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Itraconazole- and fluconazole-induced toxicity in rat hepatocytes: a comparative in vitro study

Somchit N, Hassim SM, Samsudin SH

Hum Exp Toxicol, 2002 Jan;21(1):43-8.
PMID: 12046723

This current study was to investigate the in vitro cytotoxicity of rat hepatocytes induced by the antifungal drugs, itraconazole and fluconazole. Both antifungal drugs caused dose-dependent cytotoxicity. In vitro incubation of hepatocytes with itraconazole revealed significantly higher lactate dehydrogenase (LDH) leakage when compared to fluconazole. Phenobarbital pretreated hepatocytes contained significantly higher total cytochrome P450 content than the control hepatocytes. P450 content was reduced approximately 30% for both types of hepatocytes after 6 hours incubation. Interestingly, cytotoxicity of itraconazole was reduced significantly by phenobarbital pretreatment. Phenobarbital did not have any effect on the cytotoxicity induced by fluconazole. These results demonstrate the in vitro toxicity of hepatocytes induced by itraconazole and fluconazole that were expressed in a dose- and time-dependent manner. Phenobarbital plays a role in the cytoprotection of hepatocytes to itraconazole-induced but not fluconazole-induced cytotoxicity in vitro.
A model of chlorpyrifos distribution and its biochemical effects on the liver and kidneys of rats

Tanvir EM, Afroz R, Chowdhury M, Gan SH, Karim N, Islam MN, et al.

Hum Exp Toxicol, 2016 Sep;35(9):991-1004.
PMID: 26519480 DOI: 10.1177/0960327115614384

This study investigated the main target sites of chlorpyrifos (CPF), its effect on biochemical indices, and the pathological changes observed in rat liver and kidney function using gas chromatography/mass spectrometry. Adult female Wistar rats (n = 12) were randomly assigned into two groups (one control and one test group; n = 6 each). The test group received CPF via oral gavage for 21 days at 5 mg/kg daily. The distribution of CPF was determined in various organs (liver, brain, heart, lung, kidney, ovary, adipose tissue, and skeletal muscle), urine and stool samples using GCMS. Approximately 6.18% of CPF was distributed in the body tissues, and the highest CPF concentration (3.80%) was found in adipose tissue. CPF also accumulated in the liver (0.29%), brain (0.22%), kidney (0.10%), and ovary (0.03%). Approximately 83.60% of CPF was detected in the urine. CPF exposure resulted in a significant increase in plasma transaminases, alkaline phosphatase, and total bilirubin levels, a significant reduction in total protein levels and an altered lipid profile. Oxidative stress due to CPF administration was also evidenced by a significant increase in liver malondialdehyde levels. The detrimental effects of CPF on kidney function consisted of a significant increase in plasma urea and creatinine levels. Liver and kidney histology confirmed the observed biochemical changes. In conclusion, CPF bioaccumulates over time and exerts toxic effects on animals.
Coadministration of alloxan and nicotinamide in rats produces biochemical changes in blood and pathological alterations comparable to the changes in type II diabetes mellitus

Vattam KK, Raghavendran H, Murali MR, Savatey H, Kamarul T

Hum Exp Toxicol, 2016 Aug;35(8):893-901.
PMID: 26429928 DOI: 10.1177/0960327115608246

In the present study, thirty six male Sprague Dawley rats were randomly divided into six groups and were injected with varying doses of alloxan (Ax) and nicotinamide (NA). The serum levels of glucose, insulin, and adiponectin were measured weekly up to 4 weeks.
Fulltext Kaempferol ameliorates palmitate-induced lipid accumulation in HepG2 cells through activation of the Nrf2 signaling pathway

Zhao L, Yang L, Ahmad K

Hum Exp Toxicol, 2023;42:9603271221146780.
PMID: 36607234 DOI: 10.1177/09603271221146780

