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Technological advancement and industrialization have significantly increased human exposure to xenobiotics, a diverse group of foreign chemical substances with potential toxic effects. Xenobiotics include pharmaceuticals, pesticides, personal care products, industrial chemicals, and environmental pollutants. The liver, as the primary organ responsible for biotransformation, plays a central role in the detoxification and activation of these compounds. However, metabolic processes may generate reactive intermediates that contribute to hepatocellular injury. This review provides a comprehensive overview of xenobiotic classification, mechanisms of hepatic biotransformation, and the molecular pathways underlying xenobiotic-induced hepatotoxicity. Special emphasis is placed on oxidative stress, reactive metabolite formation, and immune-mediated mechanisms. Clinical manifestations, diagnostic approaches, and current management strategies are also discussed. Understanding these processes is essential for early detection, prevention, and improved therapeutic outcomes in patients with xenobiotic-induced liver injury..

Drugs for the treatment of obesity show significant effectiveness, but the adverse effects (ADRs) of these drugs are numerous and varied, and some of them are highly cost-generating. Our research aimed to define the health care utilization pattern in treating ADRs of antiobesity therapy, to compare the costs of treating these ADRs among selected European countries, and to identify the key cost drivers. A comparative analysis of the costs of treating the ADRs of antiobesity drugs in 10 European countries (seven EU members and three from the Western Balkans) was conducted, and the impact of parameters of global health expenditures on them was assessed. There are considerable differences in costs of treating adverse antiobesity drug reactions among European countries: costs of treating gastroesophageal reflux disease varied almost 20 times between North Macedonia (12.6 EUR) and Estonia (202.9 EUR). The Gross Domestic Product per capita was an important cost driver in treating the majority of the ADRs studied (p < .001), except for retinopathy, anaphylaxis, and respiratory disorders. The Domestic Private Health Expenditure increased the costs of treating depression (p = .012), upper respiratory tract infection (p = .008), melanocytic naevus (p = .027), and drug-induced hepatitis (p = .023). Investment in pharmaceuticals, medical goods, and preventive care tended to reduce the costs of treating several ADRs, which are seemingly unrelated to the body site or mechanism. Healthcare utilization and costs of treating ADRs to antiobesity drugs vary significantly among European countries. These differences should be considered when creating inputs for cost-effectiveness and budget impact models to decrease their uncertainty.

Objectives: Olanzapine is an atypical antipsychotic that is approved across Europe, the USA, and in many other countries for oral treatment of schizophrenia and acute manic episodes in patients with bipolar disorder as well as for maintenance therapy to prevent recurrence in responders. The objective of the present study was to compare the pharmacokinetics of two 10 mg tablet formulations of Olanzapine following a single oral dose in healthy volunteers under fasting conditions, as per the European Medicine Agency (EMA) guidelines to grant marketing authorization.Methods: This study was a randomized, open-label, two-treatment, two-period, two-sequences, single-dose, cross-over design with a washout period of 14 days. Both the test and the reference products were administered as 10 mg tablets with 240 mL of water after an overnight fast in each study period. A total of twenty blood samples were collected before dosing and within 144 hours after drug administration. Adverse events were monitored, recorded, and evaluated by investigators throughout the study.Results: Of the 24 healthy adult male subjects enrolled, all of them completed both study periods. The geometric mean ratio 90% confidence intervals (CI) for fasting Cmax, AUC0-t, and AUC0-infinity were 94.83-113.71%, 95.04-105.69% and 95.94-107.00%, respectively. The 90% CI for the ratios of the three primary pharmacokinetic parameters (using log-transformed data) were within the range of 80-125%, meeting the regulatory criteria for bioequivalence.Conclusions: The generic Olanzapine was bioequivalent to the reference formulation. It was well tolerated and provides an acceptable alternative to the reference drug.

Nanotechnology presents a modern field of science that in the last twenty-five years plays a dominant role in the biomedicine. Different analytical methods are used for evaluation of the physico-chemical properties of nanoparticles including chromatography, electrophoresis, X-ray scattering, spectroscopy, mass spectrometry, zeta potential measurement and microscopy on which this article will focus.Herein, we present novel application of the long-established TEM technique that is focused on characterization and evaluation of various nanoparticles in development of drug delivery systems.Transmission electron microscopy images were taken of samples from native nanoparticles, nanoparticles labeled using stannous chloride labeling procedure, inorganic silica nanoparticles loaded with budesonide and native micelles and micelles carrier of anticancer drug camptothecin. In the case of radiolabeled nanoparticles, beside for nanoparticle characterization, TEM technique was used to confirm the stability of the nanoparticles after radiolabeling. Furthermore, the porous structure of hybrid silica particles loaded with budesonide was examined under TEM.Transmission electron microscopy technique offers exceptional benefits for nanoparticle characterization. Additionally, the necessity of ultrastructural analysis demonstrates the potential of TEM in the field of nanomedicine. Hence, the long-established and well-known TEM has been only partially exploited and offer researchers very detailed images of specimens at microscopic and nano scale.

