Endothelial cell injury and coagulation system activation during synergistic hepatotoxicity from monocrotaline and bacterial lipopolysaccharide coexposure.

A small, noninjurious dose of bacterial lipopolysaccharide (LPS; 7.4 x 106 EU/kg) administered 4 h after a small, nontoxic dose of monocrotaline (MCT; 100 mg/kg) produces synergistic hepatotoxicity in rats within 6 to 12 h after MCT exposure. The resulting centrilobular (CL) and midzonal (MZ) liver lesions are characterized by hepatic parenchymal cell (HPC) necrosis. Pronounced hemorrhage, disruption of sinusoidal architecture, and loss of central vein intima suggest that an additional component to injury may be the liver vasculature. In the present investigation, the hypothesis that sinusoidal endothelial cell (SEC) injury and coagulation system activation occur in this model was tested. Plasma hyaluronic acid (HA) concentration, a biomarker for SEC injury, was significantly increased in cotreated animals before the onset of HPC injury and remained elevated through the time of maximal HPC injury (i.e., 18 h). SEC injury was confirmed by immunohistochemistry and electron microscopy. Pyrrolic metabolites were produced from MCT by SECs in vitro, which suggests that MCT may injure SECs directly through the formation of its toxic metabolite, monocrotaline pyrrole. Inasmuch as SEC activation and injury can promote hemostasis, activation of the coagulation system was evaluated. Coagulation system activation, as marked by a decrease in plasma fibrinogen, occurred before the onset of HPC injury. Furthermore, extensive fibrin deposition was observed immunohistochemically within CL and MZ regions after MCT/LPS cotreatment. Taken together, these results suggest that SEC injury and coagulation system activation are components of the synergistic liver injury resulting from MCT and LPS coexposure.     

Synergistic hepatotoxicity from coexposure to bacterial endotoxin and the pyrrolizidine alkaloid monocrotaline

Individuals are commonly exposed to bacterial endotoxin (lipopolysaccharide [LPS]) through gram-negative bacterial infection and from its translocation from the gastrointestinal lumen into the circulation. Inasmuch as noninjurious doses of LPS augment the hepatotoxicity of certain xenobiotic agents, exposure to small amounts of LPS may be an important determinant of susceptibility to chemical intoxication. Monocrotaline (MCT) is a pyrrolizidine alkaloid phytotoxin that at large doses produces centrilobular liver lesions in rats. In the present study, MCT was coadministered with LPS to determine whether LPS would enhance its hepatotoxicity. Doses of MCT (100 mg/kg, ip) and LPS (7.4 x 10(6) EU/kg, iv), which were nonhepatotoxic when administered separately, produced significant liver injury in male, Sprague-Dawley rats when given in combination. Within 18 h after MCT administration, this cotreatment resulted in enhanced plasma alanine aminotransferase and aspartate aminotransferase activities, two markers of liver injury. Histologically, overt hemorrhage and necrosis appeared between 12 and 18 h. The lesions were centrilobular and midzonal and exhibited characteristics similar to lesions associated with larger doses of MCT and LPS, respectively. In the presence of LPS, the threshold for MCT toxicity was reduced to 13-33% of the dose required for toxicity with MCT alone. A study in isolated, hepatic parenchymal cells revealed no interaction between MCT and LPS in producing cytotoxicity. In summary, coexposure of rats to noninjurious doses of MCT and LPS resulted in pronounced liver injury. Results in vitro suggest that the enhanced toxicity does not result from a direct interaction of MCT and LPS with hepatic parenchymal cells. These results provide additional evidence that exposure to small amounts of LPS may be a determinant of susceptibility to food-borne hepatotoxins.     

The coagulation system contributes to synergistic liver injury from exposure to monocrotaline and bacterial lipopolysaccharide.

