Clinical Dose Range Research Articles

Pharmacokinetic/Pharmacodynamic Modeling of the PDE4 Inhibitor TAK‐648 in Type 2 Diabetes: Early Translational Approaches for Human Dose Prediction

TAK‐648 is a PDE4 inhibitor with demonstrated preclinical antidiabetic properties. Our objective was to develop a translational pharmacokinetic/pharmacodynamic (PK/PD) model for human type 2 diabetes (T2D) dose prediction using HbA1c results from a db/db mouse study. Estimated parameters in combination with tPDE4i values calculated for the clinical roflumilast dose of 500 μg were used to translate preclinical effects of TAK‐648 to required exposure in humans. A first‐in‐human study with single TAK‐648 doses of 0.05–0.85 mg in healthy volunteers yielded mean maximum TAK‐648 concentrations (Cmax) and area under the curve (AUC) values from 0.62–11.9 μg/L and 4.58–93.8 μg*h/L, respectively. Based on the performed pharmacokinetic/pharmacodynamic analysis and clinical PK results, clinical efficacy would be expected at a daily dose of 0.1 mg, which is well within the investigated clinical dose range. This result significantly enhanced the confidence in TAK‐648 for type 2 diabetes treatment and underlines the necessity of translational approaches in early preclinical phases.

A pharmacological overview of lamotrigine for the treatment of epilepsy

ABSTRACTIntroduction: Epilepsy is one of the most common neurological disorders, affecting about 2% of the population worldwide. Lamotrigine (LTG) is a second generation anti-epileptic drug (AED) with broad spectrum of activity, a favourable side-effect profile, simpler dosing than earlier drugs and efficacious in diverse epilepsy syndromes.Areas covered: The present review focuses on pharmacodynamics, pharmacokinetics, clinical efficacy, safety and tolerability of LTG and its effect on cognition, psychiatry, quality of life, women and pregnancy along with effect of enzyme inducing and enzyme inhibiting drugs over LTG and their effect on serum level fluctuations by collecting data from various studies over the years until 2016.Expert commentary: Results from various studies and clinical trials indicate that LTG possessed a favourable profile of anticonvulsant activity and good tolerability as a monotherapy/or add-on therapy in children and adult patients against several types of seizures and syndromes. It has wide clinical dose range with favourable pharmacokinetic properties making it an excellent therapeutic option in epilepsy.

Using Model-Based "Learn and Confirm" to Reveal the Pharmacokinetics-Pharmacodynamics Relationship of Pembrolizumab in the KEYNOTE-001 Trial.

Evaluation of pharmacokinetic/pharmacodynamic (PK/PD) properties played an important role in the early clinical development of pembrolizumab. Because analysis of data from a traditional 3 + 3 dose‐escalation design revealed several critical uncertainties, a model‐based approach was implemented to better understand these properties. Based on anticipated scenarios for potency and PK nonlinearity, a follow‐up study was designed and thoroughly evaluated. Execution of 14,000 virtual trials led to the selection and implementation of a robust design that extended the low‐dose range by 200‐fold. Modeling of the resulting data demonstrated that pembrolizumab PKs are nonlinear at <0.3 mg/kg every 3 weeks, but linear in the clinical dose range. Saturation of ex vivo target engagement in blood began at ≥1 mg/kg every 3 weeks, and a steady‐state dose of 2 mg/kg every 3 weeks was needed to reach 95% target engagement, supporting examination of 2 mg/kg every 3 weeks in ongoing trials in melanoma and other advanced cancers.

Clinical Pharmacokinetics and Pharmacodynamics of Afatinib.

