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Exploring the effect of bioenvironment on the ionization of drugs using the membrane mimetic properties of differently charged micelles
No full textObjective
The membrane-mimicking approach is grounded in the idea of organizing molecules into distinct
compartments within systems, which can influence reaction rates, physicochemical properties and
stereochemistry of pharmacologicaly active compounds, in ways that differ from those observed in
"pure" water [1]. There isn't a perfect model that can replicate all the complexities of biological
membranes, but a large variety of membrane mimetics are available [2]. Among them, micellar
solutions of differently charged surfactants are systems the most commonly used to mimic the
desired functions of cells membranes, since their properties are well understood at the chemical
level [1].
Methods
The pKa values of pharmacologically active compounds, with and without the presence of anionic
(SDS), cationic (CTAB) and nonionic (TX-100, Brij 35) micelles, were determined
potentiometrically, under the same experimental conditions (temperature 25°C and ionic strength
0.1 M NaCl). The experimental results were analyzed in the Hyperquad program. Compounds
which are distereomers are additionally analysed in RP-HPLC system using Chromolith
Performance using RP-18e column and phosphate buffer pH 7.0-acetonitrile mixture as a mobile
phase.
Results
The presence of micelles caused the most significant shifts in the protolytic equilibria (∆pKa) of
amino (-2.80 to +1.44) and carboxyl groups (-0.92 to +1.90). A more pronounced effect on the
change in ionization mode was observed in the presence of anionic and cationic micelles compared
to nonionic micelles. A change in the distribution of equilibrium forms of investigated drugs, in
the presence of micelles, was observed at biopharmaceutically significant pH values (1.2; 4.5; 6.8;
7.4), where the content of ionized forms changed in the range from -74% to +66% compared to
"pure" water.
Conclusions
Small changes in solution conditions can significantly affect the protolytic equilibria of drugs,
suggesting that the ionization of drugs under physiological conditions may be completely different
than expected exclusively on the basis of the pKa values determined in “pure” water
Population Pharmacokinetic-Pharmacogenetic (PopPK-PGx) Model of Efavirenz in HIV-1- Infected Patients
No full textBackground and objectives
Efavirenz (EFV) exhibits substantial inter-patient pharmacokinetics (PK) variability. Polymorphisms in
genes involved in EFV metabolism have been associated with EFV exposure, but they have not been fully
implemented to inform dosing in treatment guidelines. This work aimed to develop a population
pharmacokinetic-pharmacogenetic (PopPK-PGx) model of EFV in human immunodeficiency virus type 1
(HIV-1)-positive patients, and to simultaneously explore the influence of CYP2B6 (516G>T and c.485-
18C>T) and NR1I3 polymorphisms, as well as patient characteristics on EFV PK parameters. Additionally,
this study aimed to simulate the combined effects of genetic polymorphisms and nonadherence patterns on
EFV plasma concentrations
Assessment of structural and functional characteristics of HDL and LDL in lung cancer patients in order to elucidate mechanisms of cholesterol metabolic pathways disorders
No full textIntroduction: Cholesterol metabolism dysregulation is recognized as one of the hallmarks of the cancer with
highest mortality rate and the second most common malignancy – lung cancer (LC). LDL and HDL particles, the
latter being carriers of the antioxidant paraoxonase-1 (PON1), were already proven to be altered in cancer pa-
tients. We have tried to investigate in more depth the cholesterol metabolism perturbances in LC, by analzying
content of each of the LDL and HDL subclass and (anti)oxidative activity of each of the HDL subclass separately.
Materials and Methods: LDL and HDL subclasses from blood samples of 89 LC patients and 84 healthy subjects
were separated and HDL subclasses PON1 activity assessed using Rainwater method and Gugliucci’s zymogram
method, respectively.
Results: LC patients had higher relative proportion of HDL 2 particles, lower proportion of HDL 3 particles, and
significantly lower activity of PON1 compared to control group (CG). Relative proportion of PON1 activity was
higher on HDL 2b fraction and lower on all HDL 3 fractions of LC patients compared to CG. Relative proportions
of LDL I and LDL II particles were increased, while proportions of LDL IV and small dense LDL particles were
decreased in LC patients. Relative proportions of HDL and LDL subfractions and PON1 activities on HDL sub-
fractions were found to be dependent on LC type and size, number of comorbidities and sites of progression, and
overall response to therapy.