Coexposure to a noninjurious dose of bacterial lipopolysaccharide (LPS; 7.4 x 106 EU/kg) and a nontoxic dose of the food-borne toxin monocrotaline (MCT; 100 mg/kg) leads to synergistic hepatotoxicity in Sprague-Dawley rats. Inflammatory factors, such as Kupffer cells (KCs), tumor necrosis factor-alpha (TNF)-alpha, and neutrophils (polymorphonuclear leukocytes; PMNs), are critical to the pathogenesis. Inasmuch as activation of the coagulation system and sinusoidal endothelial cell (SEC) injury precede hepatic parenchymal cell (HPC) injury, and since fibrin deposition occurs within liver lesions, the coagulation system might be a critical component of injury. In this study, this hypothesis is tested, and the interdependence of the coagulation system and inflammatory factors is explored. Administration of the anticoagulants heparin or warfarin to MCT/LPS-cotreated animals attenuated HPC and SEC injury. Morphometric analysis revealed that anticoagulant treatment significantly reduced the area of centrilobular and midzonal lesions. Heparin treatment also reduced fibrin deposition in these regions. Furthermore, anticoagulant treatment decreased hepatic PMN accumulation but did not affect plasma TNF-alpha concentration. Neither KC inactivation nor TNF-alpha depletion prevented activation of the coagulation system. PMN depletion, however, prevented coagulation system activation, suggesting that PMNs are needed for this response. These results provide evidence that the coagulation system and its interplay with PMNs are important in the pathogenesis of MCT/LPS-induced liver injury.     

Role of neutrophils in the synergistic liver injury from monocrotaline and bacterial lipopolysaccharide exposure.

Synergistic liver injury develops in Sprague-Dawley rats from administration of a small, noninjurious dose (7.4 x 10(6) EU/kg) of bacterial lipopolysaccharide (LPS) given 4 h after a nontoxic dose (100 mg/kg) of the pyrrolizidine alkaloid, monocrotaline (MCT). Previous studies demonstrated that liver injury is mediated through inflammatory factors, such as Kupffer cells and tumor necrosis factor alpha (TNF-alpha), rather than through simple interaction between MCT and LPS. In the present study, the hypothesis that neutrophils (polymorphonuclear leukocytes or PMNs) are causally involved in this injury model is tested, and the interdependence between PMNs and other inflammatory components is explored. Hepatic PMN accumulation and the appearance of cytokine-induced neutrophil chemoattractant-1 in plasma preceded the onset of liver injury, suggesting that PMNs contribute to toxicity. Hepatic PMN accumulation was partially dependent on TNF-alpha. Prior depletion of PMNs in MCT/LPS-cotreated animals resulted in attenuation of both hepatic parenchymal cell (HPC) and sinusoidal endothelial cell (SEC) injury at 18 h. PMN depletion did not, however, protect against early SEC injury that occurred before the onset of HPC injury at 6 h. This observation suggests that SEC injury is not entirely dependent on PMNs in this model. In vitro, MCT caused PMNs to degranulate in a concentration-dependent manner. These results provide evidence that PMNs are critical to the HPC injury caused by MCT/LPS cotreatment and contribute to the progression of SEC injury.     

Reduced bactericidal activity and nitric oxide production in metallothionein-deficient macrophages in response to lipopolysaccharide stimulation

