FarFar - Repository of the Faculty of Pharmacy, University of Belgrade

    Towards optimal ph of the skin and topical formulations: From the current state of the art to tailored products

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    Acidic pH of the skin surface has been recognized as a regulating factor for the maintenance of the stratum corneum homeostasis and barrier permeability. The most important functions of acidic pH seem to be related to the keratinocyte differentiation process, the formation and function of epidermal lipids and the corneocyte lipid envelope, the maintenance of the skin microbiome and, consequently, skin disturbances and diseases. As acknowledged extrinsic factors that affect skin pH, topically applied products could contribute to skin health maintenance via skin pH value control. The obtained knowledge on skins’ pH could be used in the formulation of more effective topical products, which would add to the development of the so-called products ‘for skin health maintenance’. There is a high level of agreement that topical products should be acidified and possess pH in the range of 4 to 6. However, formulators, dermatologists and consumers would benefit from some more precise guidance concerning favorable products pH values and the selection of cosmetic ingredients which could be responsible for acidification, together with a more extensive understanding of the mechanisms underlaying the process of skin acidification by topical products

    Varijacija profila citokina u gingivalnoj zglobnoj tečnosti između različitih grupa parodontalno zdravih zuba

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    Profiling of biomarkers of physiological process represents an integrative part in optimisation of diagnostic markers in order to adjust the diagnostic ranges to the potential effects of the local factors such occlusal forces in case of periodontal tissues. The objective of this study was estimation of IL-1β, IL-2, IL-4, IL-5, IL- 6, IL-9, IL-10, IL-12, IL-13, IL-17, IL-22, TNFα and IFNγ concentrations in gingival crevicular fluid samples (GCF) between different groups of teeth. Two hundred fifty-nine systemically healthy non-smokers having at least one vital tooth without restorations, with healthy periodontal tissues, were clinically examined and the GCF sample was retrieved. The cytokine levels were estimated using flow cytometry and compared between central incisors (CI), lateral incisors, canines, first premolars, second premolars, first molars and second molars. Cytokine profiles varied between different groups of teeth with tendency of increase in proinflammatory cytokines from anterior teeth toward molars. Molars might be considered teeth with natural predisposition for faster bone resorption while the adjustment of diagnostic range of periodontal biomarkers for anterior or posterior teeth should be considered within diagnostic context. Cytokine profiles varied between different groups of teeth with tendency of increase in proinflammatory cytokines from anterior teeth toward molars. Molars might be considered teeth with natural predisposition for faster bone resorption while the adjustment of diagnostic range of periodontal biomarkers for anterior or posterior teeth should be considered within diagnostic context.Profilisanje biomarkera fiziološkog procesa predstavlja integrativni deo optimalizacije dijagnostičkih markera, kako bi se dijagnostički rasponi prilagodili potencijalnim uticajima lokalnih faktora poput okluzijskih sila u slučaju parodontalnih tkiva. Cilj ove studije bila je procena koncentracija IL-1b, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12, IL-13, IL-17, IL- 22, TNFα i IFNγ u uzorcima gingivalne tečnosti (GT) kod različitih grupa zuba. Klinički je pregledano dvesta pedeset devet sistemski zdravih nepušača sa najmanje jednim vitalnim zubom bez restauracija, sa zdravim parodontalnim tkivima, i uzet je GT uzorak. Nivoi citokina procenjeni su protočnom citometrijom i upoređeni između centralnih sekutića (CS), bočnih sekutića, očnjaka, prvih i drugih premolara, kao i prvih i drugih kutnjaka. Profil citokina varirao je između različitih grupa zuba sa tendencijom povećanja pro-upalnih citokina od prednjih zuba do kutnjaka. Molari se mogu smatrati zubima sa prirodnom predispozicijom za bržu resorpciju kosti, dok bi podešavanje dijagnostičkog raspona parodontalnih biomarkera za prednje ili zadnje zube trebalo razmotriti unutar dijagnostičkog konteksta

    Biological evaluation of oil-in-water microemulsions as carriers of benzothiophene analogues for dermal applications

