Studied Dose Range Research Articles

Gefitinib improves insulin sensitivity in Wistar diabetes rats models

To investigate the effect of Gefitinib on insulin sensitivity in rats of type-2 diabetes and its mechanism. Normal Wistar rats were fed with high sucrose-fat diet for 1 month and then injected intraperitoneally with streptozotocin (STZ). The rats satisfying the definity of type-2 diabetes were divided into 3 groups and given control solution (0.9%NaCl), low-dose Gefitinib and high-dose Gefitinib for 8 days, respectively. Body weights, FBG and FINS were recorded before, just after and 7 days after administration, respectively. After the second round of administration executed the rats and got the livers from rats. Compared the expression of insulin receptor substrate-1 (IRS-1) and phosphatidylinositol-3-kinase (PI3K) genes in liver among the 3 groups with semi-quantitative Reverse Transcription-Polymerase Chain Reaction (PCR). Normal Wistar rats fed with high sucrose-fat diet for 1 month and then injected intraperitoneally with STZ could establish type-2 diabetes model. After administration, insulin sensitivity index (ISI) of Gefitinib groups were significantly increased compared with control group (2.96 +/- 1.38 vs 0.92 +/- 0.20, P < 0.05). There Were no significant difference between the two dose groups (2.95 +/- 1.51 vs 2.96 +/- 1.38, P > 0.05). 7 days after administration, the improved ISI did not change (2.03 +/- 0.72 vs 2.99 +/- 0.63, P > 0.05). Body weights of the 3 groups had no significant difference. The expression of IRS-1 gene significantly decreased in Gefitinib groups compared with control group [(3.3 +/- 1.5)% vs (6.3 +/- 2.4)% P < 0.05] and with no obvious difference between the two dose groups [(3.3 +/- 1.5)% vs (3.2 +/- 1.8)%, P > 0.05], while the expression of PI3K gene significantly increased in Gefitinib groups compared with control group [(1.27 +/- 0.73)% vs (0.41 +/- 0.24)%, P < 0.05] also with no obvious difference between the two dose groups [(1.27 +/- 0.73)% vs (1.43 +/- 0.71)%, P > 0.05]. Gefitinib can improve insulin sensitivity in rats of type-2 diabetes. 2 t(1/2) after administration, the effect still existed. The effect probably due to the increase of PI3K/Akt pathway of insulin signaling, and had no relationship with body weight in our study dose range.

Abstract C131: CBP501 (CBP), a novel cell cycle dysregulator, in combination with cisplatin (CDDP) and pemetrexed (PM) - pharmacokinetics (PK) in two phase I/II studies

Abstract Background: CBP is a synthetic peptide that enhances intracellular CDDP and enhances DNA damage caused by bleomycin or CDDP. Activity has been demonstrated in various tumor models. Two clinical trials have evaluated CBP combinations, determining maximum tolerated dose (MTD), DLT, safety, activity and PK: Study A, phase I, CBP with CDDP in solid tumor pts; Study B, phase I part, CBP with CDDP and PM in solid tumors, randomized phase II part CDDP/ PM with or without CBP in mesothelioma pts. Materials and Methods: Eligibility criteria were standard. CBP was given i.v. over 1 hr, with prophylactic anti-allergics for a histamine release syndrome, and folic acid vitamin supplementation (PM treated pts). Study A: q3w, CBP 3.6 to 36.5 mg/m2, CDDP 75 mg/m2, with PK assessed on cycle (C) 1 Day (D) −7 (CBP alone) and C1D1. Study B: q3w, CBP/CDDP/PM doses 16 or 25/75/500 mg/m2, with PK assessed on C1D1, C2D1 (CBP) and C2D2 (CDDP/PM). Samples were drawn at 6 timepoints over 8 hours (h) and at 24 h. An LC-MS/MS assay method was used, with a 10 ng/mL limit of detection for CBP. PK parameters were determined by non-parametric methods. Results: The studies were conducted in 12 US centers. 50 pts were assessed for PK (35 Study A, 15 Study B). CBP Cmax and AUC were doseproportional over the studied dose range (r2&amp;gt;0.8). Variability of CBP PK was moderate (Coefficient of variation [CV] 20–30%). PK of CBP 25 mg/m2 were comparable in 7 pts when CBP was administered alone and with CDDP in study A, and appeared to be comparable between C1 and C2 in study B (only 3 pts so far). Results for CBP alone and in combination with CDDP are consistent with a single agent trial (Wong et al, ASCO 2008, abstract 2528). However, CBP Cmax and AUC appear to be lower in pts receiving PM; whether this is due to the co-administration of PM or to differences between study A and B has not yet been determined. PM and platinum plasma and ultrafiltrate PK parameters were consistent with those reported in the literature (Dickgreber et al, 2009, Clin Cancer Res, 15, 382–9). No significant variations according to cycle, regimen or study were observed. Conclusion: CBP displays dose-proportional PK in combination with both CDDP and PM, without any apparent effect on CDDP or PM PK, and without any observed effects over 2 cycles. PK evaluations are ongoing in study B, which should allow the clarification of the eventual effect of PM on CBP PK. Mean PK parameters (CV) on Cycle 1 Day 1 CBP 25 mg/m2 With PM/without PM N=5/N=8 CDDP 75 mg/m2 Plasma Pt/ultrafiltrate PT N=43 PM 500 mg/m2 With CBP/without CBP N=8/N=5 Cmax (µg/mL) 5.30 (24)/6.16 (26) 3.33 (22)/1.78 (46) 113.55 (19)/110.30 (25) AUC0−∞ (µg.h/mL) 15.10 (19)/18.81 (22) 142.00 (47)/4.64 (38) 248.27 (33)/275.38 (30) t½ (h) 3.48 (31)/3.79 (17) 47.68 (61)/11.01 (140) 2.57 (27)/3.19 (24) Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C131.

