Protective effects of glutathione on bromodichloromethane in vivo toxicity and in vitro macromolecular binding in Fischer 344 rats

Bromodichloromethane (BDCM), a carcinogenic water disinfection by-product, has been shown to be metabolized to intermediates that covalently bind to lipids and proteins, and this binding has been associated with trihalomethane-induced renal and hepatic toxicity. In this study, the effects of glutathione (GSH) on in vivo BDCM toxicity and in vitro BDCM macromolecular binding were evaluated. The in vivo toxicity of BDCM in animals pretreated with buthionine sulfoximine (BSO, a glutathione synthesis inhibitor) and in untreated male Fischer 344 rats was investigated. In another experiment, covalent binding to protein and lipid was quantified after [14C]BDCM was incubated with hepatic microsomal and S9 fractions and renal microsomes from F344 rats, under aerobic and anaerobic conditions, with and without added GSH. After oral dosing with BDCM, the BSO-pretreated animals had greatly increased levels of serum indicators of hepatotoxicity and serum and urinary indicators of nephrotoxicity compared to those in animals dosed solely with BDCM. Histopathological examination revealed that hepatic necrosis was more severe than renal necrosis in the BSO-treated rats. When GSH was added to an aerobic incubation, protein binding was decreased in hepatic microsomal and S9 fractions by 92 and 83%, respectively. GSH also decreased lipid binding by 55% in hepatic microsomal incubations carried out under anaerobic conditions. Addition of GSH decreased renal microsomal protein (aerobic) and lipid binding (anaerobic) by 20 and 43%, respectively. These data indicate that GSH is an important protective factor in the toxicity associated with BDCM.     

白藜芦醇对小鼠的急性经口毒性和遗传毒性试验研究

目的:了解白藜芦醇的急性经口毒性和遗传毒性,为白藜芦醇的食用、药用安全性评价提供实验依据.方法:按照的规定,对白藜芦醇进行急性经口毒性测定,并通过Ames试验(每皿分别加入5 000、1 000、200、40、8 μg白藜芦醇)、小鼠骨髓嗜多染红细胞微核试验及小鼠精子畸形试验(分别以7.500、3.750、1.875g/kg剂量的白藜芦醇给小鼠灌胃)对其遗传毒性进行评价.结果:白藜芦醇的急性经口最大耐受剂量>15.0 g/kg;3项遗传毒性试验结果均为阴性.结论:在本实验条件下,白藜芦醇对小鼠的急性经口毒性属无毒,未见遗传毒性作用.     

Vinorelbine-related acute cardiopulmonary toxicity

Three cases of possible acute cardiopulmonary toxicity following the administration of vinorelbine are reported. The symptoms mimicked acute cardiac ischemia. However, neither ECG changes nor elevations of serum enzymes were observed. The outcome is favorable in 90% of patients developing this adverse event. The putative mechanism remains to be elucidated.     

The acute toxicity of Riedeliella graciflora in calves

Three calves received 10 g Riedeliella graciflora dry leaves/kg body weight by gavage. Blood samples were taken immediately before plant administration and at 2, 4, 6, 12 and 24 hours later; serum ALT, AST, AP, TB, urea and creatinine were determined. After R graciflora administration, the calves had anorexia, profound depression and recumbency prior to death. Creatinine levels increased markedly until death. Severe tubular nephrosis was consistently observed.     

Dose-dependent effects of acute in vivo ethanol exposure on extracellular glutamate concentration in the cerebral cortex of the near-term fetal sheep

The cerebral cortex is a target site of ethanol teratogenesis. L-Glutamate is a major excitatory neurotransmitter that plays an important neurotrophic role in brain development. It has been proposed that optimal function of the glutamate neuronal system is required for normal brain development; overactivation could lead to excitotoxic-induced neuronal injury, whereas underactivation could delay/restrict brain development. The objective of this study was to test the hypothesis that acute in vivo ethanol exposure alters basal glutamate release in the fetal cerebral cortex. The experimental approach involved measuring fetal cortical extracellular glutamate concentration using the technique of in vivo microdialysis. Near-term fetal sheep were chronically instrumented with a microdialysis probe placed in the parasagittal cortex. At 124 +/- 3 days of gestation, the effects of maternal intravenous infusion of 2 g or 4 g ethanol/kg maternal body weight or an equivalent volume of saline, given as four equally divided doses over 5 hr, on fetal cerebral cortical extracellular glutamate concentration were determined. None of the three treatment regimens produced fetal or maternal demise during the time course of the study. There was an ethanol dose-dependent increase, p = 0.005, in extracellular glutamate concentration in the fetal cerebral cortex. This increase was paroxysmal in nature and was not directly related to the fetal blood ethanol concentration. In view of the proposed role for glutamate in neuronal development, this apparent ethanol-induced increase in glutamate release may be important in the pathogenesis of ethanol teratogenesis involving the cerebral cortex.     

