Antihyperlipidemic potential of dietary supplementation with carnosine in high-fat diet-fed rats.

OBJECTIVE: The aim of this study was to investigate the hypolipidemic effects of carnosine and a commercial carnosine supplement on lipid status, liver and kidney function, and inflammation associated with dyslipidemia in rats with high-fat diet-induced hyperlipidemia. MATERIALS AND METHODS: The study was conducted on adult male Wistar rats, divided into control and experimental groups. Animals were kept in standard laboratory conditions and according to groups were treated with saline, carnosine, carnosine dietary supplement, simvastatin, and their combinations. All substances were prepared fresh every day and used by oral gavage. RESULTS: Treatment with a carnosine-based supplement significantly improved total and LDL cholesterol levels in serum, especially in the combination with simvastatin as a conventional drug in dyslipidemia treatment. The effect of carnosine on the metabolism of triglycerides was not as evident as in the case of cholesterol. Nevertheless, the values of the atherogenic index showed that the combinations of carnosine and carnosine supplement with simvastatin were the most effective in lowering this comprehensive lipid index. Dietary carnosine supplementation resulted also in anti-inflammatory effects, as demonstrated by immunohistochemical analyses. Besides, the good safety profile of carnosine in terms of its effect on liver and kidney functions was also confirmed. CONCLUSIONS: The use of carnosine supplements in preventing and/or treatment of metabolic disorders requires further investigations into the mechanisms of action and potential interactions with conventional therapy.

Impact of winter savory extract (Satureja montana L.) on biochemical parameters in serum and oxidative status of liver with application of the principal component analysis in extraction solvent selection.

OBJECTIVE: Satureja montana L. is traditionally used as spice and for treatment various diseases. Many studies have shown antioxidative effect of Satureja species. Our thorough study in an animal model was performed through measurement of biochemical parameters in the serum, histology analysis and determination of oxidative status of the liver, coupled with investigation of extraction solvent selection using principal component analysis (PCA). MATERIALS AND METHODS: Winter savory dry extract (500 mg/kg) dispersion and saline solution were given to Wistar rats for 7 days after exposure to oxidative stress using toxic doses of paracetamol (600 mg/kg). Rats were sacrificed, after which a complete autopsy was performed, the blood obtained was used to determine biochemical parameters, and the liver was sliced for histological analysis and determination of oxidative stress enzymes. RESULTS: Indicators of hepatic and kidney functions, as well as the concentration of oxidative stress enzymes, were statistically significantly lower in animals treated with Satureja montana L. extract compared to the paracetamol group alone before the toxic dose of paracetamol. Liver enzymes were unaltered by pre-treatment with the extract, but the level of lipid peroxidase was decreased, and the level of catalase, glutathione reductase and superoxide dismutase increased proving in vivo antioxidant effect. In addition, the number of inflammatory cells is decreased coupled with activity of CYP2E1 enzymes proving hepatoprotective effect. CONCLUSIONS: Satureja montana L. extract in our research has shown hepatoprotective, anti-inflammatory and antioxidative effect. PCA analyses indicated that extraction mediums have a great impact on the antioxidative effect.

Measuring pharmacovigilance knowledge and attitudes among healthcare sciences students: development and validation of a universal questionnaire.

OBJECTIVE: Pharmacovigilance education and reporting of adverse drug reactions (ADRs) are important competencies that healthcare sciences students should develop before completing their studies and entering clinical practice. Since students frequently lack adequate knowledge in this area and fail to recognize the importance of ADRs monitoring and reporting, the aim of this study was to develop and validate a unique and reliable instrument for assessing health sciences students' knowledge and attitudes toward pharmacovigilance and ADRs reporting. SUBJECTS AND METHODS: A cross-sectional observational study was conducted from February to July 2021 to examine students' knowledge and attitudes toward pharmacovigilance activities. Students of medicine, dentistry, pharmacy, and nursing science of three faculties in the Autonomous Province of Vojvodina, Serbia were examined. A total of 211 of them completed the specially designed, three-section questionnaire (Demographic data section, Pharmacovigilance Knowledge test, PVKT, and Pharmacovigilance Attitude Questionnaire, PVAQ). The questionnaire was posted on the Google Forms platform, and the link was distributed to respondents via the official websites and social networks of all three faculties. RESULTS: Findings demonstrated good psychometric properties and reliability of the questionnaire. Six questions were removed from the PVKT after item analyses. After excluding these items, the calculated ordinal alpha of the final version of the PVKT, which included 14 items, was good (αord = 0.83), as were other statistical indicators. PVAQ reliability testing also revealed great performance of this questionnaire-calculated ordinal alpha for two PVAQ subscales was excellent (αord = 0.91, for both scales). CONCLUSIONS: This questionnaire has favorable validity and reliability in assessing healthcare sciences students' knowledge and attitudes toward pharmacovigilance and ADRs reporting.