Naloxone Effects on Behavior of Inbred Mice with Different Response to Emotional Stress in Open Field Test

Effects of nonspecific opiate receptor antagonist naloxone in doses of 0.1, 0.5, 1.0, 5.0, 10.0 mg/kg on open field behavior and spontaneous motor activity were studied in male BALB/c and C57Bl/6 mice. Differently directed effects of naloxone on behavioral parameters of emotional-stress reaction in BALB/c and C57Bl/6 mice were observed. Naloxone increased motor activity in the open field test in BALB/c mice, but decreased it in C57Bl/6 mice. In the absence of stress, naloxone in the studied dose range did not affect spontaneous motor activity in C57Bl/6 mice, and significantly reduced activity in BALB/c mice in doses 0.5 and 1.0 mg/kg.

Safety and pharmacokinetics of the anti-amyloid monoclonal antibody PF-04360365 following a single infusion in patients with mild-to-moderate Alzheimer's disease: Preliminary results

PF-04360365 is a humanized anti-amyloid monoclonal antibody (mAb) with several distinct features - an IgG2deltaA that recognizes amino acids 33-40 of the AB1-40 peptide and a requirement for a free carboxy terminus for binding. To date, PF-04360365 has been very well tolerated with no drug-attributed serious adverse events (AEs). Here we further evaluate its safety, as well as its pharmacokinetic (PK) profile. In this double-blind, placebo-controlled, dose-escalation study (0.1-10 mg/kg), patients with mild-to-moderate Alzheimer's disease (AD) were randomized to receive PF-04360365 as a single 2-hour intravenous infusion (N = 26) or placebo (N = 11). The most common AEs (blinded) were upper respiratory tract infection (n = 6), headache (n = 6) and diarrhea (n = 2), all mild-to-moderate in severity. One subject (10 mg/kg cohort) experienced a mild hypersensitivity reaction and another (0.1 mg/kg cohort) demonstrated slight enlargement of a pre-existing midbrain lesion at the time of the 1-year MRI. No clinical or imaging evidence of microhemorrhage, vasogenic edema or encephalitis was noted in any patient. ECG and routine safety laboratory values, including cell counts and cerebrospinal fluid (CSF) protein were unremarkable. No remarkable changes in cognition (ADAS-cog, MMSE) have been noted. The PK profile appeared linear in the studied dose range, with approximately dose-proportional increases in PF-04360365 plasma Cmax and AUC. PK parameters were similar to those of IgG-type mAbs except for a longer elimination half-life (∼6 weeks). Two of eight patients in the 10 mg/kg cohort had measurable PF-04360365 concentrations in CSF (∼0.5% of plasma values) when assessed 29 days post-dosing. Single-dose data indicate PF-04360365 is well-tolerated over the 0.1-10 mg/kg dose range. Plasma PF-04360365 exposure increased in a predictable dose-proportional manner, with evidence of mild central penetration. A multiple-dose study to evaluate PF-04360365 in patients with AD is warranted.

