Endocrine Disorders Associated with Medicinal Products: Approaches to Preclinical Safety Assessment

The endocrine system coordinates almost all organs and other systems in vertebrates. In particular, it regulates such important biological functions as metabolism, development, reproduction, and behaviour. To date, a significant amount of information has accumulated on endocrine disorders associated with chemical compounds (endocrine disruptors) used in various fields of human activity. The aim of this study was to evaluate the possibility of preclinical risk assessment for the endocrine function disorders attributable to new medicinal products. Endocrine disruptors are associated with a wide range of adverse events, including developmental problems arising from functional abnormalities of the endocrine system. Endocrine disorders caused by endocrine-disrupting chemicals are characterised by a long latency period between exposure and manifestation of a dysfunction; a nonlinear dose–response relationship; and a linear correlation of damage severity to exposure timing and duration. The chemicals influence the endocrine system through multiple mechanisms, the main of which being the interaction with cellular receptors sensitive to certain hormones and the influence on gene expression, intracellular signalling, and hormone transport, etc. This paper discusses the possibility of using hormone levels as indicators of endocrine disruption and presents the literature and authors’ own data on normal levels of relevant hormones in the blood of animals. An analysis of animal blood hormone levels in preclinical programmes will provide an opportunity to evaluate potential iatrogenic risks

A Study of Embryotoxic, Foetotoxic, and Teratogenic Effects of the Original Antituberculosis Agent Thiozonide in Pregnant Rabbits

Several treatment regimens with antituberculosis medicinal products are available for tuberculosis. Thiozonide is a newly developed original antimicrobial agent that exhibits bacteriostatic activity against Mycobacterium tuberculosis strains H37Rv, CN-37, CN-40, and MS-115.The aim of the study was to investigate the embryotoxic, foetotoxic, and teratogenic effects of thiozonide in pregnant rabbits.Materials and methods. The study involved 66 pregnant rabbits (4 groups of 16–17 animals each). The rabbits received oral thiozonide from day 6 to day 19 of gestation at doses of 20.6 mg/kg (1 TD (therapeutic dose)), 103 mg/kg (5 TDs), and 206 mg/kg (10 TDs). The control group received a 1% starch solution. The authors conducted a macroscopic examination of the reproductive organs and a histological evaluation of the placenta in eutha nised pregnant rabbits. Live foetuses underwent a check for developmental abnormalities, a skeletal development evaluation with a modified Dawson’s method, and a histologic examination of the internal organs.Results. The study showed no clinical signs of toxicity and no mortality associated with thiozonide in pregnant rabbits across all dose groups. Macroscopic and histological examinations revealed no pathological changes in the reproductive organs of pregnant rabbits. The evaluation of embryotoxic and foetotoxic effects did not identify any differences between the foetuses of the animals assigned to different doses of thiozonide and the control group. The authors found no developmental abnormalities in the foetuses. Examinations of foetal skeleton development and internal organ condition identified no differences between the groups and no abnormalities. The authors registered the death of all foetuses (late resorption) in one rabbit from the 206 mg/kg group. Therefore, the 103 mg/kg dose (5 TDs) was selected as a reasonable No Observed Adverse Effect Level (NOAEL).Conclusions. Thiozonide has no embryotoxic, foetotoxic, or teratogenic effects

Anti-inflammatory and immunomodulating effects of the bacterial lysate in the <em>in vivo</em> models of aseptic lymphadenitis and pneumococcal pneumonia

Bacterial lysates may produce immunoregulatory effects in the inflammatory diseases that are not directly caused by infectious agents; they may also stimulate the immune response against pathogens which are not a part of the lysate composition. Imudon® is a polyvalent bacterial lysate that is available in orodispersible tablets. However, the influence of this drug product on aseptic inflammation and immune defense against the infectious agents, the antigens of which are not contained in this preparation have not been studied so far. The aim of this study, therefore, was to determine the anti-inflammatory and immunomodulating effects of Imudon® using the models of aseptic lymphadenitis (in Wistar rats) and pneumococcal pneumonia (in Balb/c mice), i.e., the conditions not related to the specific components of the bacterial lysate. Lymphadenitis was induced in rats by administration of λ-carrageenan into a cervical lymph node via an open operative approach. Whereas pneumonia was induced in mice by administering Streptococcus pneumoniae suspension intranasally. The choice of pneumococcus was determined by the absence of pneumococcal antigens in Imudon®, i.e., it cannot be a direct inducer of adaptive immune response against pneumococcal infection. Imudon® was administered intragastrically as a crushed tablet suspension following a therapeutic-preventive regimen (for 14 days daily until the induction of inflammation and for 3 [in the lymphadenitis model] or 5 days [in the model of pneumonia] in three doses thereafter). In the lymphadenitis model, Imudon® demonstrated both local and systemic anti-inflammatory responses manifested in the reduced number of circulating leucocytes and lower TNFα levels and by ameliorated histological features of inflammation in the operated lymph node. In rats, the anti-inflammatory effect was most pronounced when the product was administered at a dose of 2.2 mg/kg (equivalent to a human therapeutic dose) and 6.6 mg/kg. In the model of pneumonia, administration of Imudon® at 4.44 mg/kg (equivalent to a human therapeutic dose) and 13.32 mg/kg demonstrated a trend towards increased survival rate as compared to the control group. On Day 5 after infection Imudon® (4.44 and 13.32 mg/kg) decreased significantly the severity of inflammation and bacterial titer in the lungs. The titer of anti-pneumococcal immunoglobulins A in the bronchoalveolar lavage fluid were found to be higher in the Imudon® treated group (13.32 mg/kg) compared to control group. The results of this study showed high antiinflammatory and immunomodulatory activities of Imudon® and provided an insight into the mechanisms that underlie the clinical effects of this drug in various inflammatory diseases

