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Investigating the influence of croscarmellose sodium content on the properties of liquisolid systems prepared with different mesoporous carriers
No full textINTRODUCTION
The disintegration of tablets in the gastrointestinal fluids is one of the prerequisites for drug absorption and ultimate therapeutic effect (Bhalani, 2022), which is why most tablet formulations require the use of a suitable disintegrant. Liquisolid systems (LSS) are considered a promising technique for improving the oral bioavailability of poorly soluble drugs. The excipients used for their formulation, such as carriers and coating materials, are usually characterised by a large specific surface area required for their intended use. However, they are often hydrophobic, which leads to slow disintegration of the LS tablets. To ensure adequate wetting and disintegration properties, the choice of the appropriate disintegrant and its concentration in these formulations must be carefully considered (Gavali, 2011). The aim of this study was to investigate how different concentrations of croscarmellose sodium (CCS), a widely used superdisintegrant, affect the mechanical properties of LSS prepared with four different mesoporous carriers, their disintegration time and wetting ability
Film-forming solutions for cutaneous application: Current challenges and future directions in formulation design and characterization framework
No full textFilm-forming solution (FFS) implies a novel formulation strategy for liquid preparations for cutaneous application with numerous advantages in comparison with compendial dosage forms, including flexibility of composition (active pharmaceutical ingredient (API) solution in volatile and non-volatile solvents, with film-forming polymers, plasticizers and chemical permeation agents) and the method of administration (rubbing or spraying). Research over the past two decades indicates the potential of FFS for comparable or improved dermal, regional and transdermal delivery of small-molecule drugs due to improved passive diffusion through: volatile solvents evaporation and API (super)saturation, and potential increase in stratum corneum (SC) permeability caused by excipients. Current commercial exploitation of FFS is limited due to demanding pharmaceutical development, the backbone of which is formulation design and product characterization. This comprehensive review gives insight into the complex relationship between the formulation composition, quality attributes (physicochemical properties, microstructure) and in vitro performance (drug release and permeation) of FFS. A characterization framework is proposed, taking into account published studies, relevant pharmacopoeial standards and announced guidelines of the European Medicines Agency (EMA) and The United States Food and Drug Administration (FDA). The importance of specific tests for evaluating the transformation of FFS at the site of application and the quality attributes of the in situ formed film, was pointed out. Directions for pharmaceutical development improvement are given, including the favoring of environmentally acceptable and biocompatible excipients, introduction of in silico formulation optimization techniques and development of standardized methodology for reliable and comparable assessment of quality, efficiency and safety of FFS
Metformin reduces inflammatory nociception in mice through a serotonin-dependent mechanism
No full textThe antidiabetic drug metformin has demonstrated antinociceptive efficacy in different pain models, and these effects are usually attributed to activation of the AMP-dependent protein kinase (AMPK). However, the downstream targets that contribute to inhibition of nociception following AMPK activation have been only partially elucidated. Here, we examined the contribution of serotonergic mechanisms in mediating metformin's antinociceptive effects, seeing as AMPK activators (including metformin) have been shown to modulate serotonergic neurotransmission. The formalin test in mice was used as an inflammatory pain model. First, we examined metformin's effects following systemic (intraperitoneal) and local peripheral (intraplantar) administration. In the second part, we examined the roles of the AMPK and serotonin system in mediating metformin's