Studied Dose Range Research Articles

5'-Noraristeromycin Repurposing: Well-known S-Adenosyl-L-homocysteine Hydrolase Inhibitor As a Potential Drug Against Leukemia

5ˊ-Noraristeromycin as a racemic mixture of enantiomers was found to exhibit a pronounced cytotoxic effect on leukemia cells; IC50 for the Jurkat, K562, and THP-1 cell lines was 7.3, 1.3, and 3.7 μM, respectively. The general toxicity of 5'-noraristeromycin was studied in experiments on white mice upon single-dose intragastric administration; toxicometric parameters were determined, and the clinical and pathomorphological presentation of acute intoxication was studied. LD50 of the substance was shown to be 63.2 (52.7÷75.8) mg/kg; LD16, 44.7 mg/kg, and LD84, 89.4 mg/kg. Administration of the substance at a dose within the studied dose range is accompanied by systemic damage to the internal organs and tissues of the experimental animals.

Investigating thermoluminescence signal saturation in quartz and feldspar using emission spectrometry

Luminescence-based thermometry and dating often requires determination of the saturation level for specific signals and the corresponding dose. However, previous studies found non-monotonic dose responses for some monochromatic thermoluminescence (TL) and optically stimulated luminescence (OSL) signals from quartz as well as spectral overlap of emission bands, substantially complicating data interpretation. Therefore, the present study examines (1) the variability in the TL emission spectrum of quartz and feldspar from bedrock and sediment of different provenances and, (2) the saturation characteristics of the blue emission band for both quartz and feldspar in the dose range from 0.25 kGy to 50 kGy. The experimental results confirm differences in the spectra which appear to be characteristic of their geological origin and chemical composition. Spectral analysis shows that in the temperature range 175–220 °C the blue emission band at ∼2.5 eV dominates over other bands for all quartz samples studied. A broad UV-blue TL signal peaking at ∼2.5−3.0 eV and composed of probably three overlapping, individual bands is characteristic for K-feldspar, while one Na-feldspar exhibits an additional band at ∼2.2 eV.In the studied dose range, the emissions at ∼2.5 eV and ∼2.6 eV increase as a function of dose up to 6 kGy for both quartz and feldspar. A difference in dose response was observed for high doses (>6 kGy) where feldspar samples reached a stable saturation level while for quartz the blue emission band intensity decays until 50 kGy after having attained a maximum. Our results suggest the suitability of feldspar TL for palaeothermometry and thermochronometry from the perspective of signal saturation characteristics. However, the spectral overlap of several bands in the UV-blue emission requires careful optical filter selection to isolate the signal of interest. The non-monotonic dose response of the ∼2.5 eV emission of quartz around 200 °C glow curve temperature probably precludes its use for temperature sensing based on relative trap saturation levels.

Molecular mechanisms of neutron radiation dose effects on M1 generation peas

The dose effect of radiation has long been a topic of concern, but the molecular mechanism behind it is still unclear. In this study, dried pea seeds were irradiated with 252Cf fission neutron source. Through analyzing the transcriptome and proteome of M1 generation pea (Pisum sativum L.) leaves, we studied the molecular rule and mechanism of neutron dose effect. Our results showed three important rules of global gene expression in the studied dose range. The rule closely related to the neutron absorbed dose at the transcription and translation levels is: the greater the difference in neutron absorbed dose between two radiation treatment groups, the greater the difference in differential expression between the two groups and the control group. We also obtained important sensitive metabolic pathways of neutron radiation, as well as related key genes. Furthermore, the overall molecular regulation mechanism of dose effect was revealed based on the main functional items obtained. Our research results can be applied to appropriate radiation dose estimation and agricultural production practice.

