The beneficial effects of ciprofloxacin on survival and hepatic regenerative activity in a rat model of fulminant hepatic failure

Recently, we reported that ciprofloxacin, an antimicrobial agent with gamma-aminobutyric acid (GABA(A)) receptor antagonist properties, significantly increases hepatic regenerative activity in animal models of alcohol-induced liver disease and cirrhosis. In the present study, we documented the effects of ciprofloxacin on survival and hepatic regeneration in a D-galactosamine (D-gal)-induced model of acute hepatic injury in rats. One hundred nineteen adult, male Sprague-Dawley rats (n = 19-20/group) were treated with intraperitoneal D-gal (total dose: 2.5 g/kg), followed by gastric gavage with either saline, ciprofloxacin (10, 50, or 100 mg/kg), norfloxacin (250 mg/kg), or intraperitoneal putrescine (300 micromol/kg), a potent hepatic growth promoter. Mortality rates were then documented over a 4-day period. An additional 45 rats (n = 15/group) received a sublethal dose of D-gal (1.0 g/kg), followed by gastric gavage with either saline or ciprofloxacin (100 mg/kg), or intraperitoneal putrescine (300 micromol/kg). In these rats, hepatic regenerative activity was documented at 12, 24, and 60 hours post-D-gal by 3H-thymidine incorporation into hepatic DNA and proliferating cell nuclear antigen (PCNA) staining. In the survival study, a dose-response effect of ciprofloxacin on survival was observed (ciprofloxacin: 10 mg/kg, 10%; 50 mg/kg, 26%; and 100 mg/kg, 35%) with the results in the 100-mg/kg-treated group being significant when compared with the 5% survival rate in saline-treated controls (P < .05). Survival figures in the norfloxacin- and putrescine-treated groups were not significantly improved (15% and 25%, respectively). In the regeneration study, compared with the D-gal + saline-treated control group, DNA synthesis rates at 60 hours were increased in the D-gal + ciprofloxacin and D-gal + putrescine groups (10.2 +/- 3.3 vs. 18.2 +/- 5.1 and 18.8 +/- 6.8 x 10(3) dpm/mg DNA respectively; P < .05). The results of PCNA staining also supported enhanced hepatic regeneration in the ciprofloxacin-treated group at 60 hours (saline, 13.4 +/- 3.7; ciprofloxacin, 47.4 +/- 7.3; and putrescine, 8.4% +/- 2.8% hepatocytes staining positive). Ciprofloxacin at a dose of 100 mg/kg significantly improves survival and hepatic regenerative activity in this animal model of acute hepatic injury.     

Synergistic increases in rat hepatic cytochrome P450s by ethanol and isopentanol

The purpose of this study was to determine if isopentanol alone or in combination with ethanol increased CYP2B1/2, CYP2E or CYP3A in the livers of rats. Increasing doses of isopentanol (0.5, 1, 2 or 3%) were administered in combination with 5.6% ethanol in the Lieber-DeCarli liquid diet for 7 days. Doses of 0.5 or 3% isopentanol were also administered alone. Isopentanol alone caused small increases in CYP2B1/2 and CYP3A. However, when isopentanol (2 or 3%) was combined with ethanol a synergistic increase in P4502B1/2 was observed. The combined alcohol treatment also resulted in a greater increase in immunoreactive CYP3A than either alcohol alone. Ethanol alone increased CYP2E 5-fold. Inclusion of isopentanol with ethanol resulted in either small or no additional increases in CYP2E. These results confirm our previous findings in cultured hepatocytes that when isopentanol is combined with ethanol, there is a synergistic increase in CYP2B1/2. Increases in CYP2B1/2, CYP2E and CYP3A protein moieties by ethanol, and by ethanol in combination with isopentanol, were associated with increases in their mRNAs. Blood isopentanol levels were 10-fold greater in rats administered 3% isopentanol in combination with ethanol compared to rats administered 3% isopentanol alone. From these results we suggest that isopentanol, a higher chain alcohol in alcoholic beverages, can contribute to increases in hepatic cytochrome P450 observed following consumption of alcoholic beverages.     