OBJECTIVES: Kaempferol (KMF), has beneficial effects against hepatic lipid accumulation. In this study, we aimed to investigate molecular mechanism underlying the protective effect of KMF on lipid accumulation.
METHODS: HepG2 cells were treated with different concentrations of KMF and 0.5 mM palmitate (PA) for 24 h. The mRNA and protein levels of genes involved in lipid metabolism were evaluated using real-time PCR and western blot. The expression of Nrf2 was silenced using siRNA.
RESULTS: Data indicated that KMF (20 μM) reversed PA-induced increased triglyceride (TG) levels and total lipid content. These effects were accompanied by down-regulation of the mRNA and protein levels of lipogenic genes (FAS, ACC and SREBP1), and up-regulation of genes related to fatty acid oxidation (CPT-1, HADHα and PPARα). Kaempferol significantly decreased the levels of the oxidative stress markers (ROS and MDA) and enhanced the activities of antioxidant enzymes SOD and GPx in PA-challenged cells. Luciferase analysis showed that KMF increased the transactivation of Nrf2 in hepatocytes. The results also revealed that KMF-mediated activation of Nrf2 target genes was suppressed by Nrf2 siRNA. Furthermore, Nrf2 siRNA abolished the KMF-induced reduction in ROS and MDA levels in PA treated cells. In addition, the inhibitory effect of KMF on TG levels and the mRNA and protein levels of FAS, ACC and SREPB-1 were significantly abolished by Nrf2 inhibition. Nrf2 inhibition also suppressed the KMF-induced activation of genes involved in β oxidation (CPT-1 and PPAR-α).
CONCLUSION: The results suggest that KMF protects HepG2 cells from PA-induced lipid accumulation via activation of the Nrf2 signaling pathway.
Scientific research related to calcium channel blockers poisoning: Bibliometric analysis in Scopus, 1968-2012

Zyoud SH, Al-Jabi SW, Sweileh WM, Waring WS

Hum Exp Toxicol, 2015 Nov;34(11):1162-70.
PMID: 25673180 DOI: 10.1177/0960327115571768

PURPOSE: Calcium channel blockers (CCBs) were the most common agents associated with a significant morbidity and mortality rate. The main objective of this study was to examine the publication pattern related to CCBs poisoning at the global level using bibliometric analysis of articles published in SciVerse Scopus online database.
METHODS: Data were searched for documents that contained specific words regarding CCB poisoning as keywords in the title. No time period limitations were specified in the search regarding the starting year. The ending date of the search was 31 December 2012.
RESULTS: The criteria were met by 713 publications from 53 countries. The largest number of articles associated with CCBs was from the United States (30%), followed by the United Kingdom (7.4%), Japan (6%), and Germany (5.6%). No data related to CCBs were published from 159 (75%) of 212 countries registered in World Bank online database. There was no correlation between the number of published articles in the country and its population size (r = 0.03, p > 0.926). United Kingdom and Australia were the leading countries in terms of number of CCBs publications per million inhabitants (0.83 and 0.82 articles per million inhabitants, respectively), followed by the United States (0.68). Countries with a large population, such as India, tended to rank relatively low (0.01 articles per million inhabitants). The total number of citations at the time of data analysis (23 October 2014) was 6462, with an average of 9.1 citations per document. The highest median (interquartile range) number of citations was 8 (8-18) for the United States, followed by 6 (1-21) for Australia, 5 (1-15) for the United Kingdom, and 5 (1-24) for Canada. The h-index of the retrieved documents was 37.
CONCLUSIONS: Scientific production on CCBs poisoning is increasing; nonetheless, the international collaboration is still rare. The amount of CCBs-based research activity was low or not available in most countries. More regional epidemiological studies are required to bridge the gap in CCBs-based research and to promote better evaluation of CCBs poisoning worldwide.
KEYWORDS: Bibliometric; Scopus; calcium channel blockers; citations; drug overdose; poisoning; toxicity
Worldwide research productivity of paracetamol (acetaminophen) poisoning: a bibliometric analysis (2003-2012)

Zyoud SH, Al-Jabi SW, Sweileh WM

Hum Exp Toxicol, 2015 Jan;34(1):12-23.
PMID: 24758786 DOI: 10.1177/0960327114531993

PURPOSE: There is a lack of data concerning the evaluation of scientific research productivity in paracetamol poisoning from the world. The purposes of this study were to analyse the worldwide research output related to paracetamol poisoning and to examine the authorship pattern and the citations retrieved from the Scopus database for over a decade.
METHODS: Data were searched for documents with specific words regarding paracetamol poisoning as 'keywords' in the title or/and abstract. Scientific output was evaluated based on a methodology developed and used in other bibliometric studies. Research productivity was adjusted to the national population and nominal gross domestic product (GDP) per capita.
RESULTS: There were 1721 publications that met the criteria during study period from the world. All retrieved documents were published from 72 countries. The largest number of articles related to paracetamol poisoning was from the United States (US; 30.39%), followed by India (10.75%) and the United Kingdom (UK; 9.36%). The total number of citations at the time of data analysis was 21,109, with an average of 12.3 citations per each documents and median (interquartile range) of 4 (1-14). The h-index of the retrieved documents was 57. After adjusting for economy and population power, India (124.2), Nigeria (18.6) and the US (10.5) had the highest research productivity. Countries with large economies, such as the UK, Australia, Japan, China and France, tended to rank relatively low after adjustment for GDP over the entire study period.
CONCLUSION: Our study demonstrates evidence that research productivity related to paracetamol poisoning has increased rapidly during the recent years. The US obviously dominated in research productivity. However, certain smaller country such as Nigeria has high scientific output relative to their population size and GDP. A highly noticeable increase in the contributions of Asia-Pacific and Middle East regions to scientific literature related to paracetamol poisoning was also observed.
KEYWORDS: Bibliometric; Scopus; acetaminophen; citations; paracetamol; poisoning
An analysis of the length of hospital stay after acetaminophen overdose

