Biochemical disturbances caused by ranitidine in rats: attention to bilirubin–lipids relation and benefits of capsiate

The H2-receptor antagonists exhibit unusual absorption behavior in that double peaks often occur after oral administration. Moreover, administration with some high potency antacids decreases the extent of absorption. To date, no explanation that can completely account for these observations has been advanced. One problem is that there is a lack of consensus as to the mechanism of absorption of the H2-receptor antagonists from the gastrointestinal tract. In the studies reported here, the mechanism and regional dependence of intestinal uptake of two H2-receptor antagonists, cimetidine and ranitidine, were investigated in rats using the in vitro everted ring technique. The uptake rate of cimetidine from both jejunum and colon was linear with concentration (in the range of 0.0005-40 mM), and there was no significant competition for uptake in the presence of the structurally similar H2-receptor antagonists, famotidine and ranitidine. In the case of ranitidine too, the uptake rate from the jejunum and colon was linear with concentration (in the range of 0.0005-5 mM), and there was no competition for uptake by either famotidine or cimetidine. These data indicate that uptake of cimetidine and ranitidine in the rat jejunum and colon occurs by a predominantly passive process. Both cimetidine and ranitidine exhibited regional differences in uptake rate. Uptake tended to be greatest in the ileum, similar in duodenum and jejunum, and lowest in the colon. However, differences in uptake rates between locations in the small intestine appeared to be too modest to account for the double peak behavior of either compound.

Objectives:To evaluate the effect of various herbal adaptogens such as shade-dried powders of Withania somnifera, Ocimum sanctum, Asperagus recemosus, Andrographis paniculata, Asphaltum panjabinum (Shilajith), Gymnema sylvestre, Spirulina platensis, and Panex ginseng on cadmium (Cd)-induced oxidative stress and its accumulation in broiler chicken.Materials and Methods:A total of 80 male broiler chicks of day old age were randomly assigned to 10 equal groups. Group 1 birds were fed with basal diet throughout the experiment (1–42 days). Group 2–10 chicks were fed with basal diet containing cadmium at 100 ppm from day 1 to day 28 (4 weeks). From 29th to 42nd day (2 weeks), basal diet alone was fed to group 2 chicks which acted as toxic control and group 3–10 birds were fed with feed containing 0.1% powder of W. somnifera, O. sanctum, Aspe. recemosus, An. paniculata, Asph. panjabinum (Shilajith), G. sylvestre, S. platensis, and P. ginseng, respectively. Body weight gain, levels of non-enzymatic antioxidants such as reduced glutathione (GSH), lipid peroxidation markers such as thiobarbituric acid reacting substances (TBARS), liver functional markers such as serum alanine transaminase (ALT), kidney functional markers such as blood urea nitrogen (BUN) and serum creatinine and concentration of cadmium in liver and kidney were investigated.Results:Body weight gains were significantly decreased in birds of groups 2–10 compared to group 1 at the end of 4th week. Supplementation of various medicinal herbs in feed after 4th week significantly improved the body weight gain compared to that in group 2 chicks. The increase in TBARS and decrease in GSH concentrations of liver and kidney tissues in cadmium intoxicated birds were significantly reversed by the above-said herbs. The liver and kidney functional markers were also restored to normal levels. Highest concentration of cadmium was found accumulated in kidney, followed by liver in birds of group 2. Herbal supplementation in groups 3–10 prevented Cd bioaccumulation which was most evident in liver, followed by kidney.Conclusions:Administration of herbal adaptogens at the rate of 0.1% in feed significantly prevented the bioaccumulation of Cd and reversed the Cd-induced oxidative tissue damage.

Chronic Toxicity/Oncogenicity of Dimethylacetamide in Rats and Mice Following Inhalation Exposure

Chronic Toxicity/Oncogenicity of Dimethylacetamide in Rats and Mice Following Inhalation Exposure

Primrose, J. N.; Miller, G. V.; Preston, S. R.; Gokhale, J.; Ambrose, N. S.; Ward, U. M.; Mills, J. G.; Ehsanullah, R. S.B.; Darekar, B.