Pharmacodynamic interactions of ciprofloxacin, piperacillin, and piperacillin/tazobactam in healthy volunteers

Mathematical modeling methods were used to study pharmacokinetic and pharmacodynamic interactions of the antimicrobial combinations piperacillin plus ciprofloxacin and piperacillin plus tazobactam. Twelve healthy volunteers received the following treatments: piperacillin (4 g), ciprofloxacin (400 mg), piperacillin (4 g) plus ciprofloxacin (400 mg), and piperacillin (4 g) plus tazobactam (0.5 g), via intravenous infusion in a four-period crossover design. Serum drug concentrations were analyzed by means of high-performance liquid chromatography (HPLC), and inhibitory titers were performed against eight organisms. The pharmacodynamic response (growth or no growth) was modeled for each of the monotherapy courses using a Hill-type model where Emax was 1 (100% probability of no growth [P(NG)]), and EC50 was the concentration associated with a 50% P(NG). For piperacillin plus ciprofloxacin, P(NG) was a function of 1) plasma concentrations for both drugs; 2) EC50 values from the monotherapy courses; and 3) theta, an interaction term that accommodates synergy, additivity, or antagonism. For piperacillin/tazobactam, the serum ultrafiltrate area under the inhibitory curve was compared with that of piperacillin alone to determine the benefit of tazobactam. The interaction between piperacillin and ciprofloxacin was additive. The addition of tazobactam to piperacillin was beneficial against certain organisms. The model developed can be used to evaluate the activity of combination regimens against representative pathogens.     

Effects of hepatic stimulator substance, herbal medicine, selenium/vitamin E, and ciprofloxacin on cirrhosis in the rat

BACKGROUND & AIMS: Cirrhosis is a potentially lethal condition for which there is no proven effective therapy. The aim of this study was to compare the effects of hepatic stimulator substance, traditional Chinese herbal medicine, selenium plus vitamin E, and ciprofloxacin treatment on biochemical and histological features of fibrosis in rats with carbon tetrachloride (CCl4)/ethanol-induced cirrhosis. METHODS: One hundred twenty adult Wistar rats were divided into six study groups (20 rats/group): healthy controls, CCl4/ethanol-injured rats left untreated, and CCl4/ethanol-injured rats treated for 4 weeks with either hepatic stimulator substance, traditional Chinese herbal medicine, a combination of selenium plus vitamin E, or ciprofloxacin. After the 4-week treatment, rats were killed and the following parameters of hepatic fibrosis were determined: hepatic hydroxyproline and proline levels, serum hyaluronic acid concentrations, and histological staining of hepatic tissue. RESULTS: Hepatic fibrosis was significantly improved in all four treated groups compared with the untreated CCl4/ethanol-injured controls. Improvements were most striking in the groups treated with traditional Chinese herbal medicine and ciprofloxacin. CONCLUSIONS: The data indicate that hepatic stimulator substance, traditional Chinese herbal medicine, selenium plus vitamin E, and ciprofloxacin significantly decrease the amount of hepatic fibrosis caused by CCl4/ethanol injury in rats.     

Treatment of cirrhotic rats with epidermal growth factor and insulin accelerates liver DNA synthesis after partial hepatectomy

