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Drug and chemical poisoning admissions at a teaching hospital in Malaysia

Ab Rahman AF

Hum Exp Toxicol, 2002 Jul;21(7):377-81.
PMID: 12269700

A retrospective review of medical records was carried out to determine the pattern of drug and chemical poisoning cases admitted to a teaching hospital in Malaysia. Medical records of patients admitted during the period January 1987 to December 1995 were reviewed. They accounted for 0.2% of total admissions during the period. While all ages were represented, there was predominance of children, which showed little change throughout the nine-year period. Of all cases of poisoning, 77.8% were unintentional, 12.6% intentional and 9.6% were undetermined. Kerosene, pesticides and medicinal substances remained the common agents associated with poisoning. A significant number of patients sought treatment elsewhere before being admitted to the hospital. Of those who came directly to the hospital, many were presented late in the course of their poisoning. Only seven patients died and none were children. This study supports the need for greater emphasis on prevention of poisoning in children and among farmers in the state.
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.
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.
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.
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.
Diallyl sulphide, a component of garlic, abrogates ferric nitrilotriacetate-induced oxidative stress and renal damage in rats

Ansar S, Iqbal M, AlJameil N

Hum Exp Toxicol, 2014 Dec;33(12):1209-16.
PMID: 24596035 DOI: 10.1177/0960327114524237

Ferric nitrilotriacetate (Fe-NTA) induces tissue necrosis as a result of lipid peroxidation (LPO) and oxidative damage that leads to high incidence of renal carcinomas. The present study was undertaken to evaluate the effect of diallyl sulphide (DAS) against Fe-NTA-induced nephrotoxicity. A total of 30 healthy male rats were randomly divided into 5 groups of 6 rats each: (1) control, (2) DAS (200 mg kg(-1)), (3) Fe-NTA (9 g Fe kg(-1)), (4) DAS (100 mg kg(-1)) + Fe-NTA (9 mg Fe kg(-1)) and (5) DAS (200 mg kg(-1)) + Fe-NTA (9 mg Fe kg(-1)). Fe-NTA + DAS-treated groups were given DAS for a period of 1 week before Fe-NTA administration. The intraperitoneal administration of Fe-NTA enhanced blood urea nitrogen and creatinine levels with reduction in levels of antioxidant enzymes. However, significant restoration of depleted renal glutathione and its dependent enzymes (glutathione reductase and glutathione-S-transferase) was observed in DAS pretreated groups. DAS also attenuated Fe-NTA-induced increase in LPO, hydrogen peroxide generation and protein carbonyl formation (p < 0.05). The results indicate that DAS may be beneficial in ameliorating the Fe-NTA-induced renal oxidative damage in rats.
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.
Insight into potential mechanisms of hypobaric hypoxia-induced learning and memory deficit - Lessons from rat studies

Qaid E, Zakaria R, Sulaiman SF, Yusof NM, Shafin N, Othman Z, et al.

Hum Exp Toxicol, 2017 Dec;36(12):1315-1325.
PMID: 28111974 DOI: 10.1177/0960327116689714

Impairment of memory is one of the most frequently reported symptoms during sudden hypoxia exposure in human. Cortical atrophy has been linked to the impaired memory function and is suggested to occur with chronic high-altitude exposure. However, the precise molecular mechanism(s) of hypoxia-induced memory impairment remains an enigma. In this work, we review hypoxia-induced learning and memory deficit in human and rat studies. Based on data from rat studies using different protocols of continuous hypoxia, we try to elicit potential mechanisms of hypobaric hypoxia-induced memory deficit.
Guggulsterone, a farnesoid X receptor antagonist lowers plasma trimethylamine-N-oxide levels: An evidence from in vitro and in vivo studies

Gautam A, Paudel YN, Abidin S, Bhandari U

Hum Exp Toxicol, 2019 Mar;38(3):356-370.
PMID: 30526076 DOI: 10.1177/0960327118817862

