B. Milijasevic

Deoxycholic Acid as a Modifier of the Permeation of Gliclazide through the Blood Brain Barrier of a Rat

Major problem for diabetic patients represents damage of blood vessels and the oxidative stress of the brain cells due to increased concentration of free radicals and poor nutrition of brain cells. Gliclazide has antioxidative properties and poor blood brain barrier (BBB) penetration. Bile acids are known for their hypoglycemic effect and as promoters of drug penetration across biological membranes. Accordingly, the aim of this study is to investigate whether the bile acid (deoxycholic acid) can change the permeation of gliclazide, through the blood brain barrier of a rat model type-1 diabetes. Twenty-four male Wistar rats were randomly allocated to four groups, of which, two were given alloxan intraperitoneally (100 mg/kg) to induce diabetes. One diabetic group and one healthy group were given a bolus gliclazide intra-arterially (20 mg/kg), while the other two groups apart from gliclazide got deoxycholic acid (4 mg/kg) subcutaneously. Blood samples were collected 30, 60, 150, and 240 seconds after dose, brain tissues were immediately excised and blood glucose and gliclazide concentrations were measured. Penetration of gliclazide in groups without deoxycholic acid pretreatment was increased in diabetic animals compared to healthy animals. Also in both, the healthy and diabetic animals, deoxycholic acid increased the permeation of gliclazide through that in BBB.

Diclofenac and ketoprofen liver toxicity in rat

SummaryIn the last years there appeared many articles about the adverse influence of non-steroidal anti-inflammatory drugs on the liver and heart. This study is concerned with the influence of the duration of treatment with diclofenac and ketoprofen on the macroscopic and microscopic changes in the liver, lungs, heart, and kidneys in rats. Experiments were carried out on mature Wistar strain rats. Animals of test groups received diclofenac and ketoprofen in a dose of 8 mg/kg/day (equivalent to the therapeutic dose for man) during 7 per os (p.o.) or 28 days intraperitoneally (i.p.), whereas controls received physiological solution p.o. A high morbidity was observed in the animals receiving diclofenac p.o. and somewhat lower in those treated with ketoprofen. On the other hand, the rats got through the 28-day i.p. treatment with both drugs mainly without significant complications. Macroscopic examinations revealed some changes in treated rats: distension of the stomach, ascites, fibrin deposits on the internal organs, lung effusion and the changes in color and structure of the liver. These changes were more frequent in the group of rats receiving diclofenac for the 7 days compared with those that received ketoprofen for the same time. It may be thought that the high mortality and macroscopic changes in the internal organs of experimental animals are a consequence of the microscopic changes in the liver and its lowered function.

Consumption of serum lipid-reducing drugs in Serbia compared with Scandinavian countries: a population-based study, 2004–2008

The aim of this study was to measure the consumption of serum lipid reducing drugs in Serbia from 2004 to 2008, to compare this data with that from Scandinavian countries, and to compare the consumption of lipid lowering drugs and the rate of mortality from cardiovascular diseases in these countries.

Antioxidative and Protective Actions of Apigenin in a Paracetamol-Induced Hepatotoxicity Rat Model

Background and ObjectivesApigenin is known to have various pharmacological properties without causing significant toxicity; however, hepatoprotective effect of apigenin is not often reported. The aim of our study was to investigate if the alterations in lipid peroxidation and antioxidant status are in favor to prove the efficacy of apigenin against paracetamol-induced hepatotoxicity.MethodsThe effect of apigenin on paracetamol-induced hepatotoxicity in rats was examined by determining biochemical parameters, histological assessment and oxidative status in liver homogenates.ResultsThe treatment of animals with both apigenin and paracetamol attenuates the parameters of hepatotoxicity, especially for ALT and ALP activity which was significantly lower compared to groups of animals treated with saline and paracetamol. Hepatotoxicity induced by toxic dose of paracetamol was revealed also by notable histopathological alterations, which were not observed in the group treated with paracetamol together with apigenin. Apigenin also prevented paracetamol-induced increase in malondialdehyde (MDA) level. The activities of both CAT (catalase) and GR (glutathione reductase) enzymes after the toxic dose of paracetamol were significantly increased in the liver homogenates, compared to control group. Apigenin reversed these parameters near to values of control group.ConclusionsThe result of our study indicates that apigenin inhibits the level of lipid peroxidation and significantly increases the enzyme antioxidant defense mechanisms in paracetamol-induced hepatotoxicity in rats.

