Determination of diclofenac residue in swine tissue following intramuscular administration

Diclofenac residue (DF) in swine tissue (liver, kidney, muscle, injection site) were examined using the method of High Performance Liquid Chromatography (HPLC) 15h, 72h,and 120h after i.m. administration of an individual therapeutic dose of diclofenac-sodium. At 15h after administration, the highest concentration of DF was found in the kidney (0.614 mg/kg), while a concentration about two times lower was found in the liver (0.316 mg/kg). At the injection site, the DF concentration was 0.432 mg/kg, while DF remained in a very low concentration (0.052 mg/kg) in the muscle outside the injection site, which was the lowest concentration in comparison with all the other examined tissues. At 72h after administration, DF was present in all examined tissues, but its concentrations were lower than the level that could be determined using the analytic procedure. Traces of the administered medicine disappeared after the waiting period of 120h in all tissues, except for the injection site. The longer presence of the medicine at the injection site could be a consequence of local inflammation, or irritation, that could cause a reduction in pH values of the area around the injection site, thus leading to slower dissolving and a longer presence of the DF at the injection site

Prognostic factors of mortality in elderly with community acquired pneumonia

Background/Aim. Community acquired pneumonia in elderly has specific clinical aspect and higher mortality in relation to younger patients. According to specific pneumonia severity assessment on admission and its importance in proper prediction of clinical course and outcome, the aim of this study was defining prognostic factors of mortality. Methods. This study included 240 patients aged ≥ 65 years with community acquired pneumonia. On admission, demographic characteristics, underlying diseases, physical symptoms and findings, laboratory values, chest radiography and oxygen blood saturation (SaO2) were analyzed. Multivariate analysis was used to identify characteristic prognostic factors which showed a statistical significance in relation to mortality. Results. Altered mental status, respiratory frequency ≥ 23/min and the presence of bilateral pneumonic infiltrates were defined as the most important prognostic factors of mortality (p < 0.001). These factors displayed 57.89% sensitivity, 100% specificity and 93.33% accuracy. Conclusion. The presence of identified characteristic prognostic factors on admission pointed out an adverse clinical course and outcome of community acquired pneumonia in elderly. Age and sex were not significantly associated with mortality

Primena metode prilagođenog indirektnog poređenja u proceni biološke ekvivalnetnosti i zamenjivosti generičkih lekova – primer klopidogrela

Generic medicines are bioequivalent (BE) and switchable with the reference medicine, however, between generics BE is not demonstrated. In practice, patients are often offered generic substitution, where information on BE between generics may be useful, especially when there is a doubt that substitution may potentially pose a risk to the patient. These information can be obtained by assessing BE between generics, applying the method of adjusted indirect comparison (AIC). This method is based on data from BE studies in which generics were compared with the same reference medicine. Thus, it is possible to identify generics for which efficacy and safety problems are not expected upon substitution (1,2). The AIC was used to compare four generic clopidogrel medicines. Publicly available data from original BE studies, in which each generic medicine was compared with the reference medicine Plavix film-coated tablets 75 mg, were analysed. Generics were considered BE if the 90% confidence interval (CI) for the ratio of their pharmacokinetic parameters maximum plasma concentration (Cmax) and area under the curve up to the last measurable concentration (PIK 0-t), was within the acceptance range 80.00-125.00%. In all the tested combinations, 90% CIs for PIK0-t were within the acceptance range, while for C max 90% CIs were within or very close to the limits, with the point estimate being within the range in all cases. The results obtained by the AIC indicated that the bioavailability of these four generic clopidogrel medicines is very similar, therefore they can be considered switchable with each other in clinical practice.Generički lekovi su biološki ekvivalentni (BE) i zamenjivi sa referentnim lekom, međutim, između samih generičkih lekova BE nije potvrđena. Pacijentima se u praksi često nudi odgovarajuća generička zamena, pri kojoj od koristi mogu biti informacije o BE između generika, naročito u slučaju kada postoji sumnja da zamena generika može potencijalno predstavljati rizik za pacijenta. Ove informacije mogu se dobiti procenom BE između generičkih lekova metodom prilagođenog indirektnog poređenja, na osnovu podataka iz već sprovedenih individualnih studija BE u kojima su generički lekovi poređeni sa istim referentnim lekom. Na taj način identifikuju se generički lekovi za koje se prilikom zamene u praksi ne očekuju problemi u pogledu efikasnosti i bezbednosti (1,2). Navedena metoda korišćena je za poređenje četiri generička leka koji sadrže klopidogrel. Analizirani su javno dostupni podaci iz studija BE u kojima je svaki generički lek poređen sa referentnim lekom Plavix film tablete 75 mg. Dva generička leka smatraju se BE ukoliko je 90% interval pouzdanosti (CI) za odnos njihovih farmakokinetičkih parametara maksimalna koncenracija u plazmi (C max) i površina ispod krive do poslednje merljive koncentracije (PIK 0-t ), unutar raspona 80,00-125,00%. U svim ispitanim kombinacijama 90% CI za PIK0-t bili su unutar dozvoljenog raspona, dok su 90% CI za Cmax bili unutar ili veoma blizu granica ovog raspona, pri čemu je point estimate u svim slučajevima bio unutar raspona. Rezultati dobijeni metodom prilagođenog indirektnog poređenja pokazali su da je biološka raspoloživost ova četiri generička leka koja sadrže klopidogrel veoma slična, te se oni mogu smatrati međusobno zamenjivim u kliničkoj praksi.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Pregled lista i preporuka za zamenljivost lekova u izabranim evropskim zemljama