Effects of arsenite pretreatment on the acute toxicity of parathion

Parathion (PA) is a phosphorotioate pesticide requiring P-450-mediated oxidations to become activated to paraoxon, or to be metabolised to its less toxic metabolites. On the other hand, sodium arsenite [As(III)] markedly decreases total hepatic P-450 content and dependent monoxygenase activities. Our aim was to determine the effects of As(III) pretreatment on the acute toxicity of PA and its possible relationship with the effects of As(III) on P-450-dependent monooxygenase activities. Adult male Wistar rats were pretreated with As(III) (5.6 mg As(III)/kg, s.c.), and 24 h later given PA (5 to 20 mg/kg, per os). As(III) pretreatment increased the acute toxicity of PA, reducing 38% its median lethal dose (LD50) from 11.68 to 7.21 mg PA/kg. In addition, As(III) pretreatment further decreased the inhibitory effect of PA on brain acetylcholinesterase activity, reducing 33% the median inhibitory dose (ID50) from 3.44 to 2.31 mg PA/kg. whereas As(III) alone had no significant effects. As(III) decreased the P-450 content to 87% of control values, reduced EROD activity to 74% and BROD activity to 41%; PA produced no significant effects on these parameters, whereas the joint administration of As(III)+ PA produced effects similar to those of As(III). PROD activity was reduced to 36% of control value by PA, whereas As(III) alone produced no significant effects. However, As(III) pretreatment apparently protected against the inhibition of CYP2B1-mediated PROD activity produced by PA, since PROD values were similar to those of control animals. Our results also indicated that the increase in PA toxicity caused by As(III) pretreatment, could also be related to the CYP2B2 isoform, since decreases in CYP2B2-dependent BROD activity were observed in both As(III) and As(III) + PA groups, but not in PA-treated animals, suggesting that CYP2B2 is involved in PA detoxification.     

Reduction by coenzyme Q10 of the acute toxicity of adriamycin in mice

Pretreatment for four days with coenzyme Q10 (COQ10) reduced the acute toxicity in mice treated with adriamycin. In two sequential protocols, adriamycin allowed only 36 and 42% survival, respectively. Pretreatment with COQ10 allowed 80 and 86% survival, respectively. The differences are significant, p less than 0.05. The mechanism for this reduction in the acute toxicity may be based upon the prevention by the supplementary COQ10 of the inhibition caused by adriamycin to COQ10-dependent enzymes in cardiac and and other tissues. The prospect of diminishing the toxicity of adriamycin in cancer patients remains promising and important.     

Dose-dependent effects of oral acyclovir in the incubation period of varicella

Dose of acyclovir (ACV) and clinical features of varicella were evaluated in 65 household contacts (0.8-9 y) who received oral ACV (5-80 mg/kg daily in four divided doses) during the latter half of the incubation period of varicella. The severity of the disease was compared with that of 23 children who did not receive ACV. Infection was confirmed by a fluorescent antibody to membrane antigen assay. The antibody titers and the rate of apparent infection increased as the dose of ACV administered decreased. The number of skin lesions in patients who received ACV was significantly reduced when compared to the control group. These data suggest dose-dependence of ACV for modification of varicella during secondary viremia in the incubation of the disease.     

Dose-dependent effects of chloroquine on secretory granule formation in the melanotroph

Intracellular calcium ([Ca2+]i) and hydrogen ion concentrations (pHi) are important regulators of cell function. Those ions also may interact and it is important, therefore, to measure their concentrations simultaneously. In the present studies we used a system developed for that purpose, a fluorescent emission ratio technique for simultaneous analysis of calcium (Indo-1) and pH (SNARF-1) in single cells at video rates, and determined if arginine vasopressin (AVP, 12.5 mumol/l) evoked [Ca2+]i and pHi signals interact in MDCK cells. We also employed a simple system for analysing the side specific (basolateral or apical) application of agonist to polarized cell layers on permeable membranes. AVP is found to evoke simultaneous changes in both pHi and [Ca2+]i. Basolateral application induced transient acidification, followed by partial recovery, and a [Ca2+]i transient with kinetic pattern similar to that of the pHi. Apical application also caused a mirror image pHi and [Ca2+]i pattern but of smaller magnitude (no peak). Selective removal of extracellular calcium ([Ca2+]e) or sodium ([Na+]e) dissociated the pHi and [Ca2+]i responses in both cases. Na+e removal abolished the pHi changes, but not the [Ca2+]i transients. [Ca2+]e removal abolished the [Ca2+]i changes and reduced, but did not abolish, the pHi responses. Thus, AVP induces pHi changes which are modified by calcium while calcium signalling is not modified by changes in pHi.     