Conclusion: PON1 activity and lipoprotein subfractions distribution seem to be indicators of possible metabolic
pathways (disorders) in L
Validation of the fermented food frequency questionnaire to assess consumption across four European regions: a study within the promoting innovation of fermented foods cost action
No full textBackground: Fermented foods are an integral part of diets worldwide, and emerging epidemiological data suggest their significant beneficial health effects. However, assessing their intake is challenging since many of these foods are sporadically and/or locally consumed, hence current traditional nutritional assessment tools lack the specificity to capture this variability. To address this gap, the Fermented Food Frequency Questionnaire (3FQ) was developed and this study aimed to evaluate its relative validity and repeatability across European regions. Methods: In the validation study of the 3FQ, 12,646 adult participants were recruited across four European regions to assess consumption of sixteen major fermented food groups. Repeatability was assessed by administering the 3FQ twice, ~6 weeks apart, to a subset of participants (n = 2,315). Validity was evaluated using 24-h dietary recalls (24 h). Statistical analyses included Spearman's rank correlation coefficients and Intra-Class Correlation coefficients (ICC) for repeatability, and Bland-Altman plots for validity. Results: Results showed high repeatability, overall and by region, for estimated quantities and frequencies of consumption for most of the fermented food groups (from 0.4 to 1.0), with a few exceptions for infrequently consumed items (e.g., fermented fish). Validity assessment via Bland-Altman plots revealed excellent agreement between the 3FQ and 24 h for most of the food groups, with over 90% of values falling within the agreement interval. Notably, fermented dairy products, coffee, and bread categories showed the strongest agreement (>95%). Conclusion: The 3FQ is a robust and reliable tool for estimating the consumption of diverse fermented food groups across four European regions and provides valid estimates of the frequency and quantity of intake for specific fermented foods. The 3FQ could be a valuable instrument for epidemiological research aiming to elucidate associations between certain fermented foods and health parameters in European diets. Copyrigh
Parenteralni preparati za primenu u pedijatrijskoj populaciji - izazovi izbora ekscipijenasa
No full textThe need for the development of age-appropriate preparations for patients under 18 years
of age is important to ensure appropriate therapy for all children via different routes of
administration. Parenteral administration of medicinal products in the pediatric population is
common in hospitalized patients, in emergency situations or when the (per)oral route of
administration is not possible. The development of a drug formulation for parenteral
administration in children requires the consideration of the route of administration (related to
physiological differences between children and adults), the site of action and the duration of the
pharmacological action of the active substance, the volume of the preparation and the general
health condition of the patient. A major challenge in the formulation of these preparations is the
selection of excipients that should ensure adequate product quality and patient tolerability.
The paper presents an overview of considerations related to the formulation of parenteral
preparations for the pediatric population. The regulatory requirements regarding the use of
excipients with confirmed effects and the labeling of preparations containing them are listed.
Also, modern approaches (databases and tools) that can be useful for the selection of appropriate
excipients were consideredPotreba za razvojem lekova koji su prilagođeni uzrastu pacijenata mlađih od 18 godina je važna da bi se obezbedila adekvatna terapija kada se lekovi primenjuju različitim putevima primene. Primena lekova parenteralnim putem u pedijatrijskoj populaciji česta je kod hospitalizovanih pacijenata, u urgentnim stanjima ili u situacijama kada nije moguć (per)oralni put primene. Pri razvoju formulacije leka za parenteralnu primenu kod dece neophodno je uzeti u obzir put primene leka (povezan sa fiziološkim razlikama između dece i odraslih), mesto delovanja i dužinu trajanja farmakološkog efekta aktivne supstance, zapreminu preparata i opšte zdravstveno stanje pacijenta. Veliki izazov u formulaciji ovih preparata predstavlja izbor ekscipijenasa koji treba da obezbede odgovarajući kvalitet proizvoda i podnošljivost od strane pacijenta. U radu je dat prikaz razmatranja vezanih za formulaciju parenteralnih preparata za primenu u pedijatrijskoj populaciji. Navedeni su regulatorni zahtevi koji se odnose na primenu ekscipijenasa sa potvrđenim dejstvom i obeležavanje preparata koji ih sadrže. Takođe, razmotreni su savremeni pristupi (baze podataka i alati) koji mogu biti od koristi pri izboru odgovarajućih ekscipijenasa
Bottlenecks in advancing and applying multiomic data integration—common data resources as rate-limiting drivers—the high-impact use case of atherosclerotic cardiovascular disease