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    During the last decade, many studies have been reported on the design and formulation of novel drug delivery systems proposed for dermal or transdermal administration. The efforts focus on the development of biocompatible nanodispersions that can be delivered to the skin and treat severe skin disorders, including cancer. In this context, oil-in-water (O/W) microemulsions have been developed to encapsulate and deliver lipophilic bioactive molecules for dermal application. An O/W biocompatible microemulsion composed of PBS buffer, Tween 80, and triacetin was assessed for its efficacy as a drug carrier of DPS-2, a lead compound, initially designed in-house to inhibit BRAFV600E oncogenic kinase. The system was evaluated through both in vitro and ex vivo approaches. The cytotoxic effect, in the presence and absence of DPS-2, was examined through the thiazolyl blue tetrazolium bromide (MTT) cell proliferation assay using various cell lines. Further investigation through Western blotting revealed that cells died of necrosis. Porcine ear skin was used as a skin model to evaluate the degree of permeation of DPS-2 through skin and assess its retention. Through the ex vivo experiments, it was clarified that encapsulated DPS-2 was distributed within the full thickness of the stratum corneum (SC) and had a high affinity to hair follicles

    Bcs class iv oral drugs and absorption windows: Regional-dependent intestinal permeability of furosemide

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    Biopharmaceutical classification system (BCS) class IV drugs (low-solubility low-permeability) are generally poor drug candidates, yet, ~5% of oral drugs on the market belong to this class. While solubility is often predictable, intestinal permeability is rather complicated and highly dependent on many biochemical/physiological parameters. In this work, we investigated the solubility/permeability of BCS class IV drug, furosemide, considering the complexity of the entire small intestine (SI). Furosemide solubility, physicochemical properties, and intestinal permeability were thoroughly investigated in-vitro and in-vivo throughout the SI. In addition, advanced in-silico simulations (GastroPlus®) were used to elucidate furosemide regional-dependent absorption pattern. Metoprolol was used as the low/high permeability class boundary. Furosemide was found to be a low-solubility compound. Log D of furosemide at the three pH values 6.5, 7.0, and 7.5 (representing the conditions throughout the SI) showed a downward trend. Similarly, segmental-dependent in-vivo intestinal permeability was revealed; as the intestinal region becomes progressively distal, and the pH gradually increases, the permeability of furosemide significantly decreased. The opposite trend was evident for metoprolol. Theoretical physicochemical analysis based on ionization, pKa, and partitioning predicted the same trend and confirmed the experimental results. Computational simulations clearly showed the effect of furosemide’s regional-dependent permeability on its absorption, as well as the critical role of the drug’s absorption window on the overall bioavailability. The data reveals the absorption window of furosemide in the proximal SI, allowing adequate absorption and consequent effect, despite its class IV characteristics. Nevertheless, this absorption window so early on in the SI rules out the suitability of controlled-release furosemide formulations, as confirmed by the in-silico results. The potential link between segmental-dependent intestinal permeability and adequate oral absorption of BCS Class IV drugs may aid to develop challenging drugs as successful oral products

    Genomic characteristics of colistin-resistant salmonella enterica subsp. Enterica serovar infantis from poultry farms in the Republic of Serbia

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    The antimicrobial susceptibility testing was conducted on 174 single isolates from poultry farms in Serbia and it was determined that seven Salmonella spp. were multidrug resistant. Sixteen serotypes were detected, but only serotype Infantis confirmed reduced susceptibility to colistin. Seven colistin resistant Salmonella Infantis were studied in detail using the WGS approach. Three sequence types were identified corresponding to different epizootiology region. The isolate from the Province of Vojvodina 3842 and isolates from Jagodina (92 and 821) are represented by the sequence type ST413 and ST11, respectively. Four isolates from Kraljevo are ST32, a common S. Infantis sequence type in humans, poultry and food. The fosfomycin resistance gene fosA7 in isolate 3842 and the vgaA gene in isolate 8418/2948 encoding resistance to pleuromutilins were reported for the first time in serovar Infantis. The changes in relative expression of the phoP/Q, mgrB and pmrA/B genes were detected. Single nucleotide polymorphisms of the pmrB gene, including transitions Val164Gly or Val164Met, and Arg92Pro are described. Analyses of quinolone resistance determining region revealed substitutions Ser83Tyr in GyrA protein and Thr57Ser and Ser80Arg in ParC protein. Based on WGS data, there are two major clusters among analyzed Salmonella Infantis isolates from central Serbia

    Redoks status i razine bioelemenata u mozgu štakora akutno izloženih smjesi kadmija i olova

