Elevated Liver Enzyme Activities Research Articles

A clinical study and laboratory evaluation of the cardiac and hepatic toxic effects of paraphenylenediamine

Introduction Paraphenylenediamine is the main component in many commercial hair dyes, and can produce severe local and systemic toxicity reactions after acute ingestion or dermal absorption. The aim of this study was to assess the factors contributing to morbidity and mortality in cases of acute paraphenylenediamine poisoning, with a focus on evaluating the resultant hepatic and cardiac toxicity. Methods This observational study was conducted on patients with acute paraphenylenediamine poisoning presenting to Sohag University Hospitals, and included a retrospective part from February 2021 to January 2022 and a prospective part from February 2022 to July 2022. Clinical data were extracted and receiver operating characteristic curves created to identify prognostic markers. Results Among 50 eligible patients 39 (78 percent) recovered, and 11 (22 percent) died or had permanent complications. Angioedema and anuria were the most frequent features in complicated cases. By receiver operating characteristic analysis, either an increase in aspartate aminotransferase activity greater than 644 IU/L or alanine aminotransferase activity greater than 798 IU/L, a time delay to presentation of greater than 4.5 hours, and a pH of less than 7.32 were associated with a significant increase in morbidity and mortality. While cardiac enzyme activities, and concentrations of blood urea nitrogen and creatinine increased in most cases, they were not associated with mortality. Discussion Management of patients with paraphenylenediamine poisoning is mainly supportive, as there is no specific antidote. Respiratory failure and kidney failure are the most life threatening complications. Hepatoxicity and cardiotoxicity also occur. The ability to predict the events can help guide patient disposition and care. Conclusion Elevated liver enzyme activities, increased time delay to admission, decreased pH, and the presence of angioedema and anuria can be used as predictors of morbidity and mortality in patients with acute paraphenylenediamine poisoning.

Pancreatitis associated with Mycoplasma felis infection in a cat

Case summary A 7-year-old domestic shorthair cat was presented for periuria, apathy, fever, inappetence, diarrhoea and vomiting. A complete blood count and biochemistry analysis revealed severe thrombocytopenia, severe azotaemia, moderate panhypoproteinemia, mildly elevated DGGR lipase activity and mildly elevated liver enzyme activity. Abdominal ultrasound showed a hypoechoic pancreas with surrounding hyperechoic fat demonstrating dirty shadowing and ascites (protein-poor transudate). The cat was treated medically for pancreatitis with fluid therapy, antiemetics and pain medication. During the hospitalisation period, the cat developed severe anaemia and received multiple whole blood transfusions yet showed no signs of clinical improvement. A repeat ultrasound examination performed after 8 days showed progressive pancreatic lesions and ongoing ascites. Analysis of the free abdominal fluid revealed neutrophilic inflammation despite low protein and cell concentration, with the presence of numerous very small, coccoid, basophilic inclusions within neutrophils, raising the concern for a septic peritonitis due to Mycoplasma species. Quantitative PCR (qPCR) confirmed the presence of Mycoplasma felis. After 10 days of hospitalisation, the cat developed refractory septic shock and was euthanased. Necropsy revealed severe necrotising pancreatitis with systemic changes consistent with sepsis and microthrombi. qPCR testing for M felis in pancreatic tissue also yielded a positive result. Relevance and novel information Although pancreatitis is a common disease in cats, this case report presents the first documented occurrence of M felis as the suspected primary pathogen causing pancreatitis in a cat.