Afatinib is an oral, irreversible ErbB family blocker that covalently binds to the kinase domains of epidermal growth factor receptor (EGFR), human EGFRs (HER) 2, and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation. Studies in healthy volunteers and patients with advanced solid tumours have shown that once-daily afatinib has time-independent pharmacokinetic characteristics. Maximum plasma concentrations of afatinib are reached approximately 2–5 h after oral administration and thereafter decline, at least bi-exponentially. Food reduces total exposure to afatinib. Over the clinical dose range of 20–50 mg, afatinib exposure increases slightly more than dose proportional. Afatinib metabolism is minimal, with unchanged drug predominantly excreted in the faeces and approximately 5 % in urine. Apart from the parent drug afatinib, the major circulation species in human plasma are the covalently bound adducts to plasma protein. The effective elimination half-life is approximately 37 h, consistent with an accumulation of drug exposure by 2.5- to 3.4-fold based on area under the plasma concentration–time curve (AUC) after multiple dosing. The pharmacokinetic profile of afatinib is consistent across a range of patient populations. Age, ethnicity, smoking status and hepatic function had no influence on afatinib pharmacokinetics, while females and patients with low body weight had increased exposure to afatinib. Renal function is correlated with afatinib exposure, but, as for sex and body weight, the effect size for patients with severe renal impairment (approximately 50 % increase in AUC) is only mildly relative to the extent of unexplained interpatient variability in afatinib exposure. Afatinib has a low potential as a victim or perpetrator of drug–drug interactions, especially with cytochrome P450-modulating agents. However, concomitant treatment with potent inhibitors or inducers of the P-glycoprotein transporter can affect the pharmacokinetics of afatinib. At a dose of 50 mg, afatinib does not have proarrhythmic potential.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-016-0440-1) contains supplementary material, which is available to authorized users.

Safety and pharmacodynamic dose response of short-term prednisone in healthy adult subjects: a dose ranging, randomized, placebo-controlled, crossover study.

BackgroundGlucocorticoids (GCs), such as prednisone, are the standard of care for several inflammatory and immunologically mediated diseases, but their chronic systemic administration is severely limited by serious adverse effects that are both dose and time dependent. Short-term treatment (7–14 days) with oral prednisone is used for many acute inflammatory and allergic conditions. This study was conducted to characterize the safety and pharmacodynamic (PD) dose–response of a 7-day course of oral prednisone on biomarkers of GC receptor agonism.MethodsIn this randomized, single-blind, placebo-controlled, crossover study (A9001309), 37 healthy subjects received placebo or a prednisone dose from 2.5–60 mg daily over 7 days in each of three treatment periods. White blood cell counts and plasma samples for measuring cortisol, osteocalcin and procollagen type 1 N-propeptide (P1NP) were obtained at 2, 4, 8, and 12 h post-dose on Day 1, immediately prior to dosing on Days 1, 2, and 4, and at nominal dosing time on Days 0 and 8. Urine samples for urinary N-terminal cross-linked telopeptide of type 1 collagen (uNTX) were collected on Days 0, 1, 2, 4, and 8. Serum samples for adiponectin were obtained prior to dosing on days 0, 1, 4 and 8.ResultsDaily doses of prednisone up to 60 mg resulted in dose- and time-dependent decreases in plasma osteocalcin, plasma P1NP, serum cortisol, and absolute blood eosinophil counts. Absolute blood neutrophil counts increased, while blood lymphocyte counts rebounded to an increased level following an initial rapid decrease after dosing. An increase was observed for uNTX and adiponectin. The incidence of adverse effects with prednisone was not dose related, and nervous system disorders, mainly headache, were the most frequently reported adverse effects.ConclusionsThis characterization provides important and relevant information on safety and PD responses of short-term prednisone dosing over the commonly-used clinical dose range, and also provides a reference for early clinical development of dissociated agents targeting a differentiated PD profile.Trial registration numberNCT02767089 (retrospectively registered: 21 April 2016).

Pharmacokinetics and Pharmacodynamics of Omarigliptin, a Once-Weekly Dipeptidyl Peptidase-4 (DPP-4) Inhibitor, After Single and Multiple Doses in Healthy Subjects.