This study was designed to investigate bactericidal activity of and nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated peritoneal exudate macrophages (Mvarphi) from metallothionein (MT)-null mice. Control Mvarphi had a bactericidal effect on Staphylococcus aureus, but MT-null Mvarphi had significantly lower activity. NO is an important factor in the bactericidal function of Mvarphi. LPS-stimulated MT-null Mvarphi produced less NO than those of control mice. LPS-stimulated Mvarphi produce cytokines such as tumor necrosis factor (TNF)-alpha. TNF-alpha activate Mvarphi and stimulates NO production. We evaluated NO production by TNF-alpha-stimulated Mvarphi. MT-null Mvarphi produced less NO in response to TNF-alpha stimulation. Levels of expression of inducible NO synthase (iNOS) mRNA and production of iNOS protein in response to LPS stimulation were similar in MT-null and control cells, as were levels of expression of arginase, which competes in arginine metabolism with iNOS. No notable changes were found in arginine uptake or in expression of cationic amino acid transporter 2 (a major arginine transporter in Mvarphi) between control and MT-null Mvarphi. The rate of conversion of [(14)C]-l-arginine to citrulline, which is formed with NO by the action of iNOS, was much lower in MT-null Mvarphi than in control cells. These results indicate that the reduced production of NO in MT-deficient Mvarphi is due mainly to reduced activity of iNOS. Thus, MT plays important roles in bactericidal activity, NO production, and arginine metabolism in activated Mvarphi.     

Clonidine distribution in the rat: temporal relationship between tissue levels and blood pressure response.

1. The time course of the distribution of clonidine (20 microgram/kg, i.v.) was determined in the rat by use of a sensitive and specific radioimmunoassay, and was compared with the hypotensive response following this dose. 2. Levels of clonidine were determined in tissues at 2 min, corresponding to the beginning of the hypotensive phase of the drug, and then at 10, 30 and 120 min during recovery of blood pressure to the pre-dose level. The peak tissue concentrations of clonidine were found at 2 min, after which they declined in a mono-exponential manner. The half-lives of clonidine in the various tissues were similar to the half-life of the recovery of blood pressure. 3. Regional variations in clonidine distribution in the brain were not very great; however, the half-life was longer in the corpus striatum and shorter in the cerebellum than in other brain regions. 4. Clonidine concentrations were highest in the kidney and similarly distributed between the cortex and medulla. Concentrations of the drug in other tissues approximated those in brain. 5. Although clonidine is thought to act primarily through the central nervous system, this distribution study shows that at the peak of the hypotensive response less than 2% of the injected dose is present in brain and at least equal concentrations of the drug are found in most peripheral tissues. Thus the possibility of peripheral mechanisms contributing to the hypotensive effect cannot be dismissed.     

The relationship between temporal profiles and alcohol-related problems in University undergraduates: Results from the United Kingdom

Time perspective is an individual difference variable which assesses the extent to which orientation to the past, present and future affects current behaviors. The present study investigated the viability of temporal profiles and the degree (if any) to which these predict meaningful differences in alcohol-related problems. Participants were undergraduates recruited from a University in the North West of England. Full survey data were available for 455 individuals (aged 18–25; 49.7% male) on (a) time perspective, and (b) alcohol-related problems. Four profiles emerged and were labeled Future-Positive, Present, Past Negative-Future, and Ambivalent. As hypothesized, the Future-Positive profile was associated with the best alcohol-related outcomes. The Present profile was associated with the worst outcomes. This study demonstrates that temporal profiles are associated with alcohol-related problems.     

大鼠枯否细胞活化与TNT肝毒性的关系

目的　探讨大鼠肝脏Kupffer细胞功能活化与TNT肝毒性的关系及可能机制。方法　运用Kupffer细胞功能活化的大鼠模型 ,观察TNT和VA TNT联合处理大鼠血清中ALT和AST及肝脏和血清中SOD、CAT和GSH Px活性的变化。结果　TNT组血清中ALT和AST活性明显低于对照组 ,而VA TNT组则明显高于对照组和相应TNT组。TNT组肝脏和血清中SOD、CAT和GSH Px活性显著和非常显著高于对照组 (P <0 0 5 ,P<0 0 1) ,VA TNT组某些酶活性显著和非常显著高于对照组和相应的TNT组 (P <0 0 5 ,P <0 0 1)。TNT可加强对Kupffer细胞功能活化大鼠的肝毒性。结论　大鼠肝脏Kupffer细胞经VA活化后 ,可加强TNT肝毒性 ,推测可能与活性氧生成有关。     

