Study of the novel non-xanthine heterocyclic compound GU 285 as a potent non-selective adenosine receptor antagonist in the rat

The novel pyrazolo[3,4-d]pyrimidine compound GU285 (4-amino-6-alpha-carbamoylethylthio-1- phenylpyrazolo[3,4-d]pyrimidine, CAS 134896-40-5) was examined for its ability (1) to inhibit binding of adenosine (ADO) receptor ligands in rat brain membranes, (2) to antagonise functional responses to ADO agonists in rat right and left atria and coronary resistance vessels, and (3) to reduce the fall in heart rate and arterial blood pressure produced by the ADO A1 agonist N6-cyclopentyladenosine (CPA) in the intact, anaesthetized rat. GU285 competitively inhibited binding of the ADO A1 agonist [3H]-R-N6-phenylisopropyladenosine (R-PIA) yielding a Ki value of 11 (7-18) nmol.l-1 (geometric mean +/- 95% Cl). When assayed against the ADO A2A selective agonist [3H]-2-[p-(2-carboxyethyl)- phenethylamino]-5'-N-ethylcarboxamidoadenosine, (CGS21680), a Ki of 15 (10-24) nmol.l-1 was obtained. In spontaneously beating right atria, GU285 competitively antagonized negative chronotropic effects of R-PIA with a pA2 of 8.7 +/- 0.3 and in electrically paced left atria, GU285 competitively antagonized negative inotropic effects of R-PIA with a pA2 of 9.0 +/- 0.1. In the potassium-arrested, perfused rat heart GU285 (1 mumol.l-1) antagonized only the high sensitivity, ADO A2B mediated component of the biphasic relaxation of the coronary vasculature produced by NECA. The low sensitivity component was unchanged. GU285 (1 mumol.kg-1) antagonized the negative chronotropic and hypotensive effects of the adenosine A1 agonist CPA in anaesthetized rats, producing a 10-fold rightward shift in the dose-response relationship. These data demonstrate that in the rat, GU285 is a potent, non-selective adenosine receptor antagonist that maintains its activity in vivo.

Characterization of the sulphate mineral coquimbite, a secondary iron sulphate from Javier Ortega mine, Lucanas Province, Peru – Using infrared, Raman spectroscopy and thermogravimetry

The mineral coquimbite has been analysed using a range of techniques including SEM with EDX, thermal analytical techniques and Raman and infrared spectroscopy. The mineral originated from the Javier Ortega mine, Lucanas Province, Peru. The chemical formula was determined as ðFe3þ 1:37; Al0:63ÞP2:00ðSO4Þ3 9H2O. Thermal analysis showed a total mass loss of 73.4% on heating to 1000 C. A mass loss of 30.43% at 641.4 C is attributed to the loss of SO3. Observed Raman and infrared bands were assigned to the stretching and bending vibrations of sulphate tetrahedra, aluminium oxide/hydroxide octahedra, water molecules and hydroxyl ions. The Raman spectrum shows well resolved bands at 2994, 3176, 3327, 3422 and 3580 cm 1 attributed to water stretching vibrations. Vibrational spectroscopy combined with thermal analysis provides insight into the structure of coquimbite.

The role of knowledge integration in innovation and capability development

Purpose This paper investigates the interrelationships between knowledge integration (KI), product innovation and capability development to enhance our understanding of how firms can develop capability at the firm level, which in turn enhances their performance. One of the critical underlying mechanisms for capability building identified in the literature is the role of knowledge integration, which operates within product innovation projects and contributes to dynamic capability development. Therefore, the main research question is “how does the integration of knowledge across product innovation projects lead to the development of capability?” Design/methodology/approach We adopted a case-based approach and investigated the case of a successful firm that was able to sustain its performance through a series of product innovation projects. In particular this research focused on the role of KI and firm-level capability development over the course of four projects, during which the firm successfully managed the transformation of its product base and renewal of its competitive advantage. For this purpose an in-depth case study of capability development was undertaken at the Iran Khodro Company (IKCO), the key player in the Iranian auto industry transformation. Originality/value This research revealed that along with changes at each level of product architecture “design knowledge” and “design capability” have been developed at the same level of product architecture, leading to capability development at that level. It can be argued that along the step by step maturation of radical innovation across the four case projects, architectural knowledge and capability have been developed at the case company, resulting in the gradual emergence of a modular product and capability architecture across different levels of product architecture. Such findings basically add to extensive emphasis in the literature on the interrelationship of the concept of modularity with knowledge management and capability development. Practical implications Findings of this study indicate that firms manage their knowledge in accordance with the level of specialization in knowledge and capability. Furthermore, firms design appropriate knowledge integration mechanisms within and among functions in order dynamically align knowledge processes at different levels of the product architecture. Accordingly, the outcomes of this study may guide practitioners in managing their knowledge processes, through dynamically employing knowledge integration modes step-by-step and from the part level to the architectural level of product architecture across a sequence of product innovation projects to encourage learning and radical innovation.

