Adaptation of a human gut epithelial model in relation to the assessment of clinical pharmacokinetic parameters for selected tyrosine kinase inhibitors

The absorption, efflux and transport properties of two of the most commonly used tyrosine kinase inhibitors (TKIs), Erlotinib (E) and Gefitinib (G) were investigated using an adapted workable methodology of a 3-day Caco-2 cell monolayer transwell system, a standard model to test drug permeability and uptake of orally administered compounds. Monolayer integrity was tested using trans-epithelial electrical resistance (TEER) measurements, while drug concentrations were determined with a validated LC-MS/ MS technique. Addition of 5 % bovine serum albumin (BSA) maintained drug concentrations at 20 µM through the avoidance of chelate formation, (nevertheless, a reduced accumulative mass transport of the protein bound drug was observed). Investigation with Ko143 (a specific blocker of ABCG2) or NaN3 (a metabolic inhibitor) indicated an interplay between active transport and passive diffusion for gefitinib, while active transport proved to be absent for erlotinib (p < 0.05). The mechanism indicates that ABCG2 is partially involved with accumulation of gefitinib in the cell. This adapted methodology is well suited for absorption, efflux and transport studies and may be extended to investigate the dominant mechanism involved in the transport of TKIs

Two-color holography concept (T-CHI)

The Material Processing in the Space Program of NASA-MSFC was active in developing numerous optical techniques for the characterization of fluids in the vicinity of various materials during crystallization and/or solidification. Two-color holographic interferometry demonstrates that temperature and concentration separation in transparent (T-CHI) model systems is possible. The experiments were performed for particular (succinonitrile) systems. Several solutions are possible in Microgravity Sciences and Applications (MSA) experiments on future Shuttle missions. The theory of the T-CHI concept is evaluated. Although particular cases are used for explanations, the concepts developed will be universal. A breadboard system design is also presented for ultimate fabrication and testing of theoretical findings. New developments in holography involving optical fibers and diode lasers are also incorporated

Retrospective Study of Salinomycin Toxicosis in 66 Cats

We examined 66 cats with salinomycin intoxication. Salinomycin caused different LMN signs of varying degrees of severity in all cases. Changes in blood work were unspecific, with the most frequent being increased serum creatine kinase activity, leukocytosis, and increased liver enzymes. Pathological electrodiagnostic findings: fibrillation potentials and positive sharp waves were detected in 10 cases, motor nerve conductance velocity was mildly decreased in 8/12 cats, and sensory nerve conductance velocity and repetitive nerve stimulation were normal in all examined cases. In five cases the peripheral neuropathy was confirmed by pathohistology. Fluid therapy and supportive care were used as therapy and 52 cats recovered completely. The probability for complete remission was significantly different between mildly and severely affected cases. It seems that the severity of clinical signs and prognosis correlate well with the amount of toxin ingested. We conclude that early recognition and decontamination combined with supportive care results in complete recovery

A phase I trial of ispinesib, a kinesin spindle protein inhibitor, with docetaxel in patients with advanced solid tumours

The aim of this study is to define the maximum tolerated dose (MTD), safety, pharmacokinetics (PKs) and efficacy of ispinesib (SB-715992) in combination with docetaxel. Patients with advanced solid tumours were treated with ispinesib (6–12 mg m−2) and docetaxel (50–75 mg m−2). Docetaxel was administered over 1 h followed by a 1-h infusion of ispinesib on day 1 of a 21-day schedule. At least three patients were treated at each dose level. Blood samples were collected during cycle 1 for PK analysis. Clinical response assessments were performed every two cycles using RECIST guidelines. Twenty-four patients were treated at four dose levels. Prolonged neutropaenia and febrile neutropaenia were dose limiting in six and two patients, respectively. The MTD was ispinesib 10 mg m−2 with docetaxel 60 mg m−2. Pharmacokinetic assessment demonstrated concentrations of ispinesib and docetaxel, consistent with published data from single agent studies of the drugs. Seven patients (six hormone refractory prostate cancer (HRPC), one renal cancer) had a best response of stable disease (⩾18 weeks). One patient with HRPC had a confirmed >50% prostatic-specific antigen decrease. The MTD for ispinesib and docetaxel was defined and the combination demonstrated an acceptable toxicity profile. Preliminary PK data suggest no interaction between ispinesib and docetaxel

