This study aimed to evaluate the general, hepatoprotective and renoprotective effects of amifostine (AMI) in rats treated with a large, single dose of doxorubicin (DOX), assessed at 7 and 56 days after administration. Rats were divided into six experimental groups: Control (0.9% NaCl intraperitoneally (ip)), amifostine (AMI300, 300 mg/kg (ip)), doxorubicin (DOX6, 6 mg/kg (ip)), doxorubicin (DOX10, 10 mg/kg (ip)), doxorubicin (DOX6, 6 mg/kg (ip)) + amifostine (AMI300, 300 mg/kg (ip) 30 min before DOX6), and doxorubicin (DOX10, 10 mg/kg (ip)) + amifostine (AMI300, 300 mg/kg (ip) 30 min before DOX10). Absolute liver and kidney weights were significantly increased in AMI300 + DOX6-treated animals compared to DOX6 only on day 56. In the group of DOX10-treated rats, AMI300 significantly prevented changes in the number of white blood cells during the four weeks after treatment. The severity of hepatic and renal injuries in the DOX6-treated groups was also significantly less in rats pretreated with AMI300 on day 56 (p < 0.01). Our results indicate that hepatic and renal protection significantly contribute to the successful use of AMI against DOX-induced subacute toxicity in rats.

Background/Aim. Risk minimization measures (RMMs) for medicines are one of the most important interventions in maintaining a positive benefit-risk ratio and ensuring their safe use. Systemic formulations of diclofenac are medicines with routine and additional RMMs in place for its well-established cardiovascular (CV) safety risk. In 2021, an innovative digital tool (IDT) was implemented in the Montenegrin Information System of Primary Health Care (PHCIS). The aim of this study was to analyze diclofenac consumption in CV risk patients who did not use diclofenac before the introduction of this new IDT for RMM (diclofenac-na & iuml;ve patients), taking into account their demographic (gender and age) and clinical characteristics [CV diseases (CVD)/risk factors of CVD]. Methods. Patients with CVD/diseases posing a risk for CVD development (conditions that are contraindications/precautions for prescribing diclofenac) were selected after an automated screening of all diagnoses, classified in accordance with the International Classification of Diseases, 10th revision, from their electronic medical records. These patients also had medical diagnoses that served as indications for prescribing nonsteroidal anti-inflammatory drugs such as diclofenac. These patients were monitored for a period of one year after the introduction of the IDT (October 4, 2021-October 4, 2022). Diclofenac consumption was analyzed using the standard methodology of the World Health Organization based on daily defined doses/1,000

There is little data on the phytochemical/pharmacological properties of Erica spiculifolia Salisb. (syn. Bruckentalia spiculifolia (Salisb.) Rchb.). This study examines the antioxidative and anti-inflammatory activities of different extracts and fractions of E. spiculifolia in vitro on isolated rat peritoneal macrophages, in the carrageenan-induced rat paw oedema test, BSA test, and two complementary antioxidant assays. Ethanolic extracts of leaves, flowers, and aboveground parts, and petroleum ether, ether, ethyl acetate, and water fractionations of the ethanol extract of E. spiculifolia applied at doses of 50-200 mg/kg p.o. exhibited dose-dependent anti-inflammatory activity comparable with indomethacin. All tested samples, except for the petroleum ether fraction, exerted excellent in vitro antioxidant activity, and all of them exhibited significant and similar inhibition of BSA denaturation comparable with diclofenac. Ethanolic extract of the aboveground parts obtained by percolation, ethyl acetate and water fractions had the highest efficiency, attenuating inflammation by more than 50% in the lowest applied concentration alongside exceptional radical scavenging activity.