Background—Does the use of the histamine H2 receptor antagonist ranitidine improve the outcome of patients with gastric cancer?Patients—A total of 222 patients with gastric cancer who had received radical or...

Wistar rats (25/ sex • group) and CD-1 mice (30/sex • group) were fed either a control diet or diet supplemented with N,N-dimethylformamide at the levels of 215, 750, and 2500 ppm for rats and 160,540, and 1850 ppm for mice. The duration of feeding was 104 days for rats and 119 days for mice. Body weight gain, food consumption, hematological and clinical chemical data, ophthalmic, gross, and microscopic examinations were used to study possible toxic or pathologic effects. A significant reduction in body weight gain was noted for male and female rats at the high dosage level. Food consumption in male rats at the high-dosage level and female rats at both the middle- and high-dosage levels was decreased. A significant dose-related increase in relative liver weights was noted in male and female rats. Absolute liver weights of male rats were comparable among groups, however, a dose-related increase was noted in female rats. No significant differences among groups were noted in body weight and food consumption data for mice. A significant dose-related increase in relative and absolute liver weights was noted in male and female mice. Histopathological evaluation revealed no evidence of a toxic effect related to feeding of N.N-dimethylformamide to Wistar rats and CD-1 mice. The increase in liver weight is considered to be a normal phenomenon (physiological adaptation) required for the biotransformation of N,N-dimethylformamide. The lack of hepatotoxicity in the present study may be the result of feeding N,N-dimethylf ormamide over waking hours versus bolus dosing (in other studies) in which hepatotoxicity was noted.

In the present study, the effect of vitamin E supplementation in ochratoxin A (OTA) contaminated diet in amelioration of ochratoxicosis in broiler chickens was investigated. Day-old broiler chicks (n=240) were divided into six treatment groups (T1-control (basal diet); T2–T1 + 200 ppb OTA; T3–T1 + 100 mg vitamin E; T4–T1 + 200 mg vitamin E; T5–T2 + 100 mg vitamin E and T6–T2 + 200 mg vitamin E). Each diet was fed to 5 replicated groups of 8 birds each from 0 to 42 days of age. During overall growth period (0–6 week of age), the body weight gain (BWG) in ochratoxin contaminated diet (T2) fed group was lower than that of control. The BWG in group T5 was statistically similar to that of T2 fed diet and lower than that of control (T1). However, BWG in group T6 (200 mg vitamin E/kg) was higher than T2 and statistically similar to that of control group. Ochratoxin contamination in diet caused significant reduction in feed consumption, feed efficiency and livability percentage in broiler chickens. Addition of vitamin E (200 mg/kg) to the ochratoxin contaminated diet ameliorated the adverse effects on feed intake, FCR and livability percentage. Supplementation of vitamin E (200 mg/kg) to the ochratoxin contaminated diet also resulted in significant improvement in the relative weight of liver and bursa. It was concluded that experimentally induced ochratoxicosis with 200 ppb ochratoxin resulted in reduced production performance, enlargement of liver and regression of bursa. Addition of vitamin E (200 mg/kg) to the ochratoxin contaminated diet improved the production performance and relative weight of liver and bursa during 0–6 weeks of age of broiler chickens in experimentally induced ochratoxicosis caused by 200 ppb of dietary ochratoxin.

Isopropanol Vapor Inhalation Oncogenicity Study in Fischer 344 Rats and CD-1 Mice

Isopropanol vapor inhalation oncogenicity study in Fischer 344 rats and CD-1 mice.

