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The present studies describe the blood pressure lowering, and some other haemodynamic effects, of the potassium channel activator, BRL 38227 ((-) enantiomer of cromakalim, CAS 94470-67-4) in various animal models. BRL 38227 was a potent antihypertensive agent following oral administration to conscious spontaneously hypertensive rats, SHR, (0.038, 0.075 and 0.15 mg/kg), renal hypertensive cats (0.035 and 0.05 mg/kg) and renal hypertensive dogs (0.05 and 0.1 mg/kg). The (+) enantiomer of cromakalim (BRL 38226) was without effect on blood pressure in the conscious rat and cat confirming the stereospecific mode of action of this potassium channel activator. Tachycardia accompanied the antihypertensive effect of BRL 38227 in these models and in the rat this effect could be abolished by pretreatment with atenolol (conscious SHR), diltiazem, verapamil, propranolol and alinidine (anaesthetised rats). In addition to reflex tachycardia, BRL 38227 also increased plasma renin activity and aldosterone levels in the conscious renal hypertensive cat. In both the anaesthetised normotensive cat (0.001 mg/kg/min i.v.) and dog (0.0025 to 0.02 mg/kg i.v.) BRL 38227 lowered blood pressure and total peripheral resistance while increasing cardiac output via increased heart rate and stroke volume in the cat and via increased heart rate alone in the dog. BRL 38227 reduced renal vascular resistance in both conscious (0.01, 0.015 and 0.02 mg/kg p.o.) and anaesthetised (0.001 mg/kg/min i.v.) cats and the effect was maintained despite marked reductions in blood pressure. In the anaesthetised dog, BRL 38227 was a potent coronary arterial dilator and this effect was also maintained in the face of marked blood pressure lowering activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Antihypertensive and haemodynamic properties of the potassium channel activating (-) enantiomer of cromakalim in animal models. 190 50

The haemodynamic profile of the novel antihypertensive agent, cromakalim (BRL 34915), has been studied in conscious and anaesthetised cats. Given orally (0.03 and 0.06 mg/kg) to conscious cats and by intravenous infusion (0.002 mg/kg/min for 7-10 min) to anaesthetised animals, cromakalim reduced arterial pressure (AP; systolic/diastolic) and total peripheral resistance (TPR) while increasing cardiac output (CO) via both its components [heart rate (HR) and stroke volume (SV)]. In both models, HR changes were minimal for reductions of AP approaching 20 mm Hg. In a second group of conscious cats, cromakalim increased mean renal blood flow (MRBF) at hypotensive doses (0.03 and 0.06 mg/kg orally); HR was only significantly raised following the higher dose of cromakalim. In anaesthetised animals, intravenously infused cromakalim had little effect on central venous pressure and increased cardiac contractility. The data indicate that cromakalim lowers AP by reducing TPR with minimal increase in HR. In addition, cromakalim has a potentially beneficial effect on MRBF.
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PMID:The haemodynamic profile of cromakalim in the cat. 246 55

Clinical studies have been conducted on BRL 28500 (a formulation containing 15 parts ticarcillin (TIPC) plus 1 part clavulanic acid (CVA]. BRL 28500 was administered at doses of 1.6 g or 3.2 g b.i.d., generally for 10 days by drip infusion to patients with intraperitoneal infections or biliary tract infections. Drug concentrations in the ascites were determined. A total of 76 cases was treated with BRL 28500. These cases included 49 intraperitoneal infections (suppurative peritonitis 29, postoperative peritonitis 20) and 18 biliary tract infections (cholecystitis 5, cholangitis 13). Nine cases were excluded from evaluation according to the committee's assessment. The clinical improvement as assessed by surgeons in charge increased with the duration of continued treatment and efficacies were assessed as 57.1% on day 5, 63.1% on day 7 and 77.8% on day 10 in intraperitoneal infections. Corresponding results in biliary tract infections were 38.9%, 40.0% and 42.9%, respectively. From these results, it is clear that the degree of improvement is related to the duration of treatment. The clinical usefulness as assessed by surgeons in charge of the study was 63.8% in intraperitoneal infections (suppurative peritonitis 75.0%, postoperative peritonitis 47.4%) and 58.8% in biliary tract infections (cholecystitis 100%, cholangitis 41.7%). The overall rate of usefulness was 62.5%. The clinical efficacy rates as assessed by the committee were 81.6% in intraperitoneal infections (suppurative peritonitis 93.1%, postoperative peritonitis 65.0%) and 66.7% in biliary tract infections (cholecystitis 100%, cholangitis 53.8%). In cases where causative organisms were isolated, the efficacies were 92.9% in suppurative peritonitis, 58.8% in postoperative peritonitis, 50.0% in cholangitis and overall, 69.2%. In cases from which TIPC-resistant organisms were isolated, the overall efficacy rate was 65.4% (suppurative peritonitis 88.9%, postoperative peritonitis 58.3% and cholangitis 40.0%). Regarding bacteriological effect as assessed by the committee, the eradication rate was 76.9% in intraperitoneal infections and 40.0% in biliary tract infections (71.0% overall). In cases from whom ticarcillin-resistant organisms were isolated the corresponding rates were 68.4% and 33.3% respectively, (63.6% overall). In 4 patients with peritonitis drug levels in the ascites were determined following administration of BRL 28500 by drip infusion. Good levels of both TIPC and CVA were detected 1 to 3.5 hours after administration.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Clinical studies of BRL 28500 (clavulanic acid/ticarcillin) in the treatment of intraperitoneal infections and biliary tract infections]. 330 45