PCDD and PCDF concentrations in a traffic tunnel environment

In an effort to understand the fundamental aspects of air quality in traffic tunnel environments, field campaigns were conducted to measure polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and other important pollutants within two traffic tunnels in Nam San (NS) and Hong Ji (HJ) in Korea in 2009 and 2010. The mean concentrations of ∑PCDD/Fs (in fg/m(3)) at the two tunnel sites were 1270 (± 880) and 1200 (± 810), respectively. These values were moderately lower than those measured at a non-tunnel urban background site (1350 (± 780) fg/m(3))--selected as a reference in this study. In addition, seasonal patterns of dioxin concentrations were clearly evident at the traffic tunnels like the urban reference site, showing higher levels during the winter (and spring) than the summer (and fall). The observed seasonal variations were driven by changes in the concentrations of ∑PCDF congeners, while ∑PCDD concentrations showed little seasonality. The results of our study suggest that there is no significant difference in source characteristics between the two investigated tunnel sites and urban location, although the role of gasoline and diesel fueled vehicles are considered as the major source in determining the PCDDs and PCDF levels in a tunnel environment. However, given the relative increase in other important ambient pollutant (e.g. PM10) concentrations over ∑PCDD/Fs in tunnel air (compared to urban background air), the balance of sources in tunnels is clearly different from those in urban air overall.

The first application of wastewater-based drug epidemiology in five South Korean cities

Illicit drug consumption in five cities in South Korea was estimated by analyzing 17 drug residues in untreated wastewater samples collected during the Christmas and New Year period of 2012-13. Only methamphetamine, amphetamine, and codeine were detected at concentrations of tens of nanograms per liter or even lower concentrations in more than 90% of the samples. Other illicit drug residues (including cocaine, methadone, and benzoylecgonine) that have been detected frequently in wastewater from other countries were not found in this study. Methamphetamine was found to be the most widely used illicit drug in South Korea, and the estimated average consumption rate was 22 mg d−1 (1000 people)−1. This rate is, for example, 2-5 times lower than the estimated average consumption rates in Hong Kong and other parts of China and 4-80 times lower than the estimated average consumption rates in cities in Western countries. It should be noted that the wastewater samples analyzed in this study were collected during a holiday season, when daily consumption of illicit drugs is often higher than on an average day. The methamphetamine usage rates were calculated for different cities in South Korea, and the usage rates in smaller cities was higher (2-4 times) than the average.

Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial

Background The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting. Methods This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01466660. Findings Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27·3 months (IQR 15·3–33·9). Progression-free survival (median 11·0 months [95% CI 10·6–12·9] with afatinib vs 10·9 months [9·1–11·5] with gefitinib; hazard ratio [HR] 0·73 [95% CI 0·57–0·95], p=0·017) and time-to-treatment failure (median 13·7 months [95% CI 11·9–15·0] with afatinib vs 11·5 months [10·1–13·1] with gefitinib; HR 0·73 [95% CI 0·58–0·92], p=0·0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 [13%] of 160 patients given afatinib vs two [1%] of 159 given gefitinib) and rash or acne (15 [9%] patients given afatinib vs five [3%] of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 [9%] of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure. Interpretation Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population.

Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials

Background We aimed to assess the effect of afatinib on overall survival of patients with EGFR mutation-positive lung adenocarcinoma through an analysis of data from two open-label, randomised, phase 3 trials. Methods Previously untreated patients with EGFR mutation-positive stage IIIB or IV lung adenocarcinoma were enrolled in LUX-Lung 3 (n=345) and LUX-Lung 6 (n=364). These patients were randomly assigned in a 2:1 ratio to receive afatinib or chemotherapy (pemetrexed-cisplatin [LUX-Lung 3] or gemcitabine-cisplatin [LUX-Lung 6]), stratified by EGFR mutation (exon 19 deletion [del19], Leu858Arg, or other) and ethnic origin (LUX-Lung 3 only). We planned analyses of mature overall survival data in the intention-to-treat population after 209 (LUX-Lung 3) and 237 (LUX-Lung 6) deaths. These ongoing studies are registered with ClinicalTrials.gov, numbers NCT00949650 and NCT01121393. Findings Median follow-up in LUX-Lung 3 was 41 months (IQR 35–44); 213 (62%) of 345 patients had died. Median follow-up in LUX-Lung 6 was 33 months (IQR 31–37); 246 (68%) of 364 patients had died. In LUX-Lung 3, median overall survival was 28·2 months (95% CI 24·6–33·6) in the afatinib group and 28·2 months (20·7–33·2) in the pemetrexed-cisplatin group (HR 0·88, 95% CI 0·66–1·17, p=0·39). In LUX-Lung 6, median overall survival was 23·1 months (95% CI 20·4–27·3) in the afatinib group and 23·5 months (18·0–25·6) in the gemcitabine-cisplatin group (HR 0·93, 95% CI 0·72–1·22, p=0·61). However, in preplanned analyses, overall survival was significantly longer for patients with del19-positive tumours in the afatinib group than in the chemotherapy group in both trials: in LUX-Lung 3, median overall survival was 33·3 months (95% CI 26·8–41·5) in the afatinib group versus 21·1 months (16·3–30·7) in the chemotherapy group (HR 0·54, 95% CI 0·36–0·79, p=0·0015); in LUX-Lung 6, it was 31·4 months (95% CI 24·2–35·3) versus 18·4 months (14·6–25·6), respectively (HR 0·64, 95% CI 0·44–0·94, p=0·023). By contrast, there were no significant differences by treatment group for patients with EGFR Leu858Arg-positive tumours in either trial: in LUX-Lung 3, median overall survival was 27·6 months (19·8–41·7) in the afatinib group versus 40·3 months (24·3–not estimable) in the chemotherapy group (HR 1·30, 95% CI 0·80–2·11, p=0·29); in LUX-Lung 6, it was 19·6 months (95% CI 17·0–22·1) versus 24·3 months (19·0–27·0), respectively (HR 1·22, 95% CI 0·81–1·83, p=0·34). In both trials, the most common afatinib-related grade 3–4 adverse events were rash or acne (37 [16%] of 229 patients in LUX-Lung 3 and 35 [15%] of 239 patients in LUX-Lung 6), diarrhoea (33 [14%] and 13 [5%]), paronychia (26 [11%] in LUX-Lung 3 only), and stomatitis or mucositis (13 [5%] in LUX-Lung 6 only). In LUX-Lung 3, neutropenia (20 [18%] of 111 patients), fatigue (14 [13%]) and leucopenia (nine [8%]) were the most common chemotherapy-related grade 3–4 adverse events, while in LUX-Lung 6, the most common chemotherapy-related grade 3–4 adverse events were neutropenia (30 [27%] of 113 patients), vomiting (22 [19%]), and leucopenia (17 [15%]). Interpretation Although afatinib did not improve overall survival in the whole population of either trial, overall survival was improved with the drug for patients with del19 EGFR mutations. The absence of an effect in patients with Leu858Arg EGFR mutations suggests that EGFR del19-positive disease might be distinct from Leu858Arg-positive disease and that these subgroups should be analysed separately in future trials.

Detection of recently discovered human polyomaviruses in a longitudinal kidney transplant cohort

A large number of human polyomaviruses have been discovered in the last 7 years. However, little is known about the clinical impact on vulnerable immunosuppressed patient populations. Blood, urine, and respiratory swabs collected from a prospective, longitudinal adult kidney transplant cohort (n = 167) generally pre-operatively, at day 4, months 1, 3, and 6 posttransplant, and at BK viremic episodes within the first year were screened for 12 human polyomaviruses using real-time polymerase chain reaction. Newly discovered polyomaviruses were most commonly detected in the respiratory tract, with persistent shedding seen for up to 6 months posttransplant. Merkel cell polyomavirus was the most common detection, but was not associated with clinical symptoms or subsequent development of skin cancer or other skin abnormalities. In contrast, KI polyomavirus was associated with respiratory disease in a subset of patients. Human polyomavirus 9, Malawi polyomavirus, and human polyomavirus 12 were not detected in any patient samples.