Seminar on Evidence and Trial Practice

Outlines of speaker presentations offered during a series of one day seminars on evidence and trial practice offered by UK/CLE in late 1987-early 1988

Trade Potential and UN Peacekeeping Participation

The determinants of a country's UN peacekeeping troop contribution have been persistently studied. Trade, as a crucial self-interest motivation, is one of the important explanatory variables in the extant literature. However, the existing literature presents mixed results on the influence of trade on peacekeeping troop contributions. To capture the effect of trade on contributions precisely, we need to model expectations about future trade volume in a better way. Countries are pressured by the economic and political risks caused by the trade disruption and lobby groups to send peacekeeping troops to enable future trade or secure future investments. Therefore, trade potential, rather than realized trade, drives peacekeeping troop contributions. A gravity model is used to measure the trade potential between the UN peacekeeping mission countries and contributors, and test its relationship with the UN peacekeeping participation. Based on this measurement and a dyadic troop contribution dataset covering the period from 1990 to 2012, this article demonstrates that the counter-factual predictive trade volume is a relevant predictor of UN peacekeeping troop contributions

A Dose-Escalation Study of Recombinant Human Interleukin-18 Using Two Different Schedules of Administration in Patients with Cancer

Purpose: Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical models. A phase I study of recombinant human IL-18 (rhIL-18) was done to determine the toxicity, pharmacokinetics, and biological activities of rhIL-18 administered at different doses in two different schedules to patients with advanced cancer. Experimental design: Cohorts of three to four patients were given escalating doses of rhIL-18 as a 2-h i.v. infusion either on 5 consecutive days repeated every 28 days (group A) or once a week (group B) for up to 6 months. Toxicities were graded using standard criteria. Blood samples were obtained for safety, pharmacokinetic, and pharmacodynamic measurements. Results: Nineteen patients (10 melanoma and 9 renal cell cancer) were given rhIL-18 in doses of 100, 500, or 1,000 microg/kg (group A) or 100, 1,000, or 2,000 microg/kg (group B). Common side effects included chills, fever, headache, fatigue, and nausea. Common laboratory abnormalities included transient, asymptomatic grade 1 to 3 lymphopenia, grade 1 to 4 hyperglycemia, grade 1 to 2 anemia, neutropenia, hypoalbuminemia, liver enzyme elevations, and serum creatinine elevations. No dose-limiting toxicities were observed. Biological effects of rhIL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes. Increases in serum concentrations of IFN-gamma, granulocyte macrophage colony-stimulating factor, and IL-18-binding protein were observed following dosing. Conclusions: rhIL-18 can be given in biologically active doses by either weekly infusions or daily infusions for 5 days repeated every 28 days to patients with advanced cancer. Toxicity was generally mild to moderate, and a maximum tolerated dose of rhIL-18 by either schedule was not determined

Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments were progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease

Small molecule binding sites on the Ras:SOS complex can be exploited for inhibition of Ras activation.

Constitutively active mutant KRas displays a reduced rate of GTP hydrolysis via both intrinsic and GTPase-activating protein-catalyzed mechanisms, resulting in the perpetual activation of Ras pathways. We describe a fragment screening campaign using X-ray crystallography that led to the discovery of three fragment binding sites on the Ras:SOS complex. The identification of tool compounds binding at each of these sites allowed exploration of two new approaches to Ras pathway inhibition by stabilizing or covalently modifying the Ras:SOS complex to prevent the reloading of Ras with GTP. Initially, we identified ligands that bound reversibly to the Ras:SOS complex in two distinct sites, but these compounds were not sufficiently potent inhibitors to validate our stabilization hypothesis. We conclude by demonstrating that covalent modification of Cys118 on Ras leads to a novel mechanism of inhibition of the SOS-mediated interaction between Ras and Raf and is effective at inhibiting the exchange of labeled GDP in both mutant (G12C and G12V) and wild type Ras