Introduction Risk minimization measures are one of the most important tools in ensuring safe use of medicines. The evaluation of their effectiveness in clinical practice is a big challenge. Diclofenac is a medicine indicated for relief of all grades of pain and inflammation, in a wide range of conditions. Certain cardiovascular diseases are contraindications, whilst certain diseases require precautions for diclofenac prescribing. Objective The aim of this study is to measure impact of the new digital risk minimization tool, introduced at the level of diclofenac prescribing, on patterns of its prescription in outpatient settings in Montenegro. Methods Regulatory impact before/after drug utilization study, using electronic health records of patients with cardiovascular contraindications/precautions for diclofenac prescribing, was conducted. The period of observation was 1 year before and 1 year after introduction of the digital risk minimization tool. Results Introduction of the digital risk minimization tool was associated with significant decrease in number of patients on diclofenac and the number of diclofenac prescriptions/packages, in a cohort of patients who were prescribed diclofenac before the digital intervention. Decrease in diclofenac prescription was more obvious in patients with contraindications, as expected, compared with patients with precautions. Decrease in diclofenac prescriptions in patients with other heart diseases, cerebrovascular diseases, and ischemic heart diseases (contraindications) was 38.79%, 37.62%, and 29.85% respectively. There was also a decrease in diclofenac prescriptions in patients with hypertension (22.86%), hyperlipidemia (23.61%), and diabetes mellitus (26.32%; precautions). After the digital intervention, initiation of diclofenac in diclofenac-naive patients was significantly decreased compared with patients who were prescribed diclofenac before the digital intervention. Conclusions Although a significant decrease in diclofenac prescription in both cohorts occurred, diclofenac is still prescribed, even in diagnoses contraindicated for its use. Further improvements of existing tools and the creation of new ones are necessary for minimization of cardiovascular and other risks related to diclofenac.

Background/Aim. Diclofenac, a non -selective inhibitor of cyclooxygenase with analgesic, anti-inflammatory, and antipyretic effects, is one of the most prescribed nonsteroidal anti-inflammatory drugs (NSAIDs). The aim of this study was to analyze the prescription patterns of diclofenac systemic formulations at primary health care (PHC) level in Montenegro, in patients with cardiovascular (CV) diseases (CVD) and patients with risk factors for CVD, from 2016 to 2020. Methods. A retrospective national drug utilization study was conducted and it included patients with CVD, to whom prescribing diclofenac was contraindicated, and patients with risk factors for CVD, to whom diclofenac could be prescribed but with increased precaution. PHC information system has been used as a source of medical data for these patients. Results. Within the observed period, prescribing diclofenac systemic formulations, dominantly oral formulations in 75 mg dose, increased by 36.9% [from 4.6 of defined daily doses (DDD) /1,000 inhabitants/day in 2016 to 6.3 DDD/1,000 inhabitants/day in 2020]. A rising trend in prescribing diclofenac was also recorded in patients with CVD or those with risk factors for CVD, to whom diclofenac prescribing is contraindicated. Out of the overall number of patients who were prescribed diclofenac in 2016, 2017, 2018, 2019, and 2020, 16%, 18%, 24%, 15%, and 20% of them, respectively, already had a CVD or some risk factor for CVD. Most CV patients (39.7%), for whom the use of diclofenac was contraindicated, had ischemic heart disease and were prescribed 40.7% of the total amount of diclofenac prescribed for this group of patients (expressed in DDD/1,000 inhabitants/day for the given medicine). The majority (77.4%) of CV patients to whom the drug could be prescribed, but with increased precautions, had hypertension, and they were prescribed 77.2% of the total amount of diclofenac prescribed for this group of patients (expressed in DDD/1,000 inhabitants/day for the given medicine). Conclusion. Despite the undertaken regulatory measures aimed at a safer prescription of diclofenac to patients with CVD or at high risk of developing CVD, this medicine is still widely prescribed at the level of PHC in Montenegro, even in cases that represent a contraindication for its use.

