Search

Ototoxicity is the damage to inner ear sensory epithelia due to exposure to certain medications and chemicals. This occurs when toxins enter the tightly controlled inner ear environment inducing hair cell death, resulting in hearing loss. Recent studies have explored hydrogel-based bio-nanotechnologies and new drug delivery formulations to prevent drug-induced hearing loss, with much attention given to administration of antioxidant drugs. Bile acids have been recognized as promising excipients due to their biocompatibility and unique physiochemical properties. As yet bile acids have not been explored in improving drug delivery to the inner ear despite improving drug stability and delivery in other systems and demonstrating positive biological effects in their own right.

Despite a relatively low prevalence of primary brain tumors, they continuously attract scientific interest because of the complexity of their treatment due to their location behind the blood-brain barrier. The main challenge in treatment of brain tumors is not the efficacy of the drugs, per se, but the low efficiency of drug delivery to malignant cells. At the core of the problem is the complex structure of the blood-brain barrier. Nowadays, there is evidence supporting the claim that bile acids have the ability to cross the blood-brain barrier. That ability can be exploited by taking a part in novel drug carrier designs. Bile acids represent a drug carrier system as a part of a mixed micelle composition, bilosomes and conjugates with various drugs. This review discusses the current knowledge related to bile acid molecules as drug penetration modifying agents, with the focus on central nervous system antitumor drug delivery.

Background/Aim: Cardiac arrest (CA) is a leading cause of mortality in the last forty years worldwide. Immediately initiated cardiopulmonary resuscitation (CPR) improves chances for survival. Aim of this study was to determine the efficiency of the Emergency medical service (EMS) dispatch centre in the absence of the uniform emergency medical dispatch assessment protocols in the management of cardiac arrest. Methods: The retrospective and observational study was conducted in Institute for Emergency Medical Service Novi Sad (IEMS Novi Sad) Serbia during a one-year follow-up. The study included patients with out-of-hospital cardiac arrests who underwent CPR. Results: EMS teams of the IEMS Novi Sad had 198 CPRs in the follow-up period. In 142 (71.72 %) calls, the EMS dispatcher got information that the patient was unconscious. The reported reaction time I by the dispatchers for the unconscious patients was 1.37 ± 1.27 minutes, actual duration of the conversation between the dispatcher and a caller - was longer: 138.21 ± 103.02 seconds (p < 0.001). The average conversation time with a caller was 61.37 ± 31.13 seconds. In 6 (4.22 %) cases, the EMS team was dispatched to a patient before the phone call was terminated. At the moment of arrival, all patients were unconscious, 194 (94.37 %) were pulseless, while the remaining 8 (5.63 %) experienced cardiac arrest during the examination. The cardiac arrest was witnessed by a layman in 120 (84.51 %) cases and CPR was initiated by bystanders, before the arrival of the EMS team, only in 13 (10.83 %) patients. Twenty-seven (19.01 %) patients arrived in a hospital with vital signs. Conclusion: The absence of the uniform EMS dispatch assessment protocols for the triage of incoming calls and phone assisted CPR for lay rescuers decreases the survival rate of patients with cardiac arrest.

The microflora of the gastrointestinal tract is essential for mucosal protection, immune education, and for metabolism of humans. Disturbances of these processes results in various diseases. Regarding these processes, there is a clinical interest in the utility of microbial therapy - the feeding of non-pathogenic bacteria, originally derived from the alimentary tract. Considering the commercial success of probiotics, there is still a difficulty for consumers as well as for physicians when choosing the specific product. Since they are classified as food supplements, and not subject to drug regulations, there is ongoing skepticism about the benefits they offer. Fecal bacteriotherapy is reported as highly effective in the treatment of various diseases, including those of the digestive tract. The treatment itself consists of feces infusion from a healthy human donor to the gastrointestinal tract of patient. According to current data, fecal bacteriotherapy represents an emerging and promising low-cost solution for diseases with which antibiotic and probiotic products have been struggling for years.

Background: Recent studies have suggested that hyperglycaemia influences the bile acid profile and concentrations of secondary bile acids in the gut. Introduction: This study aimed to measure changes in the bile acid profile in the gut, tissues, and faeces in type 1 Diabetes (T1D) and Type 2 Diabetes (T2D). Method: T1D and T2D were established in a mouse model. Twenty-one seven-weeks old balb/c mice were randomly divided into three equal groups, healthy, T1D and T2D. Blood, tissue, urine and faeces samples were collected for bile acid measurements. Results: Compared with healthy mice, T1D and T2D mice showed lower levels of the primary bile acid, chenodeoxycholic acid, in the plasma, intestine, and brain, and higher levels of the secondary bile acid, lithocholic acid, in the plasma and pancreas. Levels of the bile acid ursodeoxycholic acid were undetected in healthy mice but were found to be elevated in T1D and T2D mice. Conclusion: Bile acid profiles in other organs were variably influenced by T1D and T2D development, which suggests similarity in effects of T1D and T2D on the bile acid profile, but these effects were not always consistent among all organs, possibly since feedback mechanisms controlling enterohepatic recirculation and bile acid profiles and biotransformation are different in T1D and T2D.

Since its discovery in 1945, methotrexate has become a standard therapy for number of diseases, including oncological, inflammatory and pulmonary ones. Major physiological interactions of methotrexate include folate pathway, adenosine, prostaglandins, leukotrienes and cytokines. Methotrexate is used in treatment of pulmonary sarcoidosis as a second line therapy and is drug of choice in patients who are not candidates for corticosteroid therapy, with recommended starting weekly dose of 5-15 mg. Number of studies dealt with methotrexate use in rheumatoid arthritis and oncological patients. Authors are conducting research on oral methotrexate use and pharmacokinetics in chronic sarcoidosis patients and have performed literature research to better understand molecular mechanisms of methotrexate action as well as high level pharmacokinetic considerations. Polyglutamation of methotrexate affects its pharmacokinetic and pharmacodynamic properties and prolongs its effect. Bile excretion plays significant role due to extensive enterohepatic recirculation, although majority of methotrexate is excreted through urine. Better understanding of its pharmacokinetic properties in sarcoidosis patients warrant optimizing therapy when corticosteroids are contraindicated in these patients.