The pharmacokinetics (PK) and pharmacodynamics (PD) of omarigliptin, a novel once‐weekly DPP‐4 inhibitor, were assessed following single and multiple doses in healthy subjects. Absorption was rapid, and food did not influence single‐dose PK. Accumulation was minimal, and steady state was reached after 2 to 3 weeks. Weekly (area under the curve) AUC and Cmax displayed dose proportionality within the dose range studied at steady state. The average renal clearance of omarigliptin was ∼2 L/h. DPP‐4 inhibition ranged from ∼77% to 89% at 168 hours following the last of 3 once‐weekly doses over the dose range studied. Omarigliptin resulted in ∼2‐fold increases in weighted average postprandial active GLP‐1. Omarigliptin acts by stabilizing active GLP‐1, which is consistent with its mechanism of action as a DPP‐4 inhibitor. Administration of omarigliptin was generally well tolerated in healthy subjects, and both the PK and PD profiles support once‐weekly dosing. A model‐based assessment of QTc interval risk from the single ascending dose study predicted a low risk of QTc prolongation within the likely clinical dose range, a finding later confirmed in a thorough QT trial.

Thermoluminescence Characteristics of Cylindrical Optical Fibers with Different Diameters in Radiation Dosimetry Subjected to Electron Irradiation

Thermoluminescence (TL) characteristics for various cross-sections of 6 mole% of tailor-made Ge-doped cylindrical optical fibers were determined. The general TL characteristic i.e., dose rate dependence, energy dependence, dose response and reproducibility of the samples have been investigated. The samples were irradiated using electron beam (Linac) and been exposed to dose ranging from 1 to 4 Gy. The cylindrical optical fibers provide highly linear dose response within the clinical relevant dose range, independence of radiation energy over the range of energies investigated, independence of dose rate and excellent reproducibility. This research shows that germanium doped silica fibers have high potential of dosimetric properties and suitable as TL-mode detectors in instances of radiotherapy (clinical dosimetry).

EPR/alanine dosimetry for two therapeutic proton beams

In this work the analysis of the electron paramagnetic resonance (EPR) response of alanine pellets exposed to two different clinical proton beams employed for radiotherapy is performed. One beam is characterized by a passive delivery technique and is dedicated to the eyes treatment (OPTIS2 beam line). Alanine pellets were irradiated with a 70MeV proton beam corresponding to 35mm range in eye tissue. We investigated how collimators with different sizes and shape used to conform the dose to the planned target volume influence the delivered dose. For this purpose we performed measurements with varying the collimator size (Output Factor) and the results were compared with those obtained with other dosimetric techniques (such as Markus chamber and diode detector). This analysis showed that the dosimeter response is independent of collimator diameter if this is larger than or equal to 10mm. The other beam is characterized by an active spot-scanning technique, the Gantry1 beam line (maximum energy 230MeV), and is used to treat deep-seated tumors. The dose linearity of alanine response in the clinical dose range was tested and the alanine dose response at selected locations in depth was measured and compared with the TPS planned dose in a quasi-clinical scenario. The alanine response was found to be linear in the dose in the clinical explored range (from 10 to 70Gy). Furthermore, a depth dose profile in a quasi-clinical scenario was measured and compared to the dose computed by the Treatment Planning System PSIPLAN. The comparison of calibrated proton alanine measurements and TPS dose shows a difference under 1% in the SOBP and a “quenching” effect up to 4% in the distal part of SOBP. The positive dosimetric characteristics of the alanine pellets confirm the feasibility to use these detectors for “in vivo” dosimetry in clinical proton beams.

Commissioning optically stimulated luminescence in vivo dosimeters for fast neutron therapy.