Characterization and ameliorative effects of Chenopodium murale hydroethanolic extract against diethylnitrosamine-induced hepato-renal damage and malfunction

Background/aim Chenopodium genus has broad applications in folk medicine. Chenopodium murale (C. murale) exhibited several pharmacological benefits, including hypotensive, anti-inflammatory, analgesic, antifungal, antibacterial, phytotoxic, hepatoprotective and renoprotective effects. The principal objective unveils the preventive effects of C. murale against hepato-renal damage and malfunction induced by diethylnitrosamine (DEN). Materials and methods Forty rats were included in the present study divided into 4 groups, group 1, animals were given saline solution every day for 14 weeks. Group 2, animals were injected double times per week by intraperitoneal route with DEN at 150 mg/kg body weight for 2 weeks. Animals in group 3 were injected with DEN like in group 2 and subjected orally to C. murale hydroethanolic extract (500 mg/kg body weight) daily for 14 weeks. Animals in group 4 received the same dose of the hydroethanolic extract of C. murale for a similar period. Results DEN has injurious effects, associated with elevated liver enzyme activities (AST, ALT and ALP), urea and creatinine in serum. Also, lipid peroxidation and nitric oxide were elevated markedly. DEN lowered the hepatic and renal activities of endogenous antioxidants (CAT and SOD), reduced glutathione (GSH) level. Conversely, treatment with C. murale restored liver function biomarker activities, urea and creatinine levels as well as mitigated the oxidative damage induced by DEN. C. murale reflecting its ameliorative potential which diminished obviously the DEN-induced elevated hepato-renal levels of IL-1β and TNF-α (immuno- inflammatory indicators), also down regulated Bcl-2, NF-κB, and Nrf-2 (inflammatory mediators). Conclusion These findings proved that C. murale might protect and ameliorate DEN-induced hepato-renal damage through activation of antioxidant and anti-inflammatory systems.

Candida albicans cholecystitis in a dog with diabetes mellitus

AbstractA 10‐year‐old, 8.9‐kg, spayed, female Jack Russell Terrier, with previously well‐controlled diabetes mellitus, presented with hyporexia of 2‐day duration. Cranial abdominal pain and weight loss were detected on clinical examination. Blood tests, urinalysis, urine protein:creatinine ratio, blood pressure, abdominal ultrasound and liver aspirate cytology revealed hyperglycaemia, elevated serum liver enzyme activities, glucosuria, proteinuria, hypertension, rounded liver edges, irregular hyperechoic gall bladder wall thickening, irregular hyperechoic gall bladder content and vacuolar hepatopathy. Bile cytological examination demonstrated fungal organisms, which were identified as Candida albicans on bile fungal culture. No bacteria were detected on bile cytological examination or bile bacterial aerobic and anaerobic culture. The dog was diagnosed with Candida albicans cholecystitis and recovered after a 12‐week course of oral ketoconazole. This case report highlights the value of performing bile cytology in suspect canine cholecystitis cases and is the first to describe Candida albicans fungal cholecystitis without bacterial coinfection in dogs.

Association between Fasting and Postprandial Levels of Liver Enzymes with Metabolic Syndrome and Suspected Prediabetes in Prepubertal Children.

Elevated liver enzyme activity may be associated with metabolic syndrome (MetS); however, it is not included in the MetS definition for children. Postprandial changes in the levels of biochemistry tests are related to manifestations of metabolic abnormalities. We assessed the association between fasting and postprandial liver enzymes levels with MetS and elevated hemoglobin A1c (HbA1c) in children aged 9-11. The study included 51 girls and 48 boys, all presumably healthy. In all participants' anthropometric indices, fasting glucose, insulin, lipid profile and HbA1c were measured. Enzymes, including alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT), were assayed in fasting and postprandial states. Individuals were divided into subgroups: with (MetS(+): n = 26); without MetS (MetS(-): n = 73); with HbA1c levels ≤ 5.3% (n = 39); and ≥5.7% (n = 11). Elevated fasting GGT levels were found in 23% of MetS(+) children and rarely in MetS(-) children; increased postprandial GGT was noted in 35% of MetS(+) individuals. Postprandial GGT changes tend to predict MetS (OR = 1.16; p = 0.092). Increased fasting ALT was found rarely in MetS(+) children, but did not occur in MetS(-) children. HbA1c ≥ 5.7% occurred rarely and neither fasting ALT nor GGT were related to elevated HbA1c. However, postprandial change of ALT was a good positive predictor of increased HbA1c (OR = 1.33; p = 0.021). Postprandial GGT performs better as an indicator of metabolic syndrome occurrence, and instead postprandial ALT may predict prediabetes in prepubertal children.