The current study investigated the role of guggulsterone (GS), a farnesoid X receptor antagonist, in the choline metabolism and its trimethylamine (TMA)/flavin monooxygenases/trimethylamine-N-oxide (TMAO) inhibiting potential in a series of in vitro and in vivo studies as determined by high-performance liquid chromatography (HPLC), mass spectroscopy (MS), and liquid chromatography (LC)-MS techniques. Atherosclerosis (AS) was successfully induced in a group of experimental animals fed with 2% choline diet for 6 weeks. Serum lipid profiles such as total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol were measured. Pro-inflammatory cytokines levels, markers for a hepatic injury, and oxidative stress markers were assessed. Interestingly, GS reduced the level of TMA/TMAO in both in vitro and in vivo studies as demonstrated by the peaks obtained from HPLC, MS, and LC-MS. Furthermore, GS exhibited cardioprotective and antihyperlipidemic effects as evidenced by the attenuation of levels of several serum lipid profiles and different atherogenic risk predictor indexes. GS also prevented hepatic injury by successfully restoring the levels of hepatic injury biomarkers to normal. Similarly, GS inhibited the production of pro-inflammatory cytokines levels, as well as GS, enhanced antioxidant capacity, and reduced lipid peroxidation. Histopathological study of aortic sections demonstrated that GS maintained the normal architecture in AS-induced rats. On the basis of results obtained from current investigation, we suggest that GS might have a great therapeutic potential for the treatment of AS.
S-Allyl cysteine alleviates inflammation by modulating the expression of NF-κB during chromium (VI)-induced hepatotoxicity in rats

Anandasadagopan SK, Sundaramoorthy C, Pandurangan AK, Nagarajan V, Srinivasan K, Ganapasam S

Hum Exp Toxicol, 2017 Nov;36(11):1186-1200.
PMID: 28988497 DOI: 10.1177/0960327116680275

Hexavalent chromium (Cr (VI)) is a common environmental pollutant. Cr (VI) exposure can lead to severe damage to the liver, but the preventive measures to diminish Cr (VI)-induced hepatotoxicity need further study. S-allyl cysteine (SAC) is a constituent of garlic ( Allium sativum) and has many beneficial effects to humans and rodents. In this study, we intended to analyze the mechanistic role of SAC during Cr (VI)-induced hepatotoxicity. Male Wistar albino rats were induced with 17 mg/kg body weight to damage the liver. The Cr (VI)-induced rats were treated with 100 mg/kg body weight of SAC as an optimum dosage to treat hepatotoxicity. We observed that the levels of oxidants, lipid peroxidation and hydroxyl radical (OH(•)) were increased, and enzymatic antioxidants such as superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase were found to be decreased in Cr (VI)-induced rats. While treated with SAC, the levels of oxidants were decreased and enzymatic antioxidants were significantly ( p < 0.05) increased. Lysosomal enzyme activities were increased in Cr (VI)-induced rats and on treatment with SAC, the activities were significantly decreased. The expressions of nuclear factor-kappa B (p65-NF-κB), tumor necrosis factor α (TNF-α), and inducible nitric oxide synthase (iNOS) were increased during induction with Cr (VI). Subsequent administration of SAC to animals showed a decrease in the expressions of NF-κB, TNF-α, and iNOS. Results obtained from this study clearly demonstrated that SAC protects the liver cells from the Cr (VI)-induced free radical damage.
Evaluate the impact of hospital types on the availability of antidotes for the management of acute toxic exposures and poisonings in Malaysia

Al-Sohaim SI, Awang R, Zyoud SH, Rashid SM, Hashim S

Hum Exp Toxicol, 2012 Mar;31(3):274-81.
PMID: 21478291 DOI: 10.1177/0960327111405861

The availability of antidotes may be considered essential and lifesaving in the management of certain poisonings. Surveys carried out in a number of countries have demonstrated inadequate availability of a variety of poisoning antidotes.
Cytotoxic and antioxidant effects of methoxylated stilbene analogues on HepG2 hepatoma and Chang liver cells: Implications for structure activity relationship

Hasiah AH, Ghazali AR, Weber JF, Velu S, Thomas NF, Inayat Hussain SH

Hum Exp Toxicol, 2011 Feb;30(2):138-44.
PMID: 20385705 DOI: 10.1177/0960327110368739