Comparative toxicity studies between bacterial lipopolysaccharide (endotoxin) and N-formyl methionyl peptide as factors in the pathogenesis of byssinosis

Comparative in vivo and in vitro studies were made on bacterial lipopolysaccharide (LPS) and the chemotactic peptide NF-Met-Leu-Phe with a view toward studying their possible role in the pathophysiology of byssinosis. In contrast to LPS, chemotactic peptides did not cause Limulus amebocyte lysate gelation, nor did they induce the release of endogenous pyrogen. Inhalation of LPS caused a peripheral leukocytosis in rabbits 30 min after aerosol administration, whereas peptide inhalation caused a significant leukopenia in the same period. Cellular analysis of guinea pig bronchial lavages after LPS aerosol challenge revealed immediate decreases in all cell types, with subsequent, large increases of macrophages and granulocytes 4-24 h after aerosolization. Inhalation challenge with NF-Met-Leu-Phe induced no significant cellular changes. It was concluded that it is unlikely that these microbial products could be confused with each other when administered in pure form by the inhalation route.     

Irinotecan toxicity to human blood cells in vitro: relationship between various biomarkers

Toxic effects of the antineoplastic drug irinotecan on human blood cells at concentrations of 9.0 microg/ml and 4.6 microg/ml were evaluated in vitro. Using the alkaline and neutral comet assay significantly increased levels of primary DNA damage in lymphocytes were detected. The induction of apoptosis/necrosis, as determined by a fluorescent assay, was also notably increased. Cytogenetic outcomes of the treatment were assessed by the analysis of structural chromosome aberrations and fluorescence in situ hybridization. A significantly higher incidence of chromatid breaks and complex quadriradials was observed. Painted chromosomes 1, 2 and 4 were equally involved in translocations, but only the chromosome 1 was involved in the formation of quadriradials. Sister chromatid exchange analysis was performed in parallel with the analysis of lymphocyte proliferation kinetics. The higher concentration of irinotecan caused almost seven-time increase, while the lower one caused a five-time increase of the basal sister chromatid exchange frequency, accompanied with significant lowering of the lymphocyte proliferation index. Using the cytokinesis-block micronucleus assay, a dose-dependent increase in micronucleus frequency along with the formation of nuclear buds and nucleoplasmic bridges was noticed. Inhibitory effects of irinotecan on enzyme acetylcholinesterase (AChE) were studied in erythrocytes. An IC(50) value of 5.0 x 10(-7) was established. Irinotecan was found to be strong inhibitor of the acetylcholine hydrolysis and to cause a continuous decrease of catalytic activity of AChE. The results obtained on a single donor may contribute to the understanding of irinotecan toxicity, but further in vitro and in vivo studies are essential in order to clarify remaining issues, especially on possible inter-individual variability in genotoxic responses to the drug.     

Short duration exposures to organic solvents: the relationship between neurobehavioral test results and other indicators

Short duration exposure to solvents at even low concentrations can induce signs of mild toxicity such as mucous membrane irritation, tearing, nasal irritation, headache, and nausea. These irritant effects are often used as warning properties for potential solvent toxicities and have frequently been classified in the literature as pre-narcotic effects. With higher exposures the toxic effects are more pronounced and can include intoxication, incoordination, exhilaration, sleepiness, stupor, and the beginning stages of anesthesia. Collectively these effects are taken as indicators of narcosis. Offering recommendations for safe exposure limits for these shorter term exposures is made difficult because, (1) the mild toxic effects are often reported subjectively and tolerance usually develops, (2) the solvent concentration(s) cannot be documented in all cases, and (3) the effects are reversible when individuals are removed from exposure. Laboratory experiments involving controlled exposures to solvents using neurobehavioral performance tests represent one form of investigation that can provide meaningful information in this instance. The results can be viewed in two ways with reference to issues of safe exposure limits. One is to ensure that performance functions that can compromise safety are not affected by the exposure limits prescribed. The second is to consider performance changes due to short-term exposures as possible precursors of similar but more severe effects given longer term exposures. Thus, setting exposure limits to protect against these performance changes could possibly prevent the development of more serious cases of chronic solvent neurotoxicity. This paper compares solvent concentrations from short-duration exposure studies using neurobehavioral tests with the concentrations producing irritant and narcotic effects, as documented by the two main standards recommending bodies, the National Institute for Occupational Safety and Health and the American Conference of Governmental Industrial Hygienists. Comparisons are also made with the regulatory exposure limits established by the Occupational Safety and Health Administration. In general, the neurobehavioral changes which occur following short-duration exposures are reported at concentrations between those which produce irritant effects and narcosis. For the chemicals which have been tested, the performance changes measured by the present day neurobehavioral tests in use rarely occur at or below those limits recommended by the standards recommending bodies.     