Prevention of postoperative hepatic failure is important after hepatic resection. In patients with cirrhosis, impaired liver function and regenerative capacity after major hepatic resection are associated with increased morbidity and mortality. In this study, a combination of epidermal growth factor (EGF) and insulin were used as hepatotrophic factors in an attempt to stimulate DNA synthesis after 70% hepatectomy (HTX). Regenerative capacity was evaluated in normal and cirrhotic rat liver by measuring DNA synthesis in vivo. Micronodular liver cirrhosis was established by the simultaneous oral administration of CCl4 and phenobarbital. Epidermal growth factor plus insulin was injected subcutaneously immediately after and 12 h after HTX or sham operation was performed. Rats were killed 24 h after the operation and liver regeneration was estimated by [3H]-thymidine incorporation into DNA as well as an autoradiographic nuclear labelling index. Hepatectomy increased [3H]-thymidine incorporation significantly in both normal and cirrhotic rats. In cirrhotic rats, [3H]-thymidine incorporation after HTX was significantly lower than in normal rats and administration of a combination of EGF and insulin after HTX enhanced [3H]-thymidine incorporation. In conclusion, DNA synthesis 24 h after HTX is decreased in cirrhotic rats compared with normal rats and EGF supplementation with insulin accelerates DNA synthesis in hepatectomized cirrhotic rats. The data suggest that administration of combinations of exogenous hepatotrophic factors may play a useful role in the treatment of cirrhotic patients undergoing major hepatic resection.     

Studies on genotoxic effects of iron overload and alcohol in an animal model of hepatocarcinogenesis

BACKGROUND/AIMS: In order to examine whether iron and alcohol act synergistically during tumor initiation in vivo, we investigated the effects of dietary iron overload and a liquid ethanol-containing diet on the initiation phase of the Solt & Farber model of chemical hepatocarcinogenesis. METHODS: Following dietary supplementation with carbonyl iron for 8 weeks and ethanol pair-feeding according to Lieber deCarli for 5 weeks, animals were subjected to partial hepatectomy in order to induce regenerative cell proliferation and thereby "fix" putative DNA lesions. Levels of malondialdehyde, reduced and oxidized ubiquinone-9, alpha-tocopherol and 8-oxo-2'-deoxyguanosine were analyzed in liver tissue removed at the time of partial hepatectomy, and blood was collected for determination of alanine amino-transferase activities. Following a 2-week recovery period, promotion was achieved with 0.02% dietary 2-acetylaminofluorene and carbon tetrachloride. Two weeks after the completion of promotion, animals were sacrificed and the number of preneoplastic, glutathione S-transferase 7,7-positive lesions counted. Animals initiated with diethylnitrosamine served as a positive control group. RESULTS: Serum aminotransferase activities were significantly increased, and hepatic contents of ubiquinol-9 (reduced ubiquinone-9) were significantly decreased in animals exposed to the combination of iron and ethanol in comparison to the other groups. Livers from iron-treated animals had decreased levels of alpha-tocopherol and increased contents of malondialdehyde, whereas treatment with ethanol did not further enhance these alterations. Levels of 8-oxo-2'-deoxyguanosine were not significantly different in animals treated with iron, ethanol or iron + ethanol as compared with controls. The number of preneoplastic foci at the time of sacrifice was not increased in livers exposed to iron and/or ethanol as compared with those from control animals. As expected, the number of foci was significantly increased in positive controls which were initiated with diethylnitrosamine. CONCLUSIONS: Iron potentiated the cytotoxic effects of ethanol, resulting in increased serum aminotransferase activities and decreased hepatic contents of ubiquinol. However, the combination of iron and ethanol did not exert genotoxic effects detectable as enhanced hepatic levels of 8-oxo-2'-deoxyguanosine, or increased formation of preneoplastic, glutathione S-transferase 7,7-positive lesions in the Solt & Farber model of chemical hepatocarcinogenesis.     