Clinical in vivo dosimeters intended for use with photon and electron therapies have not been utilized for fast neutron therapy because they are highly susceptible to neutron damage. The objective of this work was to determine if a commercial optically stimulated luminescence (OSL) in vivo dosimetry system could be adapted for use in fast neutron therapy. A 50.5 MeV fast neutron beam generated by a clinical neutron therapy cyclotron was used to irradiate carbon doped aluminum oxide (Al2O3:C) optically simulated luminescence dosimeters (OSLDs) in a solid water phantom under standard calibration conditions, 150 cm SAD, 1.7 cm depth, and 10.3 × 10.0 cm field size. OSLD fading and electron trap depletion studies were performed with the OSLDs irradiated with 20 and 50 cGy and monitored over a 24-h period to determine the optimal time for reading the dosimeters during calibration. Four OSLDs per group were calibrated over a clinical dose range of 0-150 cGy. OSLD measurement uncertainties were lowered to within ±2%-3% of the expected dose by minimizing the effect of transient fading that occurs with neutron irradiation and maintaining individual calibration factors for each dosimeter. Dose dependent luminescence fading extended beyond the manufacturer's recommended 10 min period for irradiation with photon or electron beams. To minimize OSL variances caused by inconsistent fading among dosimeters, the observed optimal time for reading the OSLDs postirradiation was between 30 and 90 min. No field size, wedge factor, or gantry angle dependencies were observed in the OSLDs irradiated by the studied fast neutron beam. Measurements demonstrated that uncertainties less than ±3% were attainable in OSLDs irradiated with fast neutrons under clinical conditions. Accuracy and precision comparable to clinical OSL measurements observed with photons can be achieved by maintaining individual OSLD calibration factors and minimizing transient fading effects.

Comparative Analysis of Whole-Genome Gene Expression Changes in Cultured Human Embryonic Stem Cells in Response to Low, Clinical Diagnostic Relevant, and High Doses of Ionizing Radiation Exposure.

The biological effects of low-dose ionizing radiation (LDIR) exposure in humans are not comprehensively understood, generating a high degree of controversy in published literature. The earliest stages of human development are known to be among the most sensitive to stress exposures, especially genotoxic stresses. However, the risks stemming from exposure to LDIR, particularly within the clinical diagnostic relevant dose range, have not been directly evaluated in human embryonic stem cells (hESCs). Here, we describe the dynamics of the whole genome transcriptional responses of different hESC lines to both LDIR and, as a reference, high-dose IR (HDIR). We found that even doses as low as 0.05 Gy could trigger statistically significant transient changes in a rather limited subset of genes in all hESCs lines examined. Gene expression signatures of hESCs exposed to IR appear to be highly dose-, time-, and cell line-dependent. We identified 50 genes constituting consensus gene expression signature as an early response to HDIR across all lines of hESC examined. We observed substantial differences in biological pathways affected by either LDIR or HDIR in hESCs, suggesting that the molecular mechanisms underpinning the responses of hESC may fundamentally differ depending on radiation doses.

Microdosimetric spread for cell-sized targets exposed to ⁶⁰Co, ¹⁹²Ir and ¹²⁵I sources.

The magnitude of the spread in specific energy deposition per cell may be a confounding factor in dose-response analysis motivating derivation of explicit data for the most common brachytherapy isotopes (125)I and (192)Ir, and for (60)Co radiation frequently used as reference in RBE studies. The aim of this study is to analyse the microdosimetric spread as given by the frequency distribution of specific energy for a range of doses imparted by (125)I, (192)Ir and (60)Co sources. An upgraded version of the Monte Carlo code PENELOPE was used for scoring energy deposition distributions in liquid water for each of the radiation qualities. Frequency distributions of specific energy were calculated according to the formalism of Kellerer and Chmelevsky. Results indicate that the magnitude of the microdosimetric spread increases with decreasing target size and decreasing energy of the radiation quality. Within the clinical relevant dose range (1 to 100 Gy), the spread does not exceed 4 % for (60)Co, 5 % for (192)Ir and 6 % for (125)I. The frequency distributions can be accurately approximated with symmetrical normal distributions at doses down to 0.2 Gy for (60)Co, 0.1 Gy for (192)Ir and 0.08 Gy for (125)I.