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    Most Pb and Cd neurotoxicity studies investigate exposure to either of the toxic metals alone, while data on co-exposure are scarce. The aim of our study was to fill that gap by investigating acute combined effects of Pb and Cd on redox and essential metal status in the brain of Wistar rats. Animals were randomised in four groups of six to eight rats, which received 15 or 30 mg/kg of Cd, 150 mg/kg of Pb, or 150 mg/kg of Pb + 15 mg/kg of Cd by gavage. The fifth, control, group received distilled water only. Co-treatment with Pb and Cd induced significant increase in malondialdehyde (MDA) and thiobarbituric acid-reactive substances (TBARS) compared to control and groups receiving either metal alone. This is of special importance, as MDA presence in the brain has been implicated in many neurodegenerative disorders. The groups did not significantly differ in Zn, Cu, Mn, and Fe brain levels. Our findings highlight the importance of metal mixture studies. Neurotoxicity assessments of single chemicals do not provide a real insight into exposure to mixtures in real life. Further research should look into interactions between these metals to reveal complex molecular mechanisms of their neurotoxicity.Dosadašnji podatci o neurotoksičnosti olova (Pb) i kadmija (Cd) uglavnom su opisani nakon izloženosti pojedinačnim metalima, a podatci o neurotoksičnom djelovanju smjese tih dvaju metala prilično su oskudni. Cilj ovoga rada bio je ispitati učinak akutnoga izlaganja smjesi olova i kadmija na parametre oksidacijskoga stresa i status bioelemenata u mozgu štakora. Životinje su bile podijeljene u pet skupina: Cd15 (15 mg/kg), Cd30 (30 mg/kg), Pb150 (150 mg/kg), Pb150+Cd15 i kontrolna, netretirana skupina. Smjesa olova i kadmija dovela je do značajno viših vrijednosti malondialdehida (MDA) i drugih produkata u mozgu štakora u usporedbi s kontrolnom skupinom i obama pojedinačnim metalima. To je iznimno važno, imajući u vidu da je prisutnost MDA-a u mozgu povezana s mnogim neurodegenerativnim poremećajima. Nije dobivena statistički značajna razlika između ispitivanih skupina u razinama cinka (Zn), bakra (Cu), mangana (Mn) i željeza (Fe). Rezultati ovoga istraživanja važan su doprinos budućim istraživanjima smjesa i upućuju na to da istraživanja toksičnosti u kojima se procjenjuje neurotoksičnost pojedinačnih kemikalija ne pružaju stvarni uvid u neurotoksičnost njihovih smjesa kojima smo izloženi u stvarnom životu. Dobiveni rezultati otvaraju daljnja pitanja o interakciji i mehanizmima toksičnosti smjese tih metala

    Quality indicators for measuring the level of patients' involvement in the pharmaceutical care process

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    Patient-centred counseling is an integral part of the pharmaceutical care process. Quality in- dicators can be valuable tools to measure the level of patients’ involvement in their personal healthcare. The aim of the study was to validate two quality indicators for community pharmacy care focusing on patient involvement. As part of the EDQM Pharmaceutical Care Quality Indicators Project (Council of Europe), at least 10 patients per indicator were recruited in each community pharmacy in Serbia and Po- land. Pharmacists targeted patients aged 18-65 years starting chronic treatment (Indicator 1) and elderly patients with polymorbidity receiving at least five chronic treatment medicines (Indicator 2). Based on patients’ answers to a questionnaire, patient-pharmacist consultations took place. For Indicator 2, patients were also offered a medication review. In total, 66% of Serbian patients and 29% Polish patients, for In- dicator 1, were engaged in pharmacist-patient consultations; 96% of Serbian and 84% of Polish elderly patients subsequently participated in medication reviews. Community pharmacists can increase patients’ involvement in their own pharmaceutical care, and there is a need for such services. This study defines a pragmatic approach to encourage/support the implementation of the pharmaceutical care philosophy and working methods in European community pharmacies

    Mimicking of phase I metabolism reactions of molindone by HLM and photocatalytic methods with the use of UHPLC-MS/MS

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    Establishing the metabolism pathway of the drug undergoing the hepatic biotransformation pathway is one of the most important aspects in the preclinical discovery process since the presence of toxic or reactive metabolites may result in drug withdrawal from the market. In this study, we present the structural elucidation of six, not described yet, metabolites of an antipsychotic molecule: molindone. The elucidation of metabolites was supported with a novel photocatalytical approach with the use of WO3 and WS2 assisted photochemical reactions. An UHPLC-ESI-Q-TOF combined system was used for the registration of all obtained metabolite profiles as well as to record the high resolution fragmentation spectra of the observed transformation products. As a reference in the in vitro metabolism simulation method, the incubation with human liver microsomes was used. Chemometric comparison of the obtained profiles pointed out the use of the WO3 approach as being more convenient in the field of drug metabolism studies. Moreover, the photocatalysis was used in the direction of the main drug metabolite synthesis in order to further isolation and characterization