Methotrexate is an anti-inflammatory and anticancer drug that has been used in the treatment of various oncological and inflammatory diseases (such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, sarcoidosis, etc.). Scientists are working on finding optimal formulation that will maintain its efficacy and improve safety and nanoparticles have shown to be carriers with great potential as they protect the drug from degradation while at the same time they increase absorption. In vivo and in vitro studies of numerous nanoparticle preparations have showed that they generally have appropriate characteristics and can be carriers for targeted delivery of methotrexate to the tissues affected by disease. Topical preparations of methotrexate, mainly for the treatment of psoriasis, have also been assessed in various research and have showed promising results. Further research is warranted by the obtained results and will hopefully lead to new methotrexate formulations that will be approved by regulatory authorities and used instead of existing ones to improve efficacy of the drug and patients' safety.

Advancement in the prevention of chemotherapy-induced hearing loss has proposed new nano-based delivery matrices that can target inner ear regions most damaged by chemotherapy. Chemotherapy agents (e.g., cisplatin) induce increased reactive oxygen species formation in the inner ear that damage sensory hair cells and result in irreversible hearing impairment. Exogenous antioxidants (e.g., Probucol and metformin) have been shown to block the formation of these reactive oxygen species. Delivery of these drugs in effective concentrations remains a challenge. Microencapsulation in combination with drug excipients provides one technique to effectively deliver these drugs. This paper investigates the use of probucol and metformin in combination with drug excipients for novel, inner ear, delivery.

High-dose methotrexate (HD-MTX) is the mainstream therapy of current acute lymphoblastic leukemia (ALL) regimens, but frequent intra- and interindividual differences in the clinical response to HD-MTX lead to chemotherapeutic interruption or discontinuation. The exact mechanism of transport across the cell membrane and the disposition of active methotrexate metabolites—methotrexate polyglutamates (MTXPGs)—are not well described in the literature. The aim of this study was to gain more insight into the plasma distribution of methotrexate and MTXPGs in pediatric patients with ALL and to clarify the obscure pathways of MTXPGs. We prospectively measured the concentrations of MTXPG1–7 in plasma samples from three male pediatric patients treated with HD-MTX and leucovorin rescue according to the IC-BFM 2009 protocol using liquid chromatography–mass spectrometry (LC-MS). Blood samples were obtained at 24, 36, 42, and 48 h after the start of HD-MTX treatment. Noticeable plasma concentrations of MTXPGs with a 2.2-fold interpatient variability were detected. The highest interindividual variability in total plasma MTXPG concentration was observed at 36 h, and ranged from 13.78 to 30.82 μmol/L. Among all patients, the predominant polyglutamate types in relation to the total plasma MTXPG concentration at each time point were MTXPG3 (16.71–30.02%) and MTXPG5 (26.23–38.60%), while MTXPG7 was the least abundant MTXPG (3.22–5.02%). The presence of MTXPGs in plasma of patients with ALL could be related to the action of ABC efflux transporters on blood cells and hepatocytes resulting from the administration of high doses of methotrexate. This study may not draw definitive conclusions, but it does reduce uncertainty about the dynamics of methotrexate and its active metabolites, which may be of vital importance for achieving a clinical response.

Introduction. A major obstacle in islet transplantation and graft survival pre and post transplantation is islet apoptosis due to mainly inflammatory bio molecules released during islet harvesting and post graft transplantation and hence, subsequent graft fibrosis and failure. This study aimed to investigate if incorporation of the anti-inflammatory anti-hyperlipidaemic drug probucol (PB) would improve islet-graft survival and function, post transplantation in Type 1 diabetes (T1D). Methods. T1D was induced in mice, and biological profiles of the diabetic mice transplanted PB-microencapsulated islets harvested from healthy syngeneic mice were measured. Results and Conclusion. Compared with sham (no PB), the treated group showed significant reduction in serum levels of interleukin-1β, interleukin-6, interleukin-12, interleukin-17, and tumour necrosis factor-α, accompanied by a 3-fold increase in survival duration, which suggests PB islet-protective effects, post transplantation.

The continuously increasing incidence of diabetes worldwide has attracted the attention of the scientific community and driven the development of a novel class of antidiabetic drugs that can be safely and effectively used in diabetic patients. Of particular interest in this context are complications associated with diabetes, such as renal impairment, which is the main cause of high cardiovascular morbidity and mortality in diabetic patients. Intensive control of glucose levels and other risk factors associated with diabetes and metabolic syndrome provides the foundations for both preventing and treating diabetic nephropathy. Dipeptidyl peptidase-4 (DPP-4) inhibitors represent a highly promising novel class of oral agents used in the treatment of type 2 diabetes mellitus that may be successfully combined with currently available antidiabetic therapeutics in order to achieve blood glucose goals. Beyond glycemic control, emerging evidence suggests that DPP-4 inhibitors may have desirable off-target effects, including renoprotection. All type 2 diabetes mellitus patients with impaired renal function require dose adjustment of any DPP-4 inhibitor administered except for linagliptin, for which renal excretion is a minor elimination pathway. Thus, linagliptin is the drug most frequently chosen to treat type 2 diabetes mellitus patients with renal failure.

Environmental pollution caused by pharmaceuticals and their transformation products (TPs) has become an increasingly important concern, due to the increased use of pharmaceutical formulations exposed to environmental change. Considerable concerns have been raised regarding potential toxic effects of the transformation products of pharmaceutical formulations on human health. Environmental risk assessments are mostly based on one active component, which causes different ecotoxicological effects, albeit the particular component is present in the environment as a part of a multicomponent mixture with different pharmaceuticals and excipients. The purpose of this review was to present the insight and new knowledge recently obtained by studies on the risk of pharmaceutical formulations, including all contained excipients, pharmaceuticals, and their transformation products exposed to the environment. Numerous studies have shown that the level of pharmaceuticals in the environment is below toxic concentration; however, long exposure to very low concentrations can still lead to harmful concentrations in biota. Accordingly, the findings of this study are expected to highlight the existing issues of the effect of pharmaceutical formulations to the environment, including TPs, and help to determine future research directions towards accumulating the data and improving ecological risk assessment.

Urinary tract infections (UTI) are one of the most common infectious diseases, primarily caused by bacteria present in the intestinum, affecting the entire urinary tract or only a part of it. If the urinary bladder and urethra are affected then they are considered ?lower? urinary tract infections, and the affected kidneys and ureter are considered ?upper? urinary tract infections. There is a division into uncomplicated and complicated UTIs. Approximately 15% of all prescribed antibiotics in the United States are prescribed as therapy of UTIs. The UTI data from other countries are similar. The costs incurred in the treatment of these infections are significant - in the United States, the direct costs of UTI treatments are estimated at $ 1.6 billion per year.