The suitable dose range for the calibration of EBT2 film by the PDD method with a comparison of two curve fitting algorithms

EBT2 film is a convenient dosimetry quality-assurance (QA) tool with high 2D dosimetry resolution and a self-development property for use in verifications of radiation therapy treatment planning and special projects; however, the user will suffer from a relatively higher degree of uncertainty (more than ±6% by Hartmann et al. [29]), and the trouble of cutting one piece of film into small pieces and then reintegrating them each time. To prevent this tedious cutting work, and save calibration time and budget, a dose range analysis is presented in this study for EBT2 film calibration using the Percentage–Depth–Dose (PDD) method. Different combinations of the three dose ranges, 9–26cGy, 33–97cGy and 109–320cGy, with two types of curve fitting algorithms, film pixel values and net optical densities converting into doses, were tested and compared. With the lowest error and acceptable inaccuracy of less than 3cGy for the clinical dose range (9–320cGy), a single film calibrated by the net optical density algorithm with the dose range 109–320cGy was suggested for routine calibration.

Optimized Detector Angular Configuration Increases the Sensitivity of X-ray Fluorescence Computed Tomography (XFCT).

In this work, we demonstrated that an optimized detector angular configuration based on the anisotropic energy distribution of background scattered X-rays improves X-ray fluorescence computed tomography (XFCT) detection sensitivity. We built an XFCT imaging system composed of a bench-top fluoroscopy X-ray source, a CdTe X-ray detector, and a phantom motion stage. We imaged a 6.4-cm-diameter phantom containing different concentrations of gold solution and investigated the effect of detector angular configuration on XFCT image quality. Based on our previous theoretical study, three detector angles were considered. The X-ray fluorescence detector was first placed at 145 (°) (approximating back-scatter) to minimize scatter X-rays. XFCT image quality was compared to images acquired with the detector at 60 (°) (forward-scatter) and 90 (°) (side-scatter). The datasets for the three different detector positions were also combined to approximate an isotropically arranged detector. The sensitivity was optimized with detector in the 145 (°) back-scatter configuration counting the 78-keV gold Kβ1 X-rays. The improvement arose from the reduced energy of scattered X-ray at the 145 (°) position and the large energy separation from gold K β1 X-rays. The lowest detected concentration in this configuration was 2.5 mgAu/mL (or 0.25% Au with SNR = 4.3). This concentration could not be detected with the 60 (°) , 90 (°) , or isotropic configurations (SNRs = 1.3, 0, 2.3, respectively). XFCT imaging dose of 14 mGy was in the range of typical clinical X-ray CT imaging doses. To our knowledge, the sensitivity achieved in this experiment is the highest in any XFCT experiment using an ordinary bench-top X-ray source in a phantom larger than a mouse ( > 3 cm).

P.2.f.014 Levomilnacipran inhibits both norepinephrine and serotonin reuptake across the clinical dose range

P.2.f.014 Levomilnacipran inhibits both norepinephrine and serotonin reuptake across the clinical dose range

Dosing and effectiveness of ketamine anesthesia for electroconvulsive therapy (ECT): a case series.

To provide additional data about the clinical efficacy and dosing range for ketamine used as the induction agent in electroconvulsive therapy (ECT). We reviewed the clinical data in our academic hospital ECT service over the last four years for patients who had received ketamine as the sole, or adjunctive, anesthesia induction agent. We extracted clinical data about antidepressant response as well as absolute and weight-based dosing for ketamine. We found nine patients who were treated with ketamine as the anesthetic at some point during the course of their treatment (eight as the sole agent, one as adjunctive). The median induction dose for ketamine was 1.1 mg/kg. For most patients, there was demonstrable clinical benefit. Ketamine has a role as an alternative induction anesthetic agent in ECT. Our case series adds to the literature on the concomitant use of ECT and ketamine.

Population pharmacokinetics of trastuzumab emtansine (T-DM1), a HER2-targeted antibody-drug conjugate, in patients with HER2-positive metastatic breast cancer: clinical implications of the effect of covariates.

