An experimental study about how edaravone affect the nerve cells apoptosis in the compressed spinal cord / 中国医师杂志

Objective To investigate the protective function of edaravone in the compressed spinal cord.Methods There were 150 rabbits enrolled in each group in the experiment.Rabbits in both operation group and edaravone (EDA) treating group received mild spinal cord compressionby setting a flap head screw between C6 C7 after the neck.The spinal cord decompression was conducted seven days later.After 6 hours,rabbits in the EDA treating group were injected with a large amount of EDA through ear border veins,while the rabbits in the operation group only received 0.9％ sodium chloride injection.The transmission electron microscope was used to observe the apoptotic bodies at 1 day,3 days and 7 days after compression,and 1 day,3 days,7 days,and 14 days after decompression.Flow cytometry was used to test the rate of apoptosis of spinal cord cells.Immunohistochemistry was used to test the expression of Bax protein that is related to apoptosis.Results The neuronal apoptosis appeared after compression in both operation group and EDA-treating group.The Basso Beattie Bresnahan (BBB) score,neuronal apoptosis rates,and Bax protein expressions in both groups were statistically different (P ＜ 0.05) when the spinal cord was compressed in the first day and the third day,while there was no statistically different when spinal cord compressed at the seventh day (P ＞ 0.05).After decompression of the spinal cord,the BBB score,neuronal apoptosis rates,and Bax protein expressions in both groups were becoming lower at the seventh day (P ＜0.05).Conclusions EDA has protective function for compressed spinal cord.However,only the compression of spinal cord compression period of sufficient decompression can fundamentally protect the spinal cord.

Edaravone protects against cerebral ischemia-reperfusion injury in rats by upregulation of the LMO4 expression / 国际脑血管病杂志

ObjectiveTo investigate the neuroprotective mechanism of edaravone for cerebral ischemia-reperfusion injury in rats.MethodsThirty-six healthy adult male SD rats were randomly divided into three groups: a sham operation group, an ischemic model group, and an edaravone group (n=12 in each group).A focal cerebral ischemia model was induced by the suture method.Reperfusion was resumed after 2 h of ischemia;then the animals were sacrificed at 24 h after reperfusion.Edaravone 3 mg/kg was injected intraperitoneally immediately after cerebral ischemia-reperfusion in the edaravone group.The rats in the model group were injected equal volume normal saline.HE staining was used to observe the pathological changes.TUNEL staining was used to detect apoptotic cells in the ischemic cortex.Western blot and immunofluorescent staining were used to detect the expression levels of LIM domain protein 4 (LMO4) and LMO4 positive cells.Results HE staining showed that cellular morphology was basically normal in the sham operation group;both the model group and edaravone group had cell necrosis, but the latter was less severe.The number of morphologically normal cells in the edaravone group was significantly more than that in the model group (P<0.01).TUNEL staining showed that no TUNEL positive cells in the sham operation group were observed.The TUNEL positive cells in the edaravone group was significantly less that in the model group (P<0.01).Immunofluorescence staining showed that the expression level of LMO4 in the ischemic cortex in the edaravone group was significantly higher than that in the model group (P<0.01).ConclusionsEdaravone can alleviate the cerebral ischemia-reperfusion injury and inhibit neuronal apoptosis.Its mechanism may be associated with the upregulation of LMO4 expression.

Synthesis, characterization and antibacterial screening of some Schiff bases derived from pyrazole and 4-amino antipyrine / Síntesis, caracterización y evaluación antibacteriana de algunas bases de Schiff derivadas de pirazol y 4-amino antipirina

Some Schiff bases of pyrazole and 4-amino antipyrine have been synthesized. The antibacterial screening of these synthesized compounds was done in dimethyl forma-mide against four Gram positive bacteria viz. Bacillus cereus, Staphylococcus aureus, Staphylococcus epidermidids and Micrococcus luteus, and three Gram negative bacteria viz. Proteus mirabilis, Escherichia coli and Klebsiella aerogenes. It is observed that in comparison to Schiff bases of 4-amino antipyrine, pyrazole Schiff bases are better for inhibition for these selected Gram positive and Gram negative bacterial strains.

Se sintetizaron algunas bases de Schiff a partir de pirazol y 4-amino antipirina. La evaluación de la actividad antibacteriana de estos compuestos en dimetil formamida se realizó frente a cuatro bacterias Gram positivas, Bacillus cereus, Staphylococcus aureus, Staphylococcus epidermidids y Micrococcus luteus, y frente a tres bacterias Gram negativas, Proteus mirabilis, Escherichia coli y Klebsiella aerogenes. Se observó mejor inhibición bacteriana frente a las diferentes cepas para las bases de Schiff basadas en pirazol comparadas con aquellas basadas en 4-amino antipirina.