BRL 25000, granules preparation containing 2 parts of amoxicillin (AMPC) and 1 part of clavulanic acid (CVA, beta-lactamase inhibitor) as its potassium salt, has been investigated fundamentally and clinically. An in vitro study of the antibacterial activity of BRL 25000 against clinically isolated S. aureus (34 strains) showed higher activity than for AMPC alone and demonstrated that CVA potentiated the activity of AMPC, showing a synergistic effect against beta-lactamase producing organisms. A total of 27 pediatric patients aged between 6 months and 13 years 8 months (23 with respiratory infections and 4 with urinary tract infections) were treated with a daily dose ranging from 31.7 to 54.5 mg/kg, divided into 3 or 4 doses a day for periods of 4-18 days. The clinical effect was evaluated as excellent in 26 cases, poor in 1 case and the efficacy ratio was therefore 96.3% (26/27). The bacteriological effect against 12 organisms isolated from 9 patients was studied and all were eradicated (12/12). A drug-related side effect was observed in only 1 patient who developed diarrhea on the 4th day of treatment which continued during the treatment for 10 days. However, no severe side effect and no abnormality related to the drug in laboratory findings were observed. From these results it is concluded that BRL 25000 will be a clinically effective drug in the treatment of mild and moderate infections in the pediatric field.
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PMID:[Experimental and clinical studies on BRL 25000 (clavulanic acid-amoxicillin) granules in pediatric infections]. 384 20

Bacteriological and clinical evaluations of BRL 25000 (1 part clavulanic acid plus 2 parts amoxicillin) granules in the pediatric field have been performed. The MICs of BRL 25000 against 25 clinically isolated strains of S. aureus, 40 E. coli, and 14 K. pneumoniae were compared with those of AMPC. Against beta-lactamase non-producing strains of S. aureus and E. coli, the MICs of both drugs were nearly equal, however, against beta-lactamase producing strains of these species and K. pneumoniae, BRL 25000 was superior to AMPC. The blood levels of AMPC and CVA after single oral administration of approximately 15 mg/kg of BRL 25000 granules to fasted children were studied in 3 subjects. The mean levels of AMPC and CVA peaked about 1 hour after administration at values of 11.40 and 5.49 micrograms/ml, respectively, with half-lives of 0.91 and 1.02 hours, and AUCs of 23.52 and 12.66 hr X micrograms/ml, respectively. The 6-hour urinary recovery of AMPC ranged from 30.59% to 52.03% and for CVA from 16.31% to 45.18%. There was no significant difference between the blood level of AMPC following single oral administration of approximately 10 mg/kg AMPC granules and that of AMPC following single oral administration of approximately 15 mg/kg BRL 25000 granules to the same children. Clinical evaluation of BRL 25000 granules administered orally 3-4 times a day at total daily doses of between 42.9-52.9 mg/kg resulted in improvement, judged excellent or good, in all 7 cases of tonsillitis and 2 cases of pyelonephritis. In particular, the clinical effect was excellent in the case of tonsillitis where a beta-lactamase producing H. influenzae was isolated. In the total 11 cases treated, including 2 cases of mycoplasmal pneumonia excluded from the clinical evaluation, 1 case of rash and eosinophilia was observed. No other adverse reactions or abnormal laboratory findings were observed. The taste and flavor of the drug were well accepted by the children. It was concluded that BRL 25000 granules are promising new drug which should be markedly useful in the treatment of infections in pediatric outpatients.
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PMID:[Bacteriological and clinical evaluation of BRL 25000 (clavulanic acid-amoxicillin) granules in the pediatric field]. 384 23

BRL 25000 granules (containing 2 parts amoxicillin and 1 part clavulanic acid) have been studied fundamentally and clinically. The MICs of BRL 25000 against strains of S. aureus, E. coli, K. pneumoniae which were resistant to CEZ and beta-lactamase producing strains of H. influenzae were determined. The MICs of BRL 25000