Dose-dependent pharmacokinetics of rapamycin-28-N,N-dimethylglycinate in the mouse

Rapamycin-28-N,N-dimethylglycinate methanesulfonate salt (RG), synthesized as a potential water-soluble prodrug to facilitate parenteral administration of the antineoplastic macrolide rapamycin (RA), is active against intracranially implanted human glioma in mice. Preclinical pharmacokinetic studies to evaluate the prodrug were conducted in male CD2F1 mice treated with 10, 25, 50 and 100 mg/kg doses of RG by rapid i.v. injection. The plasma concentration of RG decayed in a distinctly triphasic manner following treatment with the 100 mg/kg dose; however, prodrug disposition was apparent biexponential at each of the lower doses. RG exhibited dose-dependent pharmacokinetics, characterized by an increase in the total plasma clearance from 12.5 to 39.3 ml.min-1.kg-1 for dosage escalations in the range 10-50 mg/kg, while clearance values at doses of 50 and 100 mg/kg were similar. The terminal rate constants decreased linearly as the dose was increased from 10 to 100 mg/kg, eliciting an apparent prolongation of the biological half-life from 2.1 to 4.8 h. There was also a sequential increase in the steady state apparent volume of distribution from 1.73 to 8.75 l/kg. These observations are consistent with saturable binding of RG to plasma proteins while binding to tissue remains linear. Nevertheless, conversion to RA appeared to represent a prominent route of RG elimination. The molar plasma concentration of RA exceeded that of the prodrug within 30-90 min after i.v. treatment and declined very slowly thereafter, with plasma levels sustained between 0.1 and 10 microM for 48 h at each of the doses evaluated. Thus, RG effectively served as a slow release delivery system for RA, implying the possibility of maintaining therapeutic plasma levels of the drug from a more convenient dosing regimen than a continuous infusion schedule. The present findings, coupled with the demonstrated in vivo activity of RG against human brain tumor models, warrant its continued development as a much needed chemotherapeutic agent for the treatment of brain neoplasms.     

Early acute hepatitis with parenteral amiodarone: a toxic effect of the vehicle?

A 72 year old white man developed acute hepatic impairment and renal failure within 24 hours of starting intravenous amiodarone for paroxysmal ventricular tachycardia. After normal initial investigations, there was a noticeable rise in serum transaminases as well as an increase in clotting times, a decrease in renal function and a thrombocytopenia. These changes returned to normal within seven days of withdrawal of the drug without specific treatment, and the patient was later treated with oral amiodarone without any further evidence of hepatotoxicity. Intravenous amiodarone has been implicated in acute hepatic disease on four previous occasions, but it is suggested that polysorbate 80, an organic surfactant added to the intravenous infusion, is a more likely cause of this complication. Similar reactions have been described with polysorbate 80 in association with the 'E-ferol' syndrome in infants. The occurrence of acute hepatic impairment with intravenous amiodarone does not necessarily preclude the use of this drug by mouth.     

Dose-dependent gingival overgrowth induced by cyclosporin in rats

This study evaluated the effect of dosage on severity of cyclosporin-A (CSA) induced gingival overgrowth. Eighty (80) male Sprague-Dawley rats were randomly distributed into 4 groups. Rats in each group daily received CSA in mineral oil by gastric feeding at dosages of 0 (control), 3, 10, and 30 mg/kg, respectively, for 6 weeks. Stone models of the mandibular incisal region were obtained biweekly and were used for analysis of the gingival dimensions. Animals were sacrificed at the end of week 6 and tissue sections were processed for histopathologic evaluations. Animals were sacrificed at the end of week 6 and tissue sections were processed for histopathologic evaluation Gingival overgrowth including bucco-lingual and mesio-distal width and vertical height were significantly increased with increasing CSA dosage. Furthermore, the gingival dimensions displayed a positive linear relation to dosage and treatment duration. The histopathologic evaluation revealed a granulomatous tissue wedging the tooth-gingival interface in the 3 mg/kg group. This tissue had reached exuberant size in the 10 and 30 mg/kg groups. In summary, the analysis of gingival dimensions the histopathologic evaluation shows a dose-dependent effect on the severity of CSA-induced gingival overgrowth.     