antinociceptive effects by (locally and/or systemically) pretreating animals with the AMPK inhibitor (dorsomorphin), antagonists of serotonin 5-HT1A (WAY100635) and 5-HT1B/1D receptors (GR127935) or the tryptophan-hydroxylase inhibitor (PCPA). Metformin significantly reduced second phase nociceptive behavior following systemic and local application. In inhibitor/antagonist studies systemic application of dorsomorphin, WAY100635 or GR127935 significantly inhibited metformin's antinociceptive effects. Local application of dorsomorphin did not change metformin's antinociceptive effects, however locally administered serotonin receptor antagonists significantly reduced them. Finally, four-day pretreatment with PCPA (which depleted brainstem and spinal cord serotonin content) led to a significant reduction of metformin's antinociceptive effects. In conclusion, metformin produces serotonin-dependent antinociceptive effects against inflammatory pain via peripheral, and possibly central, serotonin 5-HT1A and 5-HT1B/1D receptors. The serotonin-mediated mechanism appears to be dependent on serotonin release, seeing as depletion of endogenous serotonin content attenuated metformin's antinociceptive effects
Improved Prediction of CYP2D6 Catalyzed Drug Metabolism by Taking Variant Substrate Specificities and Novel Polymorphic Haplotypes into Account
No full textThe polymorphic CYP2D6 enzyme plays a pivotal role in the metabolism of approximately 25% of clinically prescribed drugs. However, the impact of specific genetic variants on the interindividual variability in CYP2D6-mediated drug metabolism remains insufficiently quantified. This translational study sought to address this gap by analyzing the genotypes and phenotypes of patients in two large clinical cohorts, focusing on the metabolism of the CYP2D6 substrates risperidone and desmethyltamoxifen. The analysis incorporated novel polymorphic haplotypes and substrate-specific differences among the CYP2D6.1, CYP2D6.2, and CYP2D6.35 enzyme variants. The study revealed that CYP2D6.2 and CYP2D6.35 exhibit reduced metabolic capacity for these substrates, both in vivo and in an in vitro expression model. This was evidenced by decreased catalytic turnover (Kcat), decreased substrate affinity, and altered substrate docking. Furthermore, novel polymorphic haplotypes on the CYP2D6*1, CYP2D6*2, and CYP2D6*35 backgrounds were identified, each associated with a 30–40% increase in CYP2D6 activity. Incorporating these findings into prediction equations significantly improved the genetic prediction accuracy (R2) for CYP2D6-mediated metabolism of desmethyltamoxifen from 59% to 71% and risperidone, also metabolized by CYP3A4, from 42% to 46%. These results highlight the importance of accounting for drug-specific interactions with enzyme variants and integrating distinct polymorphic haplotypes into CYP pharmacogenomic models and guidelines for better translation into clinical practic
Challenges in the preclinical design and assessment of CAR-T cells
No full textThe advent of immunotherapy in the treatment of cancer has opened a new
dimension in the management of this complex multifaceted disease, bringing
hope to many patients whose tumors have failed to respond to conventional
therapies. The adoptive T cell therapy has since been extended to the treatment
of several hematologic malignancies, initially in relapsed settings and more
recently at the forefront of treatment due to high response rates. Despite
exciting initial results, the preclinical antitumor effects of the first long-term
studies show that CAR (Chimeric Antigen Receptor)-T cells have been slow to
translate to the clinical setting, with early clinical trials showing suboptimal
responses. The main reasons for the limited clinical performance seemed to be
related to the low activation and short persistence of CAR-T cells. Thus, began a
journey to improve the initial CAR structure, leading to the development of more
complex constructs, which are grouped into five CAR generations. In this review,
we describe the main challenges and potential solutions for the evaluation of
CAR T-cell-based therapies in the preclinical setting
Procena merne nesigurnosti primenom pristupa odozgo nadole i pristupa odozdo nagore za tačno određivanje sadržaja meloksikama u injekcionim farmaceutskim oblicima