Generic substitution has been introduced in the healthcare systems of many countries to reduce the costs and ensure the continuity of drug market supply. Common and country-specific strategies on this topic have been presented for several European countries, as well as for the Republic of Serbia. The factors that need to be considered when assessing the interchangeability of medicines may be related to the medicine or the individual patient. Particular caution is required with narrow therapeutic index drugs, drugs with non-linear pharmacokinetics, antiepileptic drugs, medicines with prolonged release formulations, medicines administered in a specific way or with a medical device. Factors such as the different appearance of the medicines, excipients, packaging, indications, but also the patient’s condition, age, concomitant diseases, pregnancy, hand function, vision, ability to swallow, and the patient’s attitude towards the alternative medicines should also be taken into account. When substituting two generic medicines, it should be noted that those medicines may not be bioequivalent, since bioequivalence is confirmed between a generic medicine and a reference (usually original) medicine, and thus pose an additional risk to the patient’s safety. Some countries have opted to form lists of interchangeable medicines and/or detailed guidelines regarding interchangeability to assist healthcare professionals in making decisions on drug substitution.Generička zamena uvedena je u zdravstvene sisteme mnogih zemalja kako bi se smanjili troškovi i obezbedio kontinuitet snabdevanja tržišta lekovima. U ovom radu predstavljene su zajedničke i specifične strategije za generičku zamenu u nekoliko evropskih zemalja, kao i u Republici Srbiji. Faktori koje treba uzeti u obzir prilikom procene zamenljivosti lekova mogu se odnositi na sam lek ili pojedinačnog pacijenta i njegove specifične potrebe. Poseban oprez je potreban kod lekova sa uskim terapijskom širinom, lekova sa nelinearnom farmakokinetikom, antiepileptika, lekova sa produženim oslobađanjem, lekova koji se primenjuju na specifičan način ili pomoću medicinskog sredstva. Takođe treba obratiti pažnju na faktore kao što su različit izgled lekova, ekscipijensi, pakovanje, indikacija, ali i stanje pacijenta, njegov uzrast, prateće bolesti, trudnoća, funkcija šaka, vid, sposobnost gutanja, odnos pacijenta prema alternativnim lekovima. Pri zameni dva generička leka, treba imati na umu mogućnost da oni nisu međusobno bioekvivalentni, budući da je biološka ekvivalentnost potvrđena između generičkog i referentnog (najćešče originalnog) leka, što predstavlja dodatni rizik po bezbednost pacijenata. Politika generičke zamene specifična je za svaku zemlju. Pojedine zemlje su formirale liste zamenljivih lekova i/ili detaljne smernice u vezi sa zamenljivošću kako bi pomogle zdravstvenim radnicima pri donošenju odluka o zameni lekova

Inhibitory effects of Ocimum basilicum and Salvia officinalis essential oils on virulence factors of Pseudomonas aeruginosa clinical isolates