    Insight into the formation of glimepiride nanocrystals by wet media milling

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    Nanocrystal formation for the dissolution enhancement of glimepiride was attempted by wet media milling. Di erent stabilizers were tested and the obtained nanosuspensions were solidified by spray drying in presence of mannitol, and characterized regarding their redispersibility by dynamic light scattering, physicochemical properties by di erential scanning calorimetry (DSC), FT-IR spectroscopy, powder X-ray di raction (PXRD), and scanning electron microcopy (SEM), as well as dissolution rate. Lattice energy frameworks combined with topology analysis were used in order to gain insight into the mechanisms of particle fracture. It was found that nanosuspensions with narrow size distribution can be obtained in presence of poloxamer 188, HPC-SL and Pharmacoat® 603 stabilizers, with poloxamer giving poor redispersibility due to melting and sticking of nanocrystals during spray drying. DSC and FT-IR studies showed that glimepiride does not undergo polymorphic transformations during processing, and that the milling process induces changes in the hydrogen bonding patterns of glimepiride crystals. Lattice energy framework and topology analysis revealed the existence of a possible slip plane on the (101) surface, which was experimentally verified by PXRD analysis. Dissolution testing proved the superior performance of nanocrystals, and emphasized the important influence of the stabilizer on the dissolution rate of the nanocrystals

    Корелација маркера оксидативног стреса и параметара спермограма са исходом вантелесне оплодње

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    Introduction/Objective The aim was to assess the effect of oxidative stress parameters on sperm count, motility, and morphology of spermatozoa, and the influence of different semen parameters on the outcome of in vitro fertilization (IVF) procedure – the number of fertilized oocytes, fertilization, and pregnancy rate of female partners. Method In 52 male patients superoxide dismutase (SOD), malondialdehyde (MDA), and sulfhydryl (-SH) groups were determined in serum, before beginning the IVF cycle. Semen samples were collected after 2–3 days of sexual abstinence. Results Patients were divided into two groups, the normozoospermic, and those with pathological sperm findings. The second group was divided into oligozoospermic, asthenozoospermic, and teratozoospermic groups. SOD activity was lower, while MDA and-SH groups, while not significantly, was higher in groups with sperm parameter disorders. Fertilization rate was significantly lower in the group of asthenozoospermia and teratozoospermia (p = 0.034), as well as delivery rate (p = 0.020). The group with oligozoospermia had significantly lower delivery rate (p = 0.013). Conclusion Our study found higher fertilization and delivery rate in men with normozoospermia. However, no significant correlation between OS markers and semen parameters was found.Увод/Циљ Циљ рада била је процена утицаја параметара оксидативног стреса на број, покретљивост и морфологију сперматозоида, као и утицаја различитих параметара спер-мограма на исход поступка in vitro фертилизације, број фер-тилисаних ооцита, стопе фертилизације и порођаја.Методе Код 52 мушка партнера одређиване су вредности супероксид-дисмутазе, малондиалдехидаи сулфидрила(-SHгрупа) у серуму, пре започињања поступка in vitro ферти-лизације. Узорци семена сакупљани су после два-три дана апстиненције. Резултати Болесници су били подељени у две групе: гру-па са нормозооспермијом и група са патолошким налазом спермограма. Друга група је затим подељена на подгрупе: олигозооспермија, астенозооспермија и тератозооспер-мија. Активност супероксид-дисмутазе била је нижа, док су вредности малондиалдехидаи -SH група биле више у гру-пама са поремећеним параметрима спермограма, али не статистички значајно. Стопа фертилизације била је значајно нижа у групи са астенозооспермијом и тератозооспермијом (p = 0,034), а такође и стопа порођаја (p = 0,020). Група са олигозооспермијом имала је значајно нижу стопу порођаја (p = 0,013).Закључак У овој студији пронађене су више стопе ферти-лизације и порођаја у групи са нормозооспермијом. Није било значајне корелације између параметара оксидативног стреса и спермограма
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