Electron paramagnetic resonance in irradiated fingernails: variability of dose dependence and possibilities of initial dose assessment

The results of electron paramagnetic resonance (EPR) measurements in irradiated fingernails are presented. In total, 83 samples of different fingernails were studied. Five different groups of samples were selected based on the collection time of fingernail samples, their level of mechanical stress, and the number and size of clippings: (1) recently (<24 h) cut, irradiated and measured with EPR without any treatment of samples, and with rigorous control of size and number of clippings (stressed-fresh, controlled); (2) recently (<24 h) cut, irradiated and measured with EPR after application of a special treatment (10 min of water soaking, 5 min of drying time) to reduce the mechanical stress caused by cutting the samples, and with rigorous control of size and number of clippings (unstressed-fresh, controlled); (3) previously (>24 h) cut, stored at room temperature, additionally cut into small pieces immediately prior to study, irradiated and measured with EPR without any treatment of samples, and with rigorous control of size and number of clippings (stressed-old, controlled); (4) previously (>24 h) cut, stored at room temperature, additionally cut into small pieces immediately prior to the study, irradiated and measured with EPR after application of a special treatment to reduce mechanical stress caused by cut, and with rigorous control of size and number of clippings (unstressed-old, controlled); and (5) recently (<24 h) cut, irradiated and measured with EPR after application of a special treatment to reduce the mechanical stress caused by cut, and without rigorous control of size and number of clippings (unstressed-fresh, uncontrolled). Except for the fifth selected group, variability of the dose dependence inside all groups was found to be not statistically significant, although the variability among the different groups was significant. Comparison of the mean dose dependences obtained for each group allowed selection of key factors responsible for radiation sensitivity (dose response per unit of mass and dose) and the shape of dose dependence in fingernails. The major factor responsible for radiation sensitivity of fingernails was identified as their water content, which can affect radiation sensitivity up to 35%. The major factor responsible for the shape of the radiation sensitivity was identified as the mechanical stress. At a significant level of mechanical stress, the shape of the dose dependence is linear in the studied dose range (<20 Gy), and in lesser-stressed samples it is of an exponential growth including saturation, which depends on the degree of mechanical stress. In view of the findings, recommendations are discussed and presented for the appropriate protocol for EPR dose measurements in fingernails.

TU-D-BRB-09: Dosimetric Validation of the Proton-Sensitive BANG® 3 PRO-2 Polymer Gel Dosimeter Irradiated by Single Field Therapeutic Proton Beams

Purpose: A dosimetric validation of the next-generation 3D polymer gel dosimeter (BANG®-3-PRO-2) developed for proton radiotherapy dosimetry is presented. Dose response curve is determined using both proton and electron beams. Lateral and depth profiles are compared to ion chamber measurements. 2D dose distributions are evaluated against those generated by a treatment planning system (TPS). Methods and Materials: The dosimeters were read out using a characterized optical computed tomography scanner. The calibration was performed by correlating the change in optical density along the beam axis to the depth-dose curve from a pristine proton beam delivery (28.4 cm range, 4.5 cm circular aperture) obtained using ion-chamber measurements. The dose range of 150–650 cGy was covered. Depth and lateral pristine-beam and spread out Bragg peak (SOBP) dose profiles were compared to ionchamber measurements. Results: The dose response exhibited a sigmoid behavior in the studied dose range. The dose distributions read out from the dosimeters showed good agreement with ion chamber scanned profiles and were able to accurately reproduce the key features of the expected dose distributions. Planar dose along the beam axis were compared to the Eclipse TPS dose maps using the gamma metric with Dd=3 mm and DD=3% or 15 cGy, whichever is greater. Over 95% of dose points pass these criteria. For SOBP delivery (315 cGy peak dose), no response quenching in the peak region (characteristic of other dosimeter types) was observed. For a pristine beam delivery (300 cGy peak dose), the gel dosimeter demonstrated a ∼5% under-response at the Bragg peak. Conclusion: This new polymer formulation is capable of reproducing single proton beam dose distributions with high spatial accuracy. Under dosing response in the BP or SOBP due to LET dependencies was found to be insignificant and superior to many other currently used proton-sensitive dosimeters.