An experiment was conducted to evaluate the effect of form and particle size of feed supplemented with L- threonine on growth performance, carcass characteristic and blood biochemical parameters of broiler chickens. The experimental design was a 2 × 2 × 2 factorial arrangement of treatments evaluating two feed forms (pellet or mash), two feed particle sizes (fine or course), and two inclusion rates of dietary L-threonine (with or without) which adopted from 7 to 42 days of age. In this experiment, 360 a day old chicks in two sexes were assigned in each treatment and each experimental unit was included 15 chicks. Feed consumption and weight gain were measured weekly. At 35 days of age, blood samples were taken to analysis blood biochemical parameters. At the end of the experimental period, two birds were slaughtered in each treatment and carcass analysis was carried out. The results showed that the effect of feed form on body weight gain and feed intake in whole of experimental period was significant (P < 0.05). Broilers fed pelleted diets had more weight gain than the mash group. Growth performance parameters were not affected by feed particle size and dietary L-threonine supplementation in whole of experimental period (P > 0.05). The results of carcass analysis showed that liver and gizzard relative weights were influenced by feed form (P < 0.05). However, pancreas and liver relative weights were affected by feed particle size and dietary L-threonine supplementation, respectively (P < 0.05). Triglyceride and VLDL levels were affected by feed form and dietary L-threonine supplementation (P < 0.05). The effect of feed particle size on blood biochemical parameters was not significant (P > 0.05). In conclusion, the experimental results indicated that feed form increased feed consumption and weight gain in whole of experimental period (1 to 42 days of age) while feed particle size and dietary L-threonine had no effect on broiler performance.

Postoperative bile leakage is a typical complication in liver surgery. The influence of bile leakage and concomitant bile peritonitis on the regenerative capacity of the liver remnant has yet not been investigated thoroughly. Methods: SD rats were randomized to the following groups: Sham operation (Sh), 70 % liver resection (LR) and 70 % liver resection with simultaneous induction of a bile leakage (LR+BL) of the right liver lobes. Six rats per group were killed 6, 24, 48 and 96 hours after surgery. Liver regeneration was evaluated by relative liver weight, mitotic index, BrdU labelling index and Ki-67 index. Markers for liver function (thromboplastin time, bilirubin, albumin, ICG disappearance rate) and hepatocellular damage (transaminases, histomorphology) were evaluated as well. In addition, the inflammatory response was determined by measurement of IL-1β, TNF-α, IL-6 mRNA, TGF-β mRNA and myeloperoxidase activity. The bacterial concentration in different organs was quantified by routine microbiologic methods. Results: Liver regeneration was significantly delayed by postoperative bile leakage. After 24 hours, the mitotic index in the LR+BL group (9 ± 6) was significantly reduced compared to the group with LR only (83 ± 20). The relative liver weight (1,42 ± 0,05 %) and the overall-growth fraction (2 ± 1 %), determined by the number of Ki-67-positive cells, were also reduced in the LR+BL group after 24 hours, compared to the LR group (rel. liver weight 1,78 ± 0,04 %, growth fraction 24 ± 2 %). In the LR group regenerative markers declined 48 hours after surgery, whereas the regenerative process reached its maximum in the LR+BL group at that time. For instance, the Ki-67 index was significantly higher 48 h after LR+BL (38 ± 7 %) than after LR alone (21 ±5 %). 96 hours after LR+BL, increased regenerative activity of hepatocytes could still be observed, but the foremost proliferative activity was seen in non-parenchymal cells (as shown by BrdU-positive non-parenchymal cells), especially bile duct epithelial cells. In the LR+BL group, liver function was markedly impaired 24 and 48 hours after surgery, compared to LR only. At early examination times, bile flow was clearly reduced; serum bilirubin was elevated and the ICG disappearance rate was significantly impaired. At no time point, histomorphologic features of liver cell necrosis or significant differences in liver histology were observed in any of the groups. Following LR and BL, the postoperative transcription of cytokines, particularly IL-6, was markedly higher. A significant bacterial super infection in the first 24 hours could be excluded, since microbiologic examination — especially of the liver — revealed no increased bacterial concentrations compared to the LR group. Conclusion: The study shows, that the inflammatory response following intraabdominal bile leakage can promote suppression of liver function as well as impairment of the regenerative capacity of the liver. However, the involved mechanisms remain to be unravelled.

