六氯对二甲苯对豚鼠肝药酶的抑制作用

六氯对二甲苯(HCX)单剂(50-100mg/kg)或多剂(100mg/kg,qd×6d或50mg/kg,qd×14d,ip)均能极显著延长豚鼠戊巴比妥钠催眠时间,HCX 100mg/kg ip使豚鼠血浆戊巴比妥t 1/2 β延长3.2倍,并使豚鼠肝匀浆内戊巴比妥侧链羟化酶和氨基比林N-脱甲基酶活性明显降低。表明HCX是豚鼠肝药酶的抑制剂。而大鼠ip HCX 100mg/kg对其血浆戊巴比妥t 1/2 β确无明显影响。     

Cyclooxygenase inhibitors protect D-galactosamine/lipopolysaccharide induced acute hepatic injury in experimental mice model

We investigated the protective effects of two non-steroid anti-inflammatory drugs, indomethacin (COX-1 and COX-2 inhibitors) and nimesulide (specific COX-2 inhibitor) on the hepatic injury induced by lipopolysaccharide in d-galactosamine sensitized (Gal/LPS) mice. ICR male mice were injected with a single dose of Gal/LPS with or without pre-treatment of 3mg/kg indomethacin or 30 mg/kg nimesulide (single i.p. injection). Sixteen hours later, blood and liver tissues of mice were collected for histological, molecular, and biochemical analyses. Our results showed marked reduction of hepatic necrosis, serum ALT, and tissue TBARS levels in both indomethacin- and nimesulide-pre-treated mice when compared with Gal/LPS-treated mice. Western blot and RT-PCR analysis showed decreased levels of iNOS mRNA, iNOS protein, and nitrotyrosine formation in both COX inhibitor pre-treated groups when compared with Gal/LPS-treated group. There was an inverse relationship between COX-1 and COX-2 expressions, as well as between COX-2 and C/EBP-α expressions in COX inhibitors groups, Gal/LPS and control groups. COX inhibitors reduced the expression of TNF-α mRNA and the activity of NF-κB which were elevated by Gal/LPS treatment. We conclude that COX inhibitors protected the liver from Gal/LPS-induced hepatotoxicity. COX inhibitors could be considered as potential agents in the prevention of acute liver failure and sepsis.     

Melatonin attenuates lipopolysaccharide (LPS)-induced apoptotic liver damage in D-galactosamine-sensitized mice

D-Galactosamine (GalN) depletes UTP primarily in liver, resulting in decreased RNA synthesis in hepatocytes. When given together with a sublethal dose of lipopolysaccharide (LPS), GalN highly sensitizes animals to produce apoptotic liver injury with severe hepatic congestion, resulting in rapid death. Melatonin is a cytokine modulator, antioxidant and anti-apoptotic agent. In the present study, we investigated the effect of melatonin on LPS-induced apoptotic liver damage in GalN-sensitized mice. Female CD-1 mice were intraperitoneally (i.p.) injected with melatonin (5.0mg/kg) 30min before GalN/LPS (700mg10microg/kg, i.p.), another two doses of melatonin (2.5mg/kg, i.p.) being administered 1 and 2h after GalN/LPS. Results showed that serum alanine aminotransferase (ALT) activities were markedly increased 8h after GalN/LPS treatment, massive hemorrhage being observed in histological sections of liver from GalN/LPS-treated mice. Melatonin significantly attenuated GalN/LPS-induced elevation of serum ALT. In parallel, melatonin distinctly improved GalN/LPS-induced congestion. Additional experiment showed that melatonin significantly attenuated GalN/LPS-induced hepatic apoptosis, measured by inhibition of caspase-3 activities and attenuation of DNA laddering. Furthermore, melatonin markedly increased hepatic Se-dependent glutathione peroxidase (GSH-Px) and glutathione reductase (GSH-Rd) activities and attenuated hepatic glutathione (GSH) depletion in GalN/LPS-treated mice. Increases in serum tumor necrosis factor alpha (TNF-alpha), which were observed in GalN/LPS-treated mice, were significantly reduced by melatonin. However, melatonin had no effect on LPS-evoked nitric oxide production in GalN-sensitized mice. Taken together, these results indicate that melatonin protected against LPS-induced liver damage in GalN-sensitized mice through its strong ROS-scavenging, antiinflammatory and antiapoptotic effects.     

