Medicinal Impact of Piper- Nigrum (Piperine) Against Arsenic Induced Hepatic and Renal Toxicity in Experimental Mice

In view of the increasing risk of arsenic on human health, the present study has been carried out to investigate the hepato-protective effect of piperine on arsenic induced-hepatic and renal toxicity in mice. Various oxidative stress parameter, antioxidant level and micro nutrients were analyses in hepatic and hepatic renal organ of mice. Methods: Mice exposed arsenic (sodium arsenate 5 mg/kg body weight p.o. for 45 days) caused a significant increases oxidative stress in hepatic and renal tissue as compared to controls group. Results: Abnormal levels of arsenic in hepatic and renal tissue increased the levels of ROS, LPO, and decreased the levels of GSH with SOD, CAT, and GPx activities in the hepatic and renal tissue of mice as compared to controls. Co-treatment of arsenic with piperine (1.5 mg/kg body weight p.o. for 45 days) decreased the levels of ROS, LPO, and increased the level of GSH, also increased SOD, CAT, and GPx activity and showed improvements in hepatic and renal tissue of mice as compared to arsenic-treated groups. Conclusion: Our results proved that piperine worked as antioxidant, anti- inflammatory in nature.

Treatment Outcome after Fractionated Conformal Radiotherapy for Hepatocellular Carcinoma in Patients with Child-Pugh Classification B in Korea (KROG 16-05) / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: There is limited data on radiotherapy (RT) for hepatocellular carcinoma (HCC) in patients with Child-Pugh classification B (CP-B). This study aimed to evaluate the treatment outcomes of fractionated conformal RT in HCC patients with CP-B. MATERIALS AND METHODS: We retrospectively reviewed the data of HCC patients with CP-B treated with RT between 2009 and 2014 at 13 institutions in Korea. HCC was diagnosed by the Korea guideline of 2009, and modern RT techniques were applied. Fraction size was ≤ 5 Gy and the biologically effective dose (BED) ≥ 40 Gy₁₀ (α/β = 10 Gy). A total of 184 patients were included in this study. RESULTS: Initial CP score was seven in 62.0% of patients, eight in 31.0%, and nine in 7.0%. Portal vein tumor thrombosis was present in 66.3% of patients. The BED ranged from 40.4 to 89.6 Gy₁₀ (median, 56.0 Gy₁₀). After RT completion, 48.4% of patients underwent additional treatment. The median overall survival (OS) was 9.4 months. The local progression-free survival and OS rates at 1 year were 58.9% and 39.8%, respectively. In the multivariate analysis, non-classic radiation-induced liver disease (RILD) (p < 0.001) and additional treatment (p < 0.001) were the most significant prognostic factors of OS. Among 132 evaluable patients without progressive disease, 19.7% experienced non-classic RILD. Normal liver volume was the most predictive dosimetric parameter of non-classic RILD. CONCLUSION: Fractionated conformal RT showed favorable OS with a moderate risk non-classic RILD. The individual radiotherapy for CP-B could be cautiously applied weighing the survival benefits and the RILD risks.

The study of the relationship between hepatic toxicity in hepatitis B virus markers seropositive cancer patients undergoing chemotherapy / 中国现代医生

Objective To evaluate the relationship between the hepatic toxicity induced by chemotherapy in patients with malignant tumor who test positive for HBV markers. Methods From January 2008 to January 2014, 887 cancer patients were treated by chemotherapy. Among 274 cases of patients were HBV positive (positive group), 613 patients were HBV negative (negative group), the liver function after chemotherapy were compared. Results Positive group patients receiving chemotherapy had higher rate of hepatic toxicity than those in negative group (24.1% vs. 11.3%,P<0.01),the incidence rate of 3-4 grade hepatic toxicity in positive group patients was 11.2%(13/116),more than that in negative group 0.65%(4/613). In the different treatment, there were statistically significant in two groups by TP regimen(paclitaxel+cisplatin), CAF(cyclophosphamide+adriamycin+5-Fluorouracil), CHOP(cyclophosphamide+doxorubicin+oncovin+prednisone)liver function after chemotherapy (P<0.05). In the TP scheme leaded to the incidence of abnor-mal liver function was the highest, the incidence rate in positive group was 36%(18/50),the incidence rate in negative group was 15.8%(19/120). Conclusion HBV infection is associated with higher risk of hepatic toxicity in patients with malignant tumor during chemotherapy(led by TP scheme).