Cannabinoid Receptor Agonist 13, a Novel Cannabinoid Agonist: First in Human Pharmacokinetics and Safety

Cannabinoid receptor agonist 13 (CRA13) is a novel cannabinoid (CB) receptor agonist with high affinity and functional activity toward both CB(1) and CB(2) receptors. This phase I study aimed to evaluate the pharmacokinetics, safety, and tolerability of single oral doses of CRA13. Sixty-three of 69 healthy adult males were randomized in seven cohorts (n = 9) to receive 1 to 80 mg of CRA13 or placebo orally in fasted condition. To investigate the diet effect, an independent group (n = 6) was randomized to receive 40 mg of CRA13 after high-fat and high-calorie breakfast in crossover design with a 2-week washout period. Peak plasma concentration (C(max)) ranged from 7.8 to 467.6 ng/ml (1-80 mg). CRA13 was rapidly absorbed and demonstrated linear pharmacokinetics (1-80 mg). Time to reach C(max) (t(max)) was 1.5 to 2 h for all doses in both fasted and fed groups. Administration of 40 mg of CRA13 with food induced approximately 2-fold increase in the C(max) and the area under the concentration-time curve, AUC(0 - tz). The apparent elimination half-life (t(1/2)) was 21 to 36 h and 30 to 41 h for fasted and fed groups, respectively. Dizziness, headache, and nausea were the most frequently reported adverse events (AEs), predominantly at the 40- and 80-mg doses. The incidence of AEs was dose-dependent and mild to moderate. No deaths and serious adverse events were reported. In conclusion, CRA13 was reasonably well tolerated and demonstrated a linear pharmacokinetics over the studied dose range (1-80 mg). Food intake increased CRA13 C(max) and AUC(0 - tz) by approximately 2-fold, whereas t(max) was unaffected.

Persistent neuropathy after treatment with cisplatin and oxaliplatin

Background. The aims of the current explorative study were to assess persistent neuropathy in 45 patients up to 6 years after treatment with cisplatin or oxaliplatin and to determine the most adequate method to evaluate neuropathy. Furthermore, the effect of possible determinants on persistent neuropathy was investigated. Material andmethods. The assessment of neuropathy was performed using a questionnaire, by neurological tests, and by vibration threshold (VT) measurements. Because VT determination gives the most objective information, VT measurements were used for further analyses. Results and discussion. The analyses revealed that neuropathy of the hands was related to follow-up time, with an observed recovery half-life of 6.8 (± 3.1) years. No significant reversibility of neuropathy of the feet within the observation period could be demonstrated. For cisplatin, the severity of neuropathy was related to the cumulative dose and sodium thiosulfate use. Oxaliplatin induced neuropathy did not appear to be related to the dose within the studied dose range. No relationship with platinum levels, renal function, glutathione transferase genotypes, diabetes mellitus, alcohol use, or co-medication could be demonstrated. This study was performed as an explorative study and the issues discussed need to be investigated further.

Effects of bone morphogenic proteins and transforming growth factor-beta on In-vitro production of endothelin-1 by human pulmonary microvascular endothelial cells

Background Altered endothelial cell (EC)-derived mediator levels, including increased endothelin-1 (ET-1), are hallmarks of human pulmonary arterial hypertension (PAH). Gene mutations for receptors for bone morphogenic proteins (BMP), or transforming growth factor-β (TGF-β) cause heritable PAH. The effects of BMPs and TGF-β on ET-1 production by human pulmonary microvascular EC (HMVEC-LBl) are unknown. Methods HMVEC-LBl were exposed in-vitro to BMPs 2, 4, and 7 or TGF-β1 in basal or complete medium. ET production was measured, as well as total cellular protein. Levels of Smad 5 and phosphorylated Smads 1/5 were also measured. Results BMP-4 did not increase ET-1 while BMP-2 increased it minimally in basal medium. BMP-7 increased ET-1, but only at 100 ng/ml. By contrast, TGF-β increased ET-1 throughout most of the studied dose range. All BMPs and TGF-β increased levels of phosphorylated Smads 1/5 without depleting levels of Smad 5. Conclusions With the exception of BMP-7 at high-concentrations, the BMPs that interact with BMP receptor 2, the receptor implicated in heritable PAH, do not or minimally modulate in-vitro constitutive ET-1 production by HMVEC-LBl. TGF-β increases ET-1 synthesis, and this may have clinical relevance in PAH.

Ion beam radiation effects in monazite

Monazite is a potential matrix for conditioning minor actinides arising from spent fuel reprocessing. The matrix behavior under irradiation must be investigated to ensure long-term containment performance. Monazite compounds were irradiated by gold and helium ions to simulate the consequences of alpha decay. This article describes the effects of such irradiation on the structural and macroscopic properties (density and hardness) of monazites LaPO 4 and La 0.73Ce 0.27PO 4. Irradiation by gold ions results in major changes in the material properties. At a damage level of 6.7 dpa, monazite exhibits volume expansion of about 8.1%, a 59% drop in hardness, and structure amorphization, although Raman spectroscopy analysis shows that the phosphate–oxygen bond is unaffected. Conversely, no change in the properties of these compounds was observed after He ion implantation. These results indicate that ballistic effects predominate in the studied dose range.