Hepatic stimulator substance administration enhances regenerative capacity of hepatocytes in cadmium-pretreated partially hepatectomized rats

The liver is of central importance in the metabolism of essential and toxic metals such as cadmium (Cd). Cd pretreatment suppressed the regenerative capacity of hepatocytes, which normally occurs 24 hr after partial hepatectomy, due to the inhibition of the activity of the enzyme thymidine kinase. The effect of hepatic stimulator substance (HSS) administration (10, 20, and 40 mg protein/kg body weight) on hepatocyte proliferation was investigated in Cd-pretreated partially hepatectomized rats. HSS administration partly restored the suppressed hepatocyte DNA biosynthesis in Cd-pretreated partially hepatectomized rats. The hepatocyte mitotic activity and the percentage of proliferating cell nuclear antigen-positive nuclei were in accordance with the liver proliferative status. The administration of HSS did not affect in a statistically significant manner the activity of the enzyme thymidine kinase in Cd-pretreated partially hepatectomized rats. It is suggested that the administration of HSS ameliorates the diminished hepatocyte regenerative response to partial hepatectomy in this model of acute liver injury, due to Cd intoxication.     

Granulocyte colony-stimulating factor administration reverses cadmium-associated inhibition of hepatocyte regeneration

OBJECTIVE: To document whether the administration of granulocyte colony-stimulating factor (G-CSF) enhances the impaired regenerative response of hepatocytes to partial hepatectomy (PH), in cadmium-pretreated partially hepatectomized rats. MATERIALS AND METHODS: Rats were injected intraperioneally with 2.5 mg CdCl2/kg body weight, 24h before PH. G-CSF (1500 or 150 micrograms/kg body weight) or saline was administered intraperitoneally in cadmium-pretreated partially hepatectomized rats at the same time as PH. The liver regenerative process was estimated 24h after PH. [3H] thymidine incorporation into liver DNA, liver thymidine kinase (TK) activity, mitotic index and proliferating cell nuclear antigen (PCNA) immunostaining were used as indices of hepatocyte proliferation. RESULTS: G-CSF administration in cadmium-pretreated partially hepatectomized rats restored the suppressed DNA biosynthesis and TK activity (P < 0.001), to levels similar to those found in rats that were partially hepatectomized only. The mitotic index and the percentage of PCNA positive nuclei in hepatocytes were also enhanced in G-CSF administered cadmium-pretreated partially hepatectomized groups of rats. CONCLUSION: The administration of G-CSF triggers events that restore the impaired liver regeneration in this model of reduced hepatocyte proliferation.     

Putrescine administration reverses cadmium-associated inhibition of liver regeneration

The liver is of central importance in the metabolism of essential and toxic metals such as cadmium. Cadmium pretreatment suppressed the liver regenerative response to partial hepatectomy, due to the inhibition of the enzymatic activity of thymidine kinase. Exogenous putrescine administration has been reported to stimulate liver regeneration in animal models of acute liver failure. The purpose of this study was to document whether the administration of this polyamine enhances the impaired regenerative capacity of hepatocytes in cadmium-pretreated partially hepatectomized rats. The intraperitoneal administration of putrescine (1 or 10 mg/kg body weight), at the time of surgery and at 4 and 8 hr postoperatively partly restored the suppressed hepatocyte deoxyribonucleic acid (DNA) biosynthesis and thymidine kinase activity in cadmium-pretreated partially hepatectomized rats. Mitotic activity and the percentage of hepatocytes positive for proliferating cell nuclear antigen nuclei were in accordance with the liver proliferative status. Our results showed that exogenous putrescine administration is able to improve diminished liver regeneration after partial hepatectomy in this animal model of acute hepatic injury.     

Pharmacological analysis of the heterogeneous discriminative stimulus effects of ethanol in rats using a three-choice ethanol-dizocilpine-water discrimination