Low Hepatic Toxicity in Primary and Metastatic Liver Cancers after Stereotactic Ablative Radiotherapy Using 3 Fractions

This study evaluated the incidence of hepatic toxicity after stereotactic ablative radiotherapy (SABR) using 3 fractions to the liver, and identified the predictors for hepatic toxicity. We retrospectively reviewed 78 patients with primary and metastatic liver cancers, who underwent SABR using 3 fractions between 2003 and 2011. To examine the incidence of hepatic toxicity, we defined newly developed hepatic toxicity> or =grade 2 according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 within 3 months after the end of SABR as a significant adverse event. To identify the predictors for hepatic toxicity, we analyzed several clinical and dosimetric parameters (rV(5Gy)-rV(35Gy): normal liver volume receiving or =grade 2 occurred in 10 patients (13%): grade 2 in 9 patients and grade 3 in 1 patient. On univariate analysis, baseline Child-Pugh (CP) score (5 vs. 6-8), normal liver volume, and planning target volume were the significant clinical predictors. All dosimetric parameters were significant: rV(20Gy) was the most significant predictor. On multivariate analysis, baseline CP score (hazard ratio, 0.026; P=0.001) was the only significant predictor. In conclusion, SABR using 3 fractions in primary and metastatic liver cancers produces low hepatic toxicity, especially in patients with a baseline CP score of 5. However, further studies are needed to minimize hepatic toxicity in patients with baseline CP scores> or =6.

Chemotherapy induced liver abnormalities: an imaging perspective

Treating patients undergoing chemotherapy who display findings of liver toxicity, requires a solid understanding of these medications. It is important for any clinician to have an index of suspicion for liver toxicity and be able to recognize it, even on imaging. Cancer chemotherapy has evolved, and newer medications that target cell biology have a different pattern of liver toxicity and may differ from the more traditional cytotoxic agents. There are several hepatic conditions that can result and keen clinical as well as radiographic recognition are paramount. Conditions such as sinusoidal obstructive syndrome, steatosis, and pseudocirrhosis are more commonly associated with chemotherapy. These conditions can display clinical signs of acute hepatitis, liver cirrhosis, and even liver failure. It is important to anticipate and recognize these adverse reactions and thus appropriate clinical action can be taken. Often times, patients with these liver manifestations can be managed with supportive therapies, and liver toxicity may resolve after discontinuation of chemotherapy.

A clinical study of preventive effect of entecavir on HBV reactivation in lung cancer with HBV carriers after chemotherapy / 实用肿瘤学杂志

Objective The present study aims to determine the correlation between liver function dam-age and hepatitis B virus ( HBV ) reactivation caused by chemotherapy , and the preventive effect of entecavir on HBV reactivation in lung cancer with HBV carriers .Methods A total of 160 lung cancer patients with HBV car-riers in the affiliated tumor hospital of Harbin Medical University from January 2011 to December 2012 was inves-tigated and the clinical data were studied retrospectively .The patients were divided into prophylactic group ( n=80)and control group(n=80).In prophylactic group,0.5 mg of daily oral entecavir was administered before the chemotherapy until 6 months after the completion of chemotherapy .Control group received no entecavir .The inci-dence of HBV reactivation ,functional damage of liver ,toxicities and disruption of chemotherapy were measured . Results The comparison between the control group (25%) and prevent group (5%) showed a statistically signifi-cant difference in the incidence of HBV reactivation (P0.05).There were significant differences in grade III and IV hepatic toxicity (P0.05).Disruption of chemo-therapy showed significant difference between control group (20%)and prevent group(5%)(P<0.05).The ma-jor grade 1 ~2 toxicities were myelosuppression,nausea,vomiting,skin rash,diarrhoea,neurotoxicity,fatigue, headache,insomnia,etc.All adverse reactions were cured after treatment .Conclusion The prophylactic adminis-tration of oral entecavir could reduce the risk of HBV reactivation in lung cancer with HBV carriers .

Evaluation of Herbalife Nutritional Supplements in the Hepatic Function of Rats.

