Background: Metamizole is a medication with analgesic, antipyretic, spasmolytic, and weak anti-inflammatory effects. The aim of our study was to evaluate a six-year trend in the utilization and expenditure of metamizole in comparison to other group of licensed non-opioid analgesics in Serbia and Croatia, in order to rationalize its use and prescribing in these countries.Methods: The data of metamizole vs. all other non-opioid analgesics utilization and expenditure in Serbia and Croatia was analyzed according to the WHO methodology and expressed as defined daily doses per 1,000 inhabitants per day (DDD/1,000 inhabitants/per day) and total costs, respectively, during the 6-year period from 2010 to 2015.Results: In the observed period, utilization of metamizole was 3.31 fold higher in Serbia than in Croatia (median in Serbia was 2.238 vs. 0.675 in Croatia DDD/1,000 inhabitants/per day/per year). Expenditure of metamizole in the same period was 5.29-fold higher in Serbia than in Croatia (median in Serbia was 1,738,192.51 €/per year vs. 328,355.03 €/per year in Croatia).Conclusion: Utilization and expenditure of non-opioid analgesics, including metamizole, in Serbia was significantly higher comparing with Croatia.Further research is needed to determine whether the current analgesic consumption in Serbia meets the needs of the patient. The benefits of metamizole should be weighed against the risk of metamizole-induced adverse effects. Until then, its prescribing should be based on indications and the appropriate duration of therapy.

Metamizole is a nonsteroidal anti-infl ammatory drug, with analgesic, antipyretic, spasmolytic, and weak anti-infl ammatory properties. The analgesic eff ect of metamizole seems to be based on the inhibition of cyclooxygenase enzyme activity and stimulation of cannabinoid receptors. Its use is still controversial, mainly due to agranulocytosis, metamizole-induced serious adverse reaction. While in many countries it is withdrawn from the market, in some countries metamizole is available as a medication prescribed for strictly defi ned indications, while in the others like Mexico, Brazil and China it can be obtained as an Over-The-Counter drug. The most common adverse eff ects of metamizole are the skin and subcutaneous tissue disorders. Metamizole appears to be of similar effi cacy to analgesics which are frequently used in the treatment of moderate to severe postoperative pain.

Itraconazole is a triazole antifungal agent with highly variable pharmacokinetics, with not yet fully identified factors as the source of this variability. Our study aimed to examine the influence of body mass index, gender, and age on the first dose pharmacokinetics of itraconazole in healthy subjects, using pharmacokinetic modeling, non-compartmental versus compartmental ones. A total of 114 itraconazole and hydroxy-itraconazole sets of plasma concentrations of healthy subjects of both genders, determined using a validated liquid chromatographic method with mass spectrometric detection (LC-MS), were obtained for pharmacokinetic analyses performed by the computer program Kinetica 5®. Genetic polymorphism in CYP3A4, CYP3A5, CYP1A1, CYP2C9, and CYP2C19 was analyzed using PCR-based methods. Multiple linear regression analysis indicated that gender had a significant effect on AUC as the most important pharmacokinetics endpoint, whereas body mass index and age did not show such an influence. Therefore, further analysis considered gender and indicated that both geometric mean values of itraconazole and hydroxy-itraconazole plasma concentrations in men were prominently higher than those in women. A significant reduction of the geometric mean values of Cmax and AUC and increment of Vd in females compared with males were obtained. Analyzed genotypes and gender differences in drug pharmacokinetics could not be related. Non-compartmental and one-compartmental models complemented each other, whereas the application of the two-compartmental model showed a significant correlation with the analysis of one compartment. They indicated a significant influence of gender on itraconazole pharmacokinetics after administration of the single oral dose of the drug, given under fed conditions. Women were less exposed to itraconazole and hydroxy-itraconazole than men due to poorer absorption of itraconazole, its more intense pre-systemic metabolism, and higher distribution of both drug and its metabolite.

At present, neither specific antiviral drugs, nor vaccine is recommended for coronavirus disease 2019 (COVID‐19) treatment. In this review we discuss the drugs suggested as therapy for COVID‐19 infection, with a focus on chloroquine and hydroxychloroquine. The list of drugs used for COVID‐19 treatment includes a combination of lopinavir and ritonavir, remdesivir, favipiravir, alpha‐interferon, ribavirin, atazanavir, umifenovir, and tocilizumab. As their efficacy and safety are under investigation, none of the regulatory agencies approved them for the treatment of COVID‐19 infection. Although chloroquine and hydroxychloroquine possess antiviral and immunomodulatory effects, in practice benefit of their use for COVID‐19 treatment is controversial. Several studies investigating hydroxychloroquine were stopped and the French national medicines regulator suspended its use in clinical trials because of safety concerns. The results from the double‐blind, randomised clinical trials, including large number of participants, will add better insight into the role of these two drugs as already available and affordable, antimalarial therapy. The ethical issue on emergency use of chloroquine and hydroxychloroquine in the settings of COVID‐19 should be carefully managed, with adherence to the “monitored emergency use of unregistered and experimental interventions” (MEURI) framework or be ethically approved as a trial, as stated by the WHO. Potential shortage of chloroquine/hydroxychloroquine on the market can be overbridged with regular prescriptions by medical doctors and national drug agency should ensure sufficient quantities of these drugs for standard indications.