Effectiveness and safety of statins on outcomes in patients with HIV infection: a systematic review and meta-analysis

Statins are hypolipidaemic in human immunodeficiency virus (HIV) positive individuals. However, their effect on all-cause mortality and rate of discontinuation is unclear. We conducted a systematic review to evaluate the impact of statins on all-cause mortality, discontinuation rates, and risk of adverse effects among HIV patients on highly active antiretroviral therapy (HAART). We searched four electronic databases from inception until October 2021 for trials and cohort studies evaluating the effects of statin treatment versus placebo in HIV patients. Forty-seven studies involving 91,594 patients were included. Statins were associated with significantly lower risk of discontinuation (RR, 0.701; 95% CI 0.508–0.967; p = 0.031). The risk of all-cause mortality (RR, 0.994; 95% CI 0.561–1.588; p = 0.827), any adverse effects (RR, 0.780; 95% CI 0.564–1.077; p = 0.131) and, diabetes mellitus (RR, 0.272; 95% CI 0.031–2.393; p = 0.241) with statin treatment were lower but not statistically significant compared to placebo/control. Statin treatment was associated with a trend of higher but statistically insignificant risk of myalgia (RR, 1.341; 95% CI 0.770–2.333; p = 0.299), elevated creatine kinase (RR, 1.101; 95% CI 0.457–2.651; p = 0.830) and liver enzyme activities (RR, 1.709; 95% CI 0.605–4.831; p = 0.312). Clinicians should consider the nocebo effect in the effective management of PLWH on statins, who present with common adverse effects such as myalgia and, elevated levels of creatine kinase and liver enzymes.

The Microbiological Quality of Concentrates for Horses-A Retrospective Study on Influencing Factors and Associations with Clinical Symptoms Reported by Owners or Referring Vets.

Simple SummaryPoor feed hygiene is also referred to as spoilage and can be measured by means of determining growth of microorganisms (bacteria, mold and yeast). Evidence has been provided of mold spores triggering equine asthma, a chronic, non-infectious respiratory disease. Furthermore, a high yeast load is suspected to trigger gastrointestinal disorders (colic) in horses. One aim of the present study was to clarify the possible connection between certain equine diseases and poor feed hygiene. For this purpose, archived reports of hygiene examinations of concentrates for horses were processed statistically. Reports contained information on disease symptoms as reported by horse owners or equine practitioners, as well as results of sensory and microbiological analyses. Further assistance to horse owners and equine practitioners should be provided in evaluating health hazards emanating from poor feed hygiene. Another objective was to assess the possibility of detecting hygiene deficiencies by means of simple examination methods such as determination of dry matter content and sensory analysis in order to estimate the validity of these field methods. It was shown that a connection can be made between mold content of oats and coughing in horses, whereas no connection could be found between poor feed hygiene and equine colic or elevated liver enzyme activities. No significant predictability of poor feed hygiene by means of sensory analysis could be established, whereas a significant association between low dry matter content and mold contamination in grains was shown.Evidence has already been provided that feed-borne mold spores and endotoxins can trigger chronic, non-infectious respiratory disease if inhaled. Furthermore, deficiencies in feed microbiology are suspected to trigger gastrointestinal and liver disorders in horses, but the connection needs further clarification. Most of the previous studies regarding horse feed hygiene focused on forage, whereas research regarding hygienic quality of concentrates is scarce. In the present study, results of reports on hygienic quality of compound feed and cereals for horses were evaluated secondarily. Results included sensory findings, and counts of aerobic bacteria, molds and yeasts determined by cultivation and lipopolysaccharide (LPS) contents. It was found that microbial counts of compound feed exceeded VDLUFA orientation values significantly more frequently than cereals (38.4 vs. 22.6%). However, average counts of bacteria, molds and yeasts were higher in cereals than in compound feeds (p < 0.0001, respectively). Mold counts in grains were significantly higher if dry matter contents were below 86% (p = 0.0201). No relation could be established between the anamnestically reported gastrointestinal disorders or elevated liver enzyme activities and microbiological deviations. Mold counts of concentrates which were suspected to cause coughing in horses were significantly higher than mold counts of control samples (3.29 vs. 2.40 log10 cfu g−1, p = 0.0313). These results indicate that hygienic status of concentrates is relevant for horse health in the respiratory tract.