Investigation of structural and TL kinetic parameters of smartphone screen protector glasses for applications in retrospective dosimetry

The study evaluated the structural and thermoluminescence (TL) kinetic parameters of smartphone screen protector glasses in order to use them for post-accident dose reconstruction from unplanned nuclear events. The fact that most individuals use mobile phones in working environments including nuclear power plant sites, served as the impetus for the study. The TL glow curves indicate the physical properties of the defects involved in the luminescence process; therefore, they have been analyzed to study the TL kinetic parameters by employing peak shape, initial rise and glow curve deconvolution method within the dose ranges from 2 to 50 Gy. The geometric factor (μg) ranges between 0.46 and 0.56, suggesting that Chen's general-order method can be used to compute the kinetic parameters, including activation energy (E), frequency factor (s) and trap lifetime (τ). The examined trapping parameters (E = 0.33–0.57 eV, s = 5.22E+03–8.65E+06 s−1 for peak shape and E = 0.36–0.96 eV, s = 2.90E+04–1.88E+11 s−1 for initial rise methods) suggest promise for TL dosimetry applications. Additionally, the observed lifetime (τ = 4.88E+5 s) implies the feasibility of dose reconstruction even several days after an accident, making it suitable for retrospective dosimetry. Micro-Raman spectroscopy revealed a clear correlation between increasing gamma radiation dose and microstructural damage. The analysis of intensity ratio (ID/ISi) for other components to silica, along with the area of deconvoluted micro-Raman spectra in high-frequency regions, indicated dose-dependent structural modifications and internal defect annealing. Further confirmation of structural alterations within the studied dose range was obtained through the analysis of crystallite size (Lc), dislocation density (δ), lattice strain (ɛ) and FWHM (Full Width at Half Maximum) from XRD (X-ray diffraction) patterns. These findings collectively suggest the potential of smartphone screen protector glass as a viable material for emergency dosimetry applications.

Nonlinear Pharmacokinetics of Topical Flurbiprofen Gel in a Phase I Study Among Chinese Healthy Adults.

PDX-02 (Flurbiprofen sodium) is a topical nonsteroidal anti-inflammatory drug in gel formulation for local analgesia and anti-inflammation. A Phase I clinical trial was conducted to assess the safety, tolerability, and pharmacokinetics of single and multiple doses of PDX-02 gel in Chinese healthy adults. The trial comprised three parts: (1) a single-dose ascending study with three dose levels (0.5%, 1% to 2% PDX-02 gel) applied on a 136 cm2 skin area; (2) a multiple-dose study with either 1% or 2% PDX-02 gel applied on a 136 cm2 skin area for 7 consecutive days; and (3) a high dose group with 2% PDX-02 gel on an 816 cm2 skin area and a frequent multiple dose group with 2% PDX-02 gel on a 272 cm2 skin area four times a day for 7 consecutive days. The safety, tolerability and pharmacokinetics of the PDX-02 gel were evaluated in each part. A total of sixty participants completed the trial, with all adverse events recovered and all positive skin reaction being transient and recovered. The overall absorption of topical PDX-02 gel was slow with a mean peak time exceeding 9h. The elimination rate remained consistent between dose groups. A less-than-dose-proportional nonlinear pharmacokinetics relationship was observed within the studied dose range, and this is likely due to the autoinduction of skin first-pass metabolism. The topical PDX-02 gel showed favorable safety and tolerability in both single and multiple dosing studies, with a less-than-dose-proportional nonlinear pharmacokinetics observed.

Safety assessment and determination of a maximally tolerated dose of an RAS-GTPase inhibitor (iRAS) in the treatment of gastrointestinal tumors: preliminary results of the phase I trial