滴滴涕和六六六对戊巴比妥体内转化的双相影响

滴滴涕和六六六对大鼠肝脏转化戊巴比妥的作用都是双相的,卽先抑制而后刺激;对小鼠的作用,六六六是双相的,滴滴涕则只有抑制相,连续多次给与滴滴涕和六六六的所以能缩短大鼠戊巴比妥睡眠时间,除刺激药物转化酶外,部分由于肝脏重量的增加。苯巴比妥能进一步缩短滴滴涕处理大鼠的戊巴比妥睡眠时间,而对六六六处理动物则无明显影响。六六六和滴滴涕都能使大鼠尿中的维生素C排泄增加。     

Comparison of the effects of acute and subchronic administration of Aroclor 1254, a commercial mixture of polychlorinated biphenyls, on pentobarbital-induced sleep time and [14C]pentobarbital disposition in mice

We have reported previously that polychlorinated biphenyls (PCBs) alter neurochemistry and suppress spontaneous locomotor activity in mice. The present study was initiated to determine whether orally administered (Aroclor 1254) would potentiate pentobarbital-induced sleep time. Sleep time was enhanced significantly by Aroclor 1254 (500 mg/kg) given 0 to 8 h prior to pentobarbital, with the peak effect occurring at 2 h. This effect was demonstrated to be dose-responsive in the range of 5 to 25 mg/kg given 2 h prior to pentobarbital, but only slightly larger increments in sleep time were observed with higher doses of PCBs (50, 100, 250, and 500 mg/kg). Administration of vehicle or Aroclor 1254 (30 or 100 mg/kg) for 14 successive days reduced sleep time when pentobarbital was given 45 min after the last dose of vehicle or Aroclor 1254, with a further reduction when pentobarbital was given 24 h after the last dose. As a correlate to the sleep-time studies, levels of pentobarbital and metabolites were measured in brain, liver, and plasma of mice that had received varying doses of Aroclor 1254 2 h prior to [14C]pentobarbital. Elevated levels of pentobarbital and decreased levels of metabolites were found after acute administration of Aroclor 1254 during a period of time when Aroclor 1254-treated mice were still asleep. These effects of Aroclor 1254 on pentobarbital disposition were found to be dose-dependent. Brain levels of pentobarbital in mice after 14 d of Aroclor 1254 treatment (30 mg/kg) were less than those in vehicle-treated animals, and these levels were consistent with the reduced sleep times. Thus, a correlation between pentobarbital brain levels and sleep time in both Aroclor 1254-treated and nontreated animals suggests that Aroclor 1254 does not alter pentobarbital narcosis by a direct action on the brain. Rather, acutely administered Aroclor 1254 may be augmenting sleep time by competing with pentobarbital for metabolic sites in the liver, while chronically administered Aroclor 1254 induces pentobarbital metabolism.     

Effect of caffeine on the hepatic microsomal mixed function oxidase system during phenobarbital and benzo[a]pyrene treatment in rats

Simultaneous administration of caffeine (100 mg/kg, i.p., 3 days) and phenobarbital (80 mg/kg, i.p., 3 days) to adult male rats resulted in a significant decrease in hepatic cytochrome P-450 and acetanilide hydroxylase activity, compared to phenobarbital administration alone. While simultaneous administration of caffeine and benzo[a]pyrene (20 mg/kg, i.p., 2 days) increased acetanilide hydroxylase, compared to benzo[a]pyrene administration, no change was seen in the cytochrome P-450 concentration. In vitro addition of 2.5 mM caffeine to microsomal incubations from untreated, phenobarbital- and benzo[a]pyrene-treated rats inhibited aminopyrine N-demethylase activity. No significant difference was seen in the extent of aminopyrine N-demethylase inhibition due to the in vitro addition of caffeine to microsomes from untreated or phenobarbital-treated rats, whereas inhibition in microsomes from benzo[a]pyrene-treated rats was greater.     