Cadmium osteotoxicity in experimental animals: Mechanisms and relationship to human exposures

Extensive epidemiological studies have recently demonstrated increased cadmium exposure correlating significantly with decreased bone mineral density and increased fracture incidence in humans at lower exposure levels than ever before evaluated. Studies in experimental animals have addressed whether very low concentrations of dietary cadmium can negatively impact the skeleton. This overview evaluates results in experimental animals regarding mechanisms of action on bone and the application of these results to humans. Results demonstrate that long-term dietary exposures in rats, at levels corresponding to environmental exposures in humans, result in increased skeletal fragility and decreased mineral density. Cadmium-induced demineralization begins soon after exposure, within 24 h of an oral dose to mice. In bone culture systems, cadmium at low concentrations acts directly on bone cells to cause both decreases in bone formation and increases in bone resorption, independent of its effects on kidney, intestine, or circulating hormone concentrations. Results from gene expression microarray and gene knock-out mouse models provide insight into mechanisms by which cadmium may affect bone. Application of the results to humans is considered with respect to cigarette smoke exposure pathways and direct vs. indirect effects of cadmium. Clearly, understanding the mechanism(s) by which cadmium causes bone loss in experimental animals will provide insight into its diverse effects in humans. Preventing bone loss is critical to maintaining an active, independent lifestyle, particularly among elderly persons. Identifying environmental factors such as cadmium that contribute to increased fractures in humans is an important undertaking and a first step to prevention.     

Perfluorooctanoic acid: relationship between repeated inhalation exposures and plasma PFOA concentration in the rat

A large database exists describing the pharmacokinetic behavior of perfluorooctanoic acid (PFOA) following oral exposure. The objective of this study was to examine the concentration- and time-dependence of the pharmacokinetics of inhaled PFOA in rat plasma to determine equivalent inhalation and oral (from literature values) exposure levels. The study was comprised of two separate experiments: a single 6-h inhalation exposure and repeated inhalation exposures for 3 weeks (6h per day, 5 days per week). In both experiments, male and female rats were exposed nose-only to aerosol atmospheres of either 0, 1, 10, or 25mg/m(3) PFOA. In the single exposure experiment, blood was drawn via the tail vein pre-exposure, four times concurrent to exposure, and six times post-exposure up to 24h. In the repeated exposure experiment, blood was collected immediately before and after exposure 3 days per week. Plasma PFOA concentrations were quantitated by liquid chromatography-mass spectrometry (LC-MS). Following the single exposures, plasma PFOA concentrations were directly proportional to airborne concentrations in both male and female rats. Elimination of PFOA from the plasma was sex-dependent, with female rats eliminating PFOA much more rapidly than male rats. Following repeated PFOA exposure, there was little daily PFOA carryover observed in plasma samples from female rats, while males demonstrated an accumulative pattern over the 3-week period. Peak post-exposure PFOA plasma concentrations in female rats averaged 1, 2, and 4 microg/mL when exposed to 1, 10, and 25mg/m(3) PFOA, respectively, and returned to baseline levels by the time of the next pre-exposure sample collection. Male rats reached steady state plasma concentrations of 8, 21, and 36 microg/mL (ppm) after 3 weeks of exposure to 1, 10, and 25mg/m(3) PFOA, respectively. These results demonstrate that the pharmacokinetic properties of inhaled PFOA in male and female rats are similar to those observed in male and female rats following oral dosing with PFOA. It is thus possible to use this internal dose metric (plasma PFOA) for route-to-route dose extrapolation, with inhalation exposures of 1, 10, and 25mg/m(3) PFOA corresponding to oral doses of approximately 0.3, 1.0, and 2.0mg/kg in rats.     