Background: Ras oncogene mutations leading to hyperactivation of the MAPK/ERK signaling pathway occur in 25% of all human tumors, and for gastrointestinal tumors, the frequency of Ras mutations amounts to 60%. The introduction of a Ras-GTPase inhibitor into clinical practice would increase the effectiveness of the treatment of socially significant diseases such as stomach and intestinal cancer.
 Aim: To select the optimal dose with a subsequent assessment of the safety of iRAS when administered to patients with gastrointestinal tract tumors, including those with peritoneal carcinomatosis.
 Materials and methods: This was a prospective open-label non-randomized phase I study for the assessment of safety and tolerability, with an adaptive design and determination of the maximally tolerated dose of the iRAS. Three dose levels were used (0.45 mg/kg, 0.9 mg/kg, 1.8 mg/kg) according to the "3 + 3" scheme. The study included 11 patients after surgery for stomach or colorectal cancer. The patients were administered PIPAC therapy with iRAS twice with a 7-days interval. The study duration was 28 ± 1 days. During the study, the patient monitoring included physical examination, assessment of vital signs, electrocardiography and echocardiography, laboratory parameters (hematology, clinical chemistry, coagulation tests, and urine analysis).
 Results: The anti-tumor iRAS agent demonstrated satisfactory tolerability of all doses studied, including the maximal 1.8 mg/kg dose. Vital sign and laboratory abnormalities were clinically non-significant and did not require additional therapeutic interventions. Statistically significant abnormalities were registered for total protein (p = 0.00028), white blood cell counts (p = 0.007), lymphocyte counts (p = 0.0008), and a number of other blood parameters; however, most of these abnormalities were within the physiological normal ranges. Vital signs such as electrocardiography and echocardiography parameters remained stable throughout the entire follow-up period (28 days after administration of the drug). There were short-term rises in body temperature, minor pains in the postoperative scar area.
 Conclusion: This trial of safety and tolerability of iRAS showed that no cases of dose-limiting toxicity in the studied dose range. The 1.8 mg/kg dose can be recommended for further clinical studies.

Thermoluminescence studies of Pakistani limestone pellets for X-rays

The quest to identify low-cost thermoluminescence (TL) materials is vital, and the identification and assessment of natural materials suitable for radiation detection is a rapidly growing area of research. In addition to their specific dosimetric characteristics, such materials must be rigid, insoluble, and chemically inert. One such promising low-cost material can be a limestone having vast deposits in Pakistan. The present study reports the TL and dosimetric features of Pakistani limestone pellets and their comparison with TLD-100.The quarried crystalline limestone rock was hand crushed, sieved, and compressed into the standard TLD chip-sized pellets. The TL response, kinetic parameters, batch homogeneity, dose linearity, individual sensitivity correction factor (i.e., elemental correction coefficient ECC), lowest detectable dose limit (LDDL), coefficient of variation (COV), energy dependency, and fading were determined, and compared with TLD-100. For TL analysis, the pellets were exposed to an 8 Gy dose of 250 kVp X-rays. These exhibited complex TL showing four peaks (P1: 90–110 °C, P2: 130–170 °C, P3: 240–280 °C and P4: 320–350 °C). The limestone response was linear in the studied dose range of X-rays (1–10 Gy), unlike the supra-linear behavior of TLD-100. The kinetic parameters (i.e., the frequency factor (f), activation energy (E), and the kinetic order (b)) were estimated through computerized glow curve deconvolution using the general order of kinetics while confirmed by the Tm-Tstop method. The values of E and f were observed in the ranges of 0.85–1.27 eV and 5.98 × 107 to 1.81 × 1013 s−1, respectively. The calculated value of figure-of-merit (FOM) (i.e., 2.37%) showed a good agreement between the experimental and fitted glow curves. The overall variation in the ECCs for TLD-100 and limestone was found within ±4% and ±7%, respectively. The results of the ECC confirmed batch homogeneity. The calculated value of LDDL was ∼1.01 Gy. The investigation found that the maximum variation in normalized intensity and COV was within the tolerance limit of 5%. The limestone pellets showed less sensitivity than TLD-100. Like TLD-100 at high energy, the pellets showed an independent response. In contrast to TLD-100, the limestone pellets showed a higher response dependency for low-energy X-rays.During the fading study, the total TL intensity decreased by 20% within the initial 24 h of irradiation and then sustained stability for the subsequent week. The results of this study indicate that limestone pellets are effective as an X-ray dosimeter for doses between 1 and 10 Gy.

Simultaneous Determination of Five Iridoids of Picrorhiza scrophulariiflora in Rat Plasma Using UHPLC-ESI-MS/MS.