No full textDespite striking successes in identifying novel biomarkers for improved patient stratification and predicting disease progression, numerous challenges remain in the effective integration and exploitation of multiomic data in biomedical applications beyond cancer, for which most bioinformatics strategies are developed and validated. That focus on cancer severely limits the effective development and advancement of algorithms in machine learning and artificial intelligence that do not suffer degraded out-of-domain performance. Generalizability and interpretability of models, however, are also required for robust insights that may translate into clinical practice. Work across different independent datasets is critical for establishing models robust towards unwanted variation in assays, protocols, and cohort populations. Disease-specific context like ethnicity, socioeconomic background, sex, lifestyle, disease phase, and tissue type also strongly affect molecular profiles. We here discuss atherosclerotic cardiovascular disease (ASCVD) as a high-impact non-cancer use case for the challenges remaining in the development and application of the latest bioinformatics approaches to multiomics data integration. ASCVD remains the leading cause of death globally. Disease aetiology, progression, and therapy outcome depend on a complex interplay of genetic, environmental, and lifestyle factors. Integrating these diverse data types effectively remains a challenge but holds transformative potential for personalized medicine. Discovery and access to data of sufficient diversity and extent form key bottlenecks. We here compile a first comprehensive overview of key data sets in ASCVD to complement the established cancer-focused resources as a foundation for future effective development and application of state-of-the-art bioinformatics tools for multiomic data integration
The histone deacetylase inhibitor Scriptaid targets G-quadruplexes
No full textScriptaid is a chemical compound with anti-tumoural effects due to its role as a histone deacetylase inhibitor. Despite sharing part of the chemical structure with other ligands of G-quadruplexes (G4s), the interaction of Scriptaid with G4s has not been explored before. We synthesized Scriptaid and screened its cytotoxic activity in cellular models of colorectal cancer (CRC). We extensively evaluated its biological activity by cell cycle, immunofluorescence, qRT-PCR and Western blot experiments. To identify the G4 targets of Scriptaid, we conducted a panel of binding assays. Here, we show that Scriptaid induced cytotoxicity, cell cycle arrest and nucleolar stress in CRC cells. Moreover, Scriptaid impaired RNA polymerase I (Pol I) transcription, stabilized G4s and caused DNA damage. Finally, we disclose that these effects were attributable to the binding of Scriptaid to G4s in ribosomal DNA. In conclusion, our work reveals that a primary impact of Scriptaid on human cells is the interaction with G4s
Lignin-Based Nanocarrier for Simultaneous Delivery of 131I and SN-38 in the Combined Treatment of Solid Tumors by a Nanobrachytherapy Approach
No full textBackground: The rapid rise in cancer incidence significantly augments efforts to improve cancer treatments. A multimodal approach in the nanobrachytherapy of solid tumors is one of the promising methods under investigation. This study presents a novel biocompatible lignin-based nanomaterial, loaded with cytostatic agent SN-38 and radionuclide 131I, for simultaneous radiation and chemotherapy of solid tumors by a nanobrachytherapy approach. Method: Nanoparticles of ~100 nm in size, composed of lignin alone or loaded with 10% (m/m) of SN-38 (SN-38@lignin), were synthesized using a bottom-up approach and characterized. Subsequent radiolabeling of the nanoparticles by 131I produced 131I-lignin and 131I-SN-38@lignin. Their antitumor efficiency was tested against luciferase-expressing 4T1 mouse breast cancer xenografts of ~100 mm3 size on Balb/c mice. Results: An intratumoral injection of 1.85 MBq of 131I-lignin was retained within the tumor and achieved a moderate twofold decrease in tumor size compared to the control group. Injecting SN-38@lignin containing 25 µg of SN-38 decreased tumor size 3.5-fold. The therapy using the same doses of 131I-SN-38@lignin produced the most potent antitumor effect, with tumors being 6-fold smaller and having extensive intratumoral necrosis, all of it without signs of systemic toxicity. Conclusions: These results support the intratumoral delivery of lignin-based nanomaterial carrying radioisotopes and camptothecins for effective multimodal anticancer therapy
Editorial: Multiomic approaches in atherosclerosis
No full textAtherosclerosis remains the leading cause of morbidity and mortality worldwide [1], highlighting the persistent clinical burden despite substantial advances in cardiovascular disease prevention and care. Recent progress in imaging, molecular diagnostics, and individualised therapies has refined our understanding of the disease mechanisms. Nevertheless, acute coronary syndrome (ACS), a major clinical manifestation, continues to pose significant diagnostic and therapeutic challenges, due to the evolving understanding of the complexity of plaque biology and inter-individual variability. The multifactorial nature of atherosclerotic disease — comprising genetic, epigenetic, (epi)transcriptomic, proteomic, and metabolic perturbations — calls for a systems-level understanding which integrates diverse layers of biological information [2]
Procena analitičkih i kliničkih karakteristika siemens IMMULITE®2000 TSI metode za određivanje antitela na receptor za tireotropin
No full textBackground: Despite commercially improved, standardised routine methods used in medical laboratories, precision laboratory medicine lacks harmonisation of results to
make the laboratory result useful for its intended purpose.