Aim: Gliclazide (G) is a drug prescribed for Type 2 diabetics, although recent studies suggest it has desirable effects in both types of diabetes, Type 1 diabetes and Type 2 diabetes. G has an inconsistent absorption due to poor formulation and bile acids (BAs) have shown significant promise in drug formulation optimization. Hence, the study aimed to examine G effects on histopathological, anti-inflammatory and antidiabetic effects when encapsulated with BAs. Materials & methods: Rats were randomized into eight groups, of which seven were made Type 1 diabetes and treated with various BA-based treatments. Tissue histopathology, inflammation and the bile acid profile were analyzed. Results & conclusion: G capsules showed no histological but the most anti-inflammatory effects, which suggest significant beneficial effects in diabetes treatment.

Background/Aim: Gliclazide is one of the most commonly prescribed oral anti-hyperglycaemic therapies in type 2 diabetes mellitus (T2D). Recently reported additional beneficial pharmacological properties of gliclazide, including immunomodulatory and anticoagulant activities, suggested its potential application in treatment of type 1 diabetes mellitus (T1D). However, following oral administration, gliclazide was shown to have poor and variable absorption directing research into development of novel pharmaceutical delivery systems of gliclazide suitable for T1D. Since bile acids have previously demonstrated stabilising and controlled-release effects on microcapsules, their use for preparation of microcapsules of gliclazide may lead to improvements in gliclazide release, absorption and antidiabetic effects. This investigation was aimed to evaluate drug absorption profiles and hypoglycaemic effects of alginate-based microcapsules of gliclazide, prepared together with or without cholic acid, in healthy rats. Methods: Thirty healthy Wistar rats with confirmed normal glucose blood concentration were allocated into five groups and administered with a single dose of either vehicle microcapsules, gliclazide in suspension, gliclazide microcapsules, gliclazide in suspension together with cholic acid or microencapsulated gliclazide in combination with cholic acid. Following respective gliclazide dose, blood was sampled over next 10 hours and blood glucose levels and gliclazide serum concentrations were measured. Results: This analysis demonstrated altered effects of different gliclazide formulations in healthy rats with the highest gliclazide absorption mirrored by the most profound hypoglycaemic effect being achieved after its oral administration as a suspension (p

Introduction: Despite the progress in breast cancer treatment, currently used methods are often aggressive and with low selectivity, thus inducing systemic toxicity while obtaining limited effect. The application of nanotechnologies is a promising novel technology, which could overcome these limitations. Corresponding section headings: Incorporation of the medication into a nanocarrier enables the administration of molecules with the suboptimal pharmacokinetic profiles if given as free agents. Furthermore, nanomedicine could improve the safety profile of currently used chemotherapeutics, by modifying pharmacokinetic properties and prolonging the half-life of the therapeutic. Most importantly, it provides a possibility of designing drug carriers with selective delivery to malignant cells, based on their characteristics. Conclusion: This advantage initiated an entirely new subset of targeted breast cancer therapy development, and has demonstrated favorable outcomes even in treatment of aggressive malignant types, metastatic developments, and multi-drug resistance.

The ratio of secondary to primary bile acids changes during Type 1 Diabetes (T1D) development and these effects might be ameliorated by using cholesterol lowering drugs or hydrophilic bile acids. Probucol is a cholesterol-lowering drug, while ursodeoxycholic acid is a hydrophilic bile acid. This study investigated whether nanoencapsulated probucol with ursodeoxycholic acid altered bile acid ratios and the development of diabetes.Balb/c mice were divided into three groups and gavaged daily with either free probucol, nanoencapsulated probucol or nanoencapsulated probucol with ursodeoxycholic acid for seven days. Alloxan was injected and once T1D was confirmed the mice continued to receive daily gavages until euthanasia. Blood, tissues, faeces and urine were collected for analysis of insulin and bile acids.Nanoencapsulated probucol-ursodeoxycholic acid resulted in significant levels of insulin in the blood, lower levels of secondary bile acids in liver and lower levels of primary bile acids in brain, while ratio of secondary to primary bile acids remains similar among all groups, except in the faeces. Findings suggests that nanoencapsulated probucol-ursodeoxycholic acid may exert a protective effect on pancreatic β-cells and reserve systemic insulin load via modulation of bile acid concentrations in the liver and brain.

Purpose: The study aimed to explore the relationship of different exposure measures with 131I therapy response in patients with benign thyroid disease, estimate the variability in the response, investigate possible covariates, and discuss dosing implications of the results. Methods: A population exposure-response analysis was performed using nonlinear mixed-effects modelling. Data from 95 adult patients with benign thyroid disease were analysed. Evaluated exposure parameters were: administered radioactivity dose (Aa) [MBq], total absorbed dose (ABD) [Gy], maximum of absorbed dose-rate (MXR) [Gy/h] and biologically effective dose (BED) [Gy]. The response was modelled as ordered categorical data: hyper-, eu- and hypothyroidism. The final model performance was evaluated by a visual predictive check. Results: The probability of the outcome following 131I therapy was best described by a proportional-odds model, including the log-linear model of 131I effect and the exponential model of the response-time relationship. All exposure measures were statistically significant with p

Aging is considered a contributing factor to many diseases such as cardiovascular disease, Alzheimer’s disease, and hearing loss. Age-related hearing loss, also termed presbycusis, is one of the most common sensory impairments worldwide, affecting one in five people over 50 years of age, and this prevalence is growing annually. Associations have emerged between presbycusis and detrimental health outcomes, including social isolation and mental health. It remains largely untreatable apart from hearing aids, and with no globally established prevention strategies in the clinical setting. Hence, this review aims to explore the pathophysiology of presbycusis and potential therapies, based on a recent advancement in bile acid-based bio-nanotechnologies. A comprehensive online search was carried out using the following keywords: presbycusis, drugs, hearing loss, bile acids, nanotechnology, and more than 150 publications were considered directly relevant. Evidence of the multifaceted oxidative stress and chronic inflammation involvement in cellular damage and apoptosis that is associated with a loss of hair cells, damaged and inflamed stria vascularis, and neuronal signalling loss and apoptosis continues to emerge. New robust and effective therapies require drug delivery deeper into the various layers of the cochlea. Bile acid-based nanotechnology has gained wide interest in its permeation-enhancing ability and potential for numerous applications in treating presbycusis.