Acute toxic effects of single dose dacarbazine: hematological and histological changes in an animal model.

Abstract Treatment of advanced soft tissue sarcoma usually includes dacarbazine (DTIC), an alkylating agent that methylates DNA and is active during all phases of the cell cycle. Common side effects of DTIC include nausea, vomiting, impaired liver and kidney function, myelosuppression, and pneumonia. There are no accounts, however, of histological and hematological changes caused by DTIC. We investigated acute hematological and morphological changes in different organs and in tumors that were caused by a single dose of DTIC. Adult Syrian golden hamsters were inoculated with a suspension of tumorigenic baby hamster kidney (BHK) cells by subcutaneous injection. On day 14 after inoculation, doses of 1.4, 1.6, 1.8 or 2.0 g/m2 DTIC were injected intraperitoneally into the hamsters. Hamsters in the control group were injected with physiological saline in the same way. Seven days after drug or saline injection the animals were sacrificed and samples of blood, heart, kidney, liver, lungs, spleen, small intestine and tumor were excised, processed and analyzed. Mitoses were counted using an ocular extension with engraved frame. Anemia, thrombocytopenia and leukocytosis were found in the control group of hamsters with fibrosarcoma, whereas animals with fibrosarcoma treated with DTIC developed anemia, thrombocytopenia and leukopenia. Severe pneumonia and moderate hepatitis were detected in all DTIC treated groups. Effects of DTIC on tumor cells included rounding and enlargement of nuclei and rarefaction of chromatin. The number of mitoses was reduced with increasing doses of DTIC. Hepatitis, myelosuppression, pneumonia, and dose-related inhibition of tumor cell proliferation were observed after a single dose of DTIC.

Interaction of diclofenac and ketoprofen with cardioactive drugs in rats.

SummaryThe 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.

Insight into anti-diabetic effect of low dose of stevioside

Diabetes mellitus is a chronic disease characterized by abnormal carbohydrate, lipid and protein metabolism due to a lack of insulin or reduced target cell sensitivity to insulin. Stevia rebaudiana is an important source of biochemically active substances with proven anti-diabetic effect. The aim of this study was to determine anti-diabetic effects of the low dose of stevioside in NMRI Haan mice. Aqueous stevioside solution (20mg/kg body weight) was administered by oral route of administration. Anti-diabetic effect of stevioside was estimated by oral glucose tolerance test, adrenaline test after a 10day stevioside treatment, and alloxan induced hyperglycaemia in mice (two experimental groups, 10day stevioside treatment before and after alloxan administration). Aqueous stevioside solution prevented significant increase in glycaemia in oral glucose tolerance test (9.22±1.13 to 9.85±1.32mmol/l, P<0.05), and not in adrenaline test. Significant difference in glycaemia was detected in mice pre-treated with saline and stevioside in alloxan induced hyperglycaemia (saline 23.32±2.14, stevioside 14.70±4.95mmol/l, P<0.05). In mice pre-treated with stevioside, smallest β cells loss was found compared to other alloxan treated groups. Preserved normal cytoarchitectonic arrangement in islets was detected. Based on the given results we presume there exist a potential therapeutic use of low dose stevioside in diabetes.