Furthermore, to obtain reliable laboratory results and precise diagnoses, it is important and recommended that each
laboratory confirms the analytical and clinical characteristics of the method used. This study aimed to evaluate the
analytical and clinical performance of the IMMULITE®2000
TSI bridge immunoassay to determine autoreactive thyroid
stimulating hormone receptor antibodies ( SH-R-Ab).
Methods: A total of 86 patients with clinically present
Graves’ orbitopathy and 23 healthy volunteers as a control
group were included in the study. The total TSH-R-Ab concentration was determined using an ECLIA (Elecsys Anti-
TSHR Immunoassay Roche Diagnostics, GmbH,
Mannheim, Germany) on the Cobas e411 analyser (Roche,
Diagnostics, GmbH). The TSH-R-Ab concentration was
measured using a CLIA method (IMMULITE TSI 2000,
Siemens Healthcare Diagnostics, UK). The inaccuracy of
the method was investigated using two levels of commercial control samples (low and high analyte concentration).
Results: The results obtained meet the general minimum
requirements for the analytical performance of laboratory
methods (CV<5%). The overall laboratory inaccuracy was
acceptable according to FDA guidelines (CV<20%). The
results showed a statistically significant correlation between
the analysed methods (r=0.9041, p < 0.0001) but with a
relative bias of 24.5%. The best ratio of sensitivity and
specificity determined by the ROC analysis (93.3% and
100%, respectively) was obtained for a cut-off value of
0.1215 IU/L, which is significantly lower compared to the
cut-off value specified by the manufacturer (0.55 IU/L).
Conclusions: The IMMULITE 2000 TSI bridge immuno-
assay for TSH-R-Ab quantification confirmed adequate precision, which is essential for routine use. However, further
studies are required to evaluate its analytical specificity.Uvod: Uprkos komercijalno poboljšanim, standardizovanim
rutinskim metodama koje se koriste u medicinskim laboratorijama, preciznoj laboratorijskoj medicini nedostaje harmonizacija rezultata kako bi laboratorijski rezultat bio koristan za njegovu namenu. Dodatno, za dobijanje pouzdanih
laboratorijskih rezultata i preciznijih dijagnoza važno je i
preporučuje se da svaka laboratorija potvrdi analitičke i
kliničke karakteristike primenjene metode. Cilj ove studije
bio je da se procene analitičke i kliničke performanse
IMMULITE®2000 TSI imunohemijskog testa za određivanje autoreaktivnih antitela na receptore hormona koji stimulišu štitnu žlezdu (TSH-R-Ab).
Metode: U studiju je uključeno ukupno 86 bolesnika sa
klinički prisutnom Gravesovom orbitopatijom i 23 zdrava
dobrovoljca kao kontrolna grupa. Ukupna koncentracija
TSH-R-Ab određena je pomoću ECLIA (Elecsys Anti-TSHR
Immunoassay Roche Diagnostics, GmbH, Mannheim,
Germany) na analizatoru Cobas e411 (Roche, Diagnostics,
GmbH). Koncentracija TSH-R-Ab merena je metodom
CLIA (IMMULITE TSI 2000, Siemens Healthcare Diagnostics, UK). Netačnost metode ispitana je pomoću dva
nivoa komercijalnih kontrolnih uzoraka (niska i visoka koncentracija analita).
Rezultati: Dobijeni rezultati ispunjavaju opšte minimalne
zahteve za analitičke performanse laboratorijskih metoda
(CV<5%). Ukupna laboratorijska netačnost bila je prihvatljiva prema smernicama FDA (CV<20%). Rezultati su
pokazali statistički značajnu korelaciju između analiziranih
metoda (r=0,9041, p<0,0001), ali sa relativnim odstupanjem od 24,5%. Najbolji odnos osetljivosti i specifičnosti
utvrđen ROC analizom (93,3% odnosno 100%) dobijen je
za graničnu vrednost od 0,1215 IU/L, što je značajno niže
u poređenju sa graničnom vrednošću koju je odredio proizvođač (0,55 IU/L).
Zaključak: IMMULITE 2000 TSI imunohemijski test za
kvantifikaciju TSH-R-Ab potvrdio je adekvatan nivo preciznosti koji je neophodan za rutinsku upotrebu. Međutim,
potrebna su dalja istraživanja kako bi se procenila njegova
analitička specifičnost