The present study used a three-choice operant drug discrimination procedure to determine if NMDA-mediated discriminative stimulus effects could be separated from other stimulus effects of 2.0 g/kg ethanol. Adult male Long-Evans rats (n = 7) were trained to discriminate dizocilpine (0.17 mg/kg; i.g.) from ethanol (2.0 g/kg; i.g.) from water (4.7 ml; i.g.) using food reinforcement. Substitution tests were conducted following administration of the GABA(A) positive modulators allopregnanolone (5.6-30.0 mg/kg; i.p.), diazepam (0.3-10.0 mg/kg; i.p.) and pentobarbital (1.0-21.0 mg/kg; i.p.), the non-competitive NMDA antagonist phencyclidine (0.3-10.0 mg/kg; i.p.), the 5-HT1 agonists TFMPP (0.3-5.6 mg/kg; i.p.) and RU 24969 (0.3-3.0 mg/kg; i.p.), and isopropanol (0.10-1.25 g/kg; i.p.). Allopregnanolone, diazepam and pentobarbital substituted completely (>80%) for ethanol. Isopropanol partially (77%) substituted for ethanol. Phencyclidine substituted completely for dizocilpine. RU 24969 and TFMPP did not completely substitute for either training drug, although RU 24969 partially (62%) substituted for ethanol. Successful training of this three-choice discrimination indicates that the discriminative stimulus effects of 0.17 mg/kg dizocilpine were separable from those of 2.0 g/kg ethanol. The finding that attenuation of NMDA-mediated effects of ethanol occurred without altering significantly GABA(A)- and 5-HT1-mediated effects suggests that the NMDA component may be independent of other discriminative stimulus effects of 2.0 g/kg ethanol.     

Preoperative fasting improves survival after 90% hepatectomy

OBJECTIVE: To assess whether alterations in preoperative fatty acid oxidation and gluconeogenesis induced by fasting will affect survival and liver regeneration following 90% hepatectomy in the rat. DESIGN: In a randomized, controlled trial, Wistar rats (N = 157) were separated into two groups. Rats in the first group fasted for 24 hours. Rats in the second group were allowed to eat ad libitum until the time of operation. These groups were further randomized to receive either 20% glucose or tap water ad libitum postoperatively. INTERVENTIONS: Ninety percent hepatectomy; 24-hour fast; 5% glucose feeding. MAIN OUTCOME MEASURES: Survival, DNA synthesis in the hepatic remnant along with glucokinase activity (GKA) and glycogen content, serum ketone bodies (KB), free fatty acid (FFA), glucose, and ad libitum glucose consumption (GC) were serially quantified. RESULTS: Fasting rats that were offered glucose (fasted/glucose) after hepatectomy demonstrated better survival at 48 hours than the rats that were fed before the procedure and given glucose following hepatectomy (fed/glucose), 95% vs 52% (P < .05). The fasted/glucose group also had a greater peak rate of DNA synthesis (550 +/- 110 vs 275 +/- 40 disintegrations per minute per 0.001 mg of DNA, P < .05). Survival was poor in both groups when only tap water was offered to the animals after hepatectomy (31% vs 12%). In the fasted/glucose group, GC 1 hour after hepatectomy was greater than that for fed rats (1.3 +/- 0.175 vs 0.73 +/- 0.176 g/h, P < .05), yet GKA was suppressed (3.4 +/- 0.42 vs 8.05 +/- 2.77 nmol/min per milligrams of protein, P < .05). Fasting before hepatectomy and consuming glucose after causes elevations in both FFA (1.26 +/- 0.19 vs 0.82 +/- 0.13 mol/mL., P < .05) and KB (18.96 +/- 2.82 vs 11.4 +/- 3.94 mmol/mL, P < .05). Normal glucose was maintained in the fasted/glucose group, but fell to 63 +/- 14 mg/dL at 8 hours after hepatectomy in the fed/glucose group. CONCLUSIONS: Fasting before hepatectomy shifts energy utilization to fat oxidation and gluconeogenesis, which appears to ameliorate liver failure after hepatectomy in this severe model of hepatic resection.     

