium. Patients remaining on mood stabilizer therapy had substantially lower total medical costs and better health outcomes compared with those who discontinued therapy.

A cost-effectiveness clinical decision analysis model for treatment of Schizophrenia.

BACKGROUND: Schizophrenia afflicts approximately 0.7% of Mexican citizens during their lifetime. This study explored whether the difference in clinical efficacy and safety between atypical antipsychotics and conventional neuroleptics results in decreases in use and cost of medical services in Mexico, offsetting the higher price of atypical antipsychotics. METHODS: A U.S. decision analytic Markov model was adapted for use in Mexico to determine cost-effectiveness of treatments and outcomes that Mexican patients with schizophrenia may experience over a 5-year period when treated with olanzapine, haloperidol, or risperidone. Model parameter estimates were based on clinical trial data, published medical literature, and where needed, clinician judgment. Direct medical costs were incorporated into the model and outcomes were estimated using lack of relapse and clinical outcomes based on the Brief Psychiatric Rating Scale (BPRS) as effectiveness indicators. All costs are reported in Mexican pesos. RESULTS: Over a 5-year period, the cost of treating schizophrenia ranged from 196,620 pesos per patient initiating therapy with haloperidol to 226,670 pesos per patient beginning therapy with risperidone. Olanzapine was estimated to have slightly better non-relapse and BPRS-based effectiveness outcomes, but comparative total medical costs compared to risperidone. Patients receiving olanzapine experienced 13 and 2% fewer relapses compared with patients on haloperidol and risperidone, respectively. The 5-year incremental cost-effectiveness ratio of olanzapine compared with haloperidol was 52,740 pesos per improved patient, BPRS-based outcome and 212,540 pesos per avoided relapse. Sensitivity analyses indicated the model was sensitive only to changes in drug costs. CONCLUSIONS: Compared with haloperidol, olanzapine therapy results in improved symptoms, fewer relapses, and is cost-effective, even with conservative values for key model parameters. Olanzapine results in slightly improved patient outcomes and comparable costs compared with risperidone.

Cost-effectiveness of gemifloxacin: results from the GLOBE study.

The cost-effectiveness of treatment with oral gemifloxacin versus oral clarithromycin for acute exacerbations of chronic bronchitis (AECB) was evaluated. Economic outcomes were assessed for the Gemifloxacin Long-term Outcomes in Bronchitis Exacerbations study. This prospective double-blind, controlled, health outcomes study compared health, economic, and clinical outcomes after randomized treatment with either oral gemifloxacin or oral clarithromycin for AECB. Base case analysis was performed from the third-party payer's perspective and considered the costs of respiratory tract infection-related medical care. Analysis from the societal perspective also included costs of lost productivity. Treatment effectiveness was measured as the proportion of patients without recurrence requiring antimicrobial treatment following resolution of the initial AECB. Data sources included the outcomes study itself and standard U.S. cost sources. Compared with clarithromycin, gemifloxacin treatment resulted in significantly more patients without AECB recurrence requiring antimicrobial treatment after 26 weeks (73.8% versus 63.8%, p = 0.024). Fewer patients receiving gemifloxacin were hospitalized (5 of 214 patients versus 14 of 224 patients, p = 0.059), and they had less time off from usual activities (8.3 days versus 10.1 days). The mean direct cost per patient receiving gemifloxacin was $127 less than with clarithromycin ($247 versus $374, respectively); mean total costs (direct plus indirect) per patient were $329 less for patients receiving gemifloxacin ($1413 versus $1742). Gemifloxacin dominated clarithromycin in cost-effectiveness analysis. Bootstrap analysis indicated that the probability of gemifloxacin being both cost saving and more effective than clarithromycin is 88% from a payer's perspective and 84% from the societal perspective. Gemifloxacin was more cost-effective, improving AECB outcomes and producing substantial cost offsets compared with clarithromycin.

Cost effectiveness of treatment of Parkinson's disease with entacapone in the United States.

OBJECTIVE: To determine the cost effectiveness of adjunctive therapy with entacapone versus standard treatment (levodopa) without entacapone for patients in the US with Parkinson's disease (PD) who experience 'off-time' (re-emergence of the symptoms of PD) while receiving levodopa. STUDY DESIGN: A Markov model was used to estimate 5-year costs and effectiveness of standard treatment with and without entacapone. METHODS: Probabilities, unit costs, resource utilisation data and utilities were obtained from published literature, clinical trial reports, a national database, and clinical experts. PD disability was measured using the daily proportion of off-time and Hoehn and Yahr scale scores. The analysis measured costs from a societal and third-party payer perspective, and effectiveness as gains in quality-adjusted life-years (QALYs) and years without progression to >25% off-time. RESULTS: From a societal perspective, entacapone therapy resulted in an incremental cost of US dollars 9327 per QALY gained compared with standard treatment. Treatment with entacapone also provided an additional 7.6 months with < or =25% off-time/day compared with standard treatment. Sensitivity analyses indicated that the model is sensitive to changes in rates of improvement/deterioration of off-time, and to the number of doses per day of levodopa with adjunctive entacapone. CONCLUSIONS: The addition of entacapone to standard treatment for patients receiving levodopa who experience off-time provides additional QALYs and gain in time with minimal fluctuations. Results of this modelling exercise suggest that therapy with entacapone may be cost effective when compared with standard treatment for PD.

Utility assessments of opioid treatment for chronic pain.

OBJECTIVE: The primary study objective was to assess preferences for pain treatment outcomes among patients with cancer and noncancer chronic pain. A secondary objective was to assess their quality of life. METHODS: Patients with cancer or noncancer chronic pain completed an interview using a computer to estimate utilities, or preference ratings, for health states related to pain treatment. The interview was devised using conjoint analysis methodology. Health states were characterized by four attributes (effectiveness of pain control, side effects, side effect severity, and opioid route of administration) and their levels, and each was assumed to last for a 14-day period. Participants also completed health-related quality of life and demographic questionnaires. RESULTS: Mean preference ratings for participants with noncancer chronic pain (N = 96) ranged from a high of 0.87 (well-controlled pain with no side effects) to a low of 0.18 (poorly controlled pain with severe mood changes/alterations, severe respiratory depression, or severe vomiting). Mean preference ratings for participants with cancer pain (N = 25) were similar and ranged from a high of 0.89 (well-controlled pain with no side effects) to a low of 0.19 (poorly controlled pain with severe respiratory depression or severe vomiting). Results confirmed previous findings that chronic pain has a severe, multidimensional impact on patients, and that the quality of life of persons with chronic pain is among the lowest observed for any medical condition. CONCLUSIONS: This study provides a valuable assessment, from the patient's perspective, of the balance between treatment tolerability and manifestation of disease symptoms. Heightened awareness of patients' preferences for treatment outcomes may lead to improved selection of treatments, better adherence, and ultimate treatment success.