Effect of selective beta-adrenoceptor blockade and surgical resection of the celiac-superior mesenteric ganglion complex on delayed liquid gastric emptying induced by dipyrone, 4-aminoantipyrine, and antipyrine in rats

There is evidence for participation of peripheral β-adrenoceptors in delayed liquid gastric emptying (GE) induced in rats by dipyrone (Dp), 4-aminoantipyrine (AA), and antipyrine (At). The present study aimed to determine whether β-adrenoceptors are involved in delayed GE induced by phenylpyrazole derivatives and the role of the prevertebral sympathetic nervous system in this condition. Male Wistar rats weighing 220-280 g were used in the study. In the first experiment rats were intravenously pretreated with vehicle (V), atenolol 30 mg/kg (ATE, β1-adrenergic antagonist), or butoxamine 25 mg/kg (BUT, β2-adrenergic antagonist). In the second experiment, rats were pretreated with V or SR59230A 2 mg/kg (SRA, β3-adrenergic antagonist). In the third experiment, rats were subjected to surgical resection of the celiac-superior mesenteric ganglion complex or to sham surgery. The groups were intravenously treated with saline (S), 240 µmol/kg Dp, AA, or At, 15 min after pretreatment with the antagonists or V and nine days after surgery. GE was determined 10 min later by measuring the percentage of gastric retention (%GR) of saline labeled with phenol red 10 min after gavage. The %GR (means±SE, n=6) values indicated that BUT abolished the effect of Dp (BUT+Dp vs V+Dp: 35.0%±5.1% vs 56.4%±2.7%) and At (BUT+At vs V+At: 33.5%±4.7% vs 52.9%±2.6%) on GE, and significantly reduced (P<0.05) the effect of AA (BUT+AA vs V+AA: 48.0%±5.0% vs 65.2%±3.8%). ATE, SRA, and sympathectomy did not modify the effects of treatments. These results suggest that β2-adrenoceptor activation occurred in delayed liquid gastric emptying induced by the phenylpyrazole derivatives dipyrone, 4-aminoantipyrine, and antipyrine. Additionally, the released neurotransmitter did not originate in the celiac-superior mesenteric ganglion complex.

Evidence for the involvement of peripheral -adrenoceptors in delayed liquid gastric emptying induced by dipyrone, 4-aminoantipyrine, and antipyrine in rats

Dipyrone (Dp), 4-aminoantipyrine (AA), and antipyrine (At) delay liquid gastric emptying (GE) in rats. We evaluated adrenergic participation in this phenomenon in a study in male Wistar rats (250-300 g) pretreated subcutaneously with guanethidine (GUA), 100 mg·kg−1·day−1, or vehicle (V) for 2 days before experimental treatments. Other groups of animals were pretreated intravenously (iv) 15 min before treatment with V, prazosin (PRA; 1 mg/kg), yohimbine (YOH; 3 mg/kg), or propranolol (PRO; 4 mg/kg), or with intracerebroventricular (icv) administration of 25 µg PRO or V. The groups were treated iv with saline or with 240 µmol/kg Dp, AA, or At. GE was determined 10 min later by measuring the percentage of gastric retention (%GR) of saline labeled with phenol red 10 min after gavage. %GR (mean±SE, n=8) indicated that GUA abolished the effect of Dp (GUA vs V=31.7±1.6 vs 47.1±2.3%) and of At (33.2±2.3 vs 54.7±3.6%) on GE and significantly reduced the effect of AA (48.1±3.2 vs 67.2±3.1%). PRA and YOH did not modify the effect of the drugs. %GR (mean±SE, n=8) indicated that iv, but not icv, PRO abolished the effect of Dp (PRO vs V=29.1±1.7 vs 46.9±2.7%) and At (30.5±1.7 vs 49±3.2%) and significantly reduced the effect of AA (48.4±2.6 vs 59.5±3.1%). These data suggest activation of peripheral β-adrenoceptors in the delayed GE induced by phenylpyrazolone derivatives.