Purpose Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate comprising the humanized monoclonal antibody trastuzumab linked to DM1, a highly potent cytotoxic agent. A population pharmacokinetic (PK) analysis was performed to estimate typical values and interindividual variability of T-DM1 PK parameters and the effects of clinically relevant covariates.MethodsSerum samples were collected from 671 patients with human epidermal growth factor receptor 2-positive locally advanced or metastatic breast cancer (MBC) who received single-agent T-DM1 in five phase I to phase III studies. Nonlinear mixed-effects modeling with the first-order conditional estimation method was used.ResultsA linear two-compartment model with first-order elimination from the central compartment described T-DM1 PKs in the clinical dose range. T-DM1 elimination clearance was 0.676 L/day, volume of distribution in the central compartment (V c) was 3.127 L, and terminal elimination half-life was 3.94 days. Age, race, region, and renal function did not influence T-DM1 PK. Given the low-to-moderate effect of all statistically significant covariates on T-DM1 exposure, none of these covariates is expected to result in a clinically meaningful change in T-DM1 exposure.ConclusionsT-DM1 PK properties are consistent and predictable in patients. A further refinement of dose based on baseline covariates other than body weight for the current 3.6 mg/kg regimen would not yield clinically meaningful reductions in interindividual PK variability in patients with MBC.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-014-2500-2) contains supplementary material, which is available to authorized users.

SAT0539 Novel Bifunctional Inhibitors of Xanthine Oxidase and URAT1 Induce Profound Hypouricemia in Human Subjects

BackgroundWe have shown that a prototype anticancer drug (RLBN1001) induced marked hypouricemia in studies comprising >350 human subjects. Preliminary exploration suggested dual effects on uric acid (UA) production and excretion.ObjectivesGiven...

SU-E-T-120: Dosimetric Characteristics Study of NanoDotâ,,¢ for In-Vivo Dosimetry

Purpose: The purpose of the study was to analyze the dosimetric characteristics (energy dependence, reproducibility and dose linearity) of nanoDot™ optically stimulated luminescence dosimeters (OSLDs) and validate their potential use during in-vivo dosimetry, specifically TBI. The manufacturer stated accuracy is ±10% for standard nanoDot™. Methods: At AKUH, the InLight microStar OSL dosimetry system for patient in-vivo dosimetry is in use since 2012. Twenty-five standard nanoDot™ were used in the analysis. Sensitivity and reproducibility was tested in the first part with 6MV and 18 MV Varian x-ray beams. Each OSLD was irradiated to 100cGy dose at nominal SSD (100 cm). All the OSLDs were read 3 times for average reading. Dose linearity and calibration were also performed with same beams in common clinical dose range of 0 - 500 cGy. In addition, verification of TBI absolute dose at extended SSD (500cm) was also performed. Results: The reproducibility observed with the OSLD was better than the manufacturer stated limits. Measured doses vary less than ±2% in 19(76%) OSLDs, whereas less than ±3% in 6(24%) OSLDs. Their sensitivity was approximately 525 counts per cGy. Better agreement was observed between measurements, with a standard deviation of 1.8%. A linear dose response was observed withmore » OSLDs for both 6 and 18MV beams in 0 - 500 cGy dose range. TBI measured doses at 500 cm SSD were also confirmed to be within ±0.5% and ±1.3% of the ion chamber measured doses for 6 and 18MV beams respectively. Conclusion: The dosimetric results demonstrate that nanoDot™ can be potentially used for in-vivo dosimetry verification in various clinical situations, with a high degree of accuracy and precision. In addition OSLDs exhibit better dose reproducibility with standard deviation of 1.8%. There was no significant difference in their response to 6 and 18MV beams. The dose response was also linear.« less

Effect of Green Tea Extract on the Interferon-Induced Testicular Apoptosis in the Adult Albino Rat: Immunohistochemical and Electron Microscopic Study