Excessive body weight gain (BWG) is a common side effect of some typical and atypical antipsychotic drugs (APs). Convergent evidence suggests a hierarchy in the magnitude of BWG that may be induced by diverse agents, being very high for clozapine and olanzapine; high for quetiapine, zotepin, chlorpromazine, and thioridazine; moderate for risperidone and sertindole; and low for ziprazidone, amisulpiride, haloperidol, fluphenazine, pimozide, and molindone. BWG may be related to increased appetite that is due to drug interaction with the brain monoaminergic and cholinergic systems and to the metabolic/endocrine effects of hyperprolactinemia. Subjects with schizophrenia and bipolar disorders manifested a significantly high prevalence of diabetes, even before the introduction of atypical APs. However, clozapine and olanzapine appear to display a high propensity to induce glucose dysregulation and dyslipidemia. Sudden BWG, insulin resistance, increased appetite, and related endocrine changes also may be involved in the development of glucose intolerance and dyslipidemia in predisposed individuals. Patients should be informed of these side effects in order to prevent excessive BWG, and their blood glucose and lipids should be monitored before treatment and then at regular intervals. Nutritional advice must be given and regular physical exercise recommended. An appropriate selection of APs ought to be based on drug efficacy for specific patients and assessment of relevant risk factors such as propensity to gain weight; family or personal history of diabetes or hyperlipidemia; and elevated fasting serum glucose, lipid, or insulin levels. At present, there is no standardized pharmacological treatment for AP-induced BWG. Some studies have assessed the effects of agents such as amantadine, orlistat, metformin, nizatidine, and topiramate on AP-induced BWG. Further studies will provide tools to identify patients at high risk for obesity and metabolic abnormalities during AP administration. Excessive body weight gain (BWG), glucose intolerance, and dyslipidemia during treatment with antipsychotic drugs (APs) were reported in the late 1950s [14,101]. However, after 1990, interest in these problems increased noticeably, mainly because of the high propensity of some new atypical APs to induce these side effects (Fig.1). The APs are currently used in diverse mental disorders. Hence, excessive BWG and metabolic dysfunction are not exclusive of subjects with schizophrenia. In the case of bipolar disorders, AP-induced BWG may be additive to that induced by mood stabilizers [14,48,101]. The clinical features [2,14,24,133,139,140] and mechanisms [14,34,68,87,93,101,130] of BWG and metabolic dysfunction have been previously reviewed. In this article, we focus on a unified theory to explain these side effects, based on the interaction of APs with brain neurotransmitters involved in appetite regulation. This review comprises the following sections: 1) the clinical features of AP-induced BWG; 2) the effects of APs on carbohydrate and lipid metabolism in humans and experimental animals; 3) mechanisms involved in BWG, glucose, and lipid dysregulation; 4) strategies for prevention and treatment of these side effects; and 5) research perspectives in the field. The following sources were consulted: MEDLINE, Cochrane database system, and PsychINFO. Numerous articles referred to in leading articles also were consulted. The literature on this subject has increased so rapidly that it was impossible to include all the data recently published. For the first two sections, references that illustrate current controversies in the field were selected.

To determine the impact of histamine2 (H2)-receptor antagonist use on the occurrence of infectious complications in severely injured patients. Some previous studies suggest an increased risk of nosocomial pneumonia associated with the use of H2-receptor blockade in critically ill patients, but other investigations suggest an immune-enhancing effect of H2-receptor antagonists. The purpose of this study was to determine whether H2-receptor antagonist use affects the overall incidence of infectious complications. Patients enrolled in a randomized trial comparing ranitidine with sucralfate for gastritis prophylaxis were examined for all infectious complications during their hospitalization. Data on the occurrence of pneumonia were prospectively collected, and other infectious complications were retrospectively obtained from the medical record. The relative risk of infectious complications associated with ranitidine use and total infectious complications were analyzed. Of 98 patients included, the charts of 96 were available for review. Sucralfate was given to 47, and 49 received ranitidine. Demographic factors were similar between the groups. Ranitidine use was associated with a 1.5-fold increased risk of developing any infectious complication (37 of 47 vs. 26 of 47; 95% confidence interval, 1.04 to 2.28). Infectious complications totaled 128 in the ranitidine-treated group and 50 in the sucralfate-treated group (p = 0.0014). These differences remained after excluding catheter-related infections (p = 0.0042) and secondary bacteremia (p = 0.0046). Ranitidine use in severely injured patients is associated with a statistically significant increase in overall infectious complications when compared with sucralfate. These results indicate that ranitidine should be avoided where possible in the prophylaxis of stress gastritis.

Xian-Ling-Gu-Bao induced inflammatory stress rat liver injury: Inflammatory and oxidative stress playing important roles