Determination of antipyrine in placental perfusate by UFLC-MS/MS / 中国药学杂志

OBJECTIVE: To establish a UPLC-MS/MS method for the determination of antipyrine in placental perfusate. METHODS: Sample was precipitated with acetonitrile. Analysis of antipyrine and estazolam(internal standard) were carried out on a Shim-pack XR-ODS II C18 column(2.0 mm × 75 mm, 2.2 μm). Gradient elution was adopted using acetonitrile and water (containing 0.1% formic acid, V/V) at a flow rate of 0.4 mL · min-1. Detection was performed with multiple reactions monitoring (MRM) using positive electrospray ionization(ESI) at m/z 189.2→56.2 for antipyrine and m/z 295.2→205.2 for estazolam. RESULTS: The calibration curve of antipyrine was linear over the range of 1.2 -1200 ng · mL-1 (r =0.9993). Inter- and intra-day RSDs were less than 15%, and the analytes were proven to be stable. CONCLUSION: This method is rapid, sensitive and specific, and can be applied to the determination of antipyrine in placental perfusate.

The effect on succinate dehydrogenase of mitochondria in myocardium and liver in sepsis rats treated with edaravone / 中国医师杂志

Objective To observe the effect on succinate dehydrogenase (SDH) of mitochondria in myocardium and liver in sepsis rats treated with edaravone. Methods 30 Sprague-Dawley rats were divided into 3 groups: sham operated group ( group A ), controlled operated group ( group B ), treated group with edaravone (group C). The model of sepsis rats was made by the way of caecum ligated and punctured and 20mg/kg lactate levofloxacin was subcutaneously injected (sci) 15min before and 3h after operation in three group. 5mg/kg edaravone were sci 15min before and 3h after operation in group C. Liver and myocardium were taken from all of them 18h after operation. The activities of SDH in myocardial and hepatic mitochondria were detected, pathological change of mitochondria in liver and myocardium were observed. Results The activities of SDH in myocardial and hepatic mitochondria in group B [ (0. 21 ± 0. 07 ) U/mgprot, (0. 23± 0. 08 ) U/mgprot ] were significantly decreased compared with group A [ ( 0. 33 ± 0. 10 ) U/mgprot, ( 0. 38±0. 12)U/mgprot]. The activities of those in group C[ (0.31 ±0. 08) U/mgprot, (0. 36 ±0. 11)U/mgprot] were significantly increased than group B. Myocardial and hepatic mitochondria swelling and endocytoplasmic reticulum expanding were found in group B by electron microscope, while it showed normal in group C. Conclusion Hepatic and myocardial mitochondrial structure were destroyed and activities of SDH were decreased in sepsis rats. They could be effectively protected by edaravone.

Phenylpyrazolone derivatives inhibit gastric emptying in rats by a capsaicin-sensitive afferent pathway

Dipyrone (Dp), 4-aminoantipyrine (AA) and antipyrine (At) administered iv and Dp administered icv delay gastric emptying (GE) in rats. The participation of capsaicin (Cps)-sensitive afferent fibers in this phenomenon was evaluated. Male Wistar rats were pretreated sc with Cps (50 mg/kg) or vehicle between the first and second day of life and both groups were submitted to the eye-wiping test. GE was determined in these animals at the age of 8/9 weeks (weight: 200-300 g). Ten minutes before the study, the animals of both groups were treated iv with Dp, AA or At (240 μmol/kg), or saline; or treated icv with Dp (4 μmol/animal) or saline. GE was determined 10 min after treatment by measuring percent gastric retention (GR) of saline labeled with phenol red 10 min after orogastric administration. Percent GR (mean ± SEM, N = 8) in animals pretreated with Cps and treated with Dp, AA or At (35.8 ± 3.2, 35.4 ± 2.2, and 35.6 ± 2 percent, respectively) did not differ from the GR of saline-treated animals pretreated with vehicle (36.8 ± 2.8 percent) and was significantly lower than in animals pretreated with vehicle and treated with the drugs (52.1 ± 2.8, 66.2 ± 4, and 55.8 ± 3 percent, respectively). The effect of icv administration of Dp (N = 6) was not modified by pretreatment with Cps (63.3 ± 5.7 percent) compared to Dp-treated animals pretreated with vehicle (62.3 ± 2.4 percent). The results suggest the participation of capsaicin-sensitive afferent fibers in the delayed GE induced by iv administration of Dp, AA and At, but not of icv Dp.

