The effects of acetaminophen on the metabolism of the isolated perfused rat liver were investigated. The following results were obtained: (1) Acetaminophen increased glucose release and glycolysis from endogenous glycogen (glycogenolysis). (2) Oxygen uptake, gluconeogenesis from either pyruvate or fructose and glycogen synthesis were inhibited. (3) In isolated rat liver mitochondria acetaminophen decreased state III and state IV respiration; it also decreased the ADP/O ratio and the respiratory control ratio. (4) The action of acetaminophen on glycogenolysis was not affected by N-acetylcysteine; this compound, however, increased glycogen synthesis. (5) The effects of acetaminophen are reversible. It was concluded that glycogen depletion by acetaminophen can be produced by two mechanisms. The first, as previously demonstrated by several workers, depends on irreversible binding of a reactive metabolite. The second, however, is reversible and depends primarily on an inhibition of mitochondrial energy metabolism.

The actions of tamoxifen, a selective estrogen receptor modulator used in chemotherapy and chemo-prevention of breast cancer, on glycolysis and gluconeogenesis were investigated in the isolated perfused rat liver. Tamoxifen inhibited gluconeogenesis from both lactate and fructose at very low concentrations (e.g., 5μM). The opposite, i.e., stimulation, was found for glycolysis from both endogenous glycogen and fructose. Oxygen uptake was unaffected, inhibited or stimulated, depending on the conditions. Stimulation occurred in both microsomes and mitochondria. Tamoxifen did not affect the most important key-enzymes of gluconeogenesis, namely, phosphoenolpyruvate carboxykinase, pyruvate carboxylase, fructose 1,6-bisphosphatase and glucose 6-phosphatase. Confirming previous observations, however, tamoxifen inhibited very strongly NADH- and succinate-oxidase of freeze-thawing disrupted mitochondria. Tamoxifen promoted the release of both lactate dehydrogenase (mainly cytosolic) and fumarase (mainly mitochondrial) into the perfusate. Tamoxifen (200μM) clearly diminished the ATP content and increased the ADP content of livers in the presence of lactate with a diminution of the ATP/ADP ratio from 1.67 to 0.79. The main causes for gluconeogenesis inhibition are probably: (a) inhibition of energy metabolism; (b) deviation of intermediates (malate and glucose 6-phosphate) for the production of NADPH required in hydroxylation and demethylation reactions; (c) deviation of glucosyl units toward glucuronidation reactions; (d) secondary inhibitory action of nitric oxide, whose production is stimulated by tamoxifen; (e) impairment of the cellular structure, especially the membrane structure. Stimulation of glycolysis is probably a compensatory phenomenon for the diminished mitochondrial ATP production. The multiple actions of tamoxifen at relatively low concentrations can represent a continuous burden to the overall hepatic functions during long treatment periods.

This study evaluated the influence of the alcohol present in a formulation of the antiophidic phytotherapic tincture, Específico-Pessôa, on rat blood biochemical and hematological parameters, and on organ histology. Three groups of rats were treated orally for 10, 15, or 30 days; one group received the tincture, the other received alcohol alone, and the third was a control group. The results of this study indicated that cholesterol levels were significantly increased after 10 days in the alcohol and tincture groups, although these decreased after 30 days in the tincture group. Triglyceride levels were significantly reduced after 15 days in the tincture group and after 30 days in the alcohol and tincture groups. A higher creatinine level was observed in the alcohol and tincture groups after 15 and 30 days. The uric acid levels in these groups were reduced at 10 and 30 days, although this metabolite was elevated at 15 days in the alcohol group. Hydropic multifocal degeneration with lymphohistiocytic infiltration and some polymorphonuclear cells was observed in the livers of rats treated with either the tincture or alcohol. These data demonstrate the importance of considering the potential actions of the alcohol present in pharmaceutical formulations.