Beneficial effect of HCL-31D in murine models of endotoxaemia

We evaluated the effect of HCL-31D, a novel cAMP-specific phosphodiesterase inhibitor, on the induction of inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma)-treated rat aortic smooth muscle cells (RASMC) and on survival in a murine model of severe endotoxaemia. Treatment of cultured RASMC with LPS and IFN-gamma resulted in an increase of nitrite, tumour necrosis factor (TNF-alpha) production and induction of iNOS mRNA. However, incubation with HCL-31D (1 approximately 50 microM) for 24 h caused significant attenuation of nitrite and TNF-alpha formation as well as iNOS mRNA induction in a dose-dependent manner but no effect on iNOS activity in RASMC. In addition, administration of HCL-31D (5 mg/kg, i.p.) resulted in that the increase of both plasma nitrate and TNF-alpha levels induced by LPS in vivo was significantly reduced in LPS-treated rats. Treatment of conscious mice with a high dose of LPS (60 mg/kg, i.p.) to ICR mice resulted in a 24-h survival rate of only 10%. However, administration of HCL-31D (5 mg/kg, i.p. at 0 h and 6 h after LPS) improved the 24-h survival to 50%, indicating that HCL-31D has a beneficial effect in murine model endotoxaemia. These effects may be mainly due to inhibition of TNF-alpha formation and of the induction of iNOS. We proposed that the elevation of cAMP levels by HCL-31D may be involved in the prevention of TNF-alpha formation and iNOS induction.     

Protective effects of butylated hydroxyanisole against the acute toxicity of monocrotaline in mice

Dietary butylated hydroxyanisole (BHA) at levels of 0.25 and 0.75% was found to protect young female mice against the acute toxicity of monocrotaline. The protective effect was associated with reduced levels of pyrrole metabolites in liver, decreased activity of hepatic aminopyrine demethylase, and a reduced rate of in vitro microsomal conversion of monocrotaline to pyrrole metabolites. BHA also increased liver sulfhydryl levels and the activity of cytosolic glutathione S-transferase. Dietary cysteine (1%) was less protective than BHA against monocrotaline toxicity. The LD50 values of monocrotaline in control and cysteine fed mice were 259 and 335 mg/kg, respectively, but for BHA-fed mice, the LD50 value was 497 (0.25% dietary BHA) or 542 mg/kg (for 0.75% dietary BHA with or without 1% cysteine). Dietary cysteine did not produce an increase in liver sulfhydryls but it increased the glutathione S-transferase activity and the in vitro production of pyrroles from monocrotaline. The ip administration of monocrotaline (280 mg/kg) did not affect liver sulfhydryl levels or aminopyrine demethylase activity but produced a significant decrease in the in vitro formation of pyrroles from monocrotaline. Although alterations in microsomal monooxygenase activities occurred after BHA, cysteine or monocrotaline treatment, the concentration of cytochrome P-450 in liver was unchanged.     

Drug interaction on antitumor drugs I. Antitumor activity of cyclophosphamide in mice consecutively administered aminopyrine, chlorpromazine, or morphine (author's transl)

Antitumor activity and lethality of cyclophosphamide alone and in combination with several drugs were investigated in male ddY mice. The antitumor activity was estimated by weighing the solid tumor on the 15th day after Ehrlich ascites cell inoculation. Pentobarbital induced sleeping time for monitoring the activity of hepatic drug-metabolizing enzymes was defined as the time between the loss and the recovery of the righting reflex. Consecutive administration of pentobarbital shortened the pentobarbital sleeping time and increased the antitumor activity after cyclophosphamide. On the contrary, a single administration of SKF 525A or cycloheximide prolonged the pentobarbital sleeping time significantly and decreased the antitumor activity after cyclophosphamide. Consecutive administration of aminopyrine, or chlorpromazine shortened the pentobarbital sleeping time and increased the antitumor activity after cyclophosphamide. These results indicate that aminopyrine and chlorpromazine may increase the levels of the hepatic drug-metabolizing components and may activate cyclophosphamide by conversion to an active form. Effect of a consecutive administration of morphine on the pentobarbital sleeping time and the antitumor activity was uncertain in individual cases.On the other hand, aminopyrine, chlorpromazine, or morphine in consecutive administration increased the lethality of cyclophosphamide.     