Liver and vitamin B12 parameters in patients with anorexia nervosa before and after short-term weight restoration

Hepatic involvement in anorexia nervosa (AN) has been previously reported, but a link to elevated vitamin B12 concentrations, which can be a sign for liver damage, has not been thoroughly examined. We measured liver enzymes (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase) and vitamin B12 parameters (total B12, holotranscobalamin, methylmalonic acid) in the plasma of young female patients with acute AN (n=77) and after short-term weight restoration (n=58, median body mass increase=25%), in comparison to healthy control participants (n=63). For a comprehensive assessment of vitamin B12 status, the combined marker cB12 was calculated. In acute AN, activities of alanine aminotransferase and gamma-glutamyltransferase as well as holotranscobalamin concentrations were elevated, and alanine aminotransferase activities positively correlated with total B12, holotranscobalamin and cB12 in patients with elevated liver enzyme activities. After weight restoration, alanine aminotransferase activities and holotranscobalamin concentrations were elevated, and cB12 increased above the level of the healthy control group. The present study provides further evidence for a hepatic involvement in acute AN in concert with vitamin B12 parameters and points to refeeding-associated alterations of liver and vitamin B12 parameters. Future studies should include non-invasive methods to characterize hepatic involvement and evaluate vitamin B12 status as a potential marker of liver damage/irritation.

Liver Involvement in Acute Respiratory Infections in Children and Adolescents - Results of a Non-interventional Study.

BackgroundIn children and adults with acute respiratory tract infections (ARTI), elevations of serum liver enzyme activities are frequently observed in clinical practice. However, epidemiological data particularly in the pediatric population are very limited. The aim of this study was to assess the incidence of hepatic involvement, to identify the viruses and to analyze risk factors in children and adolescents with ARTI in a real-world setting.MethodsWe report on a prospective, multicenter, non-interventional study with 1,010 consecutive patients aged 1–17 years with ARTI who consulted a physician within 5 days after onset of symptoms. Laboratory blood tests and PCR virus detection in nasopharyngeal lavage were performed at first presentation and after 3–7 days. Patients with elevated activities of serum liver enzymes (ASAT, ALAT, and γ-GT) were determined in local laboratories and values were normalized by dividing by the individual upper limit of the normal range (ULN). The resulting index (<1 means below ULN, >1 means above ULN) allowed to compare results from laboratories with different reference ranges.ResultsLaboratory test results of 987 patients were available at first visit. 11.1% (95% CI: 9.2–13.3%) exhibited an elevation of ASAT, ALAT, and/or γ-GT activities. Virus DNA or RNA was identified in nasopharyngeal lavages of 63% of the patients. 12.2% of patients with positive PCR and 9.7% of those with negative PCR (p = 0.25) had elevated serum liver enzyme activities. The highest rates were observed in patients with a positive result for influenza B virus (24.4%) followed by human metapneumovirus (14.6%), and human coronavirus (others than SARS-CoV-2) (13.6%). The rate of children and adolescents with ARTI and elevation of serum liver enzyme activities correlated with the virus species and with overweight of the patients but did not differ in patients with or without previous medication intake.ConclusionElevated enzyme activities are present in about 10% of children and adolescents with ARTI. In our cohort, these elevations were mild to moderate; probably resulting from an inflammation process with hepatic involvement.