Synergistic antithrombotic effects of argatroban and ticlopidine in the rat venous thrombosis model

Argatroban, a synthetic thrombin inhibitor, and ticlopidine, an anti-platelet agent, are major antithrombotic agents. We investigated the antithrombotic effects of a combination of argatroban and ticlopidine in the rat venous thrombosis model. Argatroban or ticlopidine inhibited thrombus formation in a dose-dependent manner; 50% inhibition (ED50) is obtained with 1.0 mg/kg/h (infusion) argatroban or 30 mg/kg (p.o.) ticlopidine. The combination of argatroban and ticlopidine inhibited thrombus formation in a dose-dependent manner; ED50 is obtained with 0.25 mg/kg/h argatroban plus 10 mg/kg ticlopidine and 0.5 mg/kg/h argatroban plus 3 mg/kg ticlopidine, whereas 0.5 mg/kg/h argatroban alone or 10 mg/kg ticlopidine alone had negligible effect (<20% inhibition). Isobole analysis showed that the antithrombotic effects of the combination of argatroban and ticlopidine involved synergism with potentiation. In contrast, the combination of argatroban and ticlopidine did not prolong the bleeding time synergistically. These data showed that the combination therapy of argatroban and ticlopidine should be clinically beneficial, but the different administration route may restrict the clinical usage.     

Role of nitric oxide in the regulation of the hepatic microcirculation in vivo

BACKGROUND/AIMS: Nitric oxide (NO) is an important mediator in the regulation of vascular tone. However, no data exist on the physiological role of NO in the regulation of the hepatic microcirculation. This study was designed to evaluate the role of NO in the hepatic microcirculation in vivo under physiological conditions. METHODS: The hepatic microcirculation was investigated in anesthetized rats by intravital fluorescence microscopy after injection of fluorescein-isothiocyanate-labeled erythrocytes. Following assessment of baseline sinusoidal perfusion, animals were randomly treated with L-NMMA (n=6), L-arginine (n=6), nitroprusside sodium (NPS, n=5) or a comparable volume of NaCl (n=4). Drugs were given through a portal vein catheter at three doses (Dx), each followed by intravital microscopy. L-NMMA was given: 5 mg/kg (D1), 25 mg/kg (D2), 50 mg/kg (D3); L-arginine 30 mg/kg (D1), 150 mg/kg (D2), 300 mg/kg (D3); and NPS continuously 80 microg x kg(-1) x h(-1). RESULTS: L-NMMA induced a significant increase of mean arterial blood pressure (MAP) (114 vs. 129 mm Hg; p<0.05). In contrast, MAP of NPS-treated animals decreased (107 vs. 91 mm Hg; p<0.01) whereas MAP of animals receiving L-arginine did not significantly differ. Sinusoidal blood flow revealed dose-dependent changes: L-NMMA significantly decreased perfusion of sinusoids (D1: 65%, D2: 57%, D3: 50% of baseline, p<0.05). Injection of L-arginine increased the sinusoidal flow even with the lowest dose (D1: 137%, D2: 133%, D3: 123%, p<0.05). Continuous infusion of NPS had little effect on sinusoidal blood flow at the first and second times of microscopy but sinusoidal blood flow was significantly increased at the third time (D1: 103%, D2: 106%, D3: 122%). CONCLUSIONS: Inhibition of NOS results in a dose-dependent disturbance of the hepatic microcirculation despite significantly increased MAP, whereas L-arginine increases the sinusoidal blood flow. The results indicate an important role for NO in the regulatory mechanisms of hepatic sinusoidal perfusion under physiological conditions.     

Methanol in human breath

Using proton transfer reaction-mass spectrometry for trace gas analysis of the human breath, the concentrations of methanol and ethanol have been measured for various test persons consuming alcoholic beverages and various amounts of fruits, respectively. The methanol concentrations increased from a natural (physiological) level of approximately 0.4 ppm up to approximately 2 ppm a few hours after eating about 1/2 kg of fruits, and about the same concentration was reached after drinking of 100 ml brandy containing 24% volume of ethanol and 0.19% volume of methanol.     