The intake of nutritional supplements among people who aim for weight loss has increased all over the world given the fact it is easily acquired without the need of a medical prescription.The goal of this study was to research the presence of toxicity due to the intake of Herbalife protein supplements and shakes in an animal model. Twenty-one male Wistar rats were divided in three groups: control, shake and protein. The shake and protein groups received 100 mg/kg/day of the supplement whereas the control group received 0.5 mg/kg/day of water. Supplementation regimen lasted two months and after this period laboratory exams and histological analysis were performed in order to evaluate hepatic lesions. The groups showed no differences in values of GGT, alkaline phosphatase, AST, ALT, cholesterol, HDL or triglycerides. All the toxicity reports related to Herbalife supplements are over longer periods of time of intake than the period established in this model. There are no reports on how the response of rats to this kind of supplementation works. The mechanism of hepatotoxicity in humans suggests an immune-mediated reaction. The presented model could not show the expected toxicity, it is reasonable to conclude that there is a direct relation between hepatic lesions in humans and the intake of Herbalife supplements.

Effect of Artemisinin-Based Combination Therapy on some Selected Liver Function Indices of Pregnant Wistar Albino Rats.

In the risk assessment of the effect of administration of artemisinin-based combination therapy on some selected liver function indices of pregnant wistar albino rats. Fifteen (15) pregnant wistar albino rats were divided into three groups and were allowed to acclimatize to laboratory condition for seven (7) days. Rats in group A served as the control and were administered with normal saline throughout the experimental period of seven (7) days, while rats in group B and C were administered intra-peritoneally with 3 and 6mg/kg body weight of artemisininbased combination therapy respectively throughout the experimental period. Twenty four (24) hours after the last administration, the pregnant wistar albino rats were sacrificed. Blood was obtained by cardiac puncture for analysis of serum ALP, AST, ALT and bilirubin using standard methods and enzyme kits. The result showed that the drug at both 3and 6mg/kg body weight produced a significant (P<0.05) dosage increase in serum AST, ALT and ALP. The ratio of AST: ALT and AST: ALP showed a significant (P<0.05) increase. Similar pattern was also displayed by serum bilirubin concentration. These results are clear manifestations that artemisinin-based combination therapy might pose hepatic injury, hepatobilliary toxicity or complete hepatic damage in pregnant wistar albino rats. Thus, it is suggested that special precaution needs to be exercised on the usage of artemetherlumefantrine in pregnancy.

Antituberculotic Chemotherapy-General and Hepatic Toxicity Revisited.

Severe or pertinent hepatic toxicity interferes with antituberculotic chemotherapy resulting in dose reductions, treatment delays or cessation of therapy. Hepatic toxicity by antituberculotic agents is due to anaphylactic reactions (acetylaor phenotype polymorphism) and is relative to the cumulative dose intensity. Risk of hepatic toxicity is higher in the elderly and alcoholic patients. Patients with previous hepatic diseases such as hepatitis and comorbidities i.e. HIV infections, malnutrition and renal damages are prone to an added risk of hepatic toxicity. This review consolidates the pattern of hepatic adverse effects associated with each component of the antimyobacterial regimen e.g. isoniazid, rifampicin and pyrazinamaide. Higher propensities of hepatic adverse effects are associated with the first line agents, intensified by the incorporation of second line antibiotics, primarily metabolized in the liver. In conclusion the hepatic biomarkers should be monitored in the patient under a tuberculosis treatment plan as well as purposefully assessed during follow-up visits of the patients.

Amiodarone Induced Multiorgan Toxicity in a Patient of Hypertrophic Cardiomyopathy With Atrial Fibrillation

Amiodarone is an antiarrhythmic drug known to have adverse effects on multiple organs. Most studies have reported the side effects of the drug, which may result from rapid administrations or from long-term, high dosage administrations. However, toxicity issues have also been reported from patients administered with low doses of the drug for a long period of time. Here we report a case of an 82-year-old female who had shown symptoms and signs of pulmonary, hepatic, and neurotoxicity after taking amiodarone for 14 months in order to treat her atrial fibrillation without regular outpatient follow-up. We highlight the importance of the recommended evaluations, including lung, liver, and thyroid functions, as well as the neurological examinations in patients treated with amiodarone for a long period of time during regular follow-up.