Essential competencies in prescribing: A first european cross-sectional study among 895 final-year medical students.

European medical students should have acquired adequate prescribing competencies before graduation, but it is not known whether this is the case. In this international multicenter study, we evaluated the essential knowledge, skills, and attitudes in clinical pharmacology and therapeutics (CPT) of final-year medical students across Europe. In a cross-sectional design, 26 medical schools from 17 European countries were asked to administer a standardized assessment and questionnaire to 50 final-year students. Although there were differences between schools, our results show an overall lack of essential prescribing competencies among final-year students in Europe. Students had a poor knowledge of drug interactions and contraindications, and chose inappropriate therapies for common diseases or made prescribing errors. Our results suggest that undergraduate teaching in CPT is inadequate in many European schools, leading to incompetent prescribers and potentially unsafe patient care. A European core curriculum with clear learning outcomes and assessments should be urgently developed.

Analgesic effects of rosemary essential oil and its interactions with codeine and paracetamol in mice.

OBJECTIVE: The use of herbal medicinal products in the management of pain has been increasing steadily in recent years, often in combination with conventional analgesics, which can induce significant interactions. In traditional medicine, rosemary was used as mild analgesic, for relieving renal colic pain and dysmenorrhea. The aim of our study was to examine analgesic effects of rosemary essential oil and its pharmacodynamic interactions with codeine and paracetamol in mice. MATERIALS AND METHODS: The identification and quantification of chemical constituents of the essential oil isolated from air-dried aerial parts of rosemary were carried out by GC/FID and GC/MS. The hot plate test was performed on NMRI mice by placing them individually on hot plate and assessing their response to the thermal stimulus. RESULTS: In this research, we identified 29 chemical compounds of the studied rosemary essential oil, and the main constituents were 1,8-cineole, camphor, and α-pinene. Administration of investigated essential oil increased significantly the latency time of animal response to heat-induced pain between 20th and 50th minute of the test, when compared to saline-treated group. Rosemary essential oil in the dose of 20 mg/kg was shown to be more efficient than in the dose of 10 mg/kg, in combinations with both codeine and paracetamol. CONCLUSIONS: Our findings support the use of rosemary in the management of pain and indicate a therapeutic potential of rosemary essential oil in combination with analgesic drugs. The mechanisms involved in analgesic effects of rosemary essential oil and the potential influence on cytochromes and drug metabolism should be more in-depth investigated.

Interaction of diclofenac and ketoprofen with cardioactive drugs in rats.

The interaction of diclofenac and ketoprofen, both applied intraperitoneally in a dose of 8 mg/kg for twenty-eight days, was assessed with cardioactive drugs in rats. Interaction was assessed on the basis of ECG records after the infusion of adrenaline, verapamil or lidocaine to the rats treated with diclofenac or ketoprofen vs control. The infusion time was measured in seconds to the moment of the appearance of the first heart reaction to the infusion of the cardioactive drug, then to the appearance of more frequent changes in the ECG record, and finally, to the occurrence of the toxic effect. It was also measured the plasma concentrations of sodium and potassium ions. As well as diclofenac and ketoprofen concentration, 2 hours after single and 28th dose. ECG patterns revealed no occurrence of cardiotoxic action of diclofenac and ketoprofen. The treatment with diclofenac caused significantly lower sodium plasma concentrations whereas the concentration of potassium was increased. Diclofenac concentrations were the same after a single and multiple doses, whereas concentrations of ketoprofen were significantly higher after a single dose than after its multiple applications.

The effect of celery and parsley juices on pharmacodynamic activity of drugs involving cytochrome P450 in their metabolism.

Celery (Apium graveolens) and parsley (Petroselinum sativum), plants used worldwide in human nutrition, are the natural sources of methoxsalen. In this study we investigated the effect of mice pretreatment with juices of this plants on the hypnotic action of pentobarbital and analgesic action of paracetamol and aminopyrine, the drugs involving cytochrome P450 superfamily in their metabolism. In mice pretreated with celery and parsley juices a prolonged action of pentobarbital with respect to control was observed, statistical significance being attained only with parsley-pretreated animals. Both pretreatments increased and prolonged the analgesic action of aminopyrine and paracetamol, pretreatment with parsley being again more effective. Celery and parsley juices given to animals two hours before their decapitation caused a significant decrease of cytochrome P450 in the liver homogenate as compared to control.