Hepatoprotective effect of taxiresinol and (7'R)-7'-hydroxylariciresinol on D-galactosamine and lipopolysaccharide-induced liver injury in mice

The hepatoprotective effect of taxiresinol ( 1) and (7' R)-7'-hydroxylariciresinol ( 2), two tetrahydrofuran-type lignans isolated from the wood of Taxus yunnanensis, were investigated on D-galactosamine ( D-GalN)/lipopolysaccharide (LPS)-induced hepatic liver injury in mice. Pre-administration of 1 or 2 at doses of 50 and 10 mg/kg ( i. p.) at 12 and 1 h before D-GalN/LPS injection significantly inhibited hepatocyte DNA fragmentation and apoptotic body formation. Pre-treatment of these two lignans further suppressed hepatic necrosis which occur at later stage of D-GalN/LPS intoxication as demonstrated by the significant and dose-dependent reduction in serum glutamic pyruvic transaminase (sGPT) and serum glutamic oxaloacetic transaminase (sGOT) at 8 h after intoxication. The elevation of serum tumor necrosis factor-alpha (TNF- alpha) level by D-GalN/LPS toxication was significantly inhibited by 1 or 2 at doses of 50 and 10 mg/kg. Moreover, both of these lignans significantly protected hepatocytes from D-GalN/TNF- alpha-induced cell death in primary cultured mouse hepatocytes. These results suggested that 1 and 2 had protected the hepatocytes from apoptosis via an inhibition of TNF- alpha production by activated macrophages and a direct inhibition of apoptosis induced by TNF- alpha in D-GalN/LPS-treated mice.     

Perturbation of glutathione by a central action of morphine

A series of studies were conducted in order to further characterize the previously reported effect of morphine to diminish hepatocellular concentrations of glutathione (GSH) in mice. Naive ICR mice administered morphine (i.p.) in doses up to 1000 mg/kg had diminished hepatic GSH concentrations, with a maximum depletion of approximately 50% occurring at doses of 250 mg/kg or greater. No such effect from an acute challenge with morphine was observed in morphine-tolerant mice. The intracerebro-ventricular administration of the opioid receptor antagonist naltrexone (250 micrograms) completely blocked the hepatic GSH depression resulting from the systemic (i.p.) administration of morphine (100 mg/kg). When morphine (100 micrograms) was administered by the i.c.v. route, GSH concentrations in liver and plasma were significantly altered while heart and kidney were unchanged. Variable responses to i.c.v. morphine were obtained in spleen, stomach and lung. The depression of hepatic GSH was found not to be a consequence of morphine-induced hypoxia or hypothermia, and could not be attributed to intracellular oxidation of GSH.     

Roles of nitric oxide and prostaglandins in the increased permeability of the blood-brain barrier caused by lipopolysaccharide

We investigated the involvement of nitric oxide (NO) and prostaglandins (PGs) in the damage to the blood-brain barrier (BBB) induced by lipopolysaccharide (LPS), using fluorescein as a tracer in mice. Aminoguanidine, a competitive inhibitor of inducible NO synthase (iNOS), when administered s.c. at 5 mg/kg, but not 500 mg/kg, reduced significantly the increase in brain fluorescein level after its i.v. injection in LPS-treated mice. When 1000 mg/kg of l-arginine, a substrate of NOS, were co-administered with 5 mg/kg of aminoguanidine to LPS-treated mice, the inhibitory effect of aminoguanidine on the increased fluorescein level disappeared. N(G)-Nitro-l-arginine methyl ester (l-NAME), a non-isoenzyme-selective NOS inhibitor, when administered s.c. at 5 mg/kg, only slightly reduced the LPS-induced increase in the brain fluorescein level. A pretreatment with dexamethasone, which suppressed the induction of both iNOS and cyclooxygenase 2 (COX-2), tended to decrease the brain fluorescein level in LPS-treated mice. Indomethacin, a COX inhibitor, at 5 mg/kg, but not 10 mg/kg, suppressed significantly the LPS-induced increase in the brain fluorescein level. These results involve that both the NO produced by iNOS and the PGs produced by COX contribute to enhance BBB permeability in LPS-administered mice.     

