Blood concentrations of new synthetic opioids

Author(s):  
Piotr Adamowicz ◽  
Karolina Nowak
Author(s):  
Н.В. Белобородова ◽  
В.В. Мороз ◽  
А.Ю. Бедова

Интеграция метаболизма макроорганизма и его микробиоты, обеспечивающая в норме симбиоз и саногенез, нарушается при заболеваниях, травме, критическом состоянии, и вектор взаимодействия может изменяться в пользу прокариотов по принципу «метаболиты бактерий - против хозяина». Анализ литературы показал, что, с одной стороны, имеется живой интерес к ароматическим микробным метаболитам, с другой - отсутствует четкое представление об их роли в организме человека. Публикации, касающиеся ряда ароматических микробных метаболитов (фенилкарбоновых кислот, ФКК), как правило, не связаны между собой по тематике и направлены на решение тех или иных прикладных задач в разных областях биологии и медицины. Цель обзора - анализ информации о происхождении, биологических эффектах ФКК в экспериментах in vitro и in vivo , и клинических наблюдениях. Обобщая результаты приведенных в обзоре исследований на клеточном, субклеточном и молекулярном уровнях, логично предположить участие ароматических микробных метаболитов в патогенезе полиорганной недостаточности при сепсисе. Наиболее перспективным для раскрытия роли ароматических микробных метаболитов представляется изучение механизмов вторичной почечной недостаточности и септической энцефалопатии. Важным направлением для будущих исследований является изучение влияния продуктов микробной биодеградации ароматических соединений на развитие диссеминированного внутрисосудистого свертывания крови, артериальной гипотензии и септического шока. Результаты дальнейших исследований будут иметь не только фундаментальное значение, но и обогатят практическую медицину новыми диагностическими и лечебными технологиями. Significant increases in blood concentrations of some aromatic metabolites (phenylcarboxylic acids, PhCAs) in patients with sepsis have been previously shown. Enhanced bacterial biodegradation of aromatic compounds has been demonstrated to considerably contribute to this process. Integration of macroorganism metabolism and its microbiota, which provides normal symbiosis and sanogenesis, is disturbed in diseases, trauma, and critical conditions. Direction of this interaction may change in favor of prokaryotes according to the principle, “bacterial metabolites are against the host”. Analysis of literature showed a particular interest of many investigators to aromatic microbial metabolites. However, there is no clear understanding of their role in the human body. Publications on PhCAs are generally not thematically interrelated and usually focus on solving applied tasks in different fields of biology and medicine. The aim of this work was to consolidate existing information about origin and biological effects of PhCAs in in vitro / in vivo experiments and some clinical findings. The presented summary of reported data from studies performed at cellular, sub-cellular, and molecular levels suggests participation of aromatic microbial metabolites in the pathogenesis of multiple organ failure in sepsis. Studying mechanisms of secondary renal failure and septic encephalopathy is most promising for discovering the function of aromatic microbial metabolites. Effects of microbial biodegradation products of aromatic substances on development of disseminated intravascular coagulation, hypotension, and septic shock are an important challenge for future studies. Results of further investigations will be not only fundamental, but will also enrich medical practice with new diagnostic and therapeutic technologies.


2020 ◽  
Vol 24 (5) ◽  
pp. 58-63
Author(s):  
A. M. Mambetova ◽  
M. H. Hutueva ◽  
I. K. Thabisimova ◽  
A. S. Kegaduyev