The Prevalence, Magnitude, and Reversibility of Elevated Liver Enzyme Activities in Hyperthyroid Cats Presenting for Iodine-131 Treatment.

ObjectivesThe primary objective of this study was to report the prevalence and magnitude of elevated liver enzyme activity in feline hyperthyroidism using a large cohort of cats presenting for iodine-131 treatment. The secondary objective was to determine if elevated liver enzyme activity was a reversible process following successful iodine-131 treatment.MethodsCases that presented for a single iodine-131 treatment were retrospectively reviewed. Short-term and long-term follow-up clinicopathologic data was then reviewed for the secondary objective.ResultsTwo hundred seventeen hyperthyroid cats met the inclusion criteria for the primary objective. In total, 123/217 (56.7%) of the cats had at least one liver enzyme elevation on their chemistry panel, with alanine transaminase activity being the most common. All cats who were successfully treated with iodine-131 had liver enzyme activity within the reference range at short-term follow-up and long-term follow-up points.Conclusion and RelevanceOur study demonstrates that elevated liver values are common in cats presenting for iodine-131 treatment. Additionally, our study demonstrates that even when liver values are markedly elevated prior to treatment, the liver enzyme activity will return to normal after successful resolution of hyperthyroidism using iodine-131 treatment. Investigation into hepatobiliary disease and liver function tests for cats with a diagnosis of hyperthyroidism may be unnecessary as the liver values will likely return to normal with successful iodine-131 treatment.

T-cell lymphoma-associated hemophagocytic syndrome in an American Pit Bull Terrier.

A 3-y-old, intact female, American Pit Bull Terrier was presented because of acute onset of anorexia and a large subcutaneous submandibular mass that had been present for 3 wk. The submandibular mass, 2 engorged black-legged ticks on the dorsum of the neck, pyrexia, and icterus were seen on physical examination. Abnormal laboratory test results included a positive Anaplasma antibody test, severe thrombocytopenia, mild nonregenerative anemia, hyperbilirubinemia, and elevated liver enzyme activities. Cytology of the mass was interpreted as marked septic purulent inflammation with acute hemorrhage. Treatment with doxycycline for anaplasmosis was unsuccessful, and the patient died at an emergency follow-up visit 2 d after the initial presentation. Autopsy and histopathology revealed widespread metastasis of a presumptive histiocytic neoplasm with associated hemophagocytosis seen in lymph nodes (LNs), liver, and spleen. Immunohistochemistry yielded a definitive diagnosis of a CD3+/CD18+ T-cell lymphoma. In this case of canine lymphoma-associated hemophagocytic syndrome, hemophagocytes were observed as >2% of neoplastic cells in the liver, spleen, and LN histologically, a scarce or unreported finding, to our knowledge. The prognosis was grave, with a short survival time after the onset of clinical signs.

Therapeutic potential of Ni(II) Schiff base complex on CCl4 toxicity

Carbon tetrachloride (CCl4) is a known ecological hazardous xenobiotic that could motivate hepatotoxicity. We aimed to examine, for the first time, the therapeutic potential of nickel(II) diacetyl monoxime-2-pyridyl hydrazone complex versus CCl4-induced hepatotoxicity in rats. We used six rat groups of ten animals each. The negative control, vehicle, normal rats injected i.p. with the complex (2.4 mg/kg/day), positive control rats injected i.p. with CCl4, and treated rats administered complex via injection at low and high concentrations of 1.2 and 2.4 mg/kg/day, respectively at the same time as CCl4 injection for short-term (3-weeks) and long-term (8-weeks) treatment. Intoxicated-rodents exhibited significant elevations in the liver index, hepatic serum markers, and oxidative stress with significant reductions in the hepatic, antioxidants, nucleic acids, and proteins. Complex co-treatment with CCl4 significantly suppressed the elevated liver enzyme activities, attenuated oxidative stress, reactivated antioxidant-system components, and amended the hepatic tissue injury. The complex high dose was more efficient than the low dose. Results of negative control were analogous to those of normal rats injected with the complex high dose. The histopathological analysis also supported the above findings. These results show that complex has good antioxidant and therapeutic properties, which can help in treating and preventing CCl4-induced hepatotoxicity.