Gliclazide is a drug commonly used in type 2 diabetes mellitus. Recently, gliclazide has shown desirable pharmacological effects such as immunoregulatory and anti-clotting effects, which suggests potential applications in type 1 diabetes mellitus (T1DM). Gliclazide has variable absorption after oral administration, and thus using targeted-delivery techniques, such as microencapsulation, may optimise gliclazide absorption and potential applications in T1DM. Bile acids such as cholic acid have shown microcapsule-stabilising and controlled-release effects, and thus their incorporation into gliclazide microcapsules may further optimise gliclazide release, absorption and antidiabetic effects. Accordingly, this study aimed to examine the hypoglycaemic effects of gliclazide microcapsules with and without cholic acid, in a rat model of T1DM. Thirty-five alloxan-induced T1DM rats were randomly divided into five equal groups and gavaged a single dose of empty microcapsules, gliclazide, gliclazide microcapsules, gliclazide-cholic acid or gliclazide-cholic acid microcapsules. Blood samples were collected over 10 h post-dose and analysed for blood glucose and gliclazide serum concentrations. Gliclazide microcapsules exerted a hypoglycaemic effect in the diabetic rats, and cholic acid incorporation diminished the hypoglycaemic effects, which suggests the lack of synergistic effects between gliclazide and cholic acid. In addition, neither microencapsulation nor cholic acid incorporation optimised gliclazide absorption which suggests that hypoglycaemic effects of gliclazide are independent of its absorption and serum concentrations. This also suggests that hypoglycaemic effects of gliclazide may be associated with gut-metabolic activation rather than gut-targeted delivery and systemic absorption. Gliclazide microcapsules exerted hypoglycaemic effects in T1DM rats independent of insulin and thus may have potentials in treatment of T1DM.

Cervical cancer can be cured, because it has a long preinvasive period. Early diagnosis and treatment of cervical cancer at women are crucial for reducing of rate mortality. Today, there are many methods for detecting premalignant lesions and one of them is a conventional Papanicolaou test. Cervical cancer develops through a series of changes in the epithelium called cervical intraepithelial neoplasia (CIN). The biological and genetic characteristics of the cells at cancer in situ are irreversibly altered and abnormal cells have the potential to metastasize to others anatomical regions. Infection with human Papillomavirus, which is transmitted sexually, is considered the main cause and represent the necessary, but not the only factor for the development of cervical cancer. Types of high risk human Papillomavirus are often associated with invasive cervical cancer. The carcinogenic types of HPV 16 and 18 are responsible for 70% of cervical cancer and about 50% of CIN 3. Primary prevention of cervical cancer is aimed at reducing incidence, control of causes and risk factors. In this scientific work, in addition to explaining the various treatments necessary for the treatment of cervical carcinoma, we were discussed about the anticancer effects of the synthetic derivative of ursodeoxycholic acid, such as HS-1183, and synthetic derivatives of chenodeoxycholic acid such as HS-1199 and HS-1200. Also, the effects of bile acid complexes with metals such as platinum, zinc, nickel, and copper were considered in the effective treatment of cervical cancer. KEY POINTS • Lymphogenic spreading of cervical cancer occurs relatively early in the regional lymph nodes, while this sort of progression of cervical cancer is rarer in the juxtaregional (paraaortic), mediastinal and supraclavicular nodes. Clinically proven supraclavicular metastases are not a rarity. In stages IIb and IIIa with metastases in paraaortal nodes occur a 20% metastases at the neck lymph nodes. Hematogenic metastases are relatively rare and occur in the posterior phase. Distant metastases are detected in the lungs and liver. Preinvasive and microinvasive stages of cervical cancer are without symptoms. With deeper invasion of the strome, certain clinical symptoms such as prolonged menstruation, increased vaginal secretions, vaginal bleeding between the two periods, contact bleeding (after coitus), unilateral pelvic pain with spreading in hip joint (infiltration of the pelvic nerve plexus), dysuric disturbance, anemia, islet of the lower extremities. In order to diagnose the level spreading of primary lesion of cervical cancer most commonly are used the supplemental searches such as cytoscopy, rectoscopy, urography, irigography, lung and bone radiography, scintigraphy of the liver, kidney and bone, lymphography, CT (MR) of abdomen and pelvis, as well as laboratory analysis. Surgical treatment consists of transvaginal hysterectomy, transabdominal removal of the uterus (via laparotomy), bilateral adenectomy (removal of the ovaries and the fallopian tubes), upper and middle third of the vagina and lymphonodectomy of the regional lymph nodes. The most commonly used radiotherapy, intracavitary brachytherapy, manual afterloading technique and remote afterloading techniques. The synthetic derivatives of ursodeoxycholic acid and chenodeoxycholic acid such as HS-1183, HS-1199, and HS-1200 are used to treat cervical cancer. These derivatives of chenodeoxycholic acid and ursodeoxycholic acid are capable of inhibiting cell proliferation and inducing apoptosis in SiHa human cells of cervix. Platinum compounds are used as catalysts in cervical cancer therapy. Clinical use of platinum complexes for which the bile acids bind is based on the desire to achieve the death of tumor cells and the spectrum of drug activity in the treatment of cervical cancer. Bisursodeoxycholate (ethylenediamine) platinum (II) [Pt(UDC)2(en)] is characterized by important cytotoxicity against HeLa cervical carcinoma cells and this effect already being clearly detectable after 24 h.

Purpose: To determine whether severe hypoalbuminemia (Material and Methods: Prospective, cohort, and a single-center study included 61 patients whose vancomycin serum levels were measured in steady state. Vancomycin trough levels ( C min) that were in the range 15 to 20 µg/mL were considered therapeutic and trough levels higher than 15 µg/mL were considered potentially nephrotoxic. Results: In the group of patients with severe hypoalbuminemia, C min was significantly higher compared to the those with nonsevere hypoalbuminemia (>25 mg/L; 23.04 [19.14] vs 13.28 [11.28], P = .01). In the group of patients who received the vancomycin loading dose of 2 g, C min was significantly higher in patients with severe hypoalbuminemia compared to the patients with nonsevere hypoalbuminemia (34.52 [25.93] vs 15.37 [10.48], P = .04). Conclusion: In critically ill septic patients with severe hypoalbuminemia, there is a high probability that the loading dose of vancomycin is not necessary since it is associated with potentially toxic vancomycin C min, while in the patients with nonsevere hypoalbuminemia the loading dose may be necessary to achieving therapeutic C min.