The effect methoxsalene on hypnotic and subhypnotic doses of pentobarbital.

The effect of several doses of methoxsalen on hypnotic action of 40 mg/kg of pentobarbital in mice was studied. Methoxsalen was injected 30 minutes before the barbiturate. The highest methoxsalen dose of 22 mg/kg extended the duration of the hypnotic action of pentobarbital about 10 times compared to the control. The effect decreased with time, and 96 hours after this single dose of methoxsalen it was not significantly different from that observed with the control animals receiving only 40 mg/kg pentobarbital. The other methoxsalen doses (10, 5, and 2 mg/kg) exhibited an equal effect on the hypnotic action of pentobarbital, and only in the first measuring time. The effect could not be detected after 24 hours, and no dose dependence was observed. Small doses of methoxsalen of 2 and 1 mg/kg injected 30 minutes before a subhypnotic pentobarbital dose of 30 mg/kg produced sleep in 75% of animals of the both groups. In the control group, this dose produced no sleep in none of the animals.

The activity of liver oxidative enzymes after single and multiple grapefruit juice ingestion.

In the recent time, several in vitro and in vivo studies have shown the inhibitory effect of grapefruit juice on metabolism of xenobiotics catalyzed by liver oxidative enzymes including cytochrome P450 izoenzymes. However, all these experiments were done with a single dose of grapefruit juice. The primary aim of this study was to evaluate if the chronical ingestion of grapefruit juice can cause enzyme activity alteration as well as a single dose. Three groups of male mice were used: the control group, the group which was administered 0.2 mL of grapefruit juice per os 10 days and the group which was administered single dose of 0.5 mL grapefruit juice per os 90 min. before the sacrificing. After the sacrificing of animals, liver was homogenized with appropriate buffer, and the activity of oxidative liver enzymes: xanthine oxidase (XOD), peroxidase (Px), catalase (CAT), lipid peroxidase (LPx), glutathion peroxidase (GSH-Px) and liver glutathion contents (GSH) were detected by standard methods. The results show that the enzyme activity of liver MFO was changed according to a single or multiple grapefruit juice ingestion. The grapefruit juice in a single oral dose significantly decreases the activity of xanthine oxidase, glutathion peroxidase, lipid peroxidase and liver glutathion contents, and has no effect on activity of catalase and peroxidase. The multiple grapefruit ingestion increases the activity of XOD, GSH-Px, LPx, Px and GSH, while the activity of CAT enzyme is unchanged. The chronical and single grapefruit ingestion has no effect on relative liver weight, but the liver protein content is significantly decreased after the multiple oral grapefruit juice ingestion.

The effect of paracetamol on peritoneal reflex after single and multiple grapefruit ingestion.

In the last few years, more attention has been paid to the influence of grapefruit juice on metabolism on many drugs. It has been reported that grapefruit juice increases the plasma concentrations of orally administrated drugs, that undergo metabolism in liver. However, all these experiments were done with a single dose of grapefruit juice. The primary aim of this study was to evaluate if the chronical ingestion of grapefruit juice could also cause these effects. Paracetamol is metabolized by reactions of oxidation and conjugation to nontoxic ineffective metabolites. These reactions, partly catalyzed by cytochrome P450 izoenzymes, take place in liver. The analgesic effect of paracetamol was examined by Writhing tests, where we used acetic acid as an irritating agent. We used three groups of male mice: the control group, the group which was administrated 0.2 mL of grapefruit juice per os 10 days (GPOch) and the group which was administrated single dose of 0.5 mL grapefruit juice per os 90 min. before the experiment (GPOac). Dose of 50 mg/kg of paracetamol was applicated s.c. 5 min. before i.p. application of 3 % acetic acid. The writhing phenomenon was observed in periods of 5-15 min. and 15-30 min. after the application of paracetamol. The results show that paracetamol in GPOch group significantly decreases irritant effect of acetic acid in the period of 15-30 min. after the application in relation to the control group. However, the acetic acid shows stronger irritant effect in GPOch group than in the control group and less irritant effect in GPOac group than in the control group. In the period of 5-15 min. after the application, paracetamol shows analgesic effect neither in the control nor in the other groups.