Changes in phosphorylation of histone H2A.X and p53 in response of peripheral blood lymphocytes to gamma irradiation.

The main aim of this study was to compare the reaction of quiescent and proliferating, i.e. phytohemagglutinin (PHA)-stimulated, human peripheral blood mononuclear cells (PBMCs) to gamma-radiation, and analyse changes of proteins related to repair of DNA damage and apoptosis, such as gammaH2A.X, p53, p53 phosphorylation at serines-15 and -392, and p21 and their dose dependence. Freshly isolated PBMCs in peripheral blood are predominantly quiescent, in G(0) phase, and with very low amounts of proteins p53 and p21. Using confocal microscopy we detected dose dependent (0.5-5 Gy) induction of foci containing gammaH2A.X (1 h after gamma-ray exposure), which are formed around radiation-induced double strand breaks of DNA. Apoptosis was detected from 24 h after irradiation by the dose of 4 Gy onwards by Annexin V binding and lamin B cleavage. Seventy two hours after irradiation 70% of CD3(+) lymphocytes were A(+). Neither increase in p53 nor its phosphorylation on serine-392 after irradiation was detected in these cells. However, massive increase in p21 (cyclin-dependent kinase inhibitor 1A) was detected after irradiation, which can be responsible for late occurrence of apoptosis in these quiescent cells. PHA-stimulation itself (72 h) caused an increase in early apoptosis (A(+)PI(-)) in comparison to non-stimulated PBMCs (38% A(+) resp. 13.4%). After PHA-stimulation also the amount of gammaH2A.X, p53, and p21 increased, but no phosphorylation of p53 on serine-392 or -15 was detected. Reaction to gamma-radiation was different in PHA-stimulated lymphocytes: the p53 pathway was activated and p53 was phosphorylated on serines-15 and -392 4 h after irradiation by the dose of 4 Gy. Phosphorylation of p53 at serine-15 increased in a dose-dependent manner in the studied dose range 0.2-7.5 Gy. Also the amount of p21 increased after irradiation. Seventy two hours after irradiation of PHA-stimulated CD3(+) T lymphocytes by the dose of 4 Gy 65% of cells were A(+).

Molecular mechanisms of response of human peripheral blood mononuclear cells to ionizing radiation

Introduction: The aim of this study was to compare reaction of quiescent and proliferating PHA (mitogenic lectin phytohemagglutinin)-stimulated human peripheral blood mononuclear cells (PBMCs) to γ-radiation (IR) and analyze changes of proteins related to repair of DNA damage and apoptosis, such as γH2A.X, p53 and its phosphorylations on serine 15 and 392, and p21. Materials and methods: PBMC were acquired from venous blood of normal donors by centrifugation over Histopague. The lymphocytes were cultured in IMDM medium suplemented with 20% fetal calf serum and antibiotics. For mitogenic stimulation of lymphocytes was added 10 μg/ml PHA. The viability of the PBMC has been identified by flow cytometry. Western blotting has been used for p53 and its phosphorylation form, p21 and H2AX detection. T-lymphocytes and PBMC were irradiated and lysed. To enhance detection sensitivity the Total p53 and PathScan p53ser15 Sandwich ELISA Kits were used. Results: PBMCs were stimulated to enter the cell cycle by treatment with the PHA. After 72 h long stimulation by PHA 96 % of CD3+cells were CD25+ and 12 % entered cell cycle (S+ and G2 phase). PHA-stimulation itself causes increase in γH2A.X, p53, and p21, but not phosphorylation of p53. After the irradiation of these stimulated PBMCs we detected increase in p53 and its phosphorylations on serine 15 and 392, and further increase in p21 from 4 h after the irradiation. Also level of γH2A.X increased significantly. Increase of p53 phosphorylation on serine 15 is dose-dependent 4 h after the irradiation in the whole studied dose range (0.5-7.5 Gy) in stimulated PBMCs. We compared p53, p53ser15 and ser392, p21 and H2AX between grouply of phytohemaglutinin-stimulated and non-stimulated PBMC 4 hours after 0,5-7,5Gy as well as 1-72 hours after 4Gy irradiation.. We were unable to detect p53 accumulation or phosphorylation in response unstimulated PBMC to gamma radiation induced DNA damage. We induced cell cycling by phytohemaglutinin in the T-cell fraction of PMBC preparations. Althougly total p53 protein expression was unchanged after 4 Gy irradiation, we found p53ser392 time-dependent expression (1-72 hours, 4 Gy) and p53ser15 dose-dependent expression in range of 0,5-7,5 Gy 4 hours after irradiation in phytohemaglutinin- stimulated PBMC. Neither total p53 protein nor p53ser392 was not altered by irradiation in non-stimulated PBMC. Conclusions: We suggested that p53 protein accumulation is a common mechanism for induction apoptosis of irradiated cells. We suggest that this pathway is activated in proliferating lymphocytes, unlike quiescent lymphocytes.