Emergency postcoital contraception (EPC) also known as 'emergency contraception' and 'morning after pill' is an easy way to prevent conceiving and it can be purchased in many countries without any prescription. EPC offers an important chance to prevent an unintended pregnancy when a regular method fails, no method was used, or sex was forced. The currently available options include an estrogen-progestin combination (ethinyl estradiol with levonorgestrel), progestin alone (levonorgestrel), the ulipristal acetate, the antiprogestin synthetic steroid mifepristone (RU-486), estrogen alone (high-dose ethinyl estradiol) and the Copper T intrauterine device (IUD). EPC pills, which may be more accessible than an emergency IUD, reduce the chance that pregnancy will happen after a single act of intercourse by at least 50 percent. The Copper T IUD is the most effective form of emergency contraception with an estimated failure rate of less than 1%. EPC is a simple safe emergency method to reduce the chance of pregnancy and EPC pills do not harm an existing pregnancy. EPC is not suitable for women who cannot take birth control pills, it does not protect against sexually transmitted infections and should not be used as a regular method of birth control. The sooner the pills are taken, the better it is. The effect or the potential of EPC diminishes over time. It may have some temporary side effects such as nausea and vomiting, delay in menses, irregular vaginal bleeding, abdominal pain, headache, dizziness, and fatigue. If these side effects occur, they generally resolve within 24 hours of the pill use. Side effects of the copper-containing IUD are also rare, but may include menstrual cramping or increased menstrual flow.

Introduction. Cardiac arrest (CA) is defined as a sudden cessation of normal circulation of blood due to failure of the heart to contract effectively during systole. Objective. The aim of this study was to determine the difference in outcome among patients, depending on the location of out-of-hospital CA; to determine the influence of observed determinants on the survival rate. Methods. Observational and retrospective study was conducted in the Institute for Emergency Medical Service Novi Sad (IEMS NS). It included patients who underwent cardiopulmonary resuscitation (CPR) by medical ambulance squads. Patients were divided into three groups, based on the location of CA: private place, public place, and medical institution. Results. CA occurred in private places in 151 cases (76.26%). The shortest duration of a phone call with the dispatcher and Reaction Time I was in the group of patients with CA in a public place (59.1 ± 36.4 seconds and 137.1 ± 89.8 seconds, respectively). CA was recognized in more than 80% of cases, but CPR was initiated in only 9.09% of patients in private places and in 19.35% of patients in public places. Though they initially presented with shockable rhythm in 57.14% of cases in public places, this group has the worst immediate outcome (11.43%), in contrast to the patients with CA in medical institutions (58.33%). Factors determining the survival of patients with CA were CPR attempted immediately after collapse, initial rhythm and eyewitnesses of CA. Conclusion. In order to improve survival of patients with out-of-hospital CA, both education of laymen and introduction of standard questioning protocol in the IEMS Call Centre are necessary. [Projekat Ministarstva nauke Republike Srbije, br. 175007]

Background/Aim. Polymorphisms of genes which encode transporter P-glycoprotein and most important enzymes for tacrolimus pharmacokinetics can have significant influence reflecting on blood concentrations of this drug. The aim of this study was to examine the distribution of polymorphisms of CYP3A5, CYP3A4 and ABCB1 genes in patients subjected to renal transplantation, for the first time in our transplantation center. Methods. The research was designed as a prospective cross-sectional study which included 211 patients subjected to renal transplantation in the Centre for Solid Organ Transplantation of the university tertiary health care hospital, Military Medical Academy, Belgrade, Serbia. Patients of both genders, 22?69-year-old, Caucasians, subjected to immunosuppressive regimen, including tacrolimus, were recruited for the study. CYP3A5 6986A>G (the *3 or *1, rs776746), CYP3A4 - 392A>G (the *1 or *1B, rs2740574) and ABCB1 3435C>T (rs1045642) genotypes were determined by TaqMan? SNP genotyping assays. Results. Most of our patients (94.8%) had functional CYP3A4 enzyme, while 87.7% of all the patients had diminished CYP3A5 enzymatic activity. On the other hand, about one third of them, 31.3%, had functional ABCB1 transporter. Conclusion. A total of 84.8% of our patients were found to express both the CYP3?5*3*3 genotype (associated with diminished CYP3?5 enzymatic activity) and CYP3?4*1*1/*1*1B (associated with functional CYP3?4 enzymatic activity), while out of all the patients with diminished CYP3A5 enzymatic activity, 68.7% had diminished activity of ABCB1 transporter. However, further studies are necessary in order to show the influence of these genetic polymorphisms on tacrolimus blood concentrations in patients after renal transplantation.

The aim of the study was to evaluate the bioequivalence of two itraconazole 100 mg capsule formulations.The single-center, open-label, randomized, three-period, three-sequence, reference-replicated, cross-over study included 38 healthy subjects under fed conditions. In each study period (separated by a 14-day washout), a single oral dose of the test (T) or reference (R) product was administered. Blood samples were collected at pre-dose and up to 72.0 h after administration. The calculated pharmacokinetic parameters, based on the plasma concentrations of itraconazole and hydroxy itraconazole, were AUCThe 90% CI for the test/reference geometric means ratio for the parent compound, itraconazole, was in the range from 85.29% to 116.07% for AUCThe use of the reference-scaling approach with 3-period design (TRR, RTR, and RRT) was an efficient way to demonstrate that two commercially available oral itraconazole formulations met the predetermined bioequivalence criteria.

Introduction: Rosemary essential oil can be used for treating dyspepsia, mild spasmodic disorders of thegastrointestinal tract, externally as analgetic in muscular and articular pain and minor peripheral circulatory disorders.It is important to explore its analgesic potential and its influence on the pharmacodynamic and pharmacokineticproperties of paracetamol. Methodology: Rosemary essential oil was applied to mice orally (doses: 10 and 20 mg/kgb.w.) for pharmacodynamic tests for seven days. Rats treated with rosemary essential oil for seven days orally (5 and10 mg/kg b.w.) were used for the examination of the influence of essential oil on the pharmacokinetic properties ofparacetamol (applied on the 7th day p.o. or i.v.). Pharmacokinetic parameters were analyzed in blood samples obtainedfrom rats' tail veins, with the HPLC method. Results: The essential oil of rosemary shows analgetic properties. Therosemary essential oil increases pharmacological effects of paracetamol and does not change paracetamolbioavailability. Conclusion: The herbal drugs could change the pharmacodynamic and the pharmacokinetic propertiesof classical drugs and they could also change the safety of classical drugs use in human population.