Pseudomonas aeruginosa is a Gram-negative human opportunistic pathogen, responsible for a variety of human health disorders. The virulence of each P. aeruginosa strain is strongly related to its capability of biofilm formation, different types of motility, production of toxins and pigments. Essential oils of basil and sage have a wide range of applications in the traditional and/or official medicine. The aim of the present study was to evaluate the activity of basil (Ocimum basilicum) and sage (Salvia officinalis) commercially available essential oils on P. aeruginosa virulence factors (post-adherence biofilm production, resistance of a mature biofilm, motility and production of pyocyanin). Antipseudomonal efficacy was studied using the microdilution method and the obtained minimal inhibitory concentrations (MICs) were further used to explore the anti-virulence potential. The experiments were performed against a panel of P. aeruginosa clinical isolates of different origin at 1/2 x MIC, MIC, and 2 x MIC concentrations.                The two essential oils were chemically characterized by GC and GS/MS analyses, where linalool and (E)-anethole where found to be the dominant compounds in the basil oil sample, while α-thujone and camphor were the major constituents of the sage essential oil sample. The biofilm experiments demonstrated a very high activity of both oils to biofilm production, where basil oil showed a higher efficiency by inhibiting up to 92.7% of the biofilm produced by the control, while sage oil exhibited a reduction of 9.8 to 76.8%. Promising results were also obtained when the oils were applied to mature biofilms, where reductions of 2.4-84.1% and 13.8-75.8% were measured for basil and sage oils, respectively. The results on motility evaluation showed that, in the presence of both oils, swimming, swarming and twitching motility patterns were significantly affected. Experiments on the pyocyanin production showed a reduction from 20.7-60.9% and 5.0-60.5% caused by the basil and sage oils, respectively.                Considering all the obtained results, it can be concluded that both basil and sage essential oils present highly efficient antipseudomonal agents which could be used against infections caused by this pathogen

Antimicrobial and anti-inflammatory potential of different immortelle essential-oil chemotypes

Helichrysum italicum or immortelle (Asteraceae) essential oil has been widely used in alternative medicine for wound healing and other skin conditions such as hematoma and scars. It is possible that the therapeutic efficacy of this oil changes with the natural variability of the composition, i.e. existence of chemotypes, and due to various environmental factors (soil type, altitude, sun exposure, etc.) [1]. Herein we aimed to assess the relationship of the composition and the overall antimicrobial and anti-inflammatory potentials for 4 commercial immortelle oils containing differing amounts of neryl esters (23 : 43 : 12 : 21; oils 1, 2, 3, and 4, respectively), α-pinene (17 : 2 : 20 : 5), γ- and ar-curcumenes (19 : 14 : 16 : 15), and β-diketones (3 : 12 : 5 : 7). Oils 3 and 4 displayed higher antimicrobial activity compared to oils 1 and 2, showing a prominent anti-Staphylococcus aureus effect (MIC = 0.62 and 0.31 mg/mL, respectively). The tested strains were least susceptible (MIC ≥ 5 mg/mL) to the action of oil 1, rich in mono- and sesquiterpenic hydrocarbons. However, this oil, along with oil 3, showed the highest cytotoxicity toward macrophages (LC50 ~ 0.14 mg/mL). Among the oil chromatographic fractions, those enriched in α-pinene and curcumenes displayed the highest cytotoxicity, but were inferior to the toxicity of the oils. The statistical (PCA) treatment of the obtained composition-activity data implied that the observed differences in activities among the tested oils were not only due to the different amounts of the major constituents, but also due to the presence of minor constituents (e.g. 2-methylbutyl angelate in the case of the anti-staphylococcal activity of the oils). Interestingly, based on literature data, the constituents that displayed strong negative correlations in the PCA matrix possess a lower antimicrobial potential than the tested oils. We found that immortelle oil efficiency as antimicrobial and anti-inflammatory agents strongly depends on its composition and is an outcome of synergistic action between its constituents

Anticandidal activity of Inula helenium root essential oil: synergistic potential, anti-virulence efficacy, and mechanism of action