The relationship between the locomotor response to a novel environment and behavioral disinhibition in rats

Behavioral disinhibition, a component of impulsivity, has been associated with cocaine abuse and dependence. To examine the relationship between behavioral disinhibition and vulnerability to cocaine use disorders, we employed the high responder (HR)/low responder (LR) rodent model, in which rats that exhibit high levels of activity in response to a novel environment are more sensitive to the effects of psychostimulants. In Experiment 1, performance under a differential reinforcement of low-rate (DRL) schedule was used as a measure of behavioral disinhibition in HR and LR rats. The HR rats displayed more behavioral disinhibition relative to LR rats on the DRL 20- and 35-s schedules. In Experiment 2, rats were divided into groups with high disinhibition (HD) and low disinhibition (LD) based on DRL 20-s performance, then challenged with cocaine. Rats characterized as HD and LD had similar DRL 20-s performance to rats characterized as HR and LR (Experiment 1), respectively, but did not differ in their response to cocaine. The results of this study suggest that the HR phenotype may also be characterized by greater behavioral disinhibition, and that the DRL task is a suitable animal model to investigate the role of behavioral disinhibition in vulnerability to the behavioral effects of cocaine.     

The relationship between P-glycoprotein (PGP) polymorphisms and response to olanzapine treatment in schizophrenia

P-glycoprotein (PGP) is a polymorphic efflux transporter located on the blood brain barrier that potentially affects the penetration of atypical antipsychotics into the central nervous system. Increased antipsychotic penetration to the primary site of activity may result in greater symptom improvement or the occurrence of side effects. This investigation examined the relationship between three common PGP polymorphisms (C1236T, G2677TA, and C3435T) and response to 6 weeks of open-label olanzapine treatment in patients with schizophrenia. Individuals with a PGP T allele at any of these polymorphisms would be expected to have greater antipsychotic penetration through the blood brain barrier, due to lower PGP activity. Forty-one patients were included in this reanalysis. For subjects in the 3435T allele carrier group, the plasma olanzapine level alone was positively associated with percent change in Brief Psychiatric Rating Scale score (p = 0.02). This relationship was not seen for the 3435CC group (p = 0.583). A similar trend was observed for negative symptom reduction, olanzapine plasma concentration, and the 3435T allele (p = 0.06), but this relationship did not meet statistical significance. There was no relationship between the PGP genotypes and changes in weight over the course of this 6 week study. The analysis using C1236T or G2677AT genotypes gave similar results, due to linkage of these polymorphisms.PGP polymorphisms may affect the penetration of olanzapine into the central nervous system as seen by a relationship between the 3435T allele, olanzapine plasma levels, and reduction in the positive symptoms of schizophrenia. This may stem from greater olanzapine central nervous system latency due to the presence of the 3435T allele and reduced PGP activity. The PGP C3435T genotype may help to determine positive symptom reduction from olanzapine clinically, but these findings should be replicated in a larger sample of subjects.     