No full textMeasurement uncertainty plays a critical role in ensuring the reliability, accuracy, and
regulatory compliance of analytical results in pharmaceutical quality control. This study presents
a comprehensive comparison of the Top-down and Bottom-up approaches for estimating the
uncertainty associated with the quantitative determination of Meloxicam in injectable dosage
forms using a validated HPLC method. The Top-down approach, based on method validation
data, yielded an expanded uncertainty of ±0.336 mg per injection, while the Bottom-up approach
(incorporating uncertainties from volumetric equipment, reference standards, and molar mass)
produced a broader value of ±0.646 mg per injection. The results highlight the complementary
nature of both approaches and support the integration of their respective strengths to improve the robustness of uncertainty estimation. The proposed methodology is applicable to other methods
within pharmaceutical quality control.Mernа nesigurnost ima ključnu ulogu u obezbeđivanju pouzdanosti, tačnosti i regulatorne
usklađenosti analitičkih rezultata u okviru kontrole kvaliteta farmaceutskih proizvoda. Ova
studija predstavlja sveobuhvatno poređenje pristupa odozgo nadole (Top-down) i odozdo nagore
(Bottom-up) u proceni nesigurnosti povezane sa određivanjem sadržaja meloksikama u
injekcionim farmaceutskim oblicima, primenom validirane HPLC metode. Merna nesigurnost
izračunata primenom pristupa odozgo nadole koji je zasnovan na podacima dobijenim tokom
validacije metode, iznosi ±0,336 mg po injekciji. Primenom pristupa odozdo nagore, koji
uključuje pojedinačne doprinose nesigurnosti od volumetrijske opreme, referentnih standarda i
molarne mase, dobijena je viša vrednost od ±0,646 mg po injekciji. Dobijeni rezultati ukazuju na
komplementarnost ovih pristupa i sugerišu da njihova integracija može doprineti unapređenju
robusnosti procene nesigurnosti. Predložena metodologija ima potencijal za primenu i u drugim
analitičkim metodama u okviru kontrole kvaliteta farmaceutskih proizvoda
Oksidativni stres kod adolescenata sa prekomernom telesnom težinom/gojaznošću
No full textBackground: The pathophysiological mechanism underlying obesity and related diseases is still incompletely understood. A small number of studies employed sophisticated statistical techniques, such as principal component analysis (PCA), to investigate the relationship between oxidative stress, cardiometabolic biomarkers, and obesity in the adolescent population. Hence, we aimed to examine this relationship. Methods: A total of 68 adolescents (i.e., 34 were overweight/obese, and 34 were sex-and age-matched normalweight controls) were included in the study. Total oxidant status (TOS) and total antioxidant status (TAS) were measured, whereas their ratios were calculated, i.e., prooxidant score [(TO S/TAS)*100] and antioxidant score (TAS/TOS). PCA was applied to reduce the number of determined data by grouping them into factors. Results: A significantly higher concentration of TAS, TOS, and their pro-oxidant ratio (TO S/TAS)*100, while the antioxidant score of TAS/TOS was considerably lower in overweight/obese adolescents compared to normal-weight peers. TOS was the most significant predictor of obesity status (P = 0.0 01). PCA extracted 3 factors related to obesity status: Factor 1 (gender, creatinine, uric acid, total bilirubin, TAS, waist circumference, and urea), Factor 2 (ALT and AST), and Factor 3 (age, glucose, total protein, and TO S). Among them, Factor 2 (P = 0.0 03) and Factor 3 (P = 0.0 03) were independently associated with obesity. Conclusions: The present study provides evidence of disrupted redox homeostasis in adolescents with obesity. Obesity is tightly connected with increased oxidative stress and a cluster of metabolic abnormalities. It is essential to identify risk factors promptly and develop a strategy to combat obesity and its associated diseases.Uvod: Patofizioloski mehanizmi koji leže u osnovi gojaznosti
i s njom povezanih bolesti jos uvek nisu u potpunosti
razjasnjeni. Mali broj studija koristio je sofisticirane sta-
tističke metode, poput analize glavnih komponenti (PCA),
kako bi ispitao povezanost između oksidativnog stresa, kar-
diometaboličkih biomarkera i gojaznosti kod adolescenata.
Zbog toga je cilj nase studije bio da istraži ovu povezanost.