Effect of the catecholamine-depleting agent 1-phenyl-3-(2-thiazolyl)-2-thiourea (U-14,624) on drug metabolism in the rat

Male rats injected with 1-phenyl-3-(2-thiazolyl)-2-thiourea (U-14,624) (25 mg/kg/day i.p.) for 3 days prior to induction of anesthesia with pentobarbital (40 mg/kg, i.p.) slept significantly (P < 0.05) longer than control animals. Plasma and brain half-lives of pentobarbital were also prolonged in the treated animals, but both control and treated groups awakened with similar brain levels of pentobarbital. In addition, the plasma half-life of antipyrine in treated animals was also prolonged significantly. Subacute administration of U-14,624 (50 mg/kg/day i.p.) to male rats for 5–7 days suppressed the activities of aminopyrine N-demethylase, aniline hydroxylase and p-nitroanisole O-demethylase enzymes in vitro; this effect could not be demonstrated at lower doses. Single doses of U-14,624 (100–200 mg/kg, i.p.) also suppressed the activities of the three oxidative enzymes. The suppression was positively correlated with reduced levels of hepatic microsomal cytochrome P-450. Levels of cytochrome b₅ and NADPH-cytochrome c reductase activity were not affected consistently by acute dosage with U-14,624. The inhibitory effects of single doses (100–400 mg/kg, i.p.) on all enzymatic systems were reversible, and recovery was complete within 48 hr. Whereas all three oxidative drug-metabolizing enzymes were inhibited in a mixed manner by in vitro exposure to U-14,624 (10^?5–10^?2 M), neotetrazolium diaphorase was not inhibited by U-14,624 at concentrations as high as 5 mM. Inhibition of oxidative drug metabolism by U-14,624 is mechanistically related to depletion of cytochrome P-450, but inhibition of these enzymes in vitro indicates that a second inhibitory mechanism may also be operative.     

Influence of histamine in a liver injury model induced by Propionibacterium acnes and lipopolysaccharide

In normal mice, plasma histamine levels were 29.4+/-10.1 pmol/ml. When 0.1 microg of lipopolysaccharide (LPS) was intravenously injected into Propionibacterium acnes (P. acnes)-primed ICR mice, histamine levels increased remarkably to 61.2+/-15.9 pmol/ml (p<0.001). An increase was also observed in liver tissues. Oral administration of histidine at 200 mg/kg once daily for 5 d before intravenous LPS injection increased the plasma alanine aminotransferase (ALT) activity to 2936.5+/-356.3 IU/l, a significant change compared with the controls (2244.8+/-425.5 IU/l, p<0.05). The 24 h survival rate after LPS injection was 72.7% in the mice treated with 50 mg/kg of ranitidine, in contrast with 50% in the control group although the treatment did not significantly decrease the plasma ALT activity. On the other hand, 50 mg/kg of pyrilamine significantly reduced plasma ALT activity (p<0.001). The results suggested that histamine levels are related to hepatic damage in the P. acnes plus LPS induction of liver injury.     

Inhibition of hepatic microsomal drug-metabolizing enzymes by imperatorin

The effect of imperatorin on hepatic microsomal mixed function oxidases (MFO) was investigated. On acute treatment, imperatorin (30 mg/kg, i.p.) caused a significant reduction in activities of hepatic aminopyrine N-demethylase, hexobarbital hydroxylase and aniline hydroxylase as well as cytochrome p-450 content in rats and mice. Kinetic studies on rat liver enzymes revealed that imperatorin appeared to be a competitive inhibitor of aminopyrine N-demethylase (Ki, 0.007 mM), whereas a non-competitive inhibitor of hexobarbital hydroxylase (Ki, 0.0148mM). Imperatorin also inhibited non-competitively aniline metabolism (Ki, 0.2mM). Imperatorin binds to phenobarbital-induced cytochrome p-450 to give a typical type 1 binding spectrum (max. 388nm, min 422nm). Multiple administrations of imperatorin (30 mg/kg, i.p. daily for 7 days) to mice shortened markedly the duration of hexobarbital narcosis and increased activities of hepatic aminopyrine N-demethylase and hexobarbital hydroxylase and the level of cytochrome p-450 whereas aniline hydroxylase activity was unaffected.     