The relationship between isofenphos cholinergic toxicity and the development of polyneuropathy in hens and humans

Species differences have been observed between hen and human clinical manifestations of isofenphos toxicities. Hens treated with the insecticide isofenphos (90 mg/kg p.o.) developed severe cholinergic toxicity followed by mild organophosphate-induced delayed polyneuropathy (OPIDP). However, a patient developed severe OPIDP, which was preceded by very mild cholinergic signs, after an attempted suicide with a commercial formulation containing isofenphos and phoxim, an insecticide not causing OPIDP (estimated doses were 500 and 125 mg/kg, respectively). To explain this difference the following hypotheses were tested: (1) phoxim is a promoter of isofenphos-induced OPIDP; (2) whereas neuropathy target esterase (NTE) is thought to be the target of OPIDP, activation of isofenphos by liver microsomes causes the formation of more potent NTE inhibitor(s) in humans than in hens; (3) in contrast to hen NTE, the sensitivity of the human enzyme to such inhibitor(s) is higher than that of acetylcholinesterase (AChE), the target of cholinergic toxicity. Results showed that phoxim (22.5 mg/kg p.o.) was not a promoter of OPIDP in hens and that the ratio AChE inhibition:NTE inhibition by microsome-activated isofenphos was similar for both hen and human enzymes. The schedule of antidotal treatment in hens is the likely explanation for the observed difference from the patient. Peak AChE inhibition was maintained in hen brain up to 6 days after a single dose of isofenphos, suggesting prolonged pharmacokinetics. However, the AChE reactivator pyridine-2-aldoxime (2-PAM) was given to hens before isofenphos and then every 8 h, whereas continuous 2-PAM infusion was provided to the patient. When 2-PAM was given to hens every hour after isofenphos (90 mg/kg p.o.), the birds remained asymptomatic. Since other organophosphates may have a prolonged pharmacokinetics, testing procedures for the potential of these insecticides to cause OPIDP may underestimate the risk for humans.     

The relationship between terazosin dose and blood pressure response in hypertensive patients

A double-blind, randomized, placebo-controlled, multicenter study was conducted to describe the dose-response curve for terazosin on blood pressure. A total of 128 patients with mild to moderate essential hypertension (supine diastolic blood pressure, 100 to 114 mmHg) participated in the study. The study consisted of a 4-week single-blind placebo lead-in period and a 14-week double-blind treatment period. Patients were randomized in equal numbers to four parallel treatment groups: terazosin 1, 2, and 5 mg; terazosin 2, 5, and 10 mg; terazosin 20, 40, and 80 mg; and placebo. The 24-hour ambulatory blood pressure measurements were performed at the end of the placebo lead-in period and at the end of each 4-week fixed-dose period. The nonlinear, mixed-effect model computer program was used to analyze the dose-response relationship. There was a strong dose-response relationship between fall in blood pressure and the 1 to 10 mg terazosin dose, as well as a plateauing of response for terazosin doses above 10 mg. The maximum antihypertensive response (Emax) to terazosin was 10.7 mmHg for systolic blood pressure and 8.0 mmHg for diastolic blood pressure. The daily dose of terazosin, which produced 50% of the maximum response (ED50), was 3.0 mg for systolic blood pressure and 1.5 mg for diastolic blood pressure. The results of this study suggest that although some patients may benefit from terazosin doses of greater than 10 mg, doses up to 10 mg will maximize therapeutic benefit for most patients, with acceptable side effects.     

Induction of L-arginine transport and nitric oxide synthase in vascular smooth muscle cells: synergistic actions of pro-inflammatory cytokines and bacterial lipopolysaccharide.