Induced Pluripotent Stem Cells (iPSCs) are a type of pluripotent stem cells generated by reprogramming an adult somatic cell genome to the stage of a pluripotent stem cell in vitro by inducing a forced expression of specific transcription factors that are important for the maintenance of pluripotency. The iPSCs seem to be very similar to Embryonic Stem Cells (ESCs) in terms of morphology, cell surface markers and gene expression levels, but recent studies have demonstrated some differences between the two cell types. However, iPSCs might have potential application in regenerative medicine, transplantation, drug testing, disease modelling, and avoidance of tissue rejection and with less ethical concern than ESCs. This paper aims to present the most important characteristics of iPSCs which have therapeutic significance.

No abstract

SažetakSa razvojem ambulantne hirurgije, povećao se broj hirurških zahvata koji se izvode u uslovima lokalne infiltrativne anestezije. Infiltrativna anestezija se koristi samostalno za obezbeđivanje anestezije kod manjih hirurških procedura ili kao infiltrativna analgezija duž većih operativnih incizija u kombinaciji sa analgeticima, kod operacija u opštoj anesteziji, u sklopu multimodalnog analgetskog pristupa. Jednostruka infiltracija rane, u formi bloka na kraju hirurškog zahvata u opštoj ili regionalnoj anesteziji obezbeđuje kvalitetnu analgeziju u vremenski ograničenom intervalu, te je u cilju produženog delovanja lokalnih anestetika uvedena tehnika kontinuirane infiltrativne analgezije. Infiltrativna lokalna anestezija u kontinuiranom modalitetu smanjuje upotrebu opioidnih i neopioidnih analgetika, produžava trajanje analgezije (uglavom do 72 h) i omogućava mobilizaciju bolesnika. Pozitivan efekat infiltrativne anestezije opisan je kod operacija preponskih kila, dojke, u kardiotorakalnoj, ortopedskoj i ginekološkoj hirurgiji. U abdominalnoj hirurgiji kompleksna inervacija trbušnog zida i intraabdominalnih organa zahteva primenu kombinovanja infiltrativne anestezije sa drugim modalitetima analgezije. Infiltrativna lokalna anestezija je bezbedna tehnika jer ne dovodi do infekcije hirurške rane i ne utiče na pojavu infekcije mesta hirurškog reza. Kako bi lokalna infiltrativna anestezija u potpunosti ispunila i opravdala očekivanja, neophodno je savladati relativno jednostavnu tehniku njene primene i svrsishodno je primenjivati. AbstractA large number of surgical interventions are performed ambulatory under local infiltrative anesthesia. Local anesthetic wound infiltration provides anesthesia for minor surgical procedures and perioperatively improves analgesia after surgery in general anesthesia as part of a multimodal analgesic approach. The effect of a single block wound infiltration at the end of a surgical procedure in general or regional anesthesia provides additional analgesia for several hours. Infiltrative local anesthesia performed in a continuous modality reduces the use of analgesics, prolongs duration of analgesia and enhances the patient's mobilization. Benefits of local infiltrative anesthesia are described in inguinal hernioplasty, breast surgery, sternotomy, orthopedic, and gynecological surgery. However, in abdominal surgery, continuous infiltrative local anesthesia is combined with other analgesic modalities respecting complex innervation of the abdominal wall and intra-abdominal organs,. Wound infiltration is a safe technique without the risk of surgical wound infection. There is a lack of data about cost-benefit ratio when wound infiltration is used. In order for local infiltrative anesthesia to fully meet the expectations it is necessary to have mastery of the relatively simple technique, and the knowledge of when it is suitable to appply.

Introduction: Itraconazole is an antifungal drug belonging to the triazole group. After oral application, it is rapidly absorbed, but its bioavailability is reduced due to an intensive first-pass through the liver metabolism effect. A large number of metabolites (the most important of which is hydroxyitraconazole) are produced by isoform CYP3A4 of cytochrome P450. The variability of itraconazole pharmacokinetics is the result of numerous factors that have not yet been fully clarified. Our study aimed to investigate the influence of gender on itraconazole and hydroxyitraconazole plasma concentrations in healthy adults after an oral application of a single dose of itraconazole. Methods: Pharmacokinetic analysis was performed after oral administration of itraconazole in a single dose of 100 mg to 22 male and 16 female healthy volunteers. Blood samples were collected before taking the drug and at appropriate time intervals up to 72 hours later. Itraconazole and hydroxyitraconazole concentrations were determined using a validated liquid chromatography method with mass spectrometric detection (LC-MS/MS) and their pharmacokinetic parameters were calculated by using the Kinetica programme, version 5.0: Cmax, Tmax, PIK (0-72), PIK (0-∞), T1/2, and Ke. Results: The median values of both itraconazole and hydroxyitraconazole were lower in women in comparison to men during the whole period of observation. Moreover, median values of Cmax, PIK(0-72) and PIK(0-∞) parameters were also significantly lower in women, concerning both itraconazole (p=0.005, 0.036 and 0.036, respectively) and its metabolite (p=0.004, 0.010 and 0.044, respectively). Elimination parameters - T1/2 and Ke did not differ between genders. Conclusion: Women were less exposed to itraconazole and its active metabolite than men following an oral application of the drug, possibly as a result of lower bioavailability due to a more intense pre-systemic metabolism, as a result of a higher expression and/or activity of the isoform enzyme, which metabolises itraconazole, and which would need to be confirmed by pharmacogenomic analysis.