Therapeutic Effect of Ethanol Extract of Anthocleista vogelii Stem Bark in the Treatment of Jaundice on Paracetamol-induced Hepatotoxicity in Adult Wistar Rats

This study investigated therapeutic effect of ethanol extract of Anthocleista vogelii stem bark (EEAV) in the treatment of jaundice on paracetamol-induced hepatotoxicity in adult wistar rats. A total of 30 wistar rats weighing between 160-200 g were distributed into 6 groups comprising group 1 (normal control), group 2 (paracetamol 2 g/Kg bw), group 3 (paracetamol 2 g/Kg bw + Silymarin 100mg/Kg bw) and groups 4-6 (paracetamol 2 g/Kg bw each + 250, 500, &amp; 1000 mg/Kg bw of EEAV, respectively). Experiment lasted for a period of 16 days. Paracetamol induction elevated liver indices and enzyme activities. However, administration of EEAV significantly reduced (p≤0.05) these effects in groups 3-6 when compared to group 2. A significant elevation (p≤0.05) was reported in creatinine, urea, sodium (Na+) and chloride (Cl-) when group 2 was compared with group 1. Haematological study showed that packed cell volume (PCV), haemoglobin (Hb) and red blood cell (RBC) levels significantly increased (p≤0.05) in treatment groups 3-6 when compared to group 2. The catalase (CAT) activity increased significantly (p≤0.05) in groups 3, 4 and 6 when compared to group 2. Liver histology showed normal hepatocytes architecture with normal central vein in group 1. Group 2 revealed a histologically distorted liver tissue while there was regeneration of hepatic cells in groups 3-6. The study revealed that EEAV could serve as potent herbal therapeutic agent in the treatment of jaundice triggered by paracetamol induction in adult wistar rats.

English

Hyperlipidemia is one of the major health concerns worldwide. The present study aimed at utilizing clinicopathological tools to investigate the possible improving effect of Avena sativa mucilaginous extract (ASE) on lipid metabolic and liver function profiles in albino rats. The rats were rendered hyperlipidemic by 6-week supplementation of high-fat diet ad libitum. The rats were grouped into seven groups; with different treatment applications. Rats of group-I received normal diet and served as normal control; those of group-II were kept on high-fat (cholesterol 1% + coconut oil 2%) diet for 6 weeks and served as diseased control. Rats in group-III were kept on high-fat diet and received ezetimibe (1 mg/Kg B. Wt, orally, daily) and served as standard. Those in group-IV and V were kept on high-fat diet and received ASE at doses of 25 and 50 mg/Kg B. Wt., orally, daily (small and high doses, SD and HD, respectively) and served as treated-SD and treated-HD, respectively. While the last two groups (VI and VII) were kept on normal diet and received SD and HD of ASE. Blood samples for serum were taken for clinicochemical analysis on days 28 (4 weeks) and 42 (6 weeks) of the experiment and tissue specimens were taken for histopathology. ASE significantly (P<0.05) decreased the elevated serum lipid profile parameters, including total lipids, tri-acylglycerols (TAGs), cholesterol, LDL-C, VLDL-C, but significantly (P<0.05) normalized the serum HDL-C concentrations of rats kept on high-fat diet. Administration of A. sativa extract significantly decreased elevated serum liver enzyme activities in samples taken from animals kept on high-fat diet compared to the diseased untreated ones. Observations from histopathological examination were parallel and explanatory to clinicochemical analytical results. These data may suggest that the aqueous mucilaginous extract of A. sativa seed has a good health impact in cases associated with hyperlipidemia indicated by clinical pathology. Key words: Avena sativa, antihyperlipidemic, clinical pathology, liver function, phytotherapy, phytomedicine.