BACKGROUND. The role of inflammation and uremic intoxication in the development and progression of bone mineral dis­orders, including cardiovascular calcification, has been actively studied over the past decades. PATIENTS AND METHODS. A single-stage, cohort study of 85 patients with stage 5D CKD treated with programmatic hemodialysis was conducted. The blood concentrations of interleukin-3 (IL-3) and interleukin-6 (IL-6) were determined using the enzyme immunoassay, the level of fibrinogen - using the Rutberg method, and the level of p2-microglobulins - using the nephelometric method. The blood leu­kocyte shift index (ISLC) and the Glasgow Prognostic Score (GPS) risk index for systemic inflammation were also calculated, taking into account the level of C-reactive protein (CRP) and blood albumin. The presence of valvular calcification, its severity, and calcification of the abdominal aortic wall was recorded. Statistical analysis was performed using the program STATISTICA 12.6 ("StatSoft", USA). THE AIM: to evaluate the relationship between factors of systemic inflammation and cardiovascular cal­cification in patients with stage 5D chronic kidney disease. RESULTS. The risk of detecting calcification of the aorta and heart valves was influenced by the pro-inflammatory cytokines IL-3 and IL-6, as well as ISLK and GPS. However, inflammatory fac­tors such as fibrinogen, p2-microglobulin, and CRP levels in the blood did not show a statistically significant effect. In the case when the predicted parameter was chosen not friendly calcification, but the presence of any of its components, the predictive significance of IL-3 decreased, but IL-6 remained. The 20% risk threshold was exceeded at IL-6 values of more than 33 pg/ml. The effect of ISLC on the probability of detection of calcification was shown both about friendly calcification and concerning isolated calcification of the aorta or valves. CONCLUSION. It was found that among the studied factors of inflammation, IL-6, ILK, and IL-3 demonstrate a relationship with the processes of cardiovascular calcification, GPS-only in relation to friendly calcification. Nomograms have been developed that allow predicting the detection of cardiovascular calcification in dialysis patients, depending on the state of the inflammatory circuit.


2020 ◽  
Vol 12 ◽  
Author(s):  
Francisco Basílio ◽  
Ricardo Jorge Dinis-Oliveira

Background: Pharmacobezoars are specific types of bezoars formed when medicines, such as tablets, suspensions, and/or drug delivery systems, aggregate and may cause death by occluding airways with tenacious material or by eluting drugs resulting in toxic or lethal blood concentrations. Objective: This work aims to fully review the state-of-the-art regarding pathophysiology, diagnosis, treatment and other relevant clinical and forensic features of pharmacobezoars. Results: patients of a wide range of ages and in both sexes present with signs and symptoms of intoxications or more commonly gastrointestinal obstructions. The exact mechanisms of pharmacobezoar formation are unknown but is likely multifactorial. The diagnosis and treatment depend on the gastrointestinal segment affected and should be personalized to the medication and the underlying factor. A good and complete history, physical examination, image tests, upper endoscopy and surgery through laparotomy of the lower tract are useful for diagnosis and treatment. Conclusion: Pharmacobezoars are rarely seen in clinical and forensic practice. They are related to controlled or immediate-release formulations, liquid or non-digestible substances, in normal or altered digestive motility/anatomy tract, and in overdoses or therapeutic doses, and should be suspected in the presence of risk factors or patients taking drugs which may form pharmacobezoars.


1989 ◽  
Vol 17 (2) ◽  
pp. 83-100
Author(s):  
Björn Ekwall ◽  
Inger Bondesson ◽  
José V. Castell ◽  
Maria José Gómez-Lechón ◽  
Sven Hellberg ◽  
...  

The MEIC (multicentre evaluation of in vitro cytotoxicity) programme is a five-year programme to validate in vitro tests for general toxicity, and is organised by the Scandinavian Society for Cell Toxicology. Interested laboratories are invited, on an international basis, to test 50 published reference chemicals in their respective assays. Submitted results will then be evaluated yearly by the MEIC Committee for their relevance to various types of human toxicity, including an evaluation for the same chemicals of the prediction by animal tests of human toxicity. To establish the validation methods, a preliminary validation cycle is being performed in 1989/90 with submitted results for the first ten MEIC chemicals. The present paper is the very first step of this preliminary validation process. The prediction of human toxicity by five cytotoxicity assays (altogether 14 different cell systems/endpoints) has been evaluated, and also compared with the predictive value of rodent LD50 tests. Mouse LD50 prediction of human lethal dosage for these substances was good, while rat LD50 prediction was less satisfactory. The collective predictions by all 14 cell systems/endpoints of human toxicity in the form of a multivariate PLS (partial least squares) model of human acute lethal blood concentrations, as well as the corresponding prediction by a HeLa cell assay, were comparable to the efficiency of mouse LD50 prediction of human lethal dosage. When combined with simple toxicokinetic data (absorption of chemicals in the intestine and distribution volumes), the PLS model and the HeLa assay were able to predict human lethal dosage of the ten chemicals as accurately as the mouse LD50 value. The small number of chemicals studied to date means that general conclusions cannot be drawn from these results. Further validation of more chemicals with the in vitro methods is essential and promises to be worthwhile.