Metode: U studiju je ukupno bilo uključeno 68 adolesce
nata, od kojih je 34 imalo prekomernu telesnu težinu/
gojaznost, dok je 34 činilo kontrolnu grupu adolescenata
sa normalnom telesnom težinom, usklađenih po polu i
starosti. Mereni su ukupni oksidativni status (TO S) i ukupni
antioksidativni status (TAS), a na osnovu njih su izračunati
prooksidativni skor [(TO S/TAS) x 100] i antioksidativni
skor (TAS/TO S). Za redukciju broja ispitivanih varijabli i nji-
hovo grupisanje u faktore primenjena je analiza glavnih
komponenti (PCA).
Rezultati: Uočena je značajno veca koncentracija TAS, TO S
i njihov prooksidativni odnos (TO S/TA S)*10 0, dok je anti
oksidativni skor TAS/TO S bio značajno niži kod predgo-
jaznih/gojaznih adolescenata u poređenju sa vrsnjacima
normalne težine. TO S je bio najznačajniji prediktor statusa
gojaznosti (P = 0 ,0 0 1 ). PCA je izdvojila 3 faktora povezana
sa statusom gojaznosti: Faktor 1 (pol, kreatinin, mokracna kiselina, ukupni bilirubin, TAS, obim struka i urea), Faktor
2 (ALT i A ST) i Faktor 3 (starost, glukoza, ukupni proteini i
TO S). Među njima, Faktor 2 (P = 0 ,0 0 3 ) i Faktor 3
(P = 0 ,0 0 3 ) su bili nezavisno povezani sa gojaznošću.
Zaključak: Ova studija pruža dokaze o narušenoj redoks
homeostazi kod adolescenata sa gojaznošću. Gojaznost je
usko povezana sa povišenim oksidativnim stresom i klasterom
metaboličkih poremećaja. Pravovremeno prepoznavanje fak-
tora rizika i razvoj efikasnih strategija za prevenciju i lečenje
gojaznosti i pratećih oboljenja od suštinskog su značaja
Semaglutide treatment effects on anxiety-like behavior and sucrose preference in a rat model of diabetes type 2
No full textThe blockbuster drug semaglutide, a glucagon-like peptide-1 receptor agonist, is widely used for the treatment of diabetes type 2 (T2D) connected with obesity. However, some pharmacovigilance analysis studies on psychiatric adverse events detected potentially associated mood-related changes with semaglutide treatment and suggested further exploration. ..
Uticaj TMPRSS6 genotipova na parametre statusa gvožđa kod pacijenata sa stabilnim oblikom HOBP
No full textBackground: The SNP rs855791 has been linked to
increased hepcidin levels, variations in serum iron, transfer-
rin saturation and red blood cell indices. Our goal was to
determine the prevalence of this polymorphism among
COPD patients and to assess its impact on iron status
parameters in patients with stable COPD.
Methods: We analysed iron status parameters and genetic
data from 29 COPD patients with wild-type genotype (WT
group) and 65 COPD patients with either homozygous or
heterozygous genotype (HH group). Additionally, the
prevalence of SNP rs855791 was assessed in 192 volun-
teers.
Results: The frequency distribution of SNP rs855791 was
comparable between the COPD patients and control sub-
jects (p=0.791). Iron status parameters were within their
respective reference values and showed neither statistically
nor clinically significant difference between the WT and
HH group of COPD patients. However, after excluding
patients with (sub)clinical vitamin B12 deficiency and/or
hypoxemia, WT group of patients exhibited significantly
lower erythropoietin levels (p=0.015). The area under the
curve for erythropoietin was 0.688 (95% CI: 0.545–0.830,
p=0.015), with an optimal cut-off of 9.74, sensitivity of
61.2% (95% CI: 58.1–64.3) and specificity of 65.0% (95%
CI: 61.8–68.3).