Zyoud SH, Awang R, Sulaiman SA, Al-Jabi SW

Hum Exp Toxicol, 2011 Jul;30(7):550-9.
PMID: 20630911 DOI: 10.1177/0960327110377647

Acetaminophen is one of the most commonly encountered medications in self-poisoning, with a high rate of morbidity. The prevalence and characteristics of acetaminophen intoxication associated with long hospital stay in patients are not well defined.
High prevalence of hypokalemia after acute acetaminophen overdose: impact of psychiatric illness

Zyoud SH, Awang R, Syed Sulaiman SA, Al-jabi SW

Hum Exp Toxicol, 2010 Sep;29(9):773-8.
PMID: 20144962 DOI: 10.1177/0960327110361759

Hypokalemia is not an isolated disease but an associated finding in a number of different diseases. It is also a commonly neglected condition among patients with acute acetaminophen overdose.
Incidence of adverse drug reactions induced by N-acetylcysteine in patients with acetaminophen overdose

Zyoud SH, Awang R, Syed Sulaiman SA, Sweileh WM, Al-Jabi SW

Hum Exp Toxicol, 2010 Mar;29(3):153-60.
PMID: 20071472 DOI: 10.1177/0960327109359642

Intravenous N-acetylcysteine (IV-NAC) is widely recognized as the antidote of choice for acetaminophen overdose. However, its use is not without adverse drug reactions (ADR) that might affect therapeutic outcome or lead to treatment delay.
Global research productivity of N-acetylcysteine use in paracetamol overdose: A bibliometric analysis (1976-2012)

Zyoud SH, Al-Jabi SW, Sweileh WM, Awang R, Waring WS

Hum Exp Toxicol, 2015 Oct;34(10):1006-16.
PMID: 26429951 DOI: 10.1177/0960327114565494

PURPOSE: The main objective of this study was to examine the publication pattern of N-acetylcysteine (NAC) research output for paracetamol overdose at the global level.
METHODS: Data were searched for documents that contained specific words regarding NAC and paracetamol as keywords in the title and/or abstract and/or keywords. Scientific output was evaluated based on a methodology developed and used in other bibliometric studies. Research productivity was adjusted to the national population and nominal gross domestic product per capita.
RESULTS: The criteria were met by 367 publications from 33 countries. The highest number of articles associated with the use of NAC in paracetamol overdose was from the United States of America (USA; 39.78%), followed by the United Kingdom (UK; 11.99%). After adjusting for economy and population power, USA (2.822), Iran (1.784) and UK (1.125) had the highest research productivity. The total number of citations at the time of data analysis (14 March 2014) was 8785 with an average of 23.9 citations per document and a median (interquartile range) of 6 (1-22). The h-index of the retrieved documents was 48. The highest h-index was 32 for USA, followed by 20 for UK. Furthermore, the highest number of collaborations with international authors for each country was held by USA with 11 countries, followed by Canada with 7 countries.
CONCLUSION: The amount of NAC-based research activity was low in some countries, and more effort is needed to bridge this gap and to promote better evaluation of NAC use worldwide. Our findings demonstrate that NAC use for paracetamol overdose remains a hot issue in scientific research and may have a larger audience compared with other toxicological aspects. Editors and authors in the field of toxicology might usefully promote the submission of work on NAC in future to improve their journal's impact.
KEYWORDS: Bibliometric; NAC; Scopus; acetaminophen; acetylcysteine; citations; paracetamol; poisoning
Fulltext A bibliometric analysis of research productivity of Malaysian publications in leading toxicology journals during a 10-year period (2003-2012)

Zyoud Sh, Al-Jabi S, Sweileh W, Awang R

Hum Exp Toxicol, 2014 Dec;33(12):1284-93.
PMID: 24505047 DOI: 10.1177/0960327113514101

Toxicology in Malaysia has experienced rapid development and made great progress in education and research in conjunction with economic development in Malaysia over the past two decades.