2021 ◽  
Vol 22 (3) ◽  
pp. 1022
Author(s):  
Tatyana P. Makalish ◽  
Ilya O. Golovkin ◽  
Volodymyr V. Oberemok ◽  
Kateryna V. Laikova ◽  
Zenure Z. Temirova ◽  
...  

The urgency of the search for inexpensive and effective drugs with localized action for the treatment of rheumatoid arthritis continues unabated. In this study, for the first time we investigated the Cytos-11 antisense oligonucleotide suppression of TNF-α gene expression in a rat model of rheumatoid arthritis induced by complete Freund’s adjuvant. Cytos-11 has been shown to effectively reduce peripheral blood concentrations of TNF-α, reduce joint inflammation, and reduce pannus development. The results achieved following treatment with the antisense oligonucleotide Cytos-11 were similar to those of adalimumab (Humira®); they also compared favorably with those results, which provides evidence of the promise of drugs based on antisense technologies in the treatment of this disease.


2021 ◽  
Vol 17 (1) ◽  
Author(s):  
N. Le Floc’h ◽  
F. Gondret ◽  
R. Resmond

Abstract Background Health and growth of pigs are affected by the hygiene of housing. Lower growth performance observed in poor hygiene of housing conditions is explained by reduced feed intake and metabolic changes caused by the activation of body defences. In a previous experiment, we reported contrasted average values of body weight gain, concentrations of circulating metabolites, redox and immune indicators in blood of pigs housed in good or poor hygiene conditions during the growing period. This study addressed inter-individual variability in these responses to determine whether a particular blood profile explains average daily gain (ADG) of the pig. Results The data originated from 160 growing pigs, half of which subjected to a hygiene challenge for 6 weeks (W0 to W6) and the others housed in good hygiene conditions. Pigs originated from two lines divergently selected for residual feed intake (RFI). Individual body weights were recorded during this period, and relative ADG (rADGW0-W6) was calculated as the ADG corrected by the initial body weight measured at W0. Blood samples were taken before (W0) and 3 weeks (W3) after the beginning of the challenge. The analysed dataset consisted of 51 metabolites and indicators of immune and inflammatory responses measured on 136 pigs having no missing value for any variables, when calculated as the differences W3 minus W0 in circulating concentrations. An algorithm tested all possible linear regression models and then selected the best ones to explain rADGW0-W6. Six variables were identified across the best models and correlated with rADGW0-W6 with a goodness of fit (adjusted R2) of about 67%. They were changes in haptoglobin, global antioxidant capacity of plasma (Biological Antioxidant Power or BAP), free fatty acids, and 3 amino acids: leucine, tryptophan, and 1-methylhistidine. The effects of housing conditions and RFI lines were comprised in the variables of the selected models and none of these conditions improved accuracy of the predictive models, leading to genericity of the pinpointed metabolic changes in relation to variability of ADG. Conclusions This approach allows us to identify blood variables, whose changes in blood concentrations correlated to ADG under contrasted sanitary conditions.


2000 ◽  
Vol 85 (6) ◽  
pp. 2260-2265 ◽  
Author(s):  
Giovanni Ravaglia ◽  
Paola Forti ◽  
Fabiola Maioli ◽  
Barbara Nesi ◽  
Loredana Pratelli ◽  
...  