Effects of endaravone on hypoxia-ischemia-induced brain injury in neonatal piglets / 中华麻醉学杂志

Objective To investigate the effects of endaravane on hypoxia-ischemia (HI)-induced brain injury in neonatal piglets. Methods Male piglets 3-7 days old weighing 2.0-3.0 kg were used in this study. Group Ⅰ 10 piglets were randomly collected as sham operation without HI. Twenty piglets with HI were randomly divided into 2 groups (n = 10 each) : group Ⅱ HI and group Ⅲ HI + endaravone. The animals were anesthetized with intraperitoneal pentobarbital sodium 50 mg/kg, tracheostomized and mechanically ventilated with 30% O_2. Right femoral artery and vein were cannulated. MAP, HR, PET CO_2, blood gases and glucose and rectal temperature were monitored. After 15 min stabilization cardiac arrest was induced by inhalation of hypoxic air (O_2 10%) for 40 min followed by inhalation of 21% O_2 for 5 min. The tracheal tube was then occluded for 7 min. Cardio-pulmonary resuscitation (CPR) was then started until recovery of spontaneous circulation (ROSC). CPR > 3 min was considered a failure. A bolus of endaravone 3 mg/kg was given iv over an hour at 30 min after CPR,followed by continuous infusion at 1.5 mg·kg~(-1)·h~(-1) for 5.5 h in group Ⅲ , while in group Ⅱ vehicle was given instead of endaravone. The neurological function of the animals was evaluated at 48, 72 and 96 h after ROSC and scored (0-154, 0 = normal, 154 = severest dysfunction). The animals were killed at 96 h after ROSC. The brains were removed for microscopic examination of striatum and cortex and determination of 8-hydroxy-2'-deoxyguanine (8-OHdG/OHG) expression in putamen by immuno-histochemistry. Results The neurological function scores were significantly higher at 48 h after ROSC and the number of viable neurons in striatum and sensory cortex were significantly lower and the expression of 8-OHdG/OHG in putamen was significantly higher in group Ⅱ than in group Ⅲ . Conclusion The antioxidant endaravone given after CPR can attenuate Hl-induced brain injury by inhibiting oxidative damage to DNA and RNA.

Combined intravenous recombinant tissue plasminogen activator and edaravone for ultra-acute ischemic stroke / 中华神经科杂志

Objective To investigate the efficacy of combined intravenous rt-PA and free-radical scavengen (edaravone) on Chinese patients with acute ischemic stroke. Methods Eighty-nine subjects with ultra-acute ischemic stroke were assigned to the group treated with intravenous rt-PA and another group treated with a combination of intravenous rt-PA and edaravone. The NIH Stroke Scale (NIHSS) and Barthel Index (BI) in 30 days and 90 days after thrombolysis were compared between two groups. Results There were statistically significant differences between the group of rt-PA thrombolysis and the group of combined with rt-PA and edaravon in the ratio of NIHSS 0-1 of 30 days after therapy (25.0% vs35.6%, χ2=8.259,P=0.041) and 90 days (27.3%vs 40.0%, χ2=9.158,P=0.027),as well as in the proportion of BI 95-100 of the same time points(30 days:20.5%vs33.3%,χ2=8.833,P=0.032;90 days:25.O%vs37.8%,χ2=8.221,P=0.042).The rates of hemorrhagic conversion and mortality in two groups were similar. Conclusion rt-PA combined with free radical scavenger edaravone safely and effectively decreases the loss of neurofunctions and reserves more self-dependence capability in patients with acute ischemic stroke 30 days and 90 days after treatments.

Experimental study on edaravone in prevention of restenosis in rat common carotid balloon angioplasty / 中华神经科杂志

Objective To investigate edaravane in prevention of restenosis in rat common catery arteries balloon angioplasty and the possible mechanism of this process. Methods Forty male SD rats were randomly divided into 2 groups: treatment group (whose intima was injured by balloon and was given edaravone 3 mg/kg by peritoneal injection, bid) and control group (whose intima was injured by ballon and was given the same volume NS as edaravone). 1, 3, 7, 14 and 28 days after angioplasty, rats were killed and the local arteries were sectioned for analysis of pathological morphology and the expression of matrix metalloproteinase-2 (MMP-2) analyzed by immunohistochemistry. Results Small amounts of smooth muscle cell appeared at the intima of blood vessel 3 days after the artery injured by balloon. Consecutive intima was formed 7 days after artery injury. The intima was even or uneven thickened and the lumen of artery was significant stenosed 14 and 28 days afterwards. In the control group, the intimal area reached (0.240±0.043) mm2, the intima hyperplasy index were 0.52±0.06, stenosis ratio were 30%±9% 14 days afterwards. The intimal area were (0.420±0.063 )mm2, the intima hyperplasy index were 0.67± 0.07, stenosis ratio were 54%±9% on day 28. In the treatment group, the intimal area were (0.063± 0.025)mm2, the intima hyperplasy index were 0.24±0.07, stenosis ratio were 8%±3% after 14 days. The intimal area were (0.116±0.023) mm2, the intima hyperplasy index were 0.38±0.05, stenosis ratio were 16%±4% after 28 days. Compared with control group at the same time, the intimal area (F values were 50.488 and 81.119 respectively, P < 0.05 ), the intima hyperplasy index ( F values were 41.743 and 48.122 respectively, P<0.05) and stenosis ratio (F values were 24.221 and 81.119 respectively, P< 0.05) were decreased in treatment group. The expressions of MMP-2 raised after balloon injury. In control group, the expressions of MMP-2 were 27.16%±7.15% after 3 days, 22.59%±6.68% after 7 days, 18.85%±4.91% after 14 days. In the treatment group, it decreased to 15.57%±3.62% after 3 days, 12.91%±1.88% after 7 days. Compared with control group, the expressions of MMP-2 in treatment group were lower after 3 days and 7 days ( F = 8.359, P = 0.028 and F = 7.781, P = 0.032 ). Conclusions Edaravone can prevent restenosis in rat common catery after balloon angioplasty. The possible mechanism is that edaravone can inhibit the expressions of MMP-2 in this process.