Background: Interferons (IFNs) are widely used in the treatment of various diseases and can disrupt spermatogenesis and inhibition Leydig cell steroidogenesis through the formation of reactive oxygen species (ROSs) that cause oxidative stress. Aim of the work: In this study we examine the effect of (IFN) on rat spermatogonia and investigate the possible protective effect of Grean tea on (IFN)-induced spermatogonia appotosis. Material and Methods: Forty-eight adult male albino rats (240-280 g) were used in this study. They were divided into three groups. Group I in which rats were served as a control and were given sterile normal saline. The rats in Group II were given 7.500 units of interferon (INF) α-2β, considered in clinical treatment dose range, 3 times weekly under inhalation anesthesia for 2 month (Group II a) and 3 month (Group II b). Group III received Green tea extract and interferon α-2β in the same dose of group (II) for 2 month (Group III a) and 3 month (Group III b). 200 mg of green tea extract was dissolved in distal water and solution was administrated orally through gastric tube at dose level of (40 mg/k.g.b.w.). At the end of the 2 and 3 month respectively, bilateral orchiectomy was performed through standard ilioinguinal incisions and the rats were sacrified by pentobarbital overdose (200 mg=kg) inhalation. The testes were removed and separated. A part of one testis was fixed in Bouin fixative to be used for histopathological and immunohistochemical studies for p53 and the other part was used in a fresh state to determine the level of the Superoxide Dismutase (SOD). The other testis was fixed in 1% gluteraldehyde and 4% formaldehyde in (pH 7.4) for at least 2 hours to overnight. Ultrathin sections processed for transmission electron microscopic studies. Results: Interferon induced testicular damage that is revealed by loss of testicular architecture through Hx. and E. stained sections, Immunohistochemical stained sections against p53 and the electron microscopic examination. These findings were accompanied by significant reduction in diameter of seminiferous tubules and thickness of the germinal epithelium with significant reduction in SOD. Otherwise, the green tea extract definitely reverse the above mentioned findings with improvement of testicular architecture and significant increase in diameter of seminiferous tubules, thickness of the germinal epithelium and elevated SOD. The mean of the diameter of the seminiferous tubules of Group IIa showed a significant decrease by nearly 34% in comparison to Group IIb showed a higher significant decrease by nearly 43%. The mean of the thickness of the seminiferous tubules of Group IIa showed a significant reduction by nearly 33% while in Group IIb showed a higher significant reduction by nearly 50%. The mean of the level of the Superoxide Dismutase in Group IIa showed significant decrease by nearly the half while in Group IIb revealed a higher significant decrease by nearly 59%. The mean of the diameter of the seminiferous tubules in Group IIIa showed a significant increase by nearly 32% and by nearly 43% in Group IIIb. The mean of the thickness of the seminiferous tubules in Group IIIa showed significant increase by nearly 11% while in Group IIIb the significant increase was by nearly 45%. The mean of the level of the Superoxide Dismutase of the seminiferous tubules in Group IIIa did not show significant increase while in Group IIIb revealed a higher significant increase by nearly 48% Group IIIb. Conclusion: The green tea extract has a powerful antioxidant effect that can reverse the damage caused

Vessel Size Imaging (VSI) by Robust Magnetic Resonance (MR) Relaxometry: MR-VSI of Solid Tumors in Correlation with Immunohistology and Intravital Microscopy

The aim of this study was to evaluate a robust magnetic resonance (MR) vessel size imaging (VSI) method for the noninvasive assessment of mean vessel size in solid tumors in a clinical dose range of ultrasmall superparamagnetic particles of iron oxide (USPIO). Therefore, USPIO-enhanced MR-VSI was performed on DU-4475, MDA-MB-435, and EOMA tumor-bearing mice xenografts with known differences in angiogenic activity and vessel morphology. MR results were compared to vessel sizes determined by immunohistochemistry (anti-CD31) and by intravital microscopy (IVM). MR-VSI revealed significantly different mean vessel sizes between the xenograft models at both USPIO doses (DU-4475: 20.6 ± 4.9 μm; MDA-MB-435: 37.4 ± 8.8 μm; and EOMA: 60.3 ±9.6 μm at 80 μmol/kg; p < .05). Immunohistochemistry revealed lower values for all tumor entities, whereas the size distribution was in line with MR-measurements. IVM corroborated the MR results for DU-4475 and MDA-MB435, but showed similar vessel sizes for MDA-MB-435 and EOMA. Our MR-VSI method allowed a noninvasive estimation of the mean vessel size in mice xenograft solid tumors with variable vascularity using a clinically relevant USPIO dose range.