Several micronutrients are involved in thyroid hormone metabolism, but it is unclear whether their marginal deficits may contribute to the alterations in thyroid function observed in extreme aging. The relationships among blood concentrations of thyroid hormones and selenium, zinc, retinol, and α-tocopherol were studied in 44 healthy Northern Italian oldest-old subjects (age range, 90–107 yr), selected by the criteria of the SENIEUR protocol. Control groups included 44 healthy adult (age range, 20–65 yr) and 44 SENIEUR elderly (age range, 65–89 yr) subjects. Oldest-old subjects had higher TSH (P < 0.01) and lower free T3 (FT3)/freeT4 (FT4) ratio, zinc, and selenium serum values (P < 0.001) than adult and elderly control subjects. No significant difference was found for plasma retinol and α-tocopherol values. The associations between micronutrients and thyroid hormones were evaluated by multivariate analysis. In oldest-old subjects, plasma retinol was negatively associated with FT4 (P = 0.019) and TSH serum levels (P = 0.040), whereas serum zinc was positively associated with serum FT3 (P = 0.010) and FT3/FT4 ratio (P = 0.011). In younger subjects, no significant association was found among thyroid variables and micronutrients. In conclusion, blood levels of specific micronutrients are associated with serum iodothyronine levels in extreme aging.


2021 ◽  
Vol 186 (Supplement_1) ◽  
pp. 370-377
Author(s):  
Edward Chaum ◽  
Ernő Lindner

ABSTRACT Background Target-controlled infusion anesthesia is used worldwide to provide user-defined, stable, blood concentrations of propofol for sedation and anesthesia. The drug infusion is controlled by a microprocessor that uses population-based pharmacokinetic data and patient biometrics to estimate the required infusion rate to replace losses from the blood compartment due to drug distribution and metabolism. The objective of the research was to develop and validate a method to detect and quantify propofol levels in the blood, to improve the safety of propofol use, and to demonstrate a pathway for regulatory approval for its use in the USA. Methods We conceptualized and prototyped a novel “smart” biosensor-enabled intravenous catheter capable of quantifying propofol at physiologic levels in the blood, in real time. The clinical embodiment of the platform is comprised of a “smart” biosensor-enabled catheter prototype, a signal generation/detection readout display, and a driving electronics software. The biosensor was validated in vitro using a variety of electrochemical methods in both static and flow systems with biofluids, including blood. Results We present data demonstrating the experimental detection and quantification of propofol at sub-micromolar concentrations using this biosensor and method. Detection of the drug is rapid and stable with negligible biofouling due to the sensor coating. It shows a linear correlation with mass spectroscopy methods. An intuitive graphical user interface was developed to: (1) detect and quantify the propofol sensor signal, (2) determine the difference between targeted and actual propofol concentration, (3) communicate the variance in real time, and (4) use the output of the controller to drive drug delivery from an in-line syringe pump. The automated delivery and maintenance of propofol levels was demonstrated in a modeled benchtop “patient” applying the known pharmacokinetics of the drug using published algorithms. Conclusions We present a proof-of-concept and in vitro validation of accurate electrochemical quantification of propofol directly from the blood and the design and prototyping of a “smart,” indwelling, biosensor-enabled catheter and demonstrate feedback hardware and software architecture permitting accurate measurement of propofol in blood in real time. The controller platform is shown to permit autonomous, “closed-loop” delivery of the drug and maintenance of user-defined propofol levels in a dynamic flow model.


1997 ◽  
Vol 25 (3) ◽  
pp. 343-345
Author(s):  
Ethel Thurston

The Multicenter Evaluation of In Vitro Cytotoxicity programme is most important to animal protection, since it has validated 64 in vitro tests using advanced human data for 50 chemicals as the “gold standard”. Therefore, it has been able to compare animal cell tests, human cell tests and whole-animal tests fairly with unbiased scientific evidence. Added bonuses have included the identification and development of missing in vitro information (“missing tests”), publication of time-related lethal blood concentrations for all 50 chemicals, and some preliminary plans to resolve the 50,000 untested (or poorly tested) chemicals in the chemical mountain.


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