A case of minimal change glomerulopathy without interstitial nephritis induced by non-opiate analgesics / 대한내과학회지

The use of nonsteroidal antiinflammatory drugs (NSAIDs) can be complicated by severe forms of renal dysfunction. These include fluid and electrolyte abnormalities, acute renal insufficiency due to alteration in renal hemodynamics, or interstitial nephritis and proteinuria secondary to glomerular pathology, which has the histologic characteristics of minimal change glomerulopathy (MCG). While NSAID-induced nephrotic syndrome characteristically consists of MCG with interstitial nephritis, which is the most common clinical manifestation, it rarely consists of MCG without interstitial nephritis, which has been reported in a handful of patients who took fenoprofen, ibuprofen, sulindac, diclofenac, or zomepirac. We experienced a 66-year-old female patient who presented with low serum albumin, proteinuria and generalized edema and received Geworin for about 2 year before developing symptoms. She histologically had MCG without interstitial nephritis and achieved a complete remission thirty-fifth days after discontinuing the drug. A cause-and-effect relationship of this disease to Geworin administration is strongly suggested by the resolution of the proteinuria after the drug was stopped and by no evidence of any impairment in renal function after twenty eight months of follow-up.

Study of the therapeutic effects of free radical scavenger edaravone on cerebral hemorrhage in rats / 中华神经科杂志

Objective To explore therapeutic effects and mechanisms of radical scavenger edaravone on experimental cerebral hemorrhage.Methods Two hundred-forty male SD rats were divided randomly into four groups:control group,cerebral hemorrhage group,edaravone treatment group before operation (A) and edaravone treatment group after operation (B).Experimental cerebral hemorrhage model was made according to the method reported by Rosenberg.Water quantity contained in brain and nervous missing sign were observed,meanwhile the levels of superoxide dismutase (SOD) and malondialdehyde (MDA) in brain tissue were measured.Results Compared with cerebral hemorrhage group,nervous missing sign and water quantity contained in brain obviously changed in edaravone treatment group (P

Effect of Fructus Psoraleae on Elimination of Antipyrine / 中药新药与临床药理

Objective: To study the effect of Fructus Psoraleae on antipyrine elimination in rats. Methods:After the medication of Fructus Psoraleae decoction once daily for 6 days in a dose of 5. 3 g/kg, antipyrine was fed to rats in a dose of 400mg/kg. Concentration of antipyrine in various time was measured by HPLC, and the pharmacokinetics parameters of antipyrine elimination was caculated. Results: The elimination rate constant (Kel) of antipyrine in rats fed with Fructus Psoraleae decoction was 1.55 times more than that in the control group, and the elimination half - life (t1/2) was shortened by 60. 7 % . Conclusion: Fructus Psoraleae decoction accelerate the elimination of antipyrine in rats by inducing the activities of hepatic oxygenases.

THF EFFECT OF NIFEDIPINE ON ANTIPYRINE DISPOSITION IN PATIENTS WITH ESSENTIAL HYPERTENSION / 中国药理学通报

The effect of nifedipine on antipyrine ( AP ) disposition was evaluated in 10 patients with essential hypertension. The disposition were measured with high perfomance liquid chromatography before and after 5d nifedipine treatment. The results showed that APt_1/2 and CL_AP were 14.88?3.1h and 31.29?5.9 ml/min respectively before treatment; APt_1/2 and CL_AP were 14.37?3.1 h and 32?6 ml/min after treatment. There were no significant differences for both parameters between the pre-treatment and after-treatment. The results showed there was no effect of nifedipine on AP disposition in patients with essential hyper ension in vivo. Namely, activation of hepatic microsomal enzymes for oxidative metabolism was not affected by nifedipine.