Aims The aim of this study was to analyse potential drug-drug interactions (pDDIs) and their potential adverse drug reactions (ADRs) among hypertensive patients. Moreover, we investigated the possibility of reducing pDDIs with different treatment choices. Methods This was a cross-sectional study including all outpatients with hypertension and two or more medications, treated in a university hospital in Serbia. Lexicomp Interact (Lexi-Comp, Inc., Hudson, OH) was used for identification of pDDIs and potential ADRs. Treatment choices were explored according to patient characteristics, treatment guidelines and the interacting potential of drugs. Data were analysed using descriptive analysis and multiple logistic regression. Results A total of 350 patients were included in this study, with average age (77 [36-98] years and 6.1 [2.5]) medications. The majority of patients (86.0%) had at least one clinically significant pDDI, and the average was 3.78 (3.90) (range 1-25). Suggestions for treatment change aimed mainly at eliminating drug duplications, reducing the use of thiazide diuretics, sulfonylureas, alpha-lipoic acid and pentoxifylline and increasing the use of calcium-channel blockers, when appropriate. pDDIs would have decreased to 2.10 (2.52), P <.001, yet male gender, >= 6 medications, cardiovascular diseases, diabetes, benign prostatic hyperplasia, would be predictive of two or more pDDIs. The main potential adverse outcomes of pDDIs were hypotension, renal failure, hypoglycaemia, bradycardia and lactic acidosis. Conclusion Careful choice of drugs can reduce but not eliminate pDDIs and their potential ADRs in hypertensive patients. Close monitoring for hypotension, renal failure, hypoglycaemia, bradycardia and lactic acidosis is necessary.

Background and Objectives: The purpose of the study was to determine the prevalence rate of potentially inappropriate prescribing (PIP), by using the Screening Tool of Older Person’s potentially inappropriate Prescriptions (STOPP) criteria in older outpatients, and its association with potential clinically significant drug–drug interactions (csDDIs). Materials and Methods: A cross-sectional study included 248 outpatients ≥65 years old divided into two groups depending on the presence of csDDIs. For estimating the clinical significance of csDDIs we used Medscape′s "Drug Interaction Checker". We applied the thirty PIP indicators from the STOPP criteria. Results: The presence of PIP (25.00%; all patients) was significantly higher in the group with potential csDDIs compared to the other group (43 vs. 19, respectively; Chi-square test, χ2 = 9.947; p < 0.01). The most common PIP included the inappropriate use of proton pump inhibitors, long acting benzodiazepines, usage of thiazide diuretic in patients with gout, and duplication of therapeutic class. Patients with potential csDDIs had 43 potentially inappropriate medications (PIMs) prescribed. Out of this number, 12 (27.91%) PIMs were identified to participate in potential csDDIs. There was a correlation between the number of medications prescribed and the number of PIMs (ρ = 0.297; p < 0.01) and between the number of PIPs and the number of potential csDDIs (ρ = 0.170; p < 0.01). Conclusions: Older outpatients with potential csDDIs in relation to those with no potential csDDIs had significantly more prescribed drugs in total as well as inappropriate drugs. Almost 30% of these PIMs were included in potential csDDIs.

Amifostine is well known cytoprotector which is efficient when administered before a wide range of antineoplastic agents. The aim of our study was to investigate amifostine effects on doxorubicin-induced toxic changes in rats. Amifostine (75 mg/kg ip) was given 30 min before each dose of doxorubicin (cumulatively 20 mg/kg ip, for 28 days). The animals' whole-body, liver, and kidney weight, serum biochemical examination, as well as microscopic examination of bone marrow, peripheral blood, liver, and kidney, were done on day 56 of the study. Hepatic and renal alterations were carefully quantified by semiquantitative grading scales-hepatic and renal damage score, respectively. In amifostine-pretreated rats, the number of peripheral blood leukocytes was significantly higher in comparison to doxorubicin-only treated group, preferentially protecting neutrophils. In the same group of rats, hepatic and renal alterations associated with polymorphonuclear cell infiltrates were significantly less severe than those observed in animals receiving only doxorubicin. Our results showed that amifostine successfully protected rats against multiple-dose doxorubicin-induced toxicity by complex, and still not fully elucidated mechanisms of action.