Platonin,a photosensitizing dye,improves circulatory failure and mortality in rat models of endotoxemia

Platonin, a cyanine photosensitizing dye, is a potent macrophage-activating agent and an immunomodulator. In this study, we compare the inhibitory effects of platonin with those of the three clinical drugs minocycline, clindamycin, and cyclosporin, on hypotension, tachycardia, and nitric oxide (NO) formation in a rat model of circulatory shock induced by Escherichia coli lipopolysaccharide (LPS). We also evaluate the effect of drugs on the 6 h survival rate in LPS-treated rats. Administration of LPS (15 mg/kg) caused a rapid drop in mean arterial blood pressure (MAP). Minocycline (10 mg/kg, i.v.) significantly prevented the fall of MAP at 3 h, and platonin (100 microg/kg, i.v.) markedly prevented the fall of MAP within the 0-3 h period after LPS administration. However, neither clindamycin (10 mg/kg, i.v.) nor cyclosporin (15 mg/kg, i.v.) had any effects in this study. On the other hand, an inducible NO synthase inhibitor, NG-nitro-L-arginine ester (L-NAME), caused a significantly increase in MAP and a moderate bradycardia after LPS administration. In addition, an increase in plasma nitrate formation elicited by endotoxemia was significantly reduced by pretreatment with either minocycline (10 mg/kg) or platonin (100 microg/kg). However, only platonin (100 microg/kg) markedly reduced the mortality and prolonged the mean survival time in LPS-treated rats. Minocycline, clindamycin, and cyclosporin had no effects under the same conditions. Further studies using an electron spin resonance (ESR) method were conducted on the scavenging activity of platonin on the free radicals formed. Platonin (10 microm) greatly reduced the ESR signal intensity of superoxide anion, hydroxyl radical, and methyl radical formation. In conclusion, platonin has beneficial effects on ameliorating endotoxaemia. This protective effect of platonin may be mediated, at least partly, by the reduced drop in MAP and the inhibition of NO and free radical formation in rat models of endotoxemia.     

Thyrotropin releasing hormone: antagonism of pentobarbital narcosis in the monkey

The effect of TRH on pentobarbital narcosis in 12 rhesus monkeys was examined. Vital signs monitored included respiration rate, heart rate, temperature, sleeping time, and time of reappearance of certain reflexes. Blood samples were obtained for pentobarbital assay. Two dose schedules for TRH administration were used. One group of 6 animals received a single dose of 20 mg/kg 30 min after barbiturate administration, while the other group received 3 injections of 20 mg/kg spaced at 30, 40 and 50 min after injection of pentobarbital. Both groups were sex balanced. TRH administration resulted in dramatically increased respiration and heart rates and arrested the progress of barbiturate induced hypothermia. The extended dose schedule prolonged increased respiration rate and a differential effect of TRH on pentobarbital induced hypothermia across sexes was observed. All animals regained reflexes sooner and sleeping time was reduced by 22%. No differences in pentobarbital blood levels with TRH were observed. These results extend earlier work in rodents to primates and suggest a possible use of TRH in cases of acute barbiturate intoxication.     