Inhibition of DNA methylation by S-adenosylethionine with the production of methyl-deficient DNA in regenerating rat liver

Ethionine, a liver carcinogen, was administered p.o. (300 mg/kg) to rats 17 hr after partial hepatectomy. At 6 hr after administration of the ethionine, hepatic S-adenosylethionine levels were 30- to 40-fold greater than the hepatic level of S-adenosylmethionine. A 10-fold ratio of S-adenosylethionine to S-adenosylmethionine still persited at 24 hr after ethionine administration. When given at 17 hr after partial hepatectomy, ethionine produced a 30% inhibition of DNA synthesis, measured by the incorporation of [methyl-3H]thymidine at 23 to 24 hr after partial hepatectomy (6 to 7 hr after ethionine administration). DNA synthesized during this interval was methyl deficient as judged by the reduced incorporation of radioactivity from L-[methyl-3H]methionine into 5-methylcytosine residues of DNA. In an assay for DNA methylation in vitro using whole nuclei, the methyl-deficient DNA was methylated by S-adenosylmethionine 8 times more than was control DNA; the DNA methylation was competitively inhibited by S-adenosylethionine. These data suggest that S-adenosylethionine, formed in vivo from ethionine, competitively inhibits the methylation of DNA in vivo by S-adenosylmethionine, resulting in the production of methyl-deficient DNA.     

Differential effects of GABA(A) and GABA(B) agonists on sensitization to the locomotor stimulant effects of ethanol in DBA/2 J mice

Contemporary theories of drug abuse suggest that behavioral sensitization plays an important role in addiction. However, few studies have examined the mechanisms underlying behavioral sensitization to ethanol. The present study examined the ability of THIP (2, 4, or 8 mg/kg) and baclofen (5.0, 6.25, or 7.5 mg/kg), GABA(A) and GABA(B) agonists, respectively, to prevent development of sensitization to the locomotor stimulant effects of ethanol (2 g/kg) in DBA/2 J mice. Ethanol was administered immediately before four 5-min activity trials conducted at 48-h intervals. Administration of ethanol on each of the four trials resulted in behavioral sensitization in control groups. While having few effects on activity when given alone, both GABA agonists completely blocked the acute stimulant response to ethanol on the first trial. Administration of THIP prior to ethanol on each trial failed to prevent development of sensitization. In contrast, all doses of baclofen blocked sensitization. Assessment of blood ethanol levels 15, 50 and 100 min after administration of ethanol indicated that baclofen did not change the pharmacokinetics of ethanol. These results indicate an important role for GABA(B) receptors, but not GABA(A) receptors, in development of sensitization to the locomotor stimulant effects of ethanol.     

Intranasal provocation with lysine acetylsalicylic acid

The adverse effects of the exposure of the liver to the interaction of ethanol with its congeners and acetaldehyde, coexisting in the contents of alcoholic beverages, have been little studied. Twenty four male Wistar rats were divided into four groups. Two groups (SH/DA; SH/FA) were submitted to daily treatment with synthetic hydroalcoholic solutions containing ethanol, methanol, higher alcohols and acetaldehyde in the same proportions as those found in most common distilled and fermented alcoholic beverages; the third group (SH/EA) was treated with a hydroalcoholic solution of ethanol; the fourth group served as control and received an equivalent volume of an isocaloric solution of dextrose. All the animals were killed at the end of the 9th week of the experiment. The ratio between the liver weight and body weight was found to be lower in the treated animals than in the control group. The histology of the liver was altered in the three groups which were submitted to treatment with the hydroalcoholic solutions, with quantitative and qualitative differences between the groups. These results suggest that the hepatoxicity of ethanol in alcoholic beverages is enhanced by interaction with its congeners and acetaldehyde; they also suggest that alcoholic beverages are not equivalent in their potential to cause liver damage.     