In this study, we developed an ultra-performance liquid chromatography-electrospray tandem quadrupole mass spectrometry (UHPLC-ESI-MS/MS) method to simultaneously determine Picroside-I, Picroside-II, Picroside-III, minecoside, and sweroside in rat plasma. The chromatographic column was an ACQUITY UHPLC® BEH Amide Column (2.1 × 100 mm, 1.7 µm; Waters, MA, USA), column temperature 40 °C. The mobile phase was 0.1% formic acid aqueous solution-0.1% formic acid acetonitrile solution. The flow rate was 0.4 mL/min. Multiple reaction monitoring (MRM) and negative ion modes were adopted. The results showed that the calibration curves of five compounds in plasma showed good linearity (r > 0.9911) over the studied dose range. The lower limits of quantification (LLOQ) for Picroside-I, Picroside-II, Picroside-III, minecoside, and sweroside were 6.876, 5.193, 5.040, 1.260, and 4.527 ng/mL, respectively. The intra-day and inter-day precision were <15%. The matrix effects ranged from 95.77 to 101.9%. The Tmax were 1.1 ± 0.2, 1.1 ± 0.1, 0.8 ± 0.1, 1.0 ± 0.2, and 2.1 ± 0.1 h. This study will be useful in understanding the behavior of drugs in the body and the body's effect on drugs. It also offers theoretical underpinnings and highlights the importance of clinical applications and creating novel drugs.

Investigation of dosimetric properties of CaSO4:Mn phosphor prepared using slow evaporation route

The objective of this work was to investigate the luminescent properties of CaSO4:Mn synthesized by slow evaporation route. The crystalline structure, morphology, thermal and optical properties of the phosphors were characterized by X-ray diffraction analysis (XRD), Scanning electron microscopy (SEM), photoluminescence (PL) and thermogravimetric analysis (TGA). Moreover, using thermoluminescence (TL) and optically stimulated luminescence (OSL) techniques, the dosimetric properties of the phosphors, such as emission spectra, glow curve reproducibility, dose-response linearity, fading of the luminescent signal, variation of the TL intensity with the heating rate, OSL decay curves, correlation between TL and OSL emissions and minimum detectable dose (MDD) were comprehensively investigated. For dosimetric analyses, the samples were irradiated with doses from 169 mGy to 10 Gy. The emission band fits with the characteristic line of the Mn2+ emission features, ascribed to 6A1→4T1 transition. CaSO4:Mn pellets present a TL glow curve with a single typical peak centered around 494 nm, an OSL decay curve with predominance of a fast decay component, and a MDD on the order of mGy. The luminescent signals showed to be linear and reproducible in the studied dose range. The trapping centers located between 0.83 eV and 1.07 eV were revealed for different heating rates in the TL study. The high TL sensitivity of CaSO4:Mn was proven when comparing with commercially available dosimeters. The luminescent signals exhibit a smaller fading than described in the literature for CaSO4:Mn produced by other methods.

The Potentially Significant Role of CYP3A-Mediated Oxidative Metabolism of Dabigatran Etexilate and its Intermediate Metabolites in Drug-Drug Interaction Assessments Using Microdose Dabigatran Etexilate.

Dabigatran etexilate (DABE), a double ester prodrug of dabigatran (DAB), is a probe substrate of intestinal P-glycoprotein (P-gp) commonly used in clinical drug-drug interaction (DDI) studies. When compared to its therapeutic dose at 150 mg, microdose DABE (375 µg) showed approximately 2-fold higher in DDI magnitudes with CYP3A/P-gp inhibitors. In this study, we conducted several in vitro metabolism studies to demonstrate that DABE at a theoretical gut concentration after microdosing significantly underwent NADPH-dependent oxidation (~40-50%) in parallel to carboxylesterase-mediated hydrolysis in human intestinal microsomes. Furthermore, NADPH-dependent metabolism of its intermediate monoester BIBR0951 was also observed in both human intestinal and liver microsomes, accounting for 100% and 50% of total metabolism, respectively. Metabolite profiling using LC-MS/MS confirmed the presence of several novel oxidative metabolites of DABE and of BIBR0951 in the NADPH-fortified incubations. CYP3A was identified as the major enzyme catalyzing the oxidation of both compounds. The metabolism of DABE and BIBR0951 was well described by Michaelis-Menten kinetics, with Km ranging 1-3 µM, significantly below the expected concentrations following the therapeutic dose of DABE. Overall, the present results suggested that CYP3A played a significant role in the presystemic metabolism of DABE and BIBR0951 following microdose DABE administration, thus attributing partly to the apparent overestimation in the DDI magnitude observed with the CYP3A/P-gp inhibitors. Therefore, DABE at the microdose, unlike the therapeutic dose, would likely be a less predictive tool and should be considered as a clinical dual substrate for P-gp and CYP3A when assessing potential P-gp-mediated impacts by dual CYP3A/P-gp inhibitors. Significance Statement This is the first study demonstrating a potentially significant role of CYP-mediated metabolism of the prodrug DABE following a microdose, but not a therapeutic dose. This additional pathway coupled with its susceptibility to P-gp may make DABE a clinical dual substrate for both P-gp and CYP3A at a microdose. The study also highlights the need for better characterization of the pharmacokinetics and metabolism of a clinical DDI probe substrate over the intended study dose range for proper result interpretations.