Inula helenium L. (elecampane) is a widely occurring perennial plant species in Europe and East Asia, belonging to the Compositae family. Roots of I. helenium have been traditionally used for the treatment of various diseases and it is officially listed in pharmacopeias as a diuretic, diaphoretic, expectorant and anthelmintic [1]. The present study investigated the anticandidal potential of I. helenium essential oil, isolated from roots and chemically characterized by GC and GC/MS. Antifungal efficacy was studied using the microdilution method and the determined minimal inhibitory concentrations (MICs) were further used to study a potential synergistic interaction of the oil and an antifungal. Together with this, the mode of action (sorbitol and cholesterol assays) and anti-virulence effects (antibiofilm, germ-tube reducing and phospholipase-inhibitory activities) were also investigated.                The results showed that the isolated essential oil contained alantolactone and isoalantolactone as the dominant constituents (65.8 and 25.5%, respectively). The obtained MICs varied among the strains, but the oil generally exhibited a high anticandidal potential (0.009-0.312 mg/mL). The oil displayed a high synergistic effect in combination with the antifungal agent nystatin. Experiments on the mode of action demonstrated that the oil affected the cell membrane function, due to the enhancement of the oil's activity (lowering of active concentrations) in the presence of sorbitol and cholesterol. Considering the virulence factors, the oil exhibited an antibiofilm activity, as well as a very high germ-tube reducing potential (93.3-100% at MIC). Additionally, a complete inhibition of the enzyme phospholipase in the presence of I. helenium root essential oil was demonstrated.                Based on the presented results, the essential oil of I. helenium can be considered as a good candidate for a natural agent that can be further explored in the sense of candidiasis treatment

Adjusted indirect comparisons to assess bioequivalence between generic clopidogrel products in Serbia

Aims Generic products can be regarded as therapeutically equivalent and switchable with the reference product. However, switchability between generics is unknown, as direct comparisons between generics are not performed. The aim of this study was to investigate the bioequivalence between generic clopidogrel products by means of adjusted indirect comparisons (AICs). Methods AICs were conducted to assess bioequivalence between 4 generic clopidogrel products that are authorised in Serbia. Generics are considered equivalent to the reference if the 90% confidence intervals (CIs) for the ratios test/reference of the maximum concentration (C-max) and area under the curve up to the last measurable concentration (AUC(0-t)) fall within the acceptance range 80.00-125.00%. However, for AICs between generics, the Canadian acceptance criterion for C-max was employed, where only the point estimate of C-max needs to be within 80.00-125.00%. Results The 90% CIs of the AICs demonstrated bioequivalence within 80.00-125.00% for all AUC(0-t) comparisons. The point estimates of C-max in all AICs were also within this range. Conclusion This study demonstrates that the bioavailability of these 4 generic clopidogrel products authorised in Serbia is very similar. Despite the limited power of AICs, bioequivalence was demonstrated for all 90% CIs of AUC(0-t) and all 90% CIs of C-max comparisons were within or very close to the acceptance range, being able to comply with the acceptance criterion employed in Canada for C-max. Therefore, these 4 generic clopidogrel products authorised in Serbia can be considered switchable with each other in clinical practice based on the adjusted indirect comparisons

Integrating Clopidogrel’s First-Pass Effect in a Joint Semi-Physiological Population Pharmacokinetic Model of the Drug and Its Inactive Carboxylic Acid Metabolite

Clopidogrel (CLO), a pro-drug for preventing thrombotic events, undergoes rapid absorption and extensive metabolism, with approximately 85–90% converted to an inactive carboxylic acid metabolite (CLO-CA) and the remaining to an active thiol (CLO-TH). Few pharmacokinetic models for the drug and its metabolites exist, with most focusing on CLO-TH. Although CLO-CA is inactive, its predominant (compared to its parent drug and metabolites) presence in plasma underscores the importance of characterizing its formation and pharmacokinetic profile. This study aimed to characterize the process of the absorption of CLO and its conversion to CLO-CA via developing a population pharmacokinetic model. Individual participants’ data from two bioequivalence studies were utilized. Extensive blood samples were collected at predetermined intervals, including 841 concentrations of CLO and 1149 of CLO-CA. A nonlinear, mixed-effects modelling approach using NONMEM® software (v 7.5) was applied. A one-compartment model was chosen for CLO, while a two-compartment proved optimal for CLO-CA. Absorption from the depot compartment was modeled via two transit compartments, incorporating transit rate constants (Ktr). A semi-physiological model explained the first-pass effect of CLO, integrating a liver compartment. The estimated mean transit times (MTTs) for the studies were 0.470 and 0.410 h, respectively. The relative bioavailability for each study’s generic medicine compared to the reference were 1.08 and 0.960, respectively. Based on the estimated parameters, the fractions metabolized to inactive metabolites (FiaM_st1 and FiaM_st2) were determined to be 87.27% and 86.87% for the two studies, respectively. The appropriateness of the final model was confirmed. Our model offers a robust framework for elucidating the pharmacokinetic profiles of CLO and CLO-CA