Stilbenes possess a variety of biological activities including chemopreventive activity. This study was conducted to evaluate the structural activity relationships of six methoxylated stilbene analogues with respect to their cytotoxic effects and antioxidant activities on HepG2 hepatoma and Chang liver cells. The cytotoxic and total antioxidant activities of six stilbene analogues were determined by MTT and Ferric Reducing Antioxidant Power (FRAP) assays, respectively. We found that the cis-methoxylated stilbene: (Z)-3,4,4'-trimethoxystilbene was the most potent and selective antiproliferative agent (IC₅₀ 89 µM) in HepG2 cells. For the total antioxidant activity, compounds possessing hydroxyl groups at the 4' position namely (E)-3-methoxy-4'-hydroxystilbene, (E)-3,5-dimethoxy-4'-hydroxystilbene (pterostilbene), (E)-4-methoxy-4'-hydroxystilbene showed the highest antioxidant activity. Structure activity relationship studies of these compounds demonstrated that the cytotoxic effect and antioxidant activities of the tested compounds in this study were structurally dependent.
Antioxidant potential of Cymbopogon citratus extract: alleviation of carbon tetrachloride-induced hepatic oxidative stress and toxicity

Koh PH, Mokhtar RA, Iqbal M

Hum Exp Toxicol, 2012 Jan;31(1):81-91.
PMID: 21508074 DOI: 10.1177/0960327111407226

This study was aimed to evaluate the effect of Cymbopogon citratus against carbon tetrachloride (CCl(4))-mediated hepatic oxidative damage in rats. Rats were administrated with C. citratus extract (100, 200 and 300 mg/kg b.w.) for 14 days before the challenge of CCl(4) (1.2 ml/kg b.w. p.o) on 13th and 14th days. Hepatic damage was evaluated by employing serum biochemical parameters (alanine aminotransferase-ALT, aspartate aminotransferase-AST and lactate dehydrogenase-LDH), malondialdehye (MDA) level, reduced GSH and antioxidant enzymes (catalase: CAT, glutathione peroxidase: GPX, quinone reductase: QR, glutathione S-transferase: GST, glutathione reductase: GR, glucose-6-phosphate dehyrogenase: G6PD). In addition, CCl(4)-mediated hepatic damage was further evaluated by histopathological examination. However, most of these changes were alleviated by prophylactic treatment of animals with C. citratus dose dependently (p < 0.05). The protection was further evident through decreased histopathological alterations in liver. The results of the present study indicated that the hepatoprotective effect of C. citratus might be ascribable to its antioxidant and free radical scavenging property.
Protective effect of diallylsulphide against mercuric chloride-induced hepatic injury in rats

Ansar S, Iqbal M

Hum Exp Toxicol, 2016 Dec;35(12):1305-1311.
PMID: 26825963

The present study was undertaken to evaluate the effect of diallylsulphide (DAS) against mercuric chloride (HgCl2)-induced oxidative stress in rat livers. Rats were randomly divided into four groups of six rats each and exposed to HgCl2 (50 mg/kg/body weight (b.w.)) intraperitoneally and/or DAS (200 mg/kg/b.w.) by gavage. HgCl2 administration enhanced alanine aminotransferase (AST) and aspartate aminotransferase (ALT) levels (p < 0.05) with reduction in the levels of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). However, treatment with DAS markedly attenuated HgCl2-induced biochemical alterations in liver and serum transaminases (AST and ALT; p < 0.05). Further, biochemical results were confirmed by histopathological changes as compared to HgCl2-intoxicated rats. Histopathology of liver also showed that administration of DAS significantly reduced the damage generated by HgCl2 The present study suggests that DAS shows antioxidant activity and plays a protective role against mercury-induced oxidative damage in the rat livers.
Antioxidant and nephroprotective potential of butylated hydroxyanisole against ferric nitrilotriacetate-induced oxidative stress and early tumor events

Ansar S, Iqbal M

Hum Exp Toxicol, 2016 Apr;35(4):448-53.
PMID: 26078281 DOI: 10.1177/0960327115591378

The present study was aimed to study protective effect of butylated hydroxyanisole (BHA), a phenolic antioxidant used in foods on ferric nitrilotriacetate (Fe-NTA)-induced nephrotoxicity. Male albino rats of Wistar strain (4-6 weeks old) weighing 125-150 g were used in this study. Animals were given a single dose of Fe-NTA (9 mg kg(-1) body weight) after treatment with BHA (1 and 2 mg animal(-1) day(-1)). Fe-NTA treatment enhanced ornithine decarboxylase (ODC) activity to 5.3-fold, and [(3)H]-thymidine incorporation in DNA to 2.5-fold in kidney compared with the corresponding saline-treated control, whereas glutathione (GSH) levels and the activities of antioxidant enzymes decreased to a range of 2- to 2.5-fold in kidney. These changes were reversed significantly in animals receiving a pretreatment of BHA. The enhanced ODC activity and DNA synthesis showed a reduction to 2.12-fold and 1.15-fold, respectively, at a higher dose of 2 mg BHA day(-1) animal(-1), compared with the Fe-NTA-treated groups. Pretreatment with BHA prior to Fe-NTA treatment increased GSH and the activities of antioxidant enzymes to a range of 1.5- to 2-fold in kidney. The results indicate that BHA suppresses Fe-NTA-induced nephrotoxicity in male Wistar rats.
Amelioration of ferric nitrilotriacetate-induced hepatotoxicity in Wistar rats by diallylsulfide