Controlling magnetic skyrmion nucleation with Ga+ ion irradiation

In this paper, we show that magnetic skyrmion nucleation can be controlled using ${\mathrm{Ga}}^{+}$ ion irradiation, which manipulates the magnetic interface effects (in particular, the magnetic anisotropy and Dzyaloshinskii-Moriya interaction) that govern the stability and energy cost of skyrmions in thin-film systems. We systematically and quantitatively investigate what effect these changes have on the nucleation of magnetic skyrmions. Our results indicate that the energy cost of skyrmion nucleation can be reduced up to $26%$ in the studied dose range and that it scales approximately linearly with the square root of the domain wall energy density. Moreover, the total number of nucleated skyrmions in irradiated devices after nucleation was found to depend linearly on the ion dose and could be doubled compared to nonirradiated devices. These results show that ion irradiation cannot only be used to enable local nucleation of skyrmions but also allows for fine control of the threshold and efficiency of the nucleation process.

A phase I dose-escalation study of SYHA1813, a VEGFR and CSF1R inhibitor, in patients with recurrent High-Grade Gliomas or Advanced Solid Tumors

SYHA1813 is a potent multikinase inhibitor that targets vascular endothelial growth factor receptors (VEGFRs)/colony-stimulating factor 1 receptor (CSF1R). This study aimed to evaluate the safety, pharmacokinetics (PK), and antitumor activity of escalating doses of SYHA1813 in patients with recurrent high-grade gliomas (HGGs) or advanced solid tumors. This study adopted a combination of accelerated titration and a 3 + 3 design for dose escalation, with a starting dose of 5 mg once daily. The dose escalation continued at successive dose levels until the maximum tolerated dose (MTD) was determined. A total of 14 patients were enrolled and treated, including 13 with WHO grade III or IV gliomas and 1 with colorectal cancer. Two patients experienced dose-limiting toxicities (grade 4 hypertension and grade 3 mucositis oral) at 30 mg SYHA1813. The MTD was defined as 15 mg once daily. Hypertension (n = 6, 42.9%) was the most frequent treatment-related adverse event. Among evaluable patients (n = 10), 2 (20%) patients achieved partial response, and 7 (70%) had stable disease. The exposure increased with increasing doses within the studied dose range of 5 to 30 mg. Biomarker assessments demonstrated significant reductions in the levels of soluble VEGFR2 (P = .0023) and increases in the levels of VEGFA (P = .0092) and placental growth factor (P = .0484). The toxicities of SYHA1813 were manageable, and encouraging antitumor efficacy was observed in patients with recurrent malignant glioma. This study is registered with the Chinese Clinical Trial Registry (www.chictr.org.cn/index.aspx; identifier ChiCTR2100045380).