The clinical observation of hepatic toxicity in hepatitis B virus markers positive cancer patients undergoing chemotherapy / 中国医师进修杂志

Objective To evaluate the liver damage induced by chemotherapy in patients with cancer and positive for hepatitis B virus (HBV) markers.Methods From January 2005 to January 2012,913 cancer patients were treated by chemotherapy including HBV-positive patients (HBV-positive group,288 cases) and HBV-negative patients (HBV-negative group,625 cases).The changes of hepatic function after chemotherapy between two groups were compared.Results The incidence of hepatic toxicity in HBV-positive group was higher than that in HBV-negative group [24.0％ (69/288) vs.11.4％ (71/625)],and there was significant difference between two groups (P＜ 0.01).The incidence of degree 11Ⅲ-Ⅳ hepatic toxicity was 11.4％ (14/123) in HBV-DNA-positive patients and 0.6％ (4/625) in HBV-negative group.In a variety of chemotherapy,there was significant difference in the incidence of hepatic toxicity in TP(paclitaxel +cisplatin),CAF(cyclophosphamide + doxorubicin + fluorouracil),CHOP(cyclophosphamide + doxorubicin +vincristine + prednisone) between two groups (P ＜ 0.05).The incidence of hepatic toxicity was highest in TP,which was 34.6％ (18/52) in HBV-positive group and 16.5％ (20/121) in HBV-negative group.Conclusion HBV infection is associated with higher risk of hepatic toxicity in patients with cancer during chemotherapy.

Folic acid supplementation reduces oxidative stress and hepatic toxicity in rats treated chronically with ethanol

Folate deficiency and hyperhomocysteinemia are found in most patients with alcoholic liver disease. Oxidative stress is one of the most important mechanisms contributing to homocysteine (Hcy)-induced tissue injury. However it has not been examined whether exogenous administration of folic acid attenuates oxidative stress and hepatic toxicity. The aim of this study was to investigate the in vivo effect of folic acid supplementation on oxidative stress and hepatic toxicity induced by chronic ethanol consumption. Wistar rats (n = 32) were divided into four groups and fed 0%, 12%, 36% ethanol, or 36% ethanol plus folic acid (10 mg folic acid/L) diets. After 5 weeks, chronic consumption of the 36% ethanol diet significantly increased plasma alanine transaminase (ALT) (P < 0.05) and aspartate transaminase (AST) (P < 0.05), triglycerides (TG) (P < 0.05), Hcy (P < 0.001), and low density lipoprotein conjugated dienes (CD) (P < 0.05) but decreased total radical-trapping antioxidant potential (TRAP) (P < 0.001). These changes were prevented partially by folic acid supplementation. The 12% ethanol diet had no apparent effect on most parameters. Plasma Hcy concentration was well correlated with plasma ALT (r = 0.612**), AST (r = 0.652*), CD (r = 0.495*), and TRAP (r = -0.486*). The results indicate that moderately elevated Hcy is associated with increased oxidative stress and liver injury in alcohol-fed rats, and suggests that folic acid supplementation appears to attenuate hepatic toxicity induced by chronic ethanol consumption possibly by decreasing oxidative stress.

The protective role of Gongronema latifolium in acetaminophen induced hepatic toxicity in Wistar rats

Objective: To evaluate the protective effect of leaf extract of Gongronema latifolium (G. latifolium) against acute acetaminophen induced hepatic toxicity in Wistar rats. Methods:Thirty six Wistar rats were divided into 6 groups with 6 rats in each group. Animals in group 1 and 2 were administered with 600 mg/kg b.w. of acetaminophen only and acetaminophen plus 100 mg/kg b.w. of caffeine by oral gavages, respectively. Experimental groups 3 and 4 were treated as in group 1 but in addition received 200 and 400 mg/kg b.w., respectively of the leaf extract of G. latifolium by oral gavages. The experimental groups 5 and 6 were treated as in group 2 and in addition received 200 and 400 mg/kg b.w. of leaf extract of G. latifolium, respectively. The treatment lasted for 14 days. Results: The results obtained showed that the serum glutamic-oxalacetic transaminease (AST), glutamic-pyruvic transaminase (ALT) and alkaline phosphatase (ALP) levels had a greater increase in group 2 than in group 1 but dropped marginally in groups 3 and 4. However, in groups 5 and 6, AST, ALT and ALP were significantly reduced (P<0.05). Similarly, serum protein levels were significantly increased in groups 3, 4, 5 and 6 when compared with group 1 and 2. Conclusions: It can be concluded that extract of G. latifolium offers protection against acetaminophen and caffeinated acetaminophen toxicity in Wistar rats.