Electron spin resonance study of γ-irradiated Anatolian chickpea (Cicer arietinum L.)

In this study, an electron spin resonance (ESR) investigation on γ-irradiated chickpea cultivated in Turkey is reported in detail. ESR spectra of unirradiated (control) chickpea were composed of an equally spaced sextet originating from the presence of Mn2+ ions and a single weak resonance signal both centered at g=2.0054±0.0006. Although irradiation was found to have no effect on the Mn2+ signals, it caused a noteworthy increase in free radical signal intensity of chickpea in the studied dose range of (0.1–4.5 kGy). In addition, the ESR spectrum of irradiated chickpea recorded at low scan range (10 mT) showed that there were more than one radical species, having different spectral features, contributing to the central resonance signal. From this point of view, we focussed on the free radical signal in the present study. The area under the ESR absorption curve which is related to the free radical concentration was determined from the experimental spectra recorded throughout the study, and its variation with microwave power, radiation dose, storage time and temperature was investigated in detail. Free radical concentration was observed to decay very fast within the first 15 days after the irradiation cessation and little thereafter. At the end of the storage period (60 days), the free radical concentration is still higher than that of the control (unirradiated) sample. The decay of free radical concentration at room and high temperatures were described well by the sum of three second-order decay functions representing three different radical species (A, B and C). The activation energies of these radicals, evaluated by Arrhenius analysis, are in the order E C>E B>E A. Simulation calculations have shown that three radical species (A, B and C) of different spectral parameters were found to best explain the experimental values.

Preclinical pharmacokinetics and bioavailability of noscapine, a tubulin-binding anticancer agent

Noscapine, a naturally occurring antitussive phthalideisoquinoline alkaloid, is a tubulin-binding agent currently in Phase I/II clinical trials for anticancer therapy. Unlike currently available antimitotics such as taxanes and vincas, noscapine is water-soluble, well tolerated, and shows no detectable toxicity. The goal was to develop a simple, sensitive, quantitative, selective, and less time-consuming high-performance liquid chromatography (HPLC) method for determination of noscapine and to study its pharmacokinetics in mice models. Noscapine was extracted from mice plasma using the protein-precipitation method and detected using a reversed-phase C8 column with mobile phase consisting of 35% acetonitrile and 65% ammonium acetate buffer (pH 4.5) at 232 nm wavelength. Pharmacokinetic studies of noscapine were performed in mice following intravenous bolus at 10 mg/kg and oral administrations at 75, 150, and 300 mg/kg. The standard curves for noscapine estimation were linear between 390 and 50,000 ng/ml (lower limit of quantification was 390 ng/ml) and the recovery was approximately 80%. Following 10 mg/kg intravenous dose, mean plasma concentrations of 7.88 microg/ml were achieved at 5 min in mice and declined with undetectable levels at 4 h. The mean total body clearance was 4.78 l/h. The mean volume of distribution (V (d)) was 5.05 l. Non-compartmental analysis yielded the mean area under the plasma concentration-time curve (AUC) for noscapine as 53.42, 64.08, and 198.35 h microg/ml reaching maximum plasma concentrations (C (max)) of 12.74, 23.24, and 46.73 microg/ml at a t (max) of 1.12, 1.50, and 0.46 h at the linearly increasing dose levels. A rapid and simple HPLC/UV method for the quantification of noscapine in plasma has been developed to study pharmacokinetics of noscapine at tumor-suppressive doses in the mouse. Since orally available anticancer drugs are rare, therefore, noscapine, an innocuous agent, having a mean oral bioavailability of 31.5% over the studied dose range merits its further advancement in humans for anticancer therapy.