Ansar S, Iqbal M

Hum Exp Toxicol, 2016 Mar;35(3):259-66.
PMID: 25904316 DOI: 10.1177/0960327115583362

Garlic contains diallylsulfide (DAS) and other structurally related compounds that are widely believed to be active agents in preventing cancer. This study shows the effect of DAS (a phenolic antioxidant used in foods, cosmetics, and pharmaceutical products) on ferric nitrilotriacetate (Fe-NTA)-induced hepatotoxicity in rats. Male albino rats of Wistar strain weighing 125-150 g were given a single dose of Fe-NTA (9 mg kg(-1) body weight, intraperitoneally) after 1 week of treatment with 100 and 200 mg kg(-1) DAS in corn oil respectively administered through the gavage. Fe-NTA administration led to 2.5-fold increase in the values of both alanine transaminase and aspartate aminotransferase, respectively, and 3.2-fold increase in the activity of lactate dehydrogenase, microsomal lipid peroxidation to approximately 2.0-fold compared to saline-treated control. The activities of glutathione (GSH) and other antioxidant enzymes decreased to a range of 2.2-2.5-fold. These changes were reversed significantly (p < 0.001) in animals receiving a pretreatment of DAS. DAS protected against hepatic lipid peroxidation, hydrogen peroxide generation, preserved GSH levels, and GSH metabolizing enzymes to 60-80% as compared to Fe-NTA alone-treated group. Present data suggest that DAS can ameliorate the toxic effects of Fe-NTA and suppress oxidant-induced tissue injury and hepatotoxicity in rats.
Hepatoprotective potential of glyceryl trinitrate against chemically induced oxidative stress and hepatic injury in rats

Rahman A, Vasenwala SM, Iqbal M

Hum Exp Toxicol, 2017 Aug;36(8):785-794.
PMID: 27758841 DOI: 10.1177/0960327116665675

Glyceryl trinitrate (GTN) has been used widely as a potent vasodilator to treat heart conditions, such as angina pectoris and chronic heart failure. This study aims to elucidate the effect of exogenous nitric oxide (NO) administration, using GTN, on carbon tetrachloride (CCl4)-induced oxidative stress and liver injury in rats. The results obtained demonstrated that NO generated by the administration of GTN affords protection against CCl4-induced oxidative stress and liver injury. Administration of CCl4resulted in a significant ( p < 0.001) increase in lipid peroxidation and tissue damage markers (aspartate and alanine transaminase and lactate dehydrogenase) release in serum. Parallel to these changes, CCl4also caused downregulation of antioxidant enzymes including glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST), and several fold induction in γ-glutamyl transpeptidase (GGT) activity. Subsequent administration of GTN resulted in significant ( p < 0.001) recovery of GSH-metabolizing enzymes in a dose-dependent manner. Further, administration of NO inhibitor, NG-nitro-l-arginine methyl ester (l-NAME), exacerbated CCl4-induced oxidative tissue injury. Overall, the study suggests that GTN might suppress oxidant-induced tissue injury and hepatotoxicity in rats.
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.
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.
Decline in sperm count in European men during the past 50 years

Sengupta P, Borges E, Dutta S, Krajewska-Kulak E

Hum Exp Toxicol, 2018 Mar;37(3):247-255.
PMID: 28413887 DOI: 10.1177/0960327117703690

PURPOSE: To investigate whether the sperm concentration of European men is deteriorating over the past 50 years of time.
MATERIALS AND METHODS: We analysed the data published in English language articles in the past 50 years in altering sperm concentration in European men.
RESULTS: A time-dependent decline of sperm concentration ( r = -0.307, p = 0.02) in the last 50 years and an overall 32.5% decrease in mean sperm concentration was noted.
CONCLUSION: This comprehensive, evidence-based meta-analysis concisely presents the evidence of decreased sperm concentration in European male over the past 50 years to serve the scientific research zone related to male reproductive health.

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