The effect of a single escalating dose of long-acting recombinant human follicle-stimulating hormone Fc fusion protein (KN015) on healthy, pituitary-suppressed women: first-in-human and randomized study on its pharmacokinetics, pharmacodynamics, and tolerability

ABSTRACT Objective KN015 is a long-acting, recombinant human follicle-stimulating hormone Fc fusion protein that induces follicle development. This first-in-human study evaluated the effect of KN015 on healthy, pituitary-suppressed women and examined its pharmacokinetics, pharmacodynamics, and tolerability. Methods This phase I study was a double-blind, randomized, and placebo-controlled design with a single ascending dose (20, 40, and 60 μg, respectively). Results After subcutaneous administration of a single dose, the maximum serum KN015 concentrations reached 1.57, 2.78, and 3.62 ng/mL, respectively, after baseline adjustment. Over this dose range, the median Tmax occurred at 240–312 h, and the half-life (t½) was 752–1160 h. Dose proportionality was shown across the studied dose range. In most subjects, follicular growth was observed, and the number and diameter of the follicles increased with an increasing dose. In the 40-μg and 60-μg groups, the mean numbers of follicles with a diameter of ≥17 mm were 3 and 4, respectively. There was no significant difference in adverse events between the KN015 and placebo groups. KN015 antibody was not detected in any of the dosage groups. Conclusion The administration of a single ascending dose of KN015 was tolerated and able to induce follicular growth. Trial registration This trial is registered at the Chinese Clinical Trials website (http://www.chinadrugtrials.org.cn/index.html # CTR20160741) and ClinicalTrials.gov (https://clinicaltrials.gov/ # NCT03192527).

Thermoluminescence kinetic parameters of proton-irradiated germanium doped flat-shape optical fibres

Glow curve is a key element in thermoluminescence (TL) studies as it provides on-the-ground understanding on the trapping mechanism inside the crystal lattice and hence stability of the TL material. In the present work, luminescence mechanism of the in-house fabricated germanium doped (Ge-doped) flat-shape silica optical fibres have been investigated following irradiation by 150-MeV proton beams. Results of TL dose-response showed that there is a linear relationship between TL response and proton doses from 1 to 10 Gy, with a coefficient of determination close to one. The structure of glow curve remains unchanged throughout the studied dose range with a maximum glow peak dominated at temperature of within 250–290 °C. A Tmax-Tstop plot reveals not only horizontal regions but also smooth slopes, indicative of the presence of a continuum distribution of glow peaks and trap depth. A computerised glow curve deconvolution analysis of the respective fibre glow-curves demonstrated that they were composed of five strongly overlapping peaks underlying a broad TL spectrum, obtaining figures of merit in the range of 0.56–1.64%. The main physical kinetic parameters (activation energy and frequency factor) of the fitted glow peaks were obtained using GlowFit software. The data suggest that the TL glow peaks of the Ge-doped silica optical fibres obey second-order kinetics.

Способность экстрактов некоторых съедобных грибов подавлять репродукцию вируса гриппа

In this work, extracts from the mycelium of some xylophytic fungi: Pleurotus eryngii, Auricularia auriculajudae, Tremella fuciformis were obtained, the toxicity of the obtained extracts was evaluated, and the antiviral activity was researched. The influenza virus was grown in the allantois cavity of chicken embryos. The infectious titer of the influenza virus was determined by titration on chicken embryos. The presence of the virus was judged by the reaction of hemagglutinating activity. The virus infectivity titer was calculated using the Reed-Muench method. The hemagglutinating activity of viruses was determined by a standard method using 0.75 % suspension of chicken red blood cells. The main criterion for studying the specific antiviral effect of compounds was the CTI (chemical-therapeutic index), that is determined by the ratio of the average toxic concentration of the substance (TC50) to the average effective viral inhibitory concentration (EC50). The antiviral activity of the obtained extracts was studied on a model of human, animal and bird influenza viruses, in the dose range from 0.025 mcg/ml to 1.25 mcg/ml using the methodological recommendations of the “Guidelines for conducting Preclinical studies of medicines”. While studying the acute toxicity of 3 obtained fungi extracts, it was found that all studied fungi compounds with a single intragastric injection to white mongrel mice, did not show a toxic effect in the studied dose range. During the study of the ability to suppress the reproduction of various strains of the influenza virus, it was found that extracts of the fungi Auricularia auricula-judae and Tremella fuciformis have possessed antiviral properties, and extracts exceed in terms of CTI to commercial anti-influenza drugs.