Investigation of the TL response of [formula omitted]: [formula omitted] crystals to X and gamma radiation fields

Double potassium yttrium fluoride crystals doped with optically active rare earth ions have been recently shown to be attractive thermoluminescence (TL) materials for ionizing radiation dosimetry. In this context appropriate studies have been performed to test TL response of K 2 YF 5 crystals doped with Dy 3 + ions to photon radiation fields. Within the framework of this research K 2 YF 5 crystals doped with 0.2, 1.0, 2.0, 5.0 and 10.0 at% Dy 3 + as well as K 2 DyF 5 and undoped K 2 YF 5 crystals have been synthesized under hydrothermal conditions. Polished crystal platelets with thickness of about 1 mm have been irradiated with X and gamma rays in order to study TL sensitivity as well as dose and energy response properties of these compositions in terms of the Dy 3 + concentration. Within this concentration series, K 2 YF 5 crystals doped with 1.0 at% Dy 3 + have been found to have maximum TL response due to a main dosimetric TL peak, which can be deconvoluted in three TL glow peaks centered at 96.4, 104.9 and 130.7 ∘ C , with reasonable linearity behavior over the studied dose range and good reproducibility of dose measurements. The sensitivity increase is observed for previously gamma-sensitized samples and this sensitization process seems also to induce the appearing of the TL glow peak at 130.7 ∘ C . As it has been turned, the linear TL signal coefficient for K 2 Y 0.99 Dy 0.01 F 5 is comparable to that of a CaSO 4 :Mn TL dosemeter, irradiated with a 137Cs gamma radiation source at the same conditions. Photon energy dependence of TL response for K 2 Y 0.99 Dy 0.01 F 5 has been evaluated and it has been found that TL response of this composition to the 41.1 keV X-rays is 30 times higher than that to the 662 keV gamma rays. This fact points out that K 2 YF 5 crystals doped with Dy 3 + have potential as promising materials to be used for low-dose dosimetry in X-rays diagnostic or industrial radiography.

Single‐Dose and Multiple‐Dose Pharmacokinetics and Safety of Telbivudine After Oral Administration in Healthy Chinese Subjects

The pharmacokinetics of telbivudine, an L-nucleoside with potent activity against hepatitis B virus, was assessed in 42 healthy Chinese volunteers. Subjects were assigned to receive a single oral dose of 200, 400, or 800 mg telbivudine or repeat doses of 600 mg/d. Telbivudine was absorbed rapidly and exhibited dose-related plasma exposure. After reaching maximum concentration (C(max)) at a median time of 2.0 to 2.5 hours, plasma disposition of the drug was biphasic with a mean terminal half-life ranging from 39.4 to 49.1 hours. Telbivudine accumulated slightly after repeat doses, and steady state was reached after 5 to 6 consecutive doses of 600 mg/d. The mean steady-state C(max) and area under the plasma concentration-time curve over the dosing interval of telbivudine 600 mg were 3.7 microg/mL and 26.1 microg x h/mL, respectively. Cumulative urinary excretion of telbivudine over 32 hours represented 24.4% of the administered dose, with a mean renal clearance of 6.6 L/h. Telbivudine was well tolerated in the studied dose range in healthy Chinese subjects, with no pattern of dose-related clinical or laboratory adverse events.

Kairomonal Response of Predators to Three Pine Bast Scale Sex Pheromones

The kairomonal activity of the sex pheromones of three pine bast scales, Matsucoccus feytaudi, Matsucoccus josephi, and Matsucoccus matsumurae, as well as a new analog of the M. feytaudi sex pheromone, were investigated in pine forests of France, Portugal, and Italy. The response of the maritime pine bast scale predators, Elatophilus spp. and Hemerobius stigma, was used to test the influence of trapping methods, kairomone composition, and dose. Both predators showed significant attraction to all compounds except to the sex pheromone of M. josephi. Significant increase in captures was observed as a function of dose, and within the studied dose range, up to 2200 mug, no threshold saturation limits were observed for any of the attractive compounds. Trap design and size did not significantly influence predator captures, except for high population levels of Elatophilus crassicornis, when plate traps were more efficient than delta traps. Geographic variations were found in the kairomonal responses patterns of both predators, with the M. matsumurae sex pheromone being more attractive to the oriental populations from Corsica and Italy, whereas the western populations in Aquitaine and Portugal were more attracted to the M. feytaudi sex pheromone.