Effects of analgesic-antipyretics on the spinal reflex potentials in cats: an analysis of the excitatory action of aminopyrine]

The effects of some analgesic-antipyretics on the spinal reflex potentials were studied in spinal cats. Aminopyrine at 25-100 mg/kg, i.v. produced a marked increase in mono- and poly-synaptic reflex potentials (MSR and PSR), and a decrease in dorsal root reflex potentials (DRR) in a dose-dependent manner. The amplitude of DRR decreased by aminopyrine was reversed by diazepam at 0.2 mg/kg, i.v.; however, the increased amplitudes of MSR and PSR were not affected by diazepam. Pretreatment of semicarbazide at 200 mg/kg, i.v. did not influence the increasing effect of aminopyrine on MSR and PSR. DL-5-Hydroxytryptophan produced facilitation of the MSR and PSR. In DL-5-hydroxytryptophan-treated cats, the amplitude of MSR was further increased by aminopyrine. Methysergide at 1 mg/kg, i.v. antagonized this increasing effect of aminopyrine on MSR and PSR. These observations suggest that the excitatory action of aminopyrine may be partly related to 5-hydroxytryptamine and not connected to the GABAergic mechanism. Other pyrazolone derivatives were also studied. Isopropylantipyrine at 50 mg/kg, i.v. produced increases in MSR and PSR. Intravenous sulpyrine at 500 mg/kg, antipyrine at 50 mg/kg or 4-aminoantipyrine at 50 mg/kg did not affect the reflex potentials. The non-pyrazolones, acetaminophen and indomethacin, did not increase the MSR and PSR. These results suggest that the N-dimethyl or isopropyl residue at the 4 position of the pyrazolone structure plays an important role in the excitatory action of analgesic-antipyretics in cat spinal cord.     

Role of aliesterase in organophosphate poisoning

Various doses of CBDP (2-(2-methylphenoxy)-4H-1,3,2-benzodioxaphosphorin-2-oxide), a metabolite of tri-o-cresyl phosphate, increased dramatically the acute toxicity of soman (pinacolyl methylphosphonofluoridate) in mice. CBDP (5 mg/kg; iv) reduced the soman LD50 value from 136 μg/kg in control to 6.95 μg/kg. The potentiation of soman toxicity following CBDP pretreatment appeared to be due primarily to inhibition of plasma aliesterase activity. Inhibition of liver aliesterase was not of primary importance in the potentiation of soman toxicity following CBDP pretreatment. In addition pretreatment with ISO-OMPA (tetraisopropyl pyrophosphoramide), a selective inhibitor of pseudocholinesterase, had no effect on the acute toxicity of soman. Similarly pretreatment of mice with pyridostigmine, a quaternary carbamate anticholinesterase which does not inhibit aliesterase, resulted in marked inhibition of diaphragm, plasma, and brain acetylcholinesterase had no effect on the acute toxicity of soman. Plasma aliesterase may be a depot for soman poisoning. The acute toxicity of soman by the ip, sc, and iv routes of administration was reduced following pretreatment of mice with phenobarbital (100 mg/kg) for 4 days. The reduced toxicity of soman following phenobarbital pretreatment was due to induction of liver aliesterase activity which subsequently resulted in an increase in plasma aliesterase activity. Thus more soman was probably bound to plasma aliesterase activity resulting in a reduction in acute toxicity of soman.Conversely pretreatment of mice with pentobarbital (70 mg/kg; ip) increased the toxicity of soman. This was probably the result of inhibition of plasma aliesterase by pentobarbital pretreatment combined with the central respiratory depression following pentobarbital administration. Following pentobarbital pretreatment soman inhibition of brain acetylcholinesterase was increased suggesting that plasma aliesterase inhibition alters the distribution of free soman in vivo. In summary, in mice plasma aliesterase appears to be an extremely important detoxification route for soman in vivo.     

Effect of ampicillin on hepatic microsomal mixed-function oxidase system in male mice

The effect of ampicillin [(D)-alpha-aminobenzyl penicillin] administration on the hepatic mixed-function oxidase (MFO) system was studied in male mice. Ampicillin (100 mg/kg, i.p., 3 days) decreased the levels of cytochrome P-450, aminopyrine N-demethylase, acetanilide hydroxylase and cytochrome c-reductase activity significantly. In carbon tetrachloride (CCl4)-pretreated mice, ampicillin increased acetanilide hydroxylation compared with CCl4 treatment alone; however, all other parameters of the MFO system remained unchanged. Ampicillin exhibited type II binding with microsomes (trough at 388 nm, peak at 430 nm). Thus ampicillin acts as an inhibitor of the MFO system.