Background/Aim. Tacrolimus concentration-dose ratio as a potential therapeutic drug monitoring strategy was suggested to be used for the patients subjected to renal transplantation. The aim of this study was examining the relationship between tacrolimus concentration-dose ratio, suggested to be used as a therapeutic drug monitoring strategy and the polymorphisms of genes encoding the most important enzymes, such as CYP3A5 and CYP3A4, as well as the transporter P-glycoprotein, for its metabolism and elimination. Methods. The study was designed as a prospective case series study, in which the unit of monitoring was the outpatient examination of 54 patients subjected to renal transplantation. Genotyping was performed by 7500 Real- Time PCR System by assessing allelic discrimination based on TaqMan? methodology. Results. Patients (n = 13) who were treated with less than 2 mg of tacrolimus/day (0.024 ? 0.006 mg/kg/day) had the tacrolimus concentration-dose ratio larger than 150 ng/mL/mg/kg. In this group, 84.62% patients had CYP3?5 *3*3 allele. All of these patients had CYP3?4 *1*1/*1*1B allele. Regarding ABCB1 C3435T gene, 30.77% of patients had the TT gene variant, while 69.23% of our patients had CC and CT gene variants. Conclusion. Tacrolimus concentration-dose ratio greater than 150 ng/mL/mg/kg is cut-off value in patients subjected to renal transplantation which might point to patients who are poor CYP3A5 metabolizers and/or with dysfunctional P-glycoprotein.

Ciprofloxacin is often used in treatment of complicated urinary tract infections in areas with high rates of resistance to first line agents. The aim of this study was to evaluate efficacy of ciprofloxacin in standard dosing regimens in treatment of complicated urinary tract infections. Plasma concentration curves were simulated and minimum inhibitory concentration (MIC) and post-antibiotic effect were determined. Ciprofloxacin MIC ranged from 0.0156 for Gram-negative and to 0.125-0.5 µg/mL for Gram-positive bacteria. Both dosing regimens were suitable for eradication of Gram-negative bacteria, with slight supremacy of 750 mg/12 hours over 500 mg/12 hours dosing regimen. Even though all strains were fully susceptible to ciprofloxacin, pharmaco-kinetic/pharmacodynamic parameters did not meet target thresholds for pathogens with MIC over 0.1-0.2 µg/mL regardless of the administered dose. Ciprofloxacin remains an excellent choice for treatment of complicated urinary tract infections caused by Gram-negative bacteria, but in infection caused by Gram-positive strains, deeper analysis is necessary in order to achieve optimal results.

Background The present study investigated the transcellular and placental permeation of cefuroxime, an antibiotic used in cesarean sections, in pregnant women with diabetes and hypertension. Methods Fifty-three women scheduled for cesarean section were divided into three groups: healthy women (n = 18), women with arterial hypertension (n = 21), and women with gestational diabetes (n = 14). All women received 1.5 g, i.v., cefuroxime. Cefuroxime concentrations were measured in maternal venous plasma before, during, and after delivery, as well as in fetal umbilical cord vein and artery plasma during delivery. The effects of diabetes and hypertension on cefuroxime placental-permeation were assessed by the fetomaternal plasma concentration ratios. Pharmacokinetic non-compartmental model analyses were performed and results were compared using anova. Results Fetomaternal drug concentration ratios were lower in the diabetic group than in the hypertensive and control groups. There were no significant differences in umbilical arterial : venous plasma drug concentration ratios in the diabetic and hypertensive groups compared with the control group. Apparent volume of distribution and clearance were significantly lower in the diabetic group compared with the control and hypertensive groups. Conclusions Diabetes led to decreased placental transfer of cefuroxime, as well as volume of distribution and clearance, but did not affect other pharmacokinetic parameters. Hypertension had no significant effect on the permeation of cefuroxime or on its pharmacokinetics. Prophylactic concentrations of cefuroxime were reached in all groups, but the dosing time of cefuroxime should not be less than 30 min or greater than 2 h prior to delivery.

Introduction: Tacrolimus, potent immunosupressive drug, has large inter- and intraindividual pharmacokinetic variability. The aim: The aim of this current topic is to describe the importance of tacrolimus drug-drug interactions. Pharmacokinetic interactions between tacrolimus and other drugs: Concerning the fact that it is also a medicine with the narrow therapeutic range, its interactions with other drugs mediated by both P-glycoprotein and CYP3A enzymes are potentially very important. Conclusion: Interactions between tacrolimus and other drugs leading to overexposure to tacrolimus is connected with significant toxicity, while the subtherapeutic blood concentrations increase the probability of transplanted organ rejection.

Cardiovascular diseases are the leading cause of morbidity and mortality worldwide. Despite considerable advances in cardiovascular pharmacology, significant inter-individual variability in response to drugs affects both their efficacy and safety profile. Drug-gene associations have emerged as important factors determining a spectrum of response to therapy. Pharmacogenomic interactions in cardiovascular medicine are also involved in etiology of adverse effects that may be life-threatening, such as statininduced myopathy or a hemorrhage/thrombosis event during anticoagulant therapy. Introduction of genetic tests prior to the initiation of therapy and implementation of genetically-guided therapy represent a step forward to achieving a goal of individualized medicine in cardiology, already present in recommendations for warfarin and clopidogrel. However, further investigations addressing genomic predictors of variability in response to drugs are still needed and translating these findings into routine clinical practice remains a substantial challenge.