Benzodiazepine receptor antagonists modulate the actions of ethanol in alcohol-preferring and -nonpreferring rats

The pyrazoloquinoline CGS 8216 (2-phenylpyrazolo-[4,3-c]-quinolin-3 (5H)-one, 0.05-2 mg/kg) and the beta-carboline ZK 93426 (ethyl-5-isopropyl-4-methyl-beta-carboline-3-carboxylate, 1-10 mg/kg) benzodiazepine receptor antagonists were evaluated for their capacity to modulate the behavioral actions of ethanol in alcohol preferring and -nonpreferring rats. When alcohol-preferring rats were presented with a two-bottle choice test between ethanol (10% v/v) and a saccharin (0.0125% g/v) solution, both antagonists dose-dependently reduced intake of ethanol by 35-92% of control levels on day 1 at the initial 15 min interval of the 4 h limited access. Saccharin drinking was suppressed only with the highest doses. CGS 8216 (0.25 mg/kg) and ZK 93426 (4 mg/kg) unmasked the anxiolytic effects of a hypnotic ethanol dose (1.5 g/kg ethanol) on the plus maze test in alcohol-preferring rats, but potentiated the ethanol-induced suppression in alcohol-nonpreferring rats. CGS 8216 (0.25 mg/kg) and ZK 93426 (4 mg/kg) attenuated the ethanol (0.5 and 1.5 g/kg)-induced suppression in the open field in alcohol-nonpreferring rats; however, CGS 8216 potentiated the depressant effects of the lower ethanol dose (0.5 g/kg) in alcohol-preferring rats. These findings provide evidence that benzodiazepine receptor antagonists may differentially modulate the behavioral actions of ethanol in alcohol-preferring and-nonpreferring rats. It is possible that the qualitative pharmacodynamic differences seen in the present study may be related to selective breeding for alcohol preference. The findings indicate the potential for development of receptor specific ligands devoid of toxic effects which may be useful in the treatment of alcohol abuse and alcoholism.     

Effect of antioxidative therapy on regeneration of ischemic liver

Ischemia is a common situation, not always desirable, in liver surgery. In any case, it implies cellular damage that would be worth avoiding. In the present study, different antioxidant drugs (superoxide-dismutase, allopurinol and folinic acid) are administered prior to liver reperfusion in order to reduce ischemic damage. Liver regeneration, following a 70% hepatectomy and 15 minutes of normothermic hepatic ischemia, serves as an indirect functional test of the reperfused liver. SOD (6 mg/kg) and allopurinol (50 mg/kg) have accelerated hepatocytic DNA synthesis without increasing the number or percentage of activated hepatocytes. However, the folinic acid has proved to be very effective, counteracting the deleterious effect of liver ischemia on hepatocytic regeneration.     

Contrast media enhanced magnetic resonance angiography for determining patency of a coronary bypass. A comparison with coronary angiography]

BACKGROUND: More data on the efficacy and safety of ciprofloxacin in pediatric cystic fibrosis patients are needed. METHODS: One hundred eight pediatric cystic fibrosis patients (ages 5 to 17 years) with acute bronchopulmonary exacerbations entered a randomized multicenter trial designed to compare the safety and efficacy of antipseudomonas therapy with oral ciprofloxacin (15 mg/kg twice daily; maximum dosage 750 mg twice daily) or intravenous ceftazidime plus tobramycin (CAZ/TM) for 14 days. RESULTS: Clinical improvement was observed in 93% of patients treated with oral ciprofloxacin and in 96% of those receiving parenteral therapy. Transient suppression of Pseudomonas aeruginosa was achieved in 63% of patients at the end of the course of iv CAZ/TM therapy and in 24% receiving ciprofloxacin. Ultrasound examination and nuclear magnetic resonance imaging scans showed no evidence of cartilage toxicity in any of the ciprofloxacin-treated patients. Musculoskeletal adverse events were reported with similar frequency in the two groups of patients (7% in the group receiving ciprofloxacin therapy and 11% in the IV CAZ/TM group). The only sustained musculoskeletal symptom was a case of synovitis in a patient receiving parenteral CAZ/TM. CONCLUSION: Ciprofloxacin thus appears to be safe and effective for use in young patients with bronchopulmonary exacerbation of cystic fibrosis.