Safety and adverse event profile of duloxetine

Duloxetine is the first relatively balanced serotonin and noradrenaline re-uptake inhibitor to be widely available for three indications including: major depressive disorder, peripheral diabetic neuropathic pain and female stress urinary incontinence, although it is not currently approved for all indications in all countries. Generally, duloxetine is safe and well-tolerated across indications, with few reported serious side effects. Common adverse events are consistent with the pharmacology of the molecule and are mainly referable to the gastrointestinal and the nervous systems. The studied dose range is up to 400 mg/day (administered 200 mg b.i.d) but the maximum dose approved for marketing is 120 mg/day (administered 60 mg b.i.d). Duloxetine is eliminated (half-life = 12.1 hours) primarily in the urine after extensive hepatic metabolism by multiple oxidative pathways, methylation and conjugation. Duloxetine would not be expected to cause clinically significant inhibition of the metabolic clearance of drugs metabolised by P450 (CYP)3A, (CYP)1A2, (CYP)2C9, or (CYP)2C19, but would be expected to cause some inhibition of CYP 2D6. Duloxetine should not be used in combination CYP 1A2 inhibitors or nonselective, irreversible monoamine oxidase inhibitors. The purpose of this review is to provide an overview of some of the most important information related to safety and tolerability of duloxetine.

ESR identification of γ-irradiated redoxon and determination of ESR parameters of radicals produced in irradiated ascorbic acid

In the present work, electron spin resonance (ESR) identification of irradiated redoxon and its potential use as a normal and/or accidental dosimetric material were investigated in details. The ground redoxon samples exhibited a single weak resonance line of peak-to-peak width Δ H pp = 0.9 mT appearing at g = 2.0057. γ-Radiation produced many resonance lines beside four different intense lines (denoted as I 1, I 2, I 3 and I 4) of different spectral features in the studied dose range of 2.5–25 kGy. Experimental dose–response curves associated with I 1, I 2, I 3 and I 4 resonance lines were found to follow an exponential function. From stability and kinetic studies at room and above room temperatures it was concluded that radicals contributing to I 3 and I 4 resonance lines were more stable than the radical species contributing to I 1 and I 2 resonance lines. Simulation calculations based on the room temperature ESR intensity data of an ascorbic acid (active ingredient of redoxon) sample irradiated at 10 kGy was performed to determine the structure and spectral parameters of the radiation-induced radical species involved in the formation of experimental ESR spectrum of ascorbic acid. The contributions of these species to the ESR spectrum of irradiated redoxon were discussed.

Results of 2 phase I studies of intravenous (iv) pelitrexol (AG2037), a glycinamide ribonucleotide formyltransferase (GARFT) inhibitor, in patients (pts) with solid tumors

3075 Background: AG2037 is a rationally designed, novel inhibitor of GARFT, which is an essential enzyme in the de novo synthesis of purines, a critical process for cell growth. Methods: The primary objectives of these studies were to determine the maximum-tolerated dose (MTD) and recommended safe dose of AG2037 for Phase II studies (RP2D). AG2037 was given by bolus or slow iv push (every 3 weeks in Study-002 and weekly for 3 consecutive weeks every 4 weeks in Study-003) to pts with advanced solid tumors in cohorts of at least 3 patients at each dose level. The dose for the next cohort was increased by 100% if no drug related Grade 3 or worse toxicity was encountered, and by ∼50% if Grade 2 toxicity was observed. Results: 45 pts in Study-002 were treated at doses ranging from 1 to 576 mg/m2 and 49 were treated in Study-003 at doses ranging from 1 to 760 mg/m2. Study-002 was terminated before MTD was determined since mechanism-based toxicities appeared to correlate to drug exposure and not to peak concentration. For Study-003, at the highest dose (720 mg/m2), Grade 3 anemia, thrombocytopenia, diarrhea, fatigue, mucosal inflammation, dehydration, hyponatremia, confusion, or mental status changes were observed in 1 or 2 of 6 pts. There were no grade 4 toxicities. The MTD was 540 mg/m2/infusion. Grade 3 nausea was the only Grade 3 or 4 related adverse events in the 7 patients treated at MTD. The pharmacokinetics of AG2037 were linear over the studied dose range; plasma concentrations declined in a triexponential manner with a terminal half-life of 85 hours and were inversely proportional to creatinine clearance. RBC polyglutamate increased with dose to a maximum concentration and showed minimal decline between doses. One pt with colorectal cancer had a partial response by RECIST at 6 mg/m2 (Study-003). Conclusions: The RP2D for AG2037 is 540 mg/m2/week for 3 consecutive weeks, every 4 weeks. Expected adverse events on this schedule include mild to moderate myelosuppression, mucositis, diarrhea, anorexia, fatigue, and peripheral neuropathy. Further study in colorectal and other solid tumors is warranted. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer, Inc. Pfizer, Inc. Pfizer, Inc. Pfizer, Inc.