Therapeutic properties of cannabis have been known since ancient times, although the application has been limited mainly due to narcotic characteristics of this plant. Nowadays, the pharmacologically active substance in cannabis - cannabinoids, presents a very interesting group of compounds with potentially significant applications in medicine and pharmacy. Research studies have clearly shown that cannabinoids are highly efficient, primarily in the treatment of nausea and vomiting and the management of chronic pain. For patients who suffer from severe, chronic diseases, such as cancer and AIDS, cannabis has been shown to relieve several symptoms at the same time, in more efficient way than some registered medicines. Besides, there is a great potential of cannabinoids to be applied for the treatment of many other pathological conditions, such as multiple sclerosis, Alzheimer's disease, epilepsy, hype­rtension, glaucoma, although it is necessary to complete the last phases of clinical trials in order to register these compounds as drugs, i.e. in order to assure the safe therapy for these diseases. Although tetrahydrocannabinol (THC) proved to be very efficient in the treatment of numerous diseases, new drugs have been intensively developing that tend to possess improved selectivity, better pharmacokinetic properties, and favorable relationship between desired pharmacological effect and side effects. Legalization of cannabis use for medical purposes is a hot topic at the global level and in most countries there have been initiatives to amend the existing laws in order to make drugs based on natural ingredients of cannabis, as well as other related products, synthetically produced, available to patients, that would certainly, based on the results of investigations, contribute to a better quality of patients' lives.

A major advancement in therapy of type 1 diabetes mellitus (T1DM) is the discovery of new treatment which avoids and even replaces the absolute requirement for injected insulin. The need for multiple drug therapy of comorbidities associated with T1DM increases demand for developing novel therapeutic alternatives with new mechanisms of actions. Compared to other sulphonylurea drugs used in the treatment of type 2 diabetes mellitus, gliclazide exhibits a pleiotropic action outside pancreatic β cells, the so-called extrapancreatic effects, such as antiinflammatory and cellular protective effects, which might be beneficial in the treatment of T1DM. Results from in vivo experiments confirmed the positive effects of gliclazide in T1DM that are even more pronounced when combined with other hypoglycaemic agents such as probiotics and bile acids. Even though the exact mechanism of interaction at the molecular level is still unknown, there is a clear synergistic effect between gliclazide, bile acids and probiotics illustrated by the reduction of blood glucose levels and improvement of diabetic complications. Therefore, the manipulation of bile acid pool and intestinal microbiota composition in combination with old drug gliclazide could be a novel therapeutic approach for patients with T1DM.

Aim: The aim of this study is to investigate the influence of bile salts, sodium cholate, sodium 12-ketocholate and sodium dehydrocholate, as excipients in ranitidine, aminophylline and phenobarbital tablets on dissolution rate. Methods: Four groups of tablets (control without bile salts and three investigational groups containing different bile salts) were prepared for three different drug substances: ranitidine, aminophylline and phenobarbital. Dissolution rate was measured. Results: Dissolution rate is increased significantly in all investigational groups comparing to the control group in all three drug substances. Discussion: Presented results are very favourable and encouraging in case of dissolution enhancing and should be further investigated, especially in drug substances that are classified in class II and IV as per Biopharmaceutical Classification System (BCS) classification. Conclusion: Bile acid salts are very promising excipients, proven to act as surfactants and as lubricants. Running title: Bile salts as excipients in ranitidine, aminophylline and phenobarbital tablets.

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/m(2) 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.

In previous studies, we have shown that a gliclazide-cholic acid derivative (G-CA) mixture resulted in an enhanced ileal permeation of G (ex vivo). When administered orally to diabetic rats, it brought about a significant hypoglycaemic effect. In this study, we aim to create a novel microencapsulated-formulation of G-CA with uniform and coherent structure that can be further tested in our rat model of type 1 diabetes (T1D). We also aim to examine the effect of CA addition to G microcapsules in the morphology, structure and excipients' compatibility of the newly designed microcapsules.Microencapsulation was carried out using our Buchi-based microencapsulating system developed in our laboratory. Using sodium alginate (SA) polymer, both formulations were prepared: G-SA (control) and G-CA-SA (test) at a constant ratio (1:3:30), respectively. Complete characterizations of microcapsules were carried out.The new G-CA-SA formulation is further optimized by the addition of CA exhibiting pseudoplastic-thixotropic rheological characteristics. Bead size remains similar after CA addition, the new microcapsules show no chemical interactions between the excipients and this was supported further by the spectral studies suggesting bead stability.The new microencapsulated-formulation has good and uniform structural properties and may be suitable for oral delivery of antidiabetic-bile acid formulations.

Herb-drug interactions are an important safety concern and this study was conducted regarding the interaction between the natural top-selling antidepressant remedy Hypericum perforatum (Hypericaceae) and conventional drugs. This study examined the influence of acute pretreatment with different extracts of Hypericum perforatum from Serbia on pentobarbital-induced sleeping time, impairment of motor coordination caused by diazepam and paracetamol pharmacokinetics in mice. Ethanolic extract, aqueous extract, infusion, tablet and capsule of Hypericum perforatum were used in this experiment. The profile of Hypericum perforatum extracts as well as paracetamol plasma concentration was determined using RP-HPLC analysis. By quantitative HPLC analysis of active principles, it has been proven that Hypericum perforatum ethanolic extract has the largest content of naphtodianthrones: hypericin (57.77 µg/mL) and pseudohypericin (155.38 µg/mL). Pretreatment with ethanolic extract of Hypericum perforatum potentiated the hypnotic effect of pentobarbital and impairment of motor coordination caused by diazepam to the greatest extent and also increased paracetamol plasma concentration in comparison to the control group. These results were in correlation with naphtodianthrone concentrations. The obtained results have shown a considerable influence of Hypericum perforatum on pentobarbital and diazepam pharmacodynamics and paracetamol pharmacokinetics.

nema

Tacrolimus is an immunosuppressant used for the prevention of kidney allograft rejection. The effects of comedication on tacrolimus trough concentrations (TTC) in kidney transplant recipients, subjected to basic immunosuppressant regime consisting of tacrolimus, corticosteroids and mycophenolate mofetil were investigated. This retrospective case series study involved 208 of these patients, with the outpatient examination recorded in the database of patients, at the unit of monitoring, with a total of 5,011 such examinations. Binary logistic regression analysis has shown that calcium channel blockers, diuretics and proton pump inhibitors (PPIs) significantly affected TTC (p < 0.001). PPIs significantly increased the number of examinations in which the TTC were in the recommended therapeutic range (from 5 to 15 ng/ml), as well as over the therapeutic range (p < 0.0001). When calcium channel blockers were added to PPIs, even more pronounced effect was obtained in comparison to triple-drug therapy only (p < 0.0001). In case a diuretic was given with a PPI, a significantly increased number of examinations with subtherapeutic TTC was observed when compared with PPI only (p = 0.0203). The combination of calcium channel blockers, diuretics and PPIs resulted in the number of examinations with TTC in the recommended therapeutic range not being different from the number of examinations with TTC in the triple-drug therapy only (p = 0.3829). β-adrenergic antagonists can be administered without fear of affecting the tacrolimus optimal therapeutic concentrations. This was confirmed with all combinations of the examined drugs used in patients subjected to kidney transplantation concomitantly with β blockers.

