Wuzhi capsule regulates chloroacetaldehyde pharmacokinetics behaviour and alleviates high-dose cyclophosphamide-induced nephrotoxicity and neurotoxicity in rats.

High-dose cyclophosphamide (HD-CTX) treatment often leads to severe nephrotoxicity and neurotoxicity, which are mainly caused by one of its metabolites, chloroacetaldehyde (CAA). However, there are no effective antidotes to prevent these side effects. The objective of this study was to evaluate the effect of Wuzhi Capsule (WZC) on the pharmacokinetics of CTX and its metabolites in rats, and the attenuation of CAA induced kidney and brain injuries, which was produced at equimolar with 2-dechloroethylcyclophosphamide. Rats were treated with single- or multiple-dose of WZC when giving HD-CTX, and the plasma concentration of CTX and its metabolites were quantitated by UHPLC-MS/MS Single-dose, not multiple-dose of WZC co-administration (300 mg/kg) significantly reduced Cmax and AUC0→24 h of DC-CTX by 33.10% and 35.51%, respectively. Biochemical assay suggested oxidative stress was involved in kidney and brain injuries by HD-CTX, which were attenuated by single-dose WZC (300 mg/kg) pre-treatment, with increased glutathione, glutathione peroxidase and superoxide dismutase contents/or activities in both tissues and plasma (P < 0.05). Meanwhile, WZC pre-treatment could also significantly decrease the plasma levels of creatinine, blood urea nitrogen and malondialdehyde (P < 0.05). Additionally, WZC treatment improved the morphology and pathology condition of the kidneys and brains in rats. In conclusion, single-dose WZC co-administration decreased CAA production and exerted protective effect on CTX-induced oxidative stress in kidney and brain, whereas repetitive WZC co-administration with CTX was probably not recommended.

Ifosfamide-induced nephrotoxicity: mechanism and prevention.

The efficacy of ifosfamide (IFO), an antineoplastic drug, is severely limited by a high incidence of nephrotoxicity of unknown etiology. We hypothesized that inhibition of complex I (C-I) by chloroacetaldehyde (CAA), a metabolite of IFO, is the chief cause of nephrotoxicity, and that agmatine (AGM), which we found to augment mitochondrial oxidative phosphorylation and beta-oxidation, would prevent nephrotoxicity. Our model system was isolated mitochondria obtained from the kidney cortex of rats treated with IFO or IFO + AGM. Oxidative phosphorylation was determined with electron donors specific to complexes I, II, III, or IV (C-I, C-II, C-III, or C-IV, respectively). A parallel study was done with (13)C-labeled pyruvate to assess metabolic dysfunction. Ifosfamide treatment significantly inhibited oxidative phosphorylation with only C-I substrates. Inhibition of C-I was associated with a significant elevation of [NADH], depletion of [NAD], and decreased flux through pyruvate dehydrogenase and the TCA cycle. However, administration of AGM with IFO increased [cyclic AMP (cAMP)] and prevented IFO-induced inhibition of C-I. In vitro studies with various metabolites of IFO showed that only CAA inhibited C-I, even with supplementation with 2-mercaptoethane sulfonic acid. Following IFO treatment daily for 5 days with 50 mg/kg, the level of CAA in the renal cortex was approximately 15 micromol/L. Taken together, these observations support the hypothesis that CAA is accumulated in renal cortex and is responsible for nephrotoxicity. AGM may be protective by increasing tissue [cAMP], which phosphorylates NADH:oxidoreductase. The current findings may have an important implication for the prevention of IFO-induced nephrotoxicity and/or mitochondrial diseases secondary to defective C-I.

Watercress has no Importance for the elimination of ethanol by CYP2E1 inhibition.

Watercress, a cruciferous vegetable, is known to inhibit the metabolism of several CYP2E1 substrates such as paracetamol and chlorzoxazone. Since ethanol and its metabolite, acetaldehyde, are CYP2E1 substrates, the influence of watercress on ethanol and acetaldehyde was investigated in healthy human volunteers. According to a randomized cross-over design, ethanol and acetaldehyde pharmacokinetic parameters were determined in 9 persons at 3 occasions: without watercress and after watercress ingestion preceding ethanol consumption from 1 or 10.5 hr, respectively. Ethanol tmax occurred significantly later when watercress was ingested 1 hr before ethanol ingestion. Likewise, acetaldehyde Cmax was significantly higher whereas acetaldehyde AUCs were increased by watercress but not significantly. All other ethanol and acetaldehyde pharmacokinetic parameters were similar between the 3 treatments. In healthy volunteers, no major watercress effect was observed on ethanol clearance but a weak inhibiting effect on acetaldehyde metabolism is possible. Ethanol absorption is also delayed by single ingestion of watercress immediately preceding ethanol consumption.

Alcohol and liver fibrosis--pathobiochemistry and treatment.

In Western societies roughly 50% of all cases of liver cirrhosis are related to alcohol abuse. The oxidative metabolite of ethanol, acetaldehyde, often in conjunction with viral or metabolic liver disease, is implicated as the major cause for liver fibrogenesis. Acetaldehyde damages cell membranes, initiates lipid peroxidation and forms noxious protein adducts, resulting in the activation of Kupffer cells and perisinusoidal lipocytes/portal fibroblasts. The activation of lipocytes and fibroblasts to a proliferative and collagen-producing myofibroblast-like phenotype is triggered by the release of fibrogenic factors such as platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) from the activated Kupffer cells. Due to the socioeconomic burden inflicted by cirrhosis, antifibrotic treatment is urgently needed. Strategies to prevent or reverse cirrhosis must interrupt the continuous process of pathological wound healing in the liver. An antifibrotic effect has been demonstrated for the interferons, prostaglandins E and relaxin. Polyunsaturated lecithin, silymarin and ursodeoxycholic acid, agents with a high hepatotropism and a good safety-profile, appear to have antifibrotic properties. Targeted approaches include the specific removal of matrix-bound fibrogenic growth factors and the induction of stress-relaxation of the activated mesenchymal cells by biologically active matrix-peptides and their stable analogues. Since serum tests for the non-invasive assessment of collagen synthesis and degradation in the liver are now available, rapid progress in the development and clinical application of antifibrotic drugs can be anticipated.

[The evaluation of the efficacy of carbamazepine and valproic acid in the alcohol postintoxication syndrome based on ethanol and acetaldehyde kinetics and the content of biogenic monoamines]. / Otsenka éffektivnosti karbamazepina i val'proevoi kisloty pri alkogol'nom postintoksikatsionnom sindrome po kinetike étanola i atsetal'degida i soderzhaniiu biogennykh monoaminov.

The effects of carbamazepine and valproic acid on disturbances of behaviour, elimination of ethanol, acetaldehyde from the blood, the contents of adrenaline, noradrenaline, dopamine, serotonin, 5-hydroxyindoleacetic acid and histamine in the brain and blood in alcoholic postintoxication syndrome were studied on male albino rats. Carbamazepine and valproic acid were shown to reduce the behavioural manifestations of the syndrome, to increase elimination of ethanol and acetaldehyde, to normalize the levels of the mediators in the brain tissues, particularly in the thalamus.