Pharmacokinetics and Disposition of Heparin-Binding Growth Factor Midkine Antisense Oligonucleotide Nanoliposomes in Experimental Animal Species and Prediction of Human Pharmacokinetics Using a Physiologically Based Pharmacokinetic Model.

Encapsulating the antisense oligonucleotide drug MK-ASODN with nanoliposomes greatly improved its potency and targeting to the heparin-binding growth factor midkine. The disposition and pharmacokinetic (PK) parameters of MK-ASODN nanoliposomes were studied in monkeys and rats, and the human PK parameters were predicted based on preclinical data using a physiologically based pharmacokinetic (PBPK) model. Following intravenous injection, the drug plasma concentration rapidly declined in a multiexponential manner, and the drug was rapidly transferred to tissues from the circulation. The terminal t1/2 in plasma was clearly longer than that of the unmodified antisense nucleic acid drug. According to the AUC,MK-ASODN nanoliposomes were mainly distributed in the kidney, spleen, and liver. . MK-ASODN nanoliposomes were highly plasma protein bound, limiting their urinary excretion. Very little MK-ASODN nanoliposomes were detected in urine or feces. The plasma disposition of MK-ASODN nanoliposomes appeared nonlinear over the studied dose range of 11.5–46 mg kg−1. The monkey PBPK model of MK-ASODN nanoliposomes was well established and successfully extrapolated to predict MK-ASODN nanoliposome PK in humans. These disposition and PK data support further development in phase I clinical studies.

Radiation Dose to the Intraprostatic Urethra Correlates Strongly With Urinary Toxicity After Prostate Stereotactic Body Radiation Therapy: A Combined Analysis of 23 Prospective Clinical Trials

Clinical trials assessing evaluation prostate stereotactic body radiation therapy (SBRT) have used a wide range of allowed doses to the intraprostatic urethra, but the relationship between urethral dose and urinary toxicity has not been thoroughly evaluated. The goal of this study was to characterize urinary toxicity outcomes according to urethral dose administered during prostate SBRT. The MEDLINE (PubMed) database was searched for published prospective studies of prostate SBRT through August 2020 that documented a maximum urethral dose metric (MUDM). Reported acute and late urinary toxicity rates were collected. Logistic regression and weighted Pearson correlation models were used to assess associations between urinary toxicity rates and MUDM. Twenty-three unique studies (n=2232 patients) met the inclusion criteria and included a wide range of MUDMs (equivalent dose in 2 Gy fractions [EQD2]: 69-141.75 Gy; α/β=3 Gy). The median follow-up ranged from 3 to 67 months (median, 32 months). On logistic regression analysis, the MUDM EQD2 was significantly associated with multiple urinary toxicity endpoints, including acute grade (G) 2+ (odds ratio [OR], 1.02; P < .001), late G2+ (OR, 1.03; P < .0001), and late G3+ (OR, 1.04; P=.003) urinary toxicity. On weighted Pearson correlation analysis, the MUDM was more closely associated with all evaluated urinary toxicity endpoints than prescription dose, including acute G2+ (r=0.51; P=.02), late G2+ (r=0.9; P < .0001), and late G3+ toxicity (r=0.7; P=.003). Multivariate analysis accounting for age, prostate size, bladder dosimetry, and baseline urinary function confirmed associations between urinary outcomes and MUDM. Within the studied dose range, each increase of 1 Gy to the MUDM corresponded to a 0.8% and 1.0% increase in acute G2+ and late G2+ toxicity, respectively. Radiation dose to the urethra correlates closely with urinary toxicity in patients with prostate cancer treated with SBRT. Attention should be paid to the urethral dose when delivering prostate SBRT to high doses, and approaches for urethral dose reduction warrant further investigation.