Pharmacokinetics and Pharmacodynamic dosage adaptation of cefaclor in systemic infections

August 2015 e81 PhArmAcokinetics And PhArmAcodynAmic dosAge AdAPtAtion of cefAclor in systemic infections A. Tomas; O. Horvat; M.P. Kusturica; N. Pavlović ; B. Milijašević ; Z. Tomić ; and A. Sabo Medical faculty, University of Novi Sad, Serbia Background: Cefaclor was one of the commonly used antimicrobials in Serbia, but due to fast development of resistance, other oral cephalosporins rapidly upstaged cefaclor and cefaclor was removed from the list of the drugs reimbursed by the National Health Insurance Fund. Use of recommended dosing regimen (250-500mg/812h) is likely to result in sub-therapeutic concentrations for a wide portion of dosing interval due to short half-life of cefaclor, which may facilitate development of resistance. The aim of this study was to determine adequate dosing interval for cefaclor in treatment of systemic infections using Pharmacokinetic (PK) and pharmacodznamic (PD) parameters with special regard to postantibiotic effect (PAE). Material and Methods: PK profile of cefaclor in healthy volunteers and PK/PD indices relating to efficacy of cephalosporins were determined, as well as minimum inhibitory concentration (MIC) and PAE of cefaclor on 4 susceptible bacteria. Results: Cmax of 23.142 ± 5.67 μg/mL was measured after 40-60 minutes. Tmax was 0.72 ± 0.13 hours. Calculated AUC(0-t) was 29.148 ± 9.27 μg/mL/h. MICs were in range of 1-2 μg/mL. Cefaclor induced PAE of 1-2h. There was inconsistency between standard dosing regimen and PK/PD parameters. Main PK/PD index relating to efficacy of cephalosporins (%t> MIC) for the 750mg dose was 33.5–42.1%. PK/PD breakpoints for cefaclor were between 0.3-1μg/mL. Even the maximum doze with standard dosing intervals is not appropriate for eradication of susceptible organisms. Short PAE can’t compensate for sub-inhibitory concentrations at the half of the dosing interval. Conclusions: In reference to PK/PD parameters cefaclor should be administered every 6h for the doses of 500mg and 750mg, and every 4-4.5h for the 250mg dose in order to maximize its therapeutic efficacy and minimize development of resistance. This work was supported by the Ministry of Science and Technological development, Republic of Serbia, project No III 41012.

Are There Striking Differences in Outpatient Use of Antibiotics Between South Backa District, Serbia, and Some Scandinavian Countries?

There is little published information about antibiotic utilization in outpatients in Serbia. The objective of this study was to determine the amount and structure of outpatient antibiotic use in South Backa District (SBD) in Serbia, to assess prescibing quality of antibiotics and to compare with results from Scandinavian countries. Data on the antibiotic use were collected from all private and state-owned pharmacies from January through March 2008 in SBD. Results were expressed as the number of defined daily doses/1,000 inhabitants/day. The drug utilization 90% method was also used. Penicillins were the most frequently used antibiotic subgroup in SBD (35.20%), followed by cephalosporins (19.16%) and macrolides (13.18%). Thirteen drugs accounted for 90% of total antibiotics consumption (DU90% segment). The average cost/DDD within the DU90% segment was 0.95 euros, whereas the average cost/DDD beyond the DU90% segment was 1.89 euros, indicating that less expensive antibiotics were more frequently used. High use of ampicillin, third-generation cefalosporins, co-trimoxazole, and gentamicin, will aggravate the alarming problem of resistance in Serbia. Differences in the amount and structure of antibiotic consumption between SBD and Scandinavian countries indicate the need of updated national guidelines for rational antimicrobial drug use in Serbia.

Protective effect of silymarin on doxorubicin-induced cardiotoxicity in rats

Background Silymarin, an extract of Silybum marianum seeds, possesses a broad spectrum of action: antifibrotic, antiinflammatory, lipid peroxidation-inhibiting and free radical-scavenging effects. It is a complex of five major compounds, and silibinin is the most biologically active component of the complex. The aim of this study was to investigate, evaluate and confirm the potential antioxidative effects of silymarin rich in silibinin.