Comparative acute toxicity and primary irritancy of the ethylidene and vinyl isomers of norbornene

Perlecan and aggrecan are proteoglycans that receive primarily heparan sulfate and chondroitin sulfate side chains, respectively. Their large multidomained core proteins have little or no homology to each other and their glycosaminoglycan (GAG) attachment sites are restricted to certain domains only. We examined the involvement of the non-GAG bearing domains in designating the GAG type added to the GAG attachment domain by preparing cDNA constructs that expressed perlecan/aggrecan chimeras as recombinant products in COS-7 cells and then determining the size and GAG composition of the recombinant products. The results showed that domain I of perlecan receives primarily (73-81%) heparan sulfate when coupled with domain II and III of perlecan, but when coupled with the G3 domain of aggrecan, it receives primarily (59-63%) chondroitin sulfate. Furthermore, the chondroitin sulfate attachment region of aggrecan received GAG side chains more readily when coupled to the G3 domain of aggrecan than when coupled to domains II and III of perlecan. The GAG side chains on all these recombinant products were small and similar in size. These findings indicate that the utilization of attachment sites for heparan and chondroitin sulfate or the sulfation of these GAGs can be influenced, in part, by non-GAG bearing domains.     

Low acute toxicity of radiotherapy and radiochemotherapy in patients with cancer of the anal canal and HIV-infection

Although not an AIDS-defining malignancy, anal cancer is an evolving problem in HIV-infected patients. Treatment-tolerance to radiotherapy as well as to chemotherapy is supposed to be reduced in patients with HIV-infection. From January 1995 to January 1997, four patients with epidermoid cancer of the anal canal and a long history of HIV-infection but without symptoms of AIDS or repeated severe infections were treated with radiotherapy (n = 1) or radiochemotherapy (n = 3). External beam radiotherapy with 45 Gy to the tumor and pelvic as well as inguinal lymphatic drainage was administered. In tumors larger than T2 N0 lesions an additional boost of 9 Gy was given. Chemotherapy consisted of 5-fluorouracil 1000 mg/m2/24 h, d 1-4 two cycles and Mitomycin C either 1 x 15 mg/m2, d 1 in the first, or 2 x 10 mg/m2, d 1, in the first and fifth week of radiotherapy. Acute reactions were mild to moderate in all patients and all but one treatment could be given as scheduled (1 patient with a delay of 4 days). No excessive acute reactions were seen. Because of the short follow-up, late reactions and local control are not yet evaluable.     

Adjuvant treatment with cyclosporin A increases the toxicity of chemotherapy for remission induction in acute non-lymphocytic leukemia

P-glycoprotein (Pgp)-related multidrug resistance (MDR) is frequently observed in acute non-lymphocytic leukemia (ANLL) and is associated with a poor response to standard chemotherapy. Cyclosporin A (CsA) is an effective downmodulator of Pgp-related MDR in vitro and has already been tested for that purpose in vivo also. Since Pgp is expressed in several normal cells and tissues, the modulation of Pgp can also modify total body exposure to antileukemic drugs and can alter and increase the toxicity of the antileukemic treatment. We report here the results of a study where 46 consecutive adult patients with ANLL were assigned to receive the same standard chemotherapy regimen of arabinosyl cytosine and idarubicin (IDA) for remission induction or consolidation, without or with CsA. Twenty-eight patients received 36 courses of chemotherapy without CsA and 18 patients received 32 courses of chemotherapy with CsA. CsA dose was 10-12.5 mg/kg/day and was given as a continuous i.v. infusion for 72 h. Whole blood CsA steady-state concentration ranged between 0.61 and 1.14 microM. The IDA area-under-the-curve was about twice as high in the cases that received CsA than in the other cases. CsA had no detectable effects on renal function and fluid balance, but significantly increased systemic blood diastolic pressure and conjugated bilirubine concentration. Furthermore, CsA-treated patients had greater, and more severe, oral and intestinal mucosal toxicity, with more severe adverse events, including more cases of gram-negative bacteremia, and with a delayed hemopoietic recovery. In conclusion, this study showed that an attempt at an effective downmodulation of Pgp-mediated MDR would substantially increase the hemopoietic and mucosal toxicity of antileukemic treatment and that the increase is accounted for, at least in part, by an increase of total body exposure to IDA.     