Discovery of DS-6930, a potent selective PPARγ modulator. Part I: Lead identification

The lead identification of a novel potent selective PPARγ agonist, DS-6930 is reported. To avoid PPARγ-related adverse effects, a partial agonist was designed to prevent the direct interaction with helix 12 of PPARγ-LBD. Because the TZD group is known to interact with helix 12, the TZD in efatutazone (CS-7017) was replaced to discover novel PPARγ intermediate partial agonist 8i. The optimization of 8i yielded 13ac with high potency in vitro. Compound 13ac exhibited robust plasma glucose lowering effects comparable to those of rosiglitazone (3 mg/kg) in Zucker diabetic fatty rats. Upon toxicological evaluation, compound 13ac (300 mg/kg) induced hemodilution to a lower extent than rosiglitazone; however, 13ac elevated liver enzyme activities. X-ray crystallography revealed no direct interaction of 13ac with helix 12, and the additional lipophilic interactions are also suggested to be related to the maximum transcriptional activity of 13ac.

Blueberry extract attenuates γ-radiation-induced hepatocyte damage by modulating oxidative stress and suppressing NF-κB in male rats.

Radiation exposure is known to produce many harmful effects in biological systems, and these effects are often mediated by oxygen free radicals. Because blueberries are rich in antioxidant compounds such as anthocyanins and phenolic acids, we divided forty adult rats into four treatment groups of 10 (G1–4) as follows: G1 rats were used as a control, G2 rats were irradiated with 8 Gy at 2 Gy/week at a dose rate of 0.5 Gy/min, G3 rats were administered blueberry extract (200 mg/kg) and G4 rats were administered blueberry extract during the same irradiation period. In subsequent determinations, γ-irradiated rats had increased levels of cholesterol, triglyceride, high density lipoprotein (HDL) and low density lipoprotein (LDL), and significantly elevated liver enzyme activities, including alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP), and total bilirubin. In contrast, significant reductions in albumin, total protein and globulin were observed, whereas gamma irradiation decreased activities of the antioxidant enzymes glutathione (GSH), catalase (CAT), xanthine dehydrogenase (XDH) and superoxide dismutase (SOD). We also observed incremental increases in DNA fragmentation percentages and histopathological changes in liver tissues. Serum pro-inflammatory cytokine levels (IL-6, IL-10 and TNF-α) were significantly elevated and hepatic NF-кB was upregulated. In G4 rats, treatments with blueberry extract restored liver pro-oxidant status, reduced cytokine levels, ameliorated histopathological parameters and reduced DNA damage. In conclusion, γ-radiation exerts toxic effects in the rat livers, and blueberry extract is protective against these.

Methotrexate treatment for rheumatoid arthritis in Poland: Retrospective analysis of patients in routine clinical practice.

ObjectivesThe aim of this study was to evaluate methotrexate (MTX) treatment administered by Polish rheumatologists in everyday practice.Material and methodsThe study was based on a retrospective analysis of a cohort of 1957 patients with rheumatoid arthritis (RA). It was conducted among 100 rheumatologists, each of whom received 20 questionnaires and completed them based on the data from their rheumatoid arthritis patients.ResultsMethotrexate was taken by 91% of patients, and 80% of them continued the treatment either as a monotherapy (65%) or concomitantly with other disease-modifying anti-rheumatic drugs. In 60% of the cases, therapy was initiated within six months of diagnosis. Dose modifications were observed in 76% of cases and were contingent on different factors, e.g. lack of efficacy, presence of adverse events. The most prevalent adverse events were nausea and vomiting, weakness, and elevated liver enzyme activity. The most common initial dose of MTX was 10 or 15 mg/week. An increase in dose to the maximum of 25 mg/week was observed in 36% of cases, with continuation for 27% of patients. Treatment interruption was noted in 21% of patients, predominantly due to MTX intolerance; however, in 13% of cases, it was due to patient choice.ConclusionsMethotrexate is the most common agent used to treat rheumatoid arthritis. Dose modifications are often applied to maximise efficacy and reduce adverse reactions, which could lead to withdrawal. Methotrexate is an effective drug for treatment of RA when used according to current recommendations. To optimise MTX therapy, regular medical visits are required.