The active metabolite of azathioprine, 6-thioguanine nucleotide (6-TGN) is the main component responsible for the immunosuppressive effect in treatment of inflammatory bowel disease (IBD).The aim of this study was to assess the correlation between the concentration of 6-thioguanine nucleotide and disease activity, azathioprine-related adverse effects and time duration of treatment in patients with inflammatory bowel disease.Thirty-four patients were included in this study. Type of disease, gender, time duration of therapy and adverse effects were recorded. Metabolite concentration was determined by high performance liquid chromatography.Twenty-one percent of patients have experienced an adverse effect, with leucocytopenia most commonly occurring (42.9%). More adverse effects were registered when patients were treated with azathioprine in a period of less than 3 months in comparison to the group of patients that have been under therapy between 3-12 months and more than 12 months (p˂0.05). Most of the patients that presented any adverse effect had high 6-TGN concentration (>450 pmol/8x108 Er). The mean value of 6-TGN metabolite concentration in IBD patients treated with azathioprine was 437.46 pmol/8x108 Er ± 198.82 pmol/8x108. The time duration of azathioprine treatment did not have any significant impact on the achieved 6-TGN concentration (p>0.05).Twenty patients (58.9%) had achieved remission after therapy initiation with azathioprine.More alertness is recommended to clinicians towards patients in the first 3 months of the therapy. Our study demonstrated that higher 6-TGN concentration is associated with azathioprine toxicity.

Herein, we present a simple and rapid high performance liquid chromatographic (HPLC) method with UV-detection for the direct determination of diazepam in whole blood and serum that can be used for monitoring diazepam levels in clinical samples analysis. The isolation of diazepam and the internal standard bromazepam from serum and whole blood samples was performed using solid phase extraction method with RP select B cartridges. The analytes were separated employing a reversed phase C8 column with a mobile phase composed of 0.1 % (V/V) triethylamine in water (pH 3.5) and acetonitrile (63:37, V/V). UV detection was carried out at 240 nm. Linearity was achieved in the range from 10.0-1000.0 ng/ml for serum and whole blood. The method was applied to spiked and real biological samples after an oral administration of 10 mg diazepam. In conclusion, the proposed method is simple, rapid and provides efficient clean-up of the complex biological matrix and high recovery of diazepam.

Salt sensitive hypertension is known to be a contributing factor for the progression of kidney disease. This study was undertaken to investigate the role of excessive dietary salt on renal function and to evaluate the effect of valsartan and amlodipin given as a combination therapy on blood pressure and parameters specific to the renal function in salt loaded SHR rats. 48 male SHR rats at age of 20 weeks and body weight ranging between 270-350 g were used. SHR rats were divided into 3 groups: control group of rats -SHRC (n = 16) given tab water ad libitum and two salt treated groups in which tab water was replaced with a solution of NaCl (1%) from age of 8 weeks given ad libitum: SHRVAL+AMLO group (n = 16) where investigated drugs were administered at a dose of 10 mg/kg/ b.w. (valsartan) and 5 mg/kg/ b.w. (amlodipin) by gavage and SHR NaCl group (n = 16) that received saline in the same volume and the same time intervals as the SHRVAL+AMLO group. For a period of 12 weeks we have investigated the effect of the VAL+AMLO drug combination on systolic blood pressure (SBP), body weight and renal function tests. Salt loading with 1% solution in the SHR NaCl group has lead to significant increase of blood pressure, proteinuria and decrease in creatinine clearance. Combined treatment with АТ1-receptor blocker and calcium antagonist has managed to control blood pressure and ameliorated renal damage. Познато е дека хипертензијата зависна од сол придонесува кон прогресија на бубрежните заболувања. Ова испитување беше преземено со цел да се одреди влијанието на екцесивното внесување сол врз бубрежната функција, како и да се одреди ефектот на валсартан и амлодипин дадени во комбинација врз крвниот притисок и параметрите специфични за бубрежната функ- ција кај спонтано хипертензивни стаорци опто- варени со сол. Во испитувањето беа употребени вкупно 48 стаорци од машки пол на возраст од 20 недели и телесна тежина меѓу 270-350 грама. Стаорците беа поделени во три групи: контролна група SHRC (n = 16), кај која во текот на целото испитување беше давана вода ad libitum, и две групи стаорци кај кои на возраст од 8 недели водата беше заменета со раствор на NaCl (1%) ad libitum: група SHRVAL+AMLO (n = 16) кај која лековите беa аплицирани во доза од 10 mg/kg/ т.т. (valsartan) и 5 mg/kg/ т.т. (amlodipin) со интрагастрична сонда и SHRNaCl група (n = 16), која примаше физиолошки раствор во ист волумен и во ист временски интервал како групата SHRVAL+AMLO. Во период од 12 не- дели беше одредуван ефектот на комбинацијата на валсартан со амлодипин врз крвниот при- тисок, телесната тежина и параметри специ- фични за бубрежната функција. Оптоварувањето со сол како 1% раствор во групата SHRNaCl до- веде до сигнификантно зголемување на крвниот притисок, појава на протеинурија и намалување на клиренсот на креатинин. Комбинираниот третман со АТ1 рецепторен блокатор и калциум антагонист соодветно го контролираше крвниот притисок и ја подобри бубрежната функција.