This article has been corrected. Link to the correction 10.2298/VSP1703298E

Background/Aim. Data on phytochemical and pharmacological investigations of genus Cirsium Mill. (Asteraceae) are scarce. Some data suggest that decoctions or infusions prepared from these plants are used in folk medicine as tonics, particularly in inflammatory, liver and stomach diseases. So far there have been no pharmacological investigations related to Cirsium ligulare (C. ligulare) Boiss. Accordingly, the aim of this study was to estimate antioxidative, anti-inflammatory and gas-troprotective activities of aqueous extracts of C. ligulare herb prepared as 5% and 10% decoctions. Methods. Antioxidative activity was determined using the method of 2,2-diphenyl-1picrylhydrazyl (DPPH) radical scavenging. Investigations of anti-inflammatory (a model of systemic inflammatory response induced by endotoxin of Escherichia coli and carrageenan-induced rat paw oedema model for local inflammatory response), as well as gastroprotective effects (a model of stress-ulcer induced by absolute ethanol), were conducted in adult female Wistar rats that were given the aqueous extracts of C. ligulare herb per os. Indomethacin and ranitidine were used as reference drugs for evaluation of local anti-inflammatory and gastroprotective effects, respectively. Results. The results demonstrated that aqueous extracts of C. ligulare herb produced strong antioxidative activity, diminished body weight loss induced by endotoxin, significantly reduced carrageenan-induced paw oedema, and prevented the ulcerogenic action of absolute ethanol. Both anti-inflammatory and gastroprotective activities of the extract tested were comparable to those of the reference drugs. Conclusion. Presented results justify the traditional use of C. ligulare herb decoctions and further phytochemical and pharmacological investigations are warranted.

The influence of naloxone on respiration impaired by the highly toxic organophosphate nerve agent soman in anaesthetized rats was investigated. Soman, administered in a dose that was ineffective in blocking the electrically induced contractions of the phrenic nerve-diaphragm preparation in situ, induced a complete block of the spontaneous respiratory movements of the diaphragm, indicating the domination of central over the peripheral effects. Naloxone dose-dependently antagonized the soman-induced respiratory blockade. Atropine, at a dose that was per se ineffective in counteracting soman-induced respiratory depression, potentiated the protective effects of naloxone and completely restored respiration. Naloxone remained completely ineffective in antagonizing respiratory depression induced by the muscarinic receptor agonist the oxotremorine. It is assumed that naloxone antagonizes soman-induced respiratory inhibition by blocking endogenous opioidergic respiratory control pathways that are independent of the stimulation of muscarinic receptors.

The discovery and introduction of antimicrobial drugs in clinical practice has been recorded as one of the greatest achievements in the history of medicine. The application of these drugs, made a big, almost revolutionary upheaval in treatment of many infectious diseases. Its significance for the humanity lies in the fact that hundreds of thousands of people, until then condemned to a certain death, has been saved now. However, it was shown that antimicrobial therapy carries some risk of possible occurrence of undesirable and toxic effects, such as direct toxic effects, development of resistance, the impact on the normal microflora or disorder of micropopulation metabolic functions in digestive tract of ruminants, unwanted interactions with other drugs, damage or necrosis of the tissue at the injection site, residues in foodstuff intended for human consumption, suppression of immune system or defense mechanisms of the body, and damage of fetal or neonatal tissue. All mentioned, directly or indirectly, to a greater or lesser degree can reduce the safety of these drugs.

Fullerenol C-60(OH)(24) nanoparticles (FNP) are promising radioprotectors in prevention of early and late ionizing radiation injury. The aim of this studywas to compare the efficacy of FNP and amifostine (AMI) in protection of rats exposed to whole-body X-ray irradiation (7 or 8 Gy). Both compounds (FNP, 100 mg/kg ip; AMI, 300 mg/kg ip) were given 30 min before irradiation throughout the study. The general radioprotective efficacy of FNP and AMI were evaluated in rats irradiated with an absolutely lethal dose of X-rays (8 Gy) and their survival were monitored during the period of 30 days after irradiation. Both compounds were of comparable efficacy. Tissue-protective effects of tested compounds were assessed in rats irradiated with an sublethal dose of X-rays (7 Gy). For this purpose, the animals were sacrificed on the 7th and 28th day after irradiation. Their lung, heart, liver, kidney, small intestine and spleen were taken for histopathological and semiquantitative analysis. Careful examination of established tissue and vascular alteration revealed better radioprotective effects of FNP compared to those of AMI on the small intestine, lung and spleen, while AMI had better radioprotective effects than FNP in protection of the heart, liver and kidney. Results of this study confirmed high radioprotective efficacy of FNP in irradiated rats that was comparable to that of AMI, a well-known radioprotector. (C) 2016 Published by Elsevier Sp. z o. o. on behalf of Faculty of Health and Social Sciences, University of South Bohemia in Ceske Budejovice.