Эндокринные нарушения при применении лекарственных средств: подходы к доклинической оценке безопасности

The endocrine system coordinates almost all organs and other systems in vertebrates. In particular, it regulates such important biological functions as metabolism, development, reproduction, and behaviour. To date, a significant amount of information has accumulated on endocrine disorders associated with chemical compounds (endocrine disruptors) used in various fields of human activity. The aim of this work was to evaluate the possibility of preclinical risk assessment for the endocrine function disorders attributable to new medicinal products. Endocrine disruptors are associated with a wide range of adverse events, including developmental problems arising from functional abnormalities of the endocrine system. Endocrine disorders caused by endocrine-disrupting chemicals are characterised by a long latency period between exposure and manifestation of a dysfunction; a nonlinear dose–response relationship; and a linear correlation of damage severity to exposure timing and duration. The chemicals influence the endocrine system through multiple mechanisms, the main of which being the interaction with cellular receptors sensitive to certain hormones and the influence on gene expression, intracellular signalling, and hormone transport, etc. This paper discusses the possibility of using hormone levels as indicators of endocrine disruption and presents the literature and authors’ own data on normal levels of relevant hormones in the blood of animals. An analysis of animal blood hormone levels in preclinical programmes will provide an opportunity to evaluate potential iatrogenic risks.Эндокринная система координирует работу практически всех органов и систем организма позвоночных, в том числе такие важные биологические функции, как метаболизм, развитие, размножение и поведение. На сегодняшний день накоплено значительное количество информации об эндокринных нарушениях при использовании химических соединений (эндокринных дизрапторов) в различных отраслях деятельности человека. Цель работы — оценка возможности проведения на стадии доклинических исследований анализа рисков функционального нарушения эндокринной системы при применении новых лекарственных средств. С эндокринными дизрапторами связан широкий спектр нежелательных явлений, включая проблемы развития, возникающие из-за нарушения функционирования эндокринной системы. Особенностями эндокринных нарушений, вызванных дизрапторами, являются длительный латентный период между воздействием и проявлением дисфункции, отсутствие линейной зависимости «доза–эффект», зависимость степени нарушений от момента начала и длительности воздействия. К основным механизмам влияния химических веществ на эндокринную систему относят их взаимодействие с рецепторами клеток, чувствительных к влиянию определенных гормонов, влияние на экспрессию генов и внутриклеточную передачу сигналов, транспорт гормонов и др. В обзоре обсуждена возможность использования показателей уровней гормонов как индикаторов эндокринной токсичности и приведены литературные и собственные данные о нормах содержания основных гормонов в крови животных. Включение анализа уровней основных гормонов крови животных в программу регистрационных доклинических исследований позволит оценить риски потенциальных угроз ятрогенного происхождения

Transverse sphericity of primary charged particles in minimum bias proton-proton collisions at s=0.9\sqrt{s}=0.9, 2.76 and 7 TeV

Measurements of the sphericity of primary charged particles in minimum bias proton--proton collisions at $\sqrt{s}=0.9$, 2.76 and 7 TeV with the ALICE detector at the LHC are presented. The observable is linearized to be collinear safe and is measured in the plane perpendicular to the beam direction using primary charged tracks with $p_{\rm T}\geq0.5$ GeV/c in $|\eta|\leq0.8$. The mean sphericity as a function of the charged particle multiplicity at mid-rapidity ($N_{\rm ch}$) is reported for events with different $p_{\rm T}$ scales ("soft" and "hard") defined by the transverse momentum of the leading particle. In addition, the mean charged particle transverse momentum versus multiplicity is presented for the different event classes, and the sphericity distributions in bins of multiplicity are presented. The data are compared with calculations of standard Monte Carlo event generators. The transverse sphericity is found to grow with multiplicity at all collision energies, with a steeper rise at low $N_{\rm ch}$, whereas the event generators show the opposite tendency. The combined study of the sphericity and the mean $p_{\rm T}$ with multiplicity indicates that most of the tested event generators produce events with higher multiplicity by generating more back-to-back jets resulting in decreased sphericity (and isotropy). The PYTHIA6 generator with tune PERUGIA-2011 exhibits a noticeable improvement in describing the data, compared to the other tested generators.Comment: 21 pages, 9 captioned figures, 3 tables, authors from page 16, published version, figures from http://aliceinfo.cern.ch/ArtSubmission/node/308