1. The interactions between pro-inflammatory cytokines and bacterial lipopolysaccharide (LPS) on L-arginine transporter and inducible nitric oxide synthase (iNOS) activities were examined in rat cultured aortic smooth muscle cells. 2. LPS induced a concentration (0.01-100 micrograms ml-1) and time (8-24 h)-dependent stimulation of nitrite production which was accompanied by a parallel increase in L-arginine transport. 3. Unlike LPS, activation of smooth muscle cells with either interferon-gamma (IFN-gamma, 100 u ml-1), tumour necrosis factor-alpha (TNF-alpha, 300 u ml-1) or interleukin-1 alpha (IL-1 alpha, 100 u ml-1) failed to stimulate L-arginine transport or increase nitrite accumulation. 4. When applied in combination with LPS (100 micrograms ml-1) both IFN-gamma and TNF-alpha, but not IL-1 alpha, enhanced the effects observed with LPS alone. Furthermore, activation of cells with LPS and IFN-gamma had no effect on uptake of the neutral amino acid L-citrulline but selectively increased the Vmax for L-arginine transport 2.8 fold and nitrite levels from 24 +/- 7 to 188 +/- 14 pmol micrograms-1 protein 24 h-1. 5. The substrate specificity, Na- and pH-independence of saturable L-arginine transport in both unactivated (K(m) = 44 microM, Vmax = 3 pmol micrograms-1 protein min-1) and activated (K(m) = 75 microM, Vmax = 8.3 pmol micrograms-1 protein min-1) smooth muscle cells were characteristic of the cationic amino acid transport system y+. 6. Cycloheximide (1 microM) abolished induction of L-arginine transport and nitrite accumulation in response to LPS and IFN-gamma. In contrast, the glucocorticoid dexamethasone (10 microM, 24 h) selectively inhibited nitrite production. 7. Our results demonstrate that pro-inflammatory mediators selectively enhance transport of L-arginine under conditions of sustained NO synthesis by vascular smooth muscle cells. In addition, the differential inhibition of iNOS and L-arginine transporter activity by dexamethasone suggests that distinct signalling pathways mediate induction of the cationic transport protein and iNOS. The close coupling between substrate supply and NO production may have important implications in the pathogenesis of several disease states including endotoxin shock.     

精神分裂症治疗前后单胺类神经递质分析及疗效评定

目的观察精神分裂症患者治疗前后血浆中单胺类神经递质含量变化及与疗效的相关性。方法采用放免法测定85例精神分裂症患者治疗前后血浆多巴胺(DA)、5-羟色胺(5-HT)、去甲肾上腺素(NE)和生长激素(GH)含量及简明精神病量表(BPRS)的减分率来评定疗效。结果治疗前后5-HT含量分别为(84.93±68.13)和(94.33±68.84)mmol/L,DA(34.14±10.24)和(32.89±9.63)mmol/L,NE(67.94±82.84)和(56.63±29.83)mmol/L,GH(3.69±10.02)和(2.28±4.20)mmol/L,前后对照均无统计学差异(P>0.05)。5-HT、DA、NE和GH含量变化与疗效无明显相关(P>0.05)。结论精神分裂症患者治疗前后血浆中单胺类神经递质未发现明显差异,与疗效是否相关需进一步细化精神症状。     

The relationship between treatment time of gemcitabine and development of hematologic toxicity in cancer patients

Although gemcitabine is frequently used in the treatment of cancer, it is associated with myelosuppression. An animal study showed that the tolerability of gemcitabine varied with changes in treatment time; however, no clinical data have verified this finding. The purpose of this study was to determine the relationship between treatment time and development of hematologic toxicity in patients treated with gemcitabine. Gemcitabine-induced hematologic toxicity was retrospectively investigated in 77 patients. Patients were divided into two treatment-time groups: 9:00 and 15:00. Hematologic toxicity was evaluated on day 8 and 15 after treatment. On day 8 and 15, the changing count of white blood cells was significantly reduced in patients treated at 15:00 compared with those treated at 9:00 (p<0.01 and p<0.05, respectively). On days 8 and 15, the changing count of platelet was significantly reduced in patients treated at 15:00 compared with those treated at 9:00 (p<0.05). The incident of over common terminology criteria for adverse events (CTCAE) grade 2 white blood cell decreased was significantly reduced in patients treated at 15:00 compared with those treated at 9:00 (p=0.048, odds ratio=2.92). In conclusion, this cohort study demonstrated that gemcitabine-induced hematologic toxicity could be alleviated by treating patients at 9:00.