The higher the dose, the greater the sex differences in escape-avoidance response in mice after acute administration of haloperidol

Sex differences in the effects of haloperidol in the escape-avoidance response have previously been found in various studies carried out in our laboratory in which mice were used as experimental subjects. Males were more affected than females by the disruptive effects of this neuroleptic of frequent clinical use. In the present work these sex differences were evaluated in a unique training session using several doses of the drug (0.075, 0.25, and 0.75 mg/kg i.p.). The number of avoidances, escapes, nonresponses, crossings during the adaptation period, crossings during intertrial intervals, and response latencies were analyzed. Statistically significant sex differences were found in the number of escapes and nonresponses: males showed fewer escape responses and more nonresponses than females. These sex differences were dose dependent: a positive correlation was obtained between doses of haloperidol and sex differences observed in the number of escapes and nonresponses. The higher the dose, the greater the sex differences. These are related not only to the impairment of motor activity, because no sex differences were found in the number of crossings during the adaptation period and intertrial intervals.     

稀土对生物机体剂量效应机理的研究进展

综述了稀土元素对生物机体剂量效应的机理 ,从稀土对细胞质膜、细胞周期及细胞凋亡、Ca M水平调节的作用到对蛋白质、DNA的影响等不同层次和水平进行了探讨 ,以期为稀土在生物学领域的进一步广泛应用奠定理论基础     

Dose-dependent character of the effect of hydrocortisone on energy metabolism of rat thymocytes

OBJECTIVES: Pancreatic hypoxia/ischemia, as a consequence of shock-induced microcirculatory failure, is considered a causative factor in the initiation and/or progression of pancreatic tissue injury. The aim of this study was to compare the effects of "small volume resuscitation" with conventional isovolemic colloid and hypervolemic crystalloid resuscitation on pancreatic microcirculation after hemorrhagic shock. DESIGN: Randomized, controlled intervention trial. SETTING: University laboratory. SUBJECTS: Twenty-three male Sprague-Dawley rats anesthetized with á-chloralose mechanically and ventilated. Interventions: Rats subjected to 1 hr of hemorrhagic shock (mean arterial pressure of 40 mm Hg) were resuscitated with lactated Ringer's solution (four-fold shed volume/20 mins), 10% hydroxyethyl starch (shed volume/5 mins), or 7.2% sodium chloride-10% hydroxyethyl starch (10% shed volume/2 mins). MEASUREMENTS AND MAIN RESULTS: The microcirculation of pancreatic acinar tissue was studied by means of intravital fluorescence microscopy and laser Doppler flowmetry. At 1 hr after resuscitation, mean arterial pressure, pancreatic capillary erythrocyte velocity, and erythrocyte flux were found to be significantly increased when compared with those values in the shock state. However, mean arterial pressure, pancreatic capillary erythrocyte velocity, and erythrocyte flux did not completely return to preshock values, regardless of the type of fluid used for resuscitation. At 15 mins and 1 hr after resuscitation, shock-induced capillary perfusion failure (reduction of functional capillary density) was restored to 91% to 94% of baseline values in all groups. Pancreatic capillary narrowing, indicating microvascular endothelial cell swelling, was abolished by resuscitation with both isotonic hydroxyethyl starch and hypertonic hydroxyethyl starch (p<.05 vs. lactated Ringer's solution). CONCLUSIONS: Despite replacement of only 10% of actual blood loss, small-volume resuscitation with hypertonic hydroxyethyl starch is as effective as the ten-fold volume of isotonic hydroxyethyl starch and, due to prevention of microvascular endothelial cell swelling, superior to the 40-fold volume of isotonic lactated Ringer's solution in regard to restoration of the shock-induced microcirculatory disturbances of rat pancreatic acinar tissue.     

Dose-dependent inactivation of extracellular human immunodeficiency virus by miramistin

BACKGROUND: There is a need for an atraumatic, fast, reliable, inexpensive, reversible-on-demand method for female sterilization which is also free from side-effects. The use of an Nd:YAG laser for occlusion of human fallopian tubes in vitro was assessed for achieving these aims. METHODS: An in vitro study was performed on coagulation of fallopian tube tissue using continuous wave Nd:YAG laser. Posthysterectomy human uteri were exposed to laser radiation either directly through an optical fibre or through a sapphire contact probe at the ostia at different laser powers and inter-action times. RESULTS: Laser-induced tissue coagulation plugged the ostia in a clean, controlled and predictable manner. Microscopic examination of the coagulated tissue showed about 50 microns wide blind holes without any continuous channel; thus eliminating the possibility of passage of sperms through such a plug. The depth of coagulation along the lumen of the fallopian tubes increased linearly with the interaction time of the laser beam at a constant power, either by direct irradiation or through a contact probe. The maximum depth of coagulation was found to be about 3 mm in case of direct irradiation at a laser power of about 6.5 W and interaction time of 50 seconds. Beyond these values, charring occurred at the surface of the tissue. CONCLUSION: Nd:YAG laser might be a suitable means for female sterilization. Further studies in experimental and clinical settings would be required to confirm its utility.