Various pesticides are applied in agriculture for crop protection. They could have toxic effects on nervous system, liver, kidneys and the other organs. The aim of the study was to investigate effects of occupational exposure to pesticides and consumption of alcoholic beverages on liver functions in agricultural workers. The study included sample of 117 male agricultural workers involved as tractor drivers in pesticide application at the workplace and the control group of 60 tractor drivers who do not applied pesticides. We collected data concerning age, use of alcohol and duration of exposure to pesticides. Parameters of liver functions in serum were determined in both groups of workers. In agricultural workers exposed to pesticides, activities of enzymes gamma-glutamyl transpeptidase, alanine and aspartate aminotransferases were higher comparing to the control group, but these differences were not statistically significant. Consumption of alcohol statistically significantly increased activity of gamma-glutamyl transpeptidase in both groups of workers. The most important measures concerning health protection of agricultural workers exposed to pesticides are continuous implementation of the safety measures at work, health promotion at workplace and regular health surveillance in occupational health services for the purpose of early detection of worker's health disorders.

Preclinical Research The development of new genomic technologies has led to an exponential increase in the number of biomarkers for drug safety and efficacy. Pharmacogenomics has the potential to impact clinically relevant outcomes in drug dosing, efficacy, toxicity, and prediction of adverse drug reactions (ADRs). Genotype-based prescribing is anticipated to improve the overall efficacy rates and minimize ADRs, making personalized medicine a reality. Genome-wide association studies have been increasingly applied to pharmacogenetics. Severe ADRs are a major issue for drug therapy because they can cause serious disorders and can be life threatening. For severe ADRs, significant associations have been reported for drug-induced liver injury, statin-induced myopathy, increased risk of hemorrhagic complications of anticoagulant use, drug-induced torsade de pointes, drug-induced long QT, and severe cutaneous ADRs. This review summarizes the current position concerning the clinical and pharmacoepidemiological relevance of pharmacogenetic biomarkers in ADR prediction and prevention, with an emphasis on genetic risk factors and biomarkers for three specific severe ADRs.

In the European Union (EU), rare diseases are defined as life-threatening or chronically debilitating diseases with prevalence lower than five in 10,000 inhabitants. Although individually rare, together, rare diseases affect a significant part of the population (27-36 million people in the EU). Therefore, patient access to orphan medicines is receiving increasing political attention in the EU. In order to assess the differences in availability of reimbursed orphan medicines among Serbia, Bulgaria and Sweden, National Reimbursement Lists were reviewed and identified orphan medicines were crossed with the List of orphan drugs in Europe, published in July 2011, available from Orphanet. The analysis of regulatory traits was based mainly on a review of the official documents setting out legislation regarding rare diseases and orphan medicines in the studied countries. Only 6.5 % (4 out of 61) of the authorised orphan medicines in Europe with prior orphan designation and 25.0 % (17 out of 68) without prior orphan designation were available and reimbursed in Serbia. In the Bulgarian Positive Drug List 44.3 % (27 out of 61) of the drugs with prior orphan designation and 50.0 % (34 out of 68) without prior orphan designation were identified. The share of reimbursed orphan medicines was the highest in Sweden among the observed countries - 52.5 % (32 out of 61) of the medicines with orphan designation and 60.3 % (41 out of 61) without prior orphan designation. According to the first level of the ATC Classification System, most of the reimbursed orphan medicines in the three studied countries belonged to the group L: "Antineoplastic and immunomodulating agents", while the most common indications for authorised and reimbursed orphan medicines were "Neoplasms" (C00-D48), with 19 available orphan drugs in Serbia, 26 in Sweden and 31 in Bulgaria. Inequities in the access to orphan medicines among Serbia, Bulgaria and Sweden may be explained by the differences in the approaches for registration, pricing and reimbursement of orphan medicines. The low share of reimbursed orphan drugs in Serbia may be due to incomplete compliance with EU legislation and existence of domestic procedure for authorisation as well. The EU legislation and policy on treatment of rare diseases obviously facilitate the penetration of orphan drugs on the EU market, but apparently there is also considerable budget impact on the availability of reimbursed orphan medicines.

Background Herbal supplements are widely used in the treatment of various liver disases, but some of them may also induce liver injuries. Regarding the infuence of thyme and its constituents on the liver, conflicting results have been reported in the literature. The objective of this study was to examine the influence of two commonly used pharmaceutical formulations containing thyme (Thymus vulgaris L.), tincture and syrup, on carbon tetrachloride-induced acute liver injury in rats. Methods Chemical composition of investigated formulations of thyme was determined by gas chromatography and mass spectrometry. Activities of enzyme markers of hepatocellular damage in serum and antioxidant enzymes in the liver homogenates were measured using the kinetic spectrophotometric methods. Liver morphology was characterized by light microscopy using routine hematoxylin and eosin staining. Results Thymol was found to be predominant active constituent in both tincture and syrup. Investigated thyme preparations exerted antioxidant effects in liver by preventing carbon tetrachloride-induced increase of lipid peroxidation. Furthermore, co-treatment with thyme preparations reversed the activities of oxidative stress-related enzymes xanthine oxidase, catalase, peroxidase, glutathione peroxidase and glutathione reductase, towards normal values in the liver. Hepatotoxicity induced by carbon tetrachloride was reflected by a marked elevation of AST and ALT activities, and histopathologic alterations. Co-administration of thyme tincture resulted in unexpected exacerbation of AST and ALT values in serum, while thyme syrup managed to reduce activites of aminotransferases, in comparison to carbon tetrachloride-treated animals. Conclusions Despite demonstrated antioxidant activity, mediated through both direct free radical scavenging and activation of antioxidant defense mechanisms, thyme preparations could not ameliorate liver injury in rats. Molecular mechanisms of diverse effects of thyme preparations on chemical-induced hepatotoxicity should be more in-depth investigated.