Tamoxifen is effective in breast cancer therapy in postmenopausal women; however, it causes adverse effects that alter the glycolytic pathway and induce hyperglycemia. Quercetin, a flavonoid with antioxidant potential, inhibits butyrylcholinesterase (BuChE), which is positively associated with hyperglycemia. Therefore, this study investigated the effect of quercetin on tamoxifen-induced hyperglycemia, using BuChE activity as a bioindicator in adult ovariectomized Wistar rats. The ovariectomized rats were treated orally for 14 days with different concentrations of quercetin (2.5, 7.5, 22.5, and 67.5 mg.kg b.w.) and tamoxifen (5 mg.kg b.w.). Subsequently, they were euthanized; blood and tissue samples were collected. The following biochemical parameters were analyzed: plasma glucose levels and BuChE activity in the plasma, liver, intestine, and adipose tissue. The most effective dose of quercetin in reducing hyperglycemia was 22.5 mg.kg b.w. (Que/TAM 4.5/1, P < .00000), although the doses of 2.5 (Que/TAM 0.5/1, P < .05) and 7.5 mg.kg b.w. (Que/TAM 1.5/1, P < .05) were also effective. The BuChE activity decreased in the intestine at all tested doses of quercetin coadministered with tamoxifen (P < .01); however, in adipose tissue, there was a biphasic activity with a decrease (P < .05) and increase (P < .05) in activity at doses of 7.5 and 22.5 mg.kg b.w. of quercetin, respectively. However, the correlation between BuChE and glucose levels was not significant (P > .05). In summary, the findings of the present study suggest that quercetin when associated with tamoxifen decreases in plasma glucose levels. Furthermore, in these cases, BuChE should not be used as an indicator of hyperglycemia.

Harpalyce brasiliana Benth, known as snakeroot, is one of the most popular herbal medicines against snakebite in South America. A hydroalcoholic solution is traditionally prepared from the roots of H. brasiliana. In the last two decades, understanding the pharmacological properties and the possible medicinal applications of H. brasiliana has increased considerably. H. brasiliana has antivenom activity and anticarcinogenic, antimicrobial and antioxidant properties. Various in vitro and in vivo studies have shown H. brasiliana's diverse biological properties and its potential for disease treatment. The different biological effects of this plant may be attributable to the presence of secondary active metabolites such as pterocarpans, triterpenoids, chalcones and flavonoids. This overview presents different aspects of this plant and the pharmacological properties of its compounds through a review of the available literature. The results support the use of H. brasiliana in the treatment of snakebite and its potential for treatment of other diseases in folk medicine.

No abstract

For more 30 years, phytotherapic tincture Específico-Pessôa has been used as supportive therapy in envenoming by snakebites in Brazilian folk medicine. However, little or no information is available in the literature about the safety/toxicity of this phytotherapic tincture. The present work was designed to investigate the effect of this tincture by maximum dose (0.75 ml kg -1 body weight) on acetyl-and butyrylcholinesterase and other biochemical parameters in male Wistar rats. Male rats were treated with 0.75 ml kg -1 body weight dose of phytotherapic tincture Específico-Pessôa, and biochemical parameters were evaluated in 24, 48 h and ten days after treatment. Clinical signs of toxicity, body weight gain and cholinesterasic activities in brain and liver were also observed. The phytotherapic tincture exhibited significant effect (P < 0.05) on weight body gain, organs weight ratio (brain, heart and lungs), aspartate transaminase (AST), acetyl-and butyrylcholinesterase activities, cholesterol and low dencity lypoproteins (LDL) levels. The results indicate that tincture is active on physiologic system. These findings suggest precaution in the use of this phytotherapic tincture at the dose utilized in this study.

This study evaluated if the oral administration of a bottled medicine containing Echinacea, Graviola, Purple Ipe, Sucupira and Cat's claw could cause changes in biochemical, coagulation, hematological and histopathological parameters in rats. This study arised after a report to Ceatox of a patient who used a bottled medicine and developed hematological, renal and histopathological changes. The bottled medicine possesses 4.32 mg alcohol.mL-1 and by the phytochemical screening and UV/Scan tests showed some classes of secondary metabolites. In experiments using Wistar rats, two treatments were performed, single dose and 30 days, administering water, alcohol and bottled medicine by gavage. In the single dose treatment, alterations of uric acid, cholesterol, creatinine, alkaline phosphatase, iron and glucose (p<0.05) were found. Already in the 30 days treatment were alterations of uric acid, total and indirect bilirubins, creatinine, alkaline phosphatase, glucose, triglycerides, erythrocytes and leukocytes (p<0.05), and hepatic sinusoidal dilatation. The data showed that the alcohol present in the bottled medicine can alter biochemical, hematological parameters and cause liver damage in rats. The bottled medicine, although not showing alterations in important biochemical and hematological parameters, had more pronounced liver histopathological alterations.