Conclusions: Iron status parameters do not differ between
WT and HH groups of stable COPD patients. Statistical but
not clinical difference in EPO levels was observed in a sub-
group of patients. In addition to promoting erythropoiesis,
EPO may regulate hepcidin levels and thus influence the
development of iron deficiency and/or anaemia. Also,
EPO’s direct effect on immune cells and down-regulation
of inflammatory reactions should be considered in this con-
text.Uvod: Polimorfizam rs855791 povezan je s povišenim vrednostima hepcidina i promenama u vrednostima serumskog gvožđa, saturacije transferina i eritrocitnim indeksima. Cilj istraživanja bio je da se odredi zastupljenost ovog polimorfizma kod pacijenata sa HOBP, kao i da se ispita njegov uticaj na vrednosti parametara statusa gvožđa kod pacijenata sa stabilnim oblikom HOBP Metode: Parametri statusa gvožđa i zastupljenost genotipova su ispitani kod 29 HOBP pacijenata s wild-type tip varijantom (WT grupa) i 65 HOBP pacijenata s homozigotnom ili heterozigotnom varijantom (HH grupa). Zastupljenost genotipova određena je i kod 192 ispitanika kontrolne grupe. Rezultati: Zastupljenosti polimorfizma rs855791 kod pacijenata s HOBP i ispitanika kontrolne grupe je bila uporediva (p=0.791). Parametri statusa gvožđa su bili u okvirima svojih referentnih vrednosti i nije bilo ni statistički ni klinički značajne razlike između WT i HH grupe pacijenata s HOBP Nakon isključenja pacijenata sa (sub)kliničkim deficitom vitamina B12 i/ili hipoksijom, dobijene su statistički značajno niže vrednosti eritropoetina kod ispitanika WT grupe (p=0.015). Površina ispod krive (AUC) iznosila je 0.688 (95% CI: 0.545-0.830, p=0.015). Određena je optimalna granična vrednost za eritropoetin od 9,74 mIU/mL sa osetljivošću od 61.2% (95% CI: 58.1-64.3) i specifičnošću od 65.0% (95% CI: 61.8-68.3). Zaključak: Kod pacijenata sa stabilnim oblikom HOBP parametri statusa gvožđa se ne razlikuju između pacijenata sa wild-type i pacijenata s homozigotnom ili heterozigotnom varijantom. Statistički, ali ne i klinički, značajna razlika u vrednosti eritropoetina je dobijena u podgrupi pacijenata. Uz svoju poznatu ulogu u eritropoezi, eritropoetin bi mogao da utiče na vrednosti hepcidina i tako spreči nastanak deficijencije gvožđa i/ili anemije. Takođe, u ovom kontekstu treba razmotriti i direktni efekat eritropoetina na ćelije imunog sistema i nishodnu regulaciju inflamacije
Valorisation of Sunflower Crop Residue as a Potentially New Source of Bioactive Compounds
No full textReducing agricultural waste through reuse has become one of the most important strategies to minimise impact on the environment—an emerging global issue. Sunflower ranks fourth in the world in the production of vegetable oilseeds and therefore generates large amounts of agricultural waste. The aim of this study was to investigate the phytochemical composition and bioactivity of sunflower crop residues in order to open up new opportunities for waste management. TPC and TFC were determined spectrophotometrically, while the dominant compounds were identified by LC-DAD-ESI-MS as ent-kaur-16-en-19-oic acid (KA) and 6Ac-7OH-dimethylchromone (DMC). Both compounds were present in higher concentrations in the ethyl acetate fraction (245.5 and 16.8 mg/g, respectively) than in the ethanol extract. None of the tested samples showed antimicrobial effects in the microdilution test. DMC showed remarkable antioxidant activity by DPPH, ABTS, FRAP and TRC in vitro assays, while both compounds proved to be promising enzyme inhibitory agents, being particularly efficient in inhibiting anti-neurodegenerative enzymes (IC50 values of DMC and KA were 1.20/1.37 mg/mL and 1.44/1.63 mg/mL for AChE/BChE, respectively) and tyrosinase. The results presented indicate that sunflower crop residues are a good candidate for the extraction of bioactive compounds with potential application in the food, pharmaceutical and cosmetic industries