Radiation Dose to the Intraprostatic Urethra Correlates Strongly With Urinary Toxicity Following Prostate SBRT: A Combined Analysis of 23 Prospective Clinical Trials

Clinical trials of prostate SBRT have utilized a wide range of allowed doses to the intraprostatic urethra but the relationship between urethral dose and urinary toxicity has not been thoroughly evaluated. We aimed to characterize urinary toxicity outcomes according to urethral dose administered during prostate SBRT.We searched MEDLINE (PubMed) for published prospective studies of prostate SBRT through August 2020 that documented a maximum urethral dose metric (MUDM). Reported acute and late urinary toxicity rates were collected. Weighted correlation and weighted linear regression models were used to assess the associations between urinary toxicity rates and MUDM.Twenty-three unique studies (n = 2232 patients) met the inclusion criteria and included a wide range of MUDMs (EQD2 69 Gy to 141.75 Gy, a/b = 3). Median follow up ranged from 3-67 months (median 32 months). MUDM was strongly associated with urinary toxicity and was more closely associated with toxicity than prescription dose, including acute G2+ (r = 0.51, P = 0.02), late G2+ (r = 0.9, P < 0.0001) and late G3+ toxicity (r = 0.7, P = 0.003). Weighted linear regression accounting for age, prostate size and baseline urinary function confirmed association between urinary outcomes and MUDM. The weighted correlation model predicted late grade 2+ urinary toxicity rates of 2.5%, 5%, 10% and 15% corresponding to MUDMs of 34.2 Gy, 37.7 Gy, 43.9 Gy and 49.4 Gy, respectively, for 5 fraction regimens. Within the studied dose range, each increase of 1 Gy to the MUDM corresponded to a 0.8% and 0.9% increase in acute G2+ and late G2+ toxicity, respectively.Radiation dose to the urethra correlates closely with urinary toxicity in prostate cancer patients treated with SBRT. Attention should be paid to urethral dose when delivering prostate SBRT to high doses and approaches for urethral dose reduction warrant further investigation. These techniques may be facilitated by online adaptive planning with daily urethral delineation.

Evaluation Of The Mutagenic Potential Of The Polyphenol Extract From Blueberries In The Ames Test

In this research, mutagenic properties of blueberry polyphenol extract were studied in gene mutation induction test (Ames test) on four strains of Salmonella typhimurium TA98, TA100, TA1535, TA1537. None of the strains of Salmonella typhimurium showed statistically reliable dose-dependent increase in number of revertant colonies in the presence of investigated drug in the studied dose range from 4,0 to 40,0 mg/ml relative to baseline of spontaneous mutations. The blueberry extract does not have any mutagenic activity in the researched dose range in relation to TA98, TA100, TA1535, TA1537 strains of Salmonella typhimurium.

An ultrasensitive LC-MS/MS method and application to clinical dose-range finding for glycopyrrolate via an e-Nebulizer.

Aim: Glycopyrrolate (GLY) has been widely used to treat chronic obstructivepulmonary disease (COPD). Recent technical advancement significantly improves the drug delivery efficiency. In a clinical dose-range determination study via electronic nebulizer, the starting dose was as low as 3-μg, thus, a bioanalytical method capable of measuring down to sub-pg/ml or fg/ml level was required to characterize pharmacokinetics of GLY. Methods: A straightforward solid-phase extraction coupled with reversed-phase LC-MS/MS method was successfully developed to quantify plasma GLY concentrations of 0.500-250 pg/mL. MS/MS detection was at ESI+by monitoring m/z 318.3→116.1 for GLY and 321.3→119.1 for the internal standard GLY-d3. Results and Conclusion: The method was validated with adequate selectivity, intra- and inter-assay precision and accuracy, dilution linearity, and sufficient stability for measuring GLY in human plasma. This method has been used for sample analysis of a clinical dose-range finding study (3-50 µg twice daily doses via an electronic nebulizer). The assay exhibited good precision, accuracy, and robustness. Pharmacokinetic analysis showed good dose proportionalityover the studied dose range, where Cmax was found to be Y = 1.354*X + 1.968 (r2 = 0.9984), and AUC0-12 h was Y = 4.661*X + 23.32 (r2 = 0.9976). The study clearly demonstrated the importance of an ultrasensitive (500 fg/ml LLOQ) method.