Charge separation relative to the reaction plane in Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}}= 2.76 TeV

Measurements of charge dependent azimuthal correlations with the ALICE detector at the LHC are reported for Pb-Pb collisions at $\sqrt{s_{\rm NN}} = 2.76$ TeV. Two- and three-particle charge-dependent azimuthal correlations in the pseudo-rapidity range $|\eta| < 0.8$ are presented as a function of the collision centrality, particle separation in pseudo-rapidity, and transverse momentum. A clear signal compatible with a charge-dependent separation relative to the reaction plane is observed, which shows little or no collision energy dependence when compared to measurements at RHIC energies. This provides a new insight for understanding the nature of the charge dependent azimuthal correlations observed at RHIC and LHC energies.Comment: 12 pages, 3 captioned figures, authors from page 2 to 6, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/286

A note on comonotonicity and positivity of the control components of decoupled quadratic FBSDE

In this small note we are concerned with the solution of Forward-Backward Stochastic Differential Equations (FBSDE) with drivers that grow quadratically in the control component (quadratic growth FBSDE or qgFBSDE). The main theorem is a comparison result that allows comparing componentwise the signs of the control processes of two different qgFBSDE. As a byproduct one obtains conditions that allow establishing the positivity of the control process.Comment: accepted for publicatio

Multiplicity dependence of jet-like two-particle correlations in p-Pb collisions at sNN\sqrt{s_{NN}} = 5.02 TeV

Two-particle angular correlations between unidentified charged trigger and associated particles are measured by the ALICE detector in p-Pb collisions at a nucleon-nucleon centre-of-mass energy of 5.02 TeV. The transverse-momentum range 0.7 $< p_{\rm{T}, assoc} < p_{\rm{T}, trig} <$ 5.0 GeV/$c$ is examined, to include correlations induced by jets originating from low momen\-tum-transfer scatterings (minijets). The correlations expressed as associated yield per trigger particle are obtained in the pseudorapidity range $|\eta|<0.9$. The near-side long-range pseudorapidity correlations observed in high-multiplicity p-Pb collisions are subtracted from both near-side short-range and away-side correlations in order to remove the non-jet-like components. The yields in the jet-like peaks are found to be invariant with event multiplicity with the exception of events with low multiplicity. This invariance is consistent with the particles being produced via the incoherent fragmentation of multiple parton--parton scatterings, while the yield related to the previously observed ridge structures is not jet-related. The number of uncorrelated sources of particle production is found to increase linearly with multiplicity, suggesting no saturation of the number of multi-parton interactions even in the highest multiplicity p-Pb collisions. Further, the number scales in the intermediate multiplicity region with the number of binary nucleon-nucleon collisions estimated with a Glauber Monte-Carlo simulation.Comment: 23 pages, 6 captioned figures, 1 table, authors from page 17, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/161

Multi-particle azimuthal correlations in p-Pb and Pb-Pb collisions at the CERN Large Hadron Collider

Measurements of multi-particle azimuthal correlations (cumulants) for charged particles in p-Pb and Pb-Pb collisions are presented. They help address the question of whether there is evidence for global, flow-like, azimuthal correlations in the p-Pb system. Comparisons are made to measurements from the larger Pb-Pb system, where such evidence is established. In particular, the second harmonic two-particle cumulants are found to decrease with multiplicity, characteristic of a dominance of few-particle correlations in p-Pb collisions. However, when a $|\Delta \eta|$ gap is placed to suppress such correlations, the two-particle cumulants begin to rise at high-multiplicity, indicating the presence of global azimuthal correlations. The Pb-Pb values are higher than the p-Pb values at similar multiplicities. In both systems, the second harmonic four-particle cumulants exhibit a transition from positive to negative values when the multiplicity increases. The negative values allow for a measurement of $v_{2}\{4\}$ to be made, which is found to be higher in Pb-Pb collisions at similar multiplicities. The second harmonic six-particle cumulants are also found to be higher in Pb-Pb collisions. In Pb-Pb collisions, we generally find $v_{2}\{4\} \simeq v_{2}\{6\}\neq 0$ which is indicative of a Bessel-Gaussian function for the $v_{2}$ distribution. For very high-multiplicity Pb-Pb collisions, we observe that the four- and six-particle cumulants become consistent with 0. Finally, third harmonic two-particle cumulants in p-Pb and Pb-Pb are measured. These are found to be similar for overlapping multiplicities, when a $|\Delta\eta| > 1.4$ gap is placed.Comment: 25 pages, 11 captioned figures, 3 tables, authors from page 20, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/87