No Increased Risk of Ketoconazole Toxicity in Drug-Drug Interaction Studies.

In July 2013 the U.S. Food and Drug Administration (FDA) released a safety announcement regarding the use of ketoconazole and its adverse drug reactions. The FDA report advised against the use ketoconazole tablets as a first-line treatment for any fungal infections because of the risk of potentially serious drug-drug interactions and liver and adrenal gland complications. The European Medicines Agency (EMA) also proposed to limit the use of oral ketoconazole in fungal infections because of the same risk of harmful effects and interactions. In addition, the FDA also advised against the use of oral ketoconazole in drug interaction studies, in which it has been extensively used as an index inhibitor of drug metabolism. The aim of this investigation was to evaluate the risks of ketoconazole-induced hepatotoxicity described by the FDA and EMA in published drug interaction studies with ketoconazole and compare these data with the toxicity reported for ketoconazole when used as antifungal treatment. In the drug interaction studies (2355 participants; healthy volunteers and patients; median treatment duration, 6 days), only 40 participants were reported to have increased liver transaminase activity (1.7%), and no deaths were reported or associated with ketoconazole. In studies investigating ketoconazole treatment, patients were treated for 276 days (median), and 5.6% of patients had elevated liver enzyme activity. Because of the short treatment period in drug interaction studies the risk of drug-induced hepatic injury is considered very low. As such, we recommend that ketoconazole remain a safe CYP3A index inhibitor for use in drug interaction studies with healthy volunteers.

Thirty-day rat toxicity study reveals reversible liver toxicity of mifepristone (RU486) and metapristone

Objective: Mifepristone (RU486) is an oral first-line contraceptive used by hundreds of millions of women, and recently it was tested for anticancer activity in both genders worldwide. We are developing metapristone (the N-monodemethyl RU486) as a potential metastasis chemopreventive. The present acute and 30-d subacute toxicity study aimed at examining and compared in parallel the potential toxicity of the two drugs.Methods: The single-dose acute toxicity and 30-d subacute toxicity studies were conducted in mice and rats, respectively, by gavaging metapristone or mifepristone at various doses. Blood samples and organs were collected for blood chemistry, hematology and histology analyses.Results: Oral mifepristone (3000 mg/kg) caused 30% and 40% death in female and male mice, respectively, within 15 h post-dosing. In comparison, the same dose of metapristone produced 30% acute death in males only. Thirty-day oral administration of the two drugs to rats (12.5, 50 and 200 mg/kg/day) caused reversible hepatotoxicity that only occurred at 200 mg/kg/day group, evidenced by the elevated liver enzyme activity and liver organ weight.Conclusion: The present study, for the first time, reveals reversible hepatotoxicity in rats caused by the 30-d consecutive administration at the high dose, and warns the potential hepatotoxicity caused by long-term administrations of high doses of mifepristone or metapristone in clinical trials but not by the acute single abortion doses.

Exocrine pancreatic insufficiency with concurrent pancreatitis, inflammatory bowel disease and cholangiohepatitis in a cat

A five-year-old male Persian cat was referred for chronic weight loss, polyphagia and clay-coloured voluminous stools. Serum biochemistry showed elevated liver enzyme activity, hypocholesterolaemia and hypocobalaminaemia. On abdominal ultrasound, a...