Savremeni pravci razvoja i upotrebe anti-mikrobnih lekova u veterinarskoj medicini

Antimicrobial drugs are compounds that kill pathogenic microorganisms in the animal body without producing adverse effects for the host. They are natural products of various species of fungi and bacteria that in low concentrations cause death (bactericidal effect) or inhibit growth (bacteriostatic effect) of microorganisms. They also include synthetic compounds that are structurally similar to the natural products and have similar mechanism of action. Numerous chemically different antimicrobial drugs are used in human and veterinary clinical practice today. At the same time, many new, more effective and safer antimicrobials with a wider spectrum of activity are being developed. The best known newer antimicrobial drugs are: members of IV generation of cephalosporins (e.g. cefepime and cefpirome), the glycopeptide antibiotic teicoplanin, the carbapenem meropenem, the macrolide antibiotic clarytromycin, fluoroquinolones of III generations, streptogramines oxa-zoiidinones, and glycilcyclines. In parallel with the effort to produce more effective and safer antimicrobial drugs, there is a tendency to reduce their excessive (non-rational) use. The main reasons for that are: to reduce the risk of bacterial resistance development and to reduce the amount of antimicrobial drugs in animal products assigned to human nutrition. Due to pronounced toxicity for both animals and humans the use of some antimicrobial drugs (e.g. chloramphenicol, nitroimidazoles, nitorfurans etc) in veterinary medicine is prohibited. In the last years, as alternatives for antimicrobial use, especially in mild and/or chronic infective diseases, the use of medicinal plants with antimicrobial and immunostimulant action is recommended. The concept of phytopharmaceutics use in veterinary medicine is in accordance with common trends of producing healthy and natural food.Antimikrobni lekovi ili hemioterapeutici su supstancije koje posle resorpcije u organizmu životinja uništavaju bakterije i druge štetne mikroorganizme, a da pri tome ne deluju toksično na organizam domaćina. Najveći deo antimikrobnih lekova čine antibiotici (produkti plesni, gljivica i bakterija), čija je "era" započela kada je Aleksandar Fleming 1928. godine otkrio penicilin. U kliničkoj praksi humane i veterinarske medicine, danas se kod nas i u svetu koristi veliki broj antimikrobnih lekova. Isto tako intenzivno se radi na pronalaženju i sintezi novih lekova, sa širim antimikrobnim spektrom, jačim (baktericidnim) dejstvom, odnosno lekova koji imaju što manje neželjenih dejstava. Najpoznatiji noviji antimikrobni lekovi su: cefalosporini IV generacije, noviji makrolidni lekovi, karbapenemi glikopeptidni antibiotici, kombinacije penicilina proširenog spektra delovanja i klavulanske kiseline ili sulbaktama, fluorohinoloni III generacije, oksazolidinoni, streptogramini i glicilciklini. Uporedo sa nastojanjima da se dobiju što efikasniji i bezbedniji antimikrobni lekovi traju i napori da se preterana (neracionalna) upotreba antimikrobnih lekova stavi u realne okvire. Razloga za to ima vise, a dva su najosnovnija smanjenje rizika od razvoja bakterijske rezistencije i smanjenje prisustva antibiotika (rezidua) u životinjskim proizvodima namenjenim ishrani ljudi. Zbog izražene toksičnosti, kako za same životinje, tako i za ljude potencijalne potrošače proizvoda od tih životinja, zabranjena je upotreba pojedinih antimikrobnih lekova u veterinarskoj medicini (na primer hloramfenikol, nitroimidazoli, nitrofurani, i tako dalje). Poslednjih godina, kao alternativa antimikrobnim lekovima, pogotovo kod blažih i/ili hroničnih infektivnih stanja, promoviše se upotreba lekovitih biljaka čiji aktivni sastojci deluju antimikrobno i imunostimulatorno. Koncept upotrebe fitofarmaka u veterinarskoj medicini u skladu je sa opštim trendovima proizvodnje zdrave i prirodne hrane