Liver Function and Inhaled Anesthetics

The liver is the major site of endogenous and exogenous drug metabolism. The primary result of drug metabolism is the production of more water-soluble and therefore more easily excreted drug metabolites. Drugs are sometimes biotransformed into more reactive metabolites, which may lead to toxicity. Volatile anesthetics, like most drugs, undergo metabolism in the body and are sometimes associated with toxic reactions. Here, author will discuss the metabolism and hepatic toxicity of inhaled anesthetics. Toxicity and liver injury have been reported after repeated exposure on subsequent occasions to different fluorinated anesthetics. This phenomenon of cross-sensitization has also been reported with the chlorofluorocarbon(CFC) replacement agents, the hydrochlorofluorocarbons(HCFCs). Halothane, enflurane, sevoflurane, isoflurane, desflurane are all metabolized to trifluoroacetic acid, which have been reported to induce liver injury in susceptible patients. The propensity to produce liver injury appears to parrel metabolism of the parent drug: halothane(20%) >>>> enflurane(2.5%) >> sevoflurane(1%) > isoflurane(0.2%) > desflurane(0.02%). The use of any anesthetic must be based on its benefits and risks, how it may produce toxicity, and in which patients it may be most safely administered. Nonhalogenated inhaled anesthetics (nitrous oxide, xenon) chemically inert and not metabolized in human tissue. The perfect anesthetic agents dose not exist. But ongoing research attempts to uncover emerging toxicities. Xenon is not currently approved for clinical use. Other than the expense associated with its use, it may be the most ideal anesthetic agent. In general, surgical manipulation or disturbance of the surgical site appears to be more important in decreasing hepatic blood flow than current anesthetic agents such as isoflurane, sevoflurane, and desflurane or technique. However, the clinician is challenged to balance new information with current clinical practices and choice the safest, most effective agents for each patient.

The hepatic toxicity of antituberculous drugs in tuberculous meningitis patients.

The retrospective analysis of 97 tuberculous meningitis patients, admitted between 1979-1986, revealed the incidence of the hepatic toxicity of antituberculous drugs to be 17.57%. The potential risk factors for the hepatic toxicity were assessed in all patient’s records. They were sex, age, duration of illness, alcoholic consumption, severity of disease, body weight, liver function tests, serum albumin and antituberculous drug combination. The probable risk factors found in the study were body weight under 50 kilograms, and abnormal liver function test. The combination of isoniazid and rifampicin in comparision to isoniazid plus pyrazinamide and rifampicin showed no significant difference of the hepatic toxicity.

Study of toxic effects on hearing, kidney and liver of mice induced by anticancer agent of cisplatin and their mechanisms / 中国药理学通报

AIM To establish an animal experimental model for study on prevention of cisplatin toxicity and explore the possible mechanisms of the toxicity induced by cisplatin administration. METHODS Cisplatin was administered i.p consecutively for five days to male mice weighted from 28 to 30 g. The toxic effects induced by different doses of cisplatin on hearing, liver and kidney were determined. RESULTS Dose dependent decrease of body weight, abnormality of kidney and liver coefficients, levels of BUN and activities of ALT in serum were induced by cisplatin administration. Furthermore, Levels of GSH, activities of GSH Px and SOD increased significantly in kidney. Reversely, levels of GSH, activities of GSH Px and SOD in liver decreased and levels of LPO increased significantly in animals given cisplatin compared with those in control animals. CONCLUSION Obvious damage on hearing, liver and kidney of mice could be induced after consecutively 5 days administration of cisplatin with doses range from 3 0 to 4 0 mg?kg -1 (body weight). Oxidative damage is one of the mechanisms of these toxic effects on liver and kidney induced by cisplatin. But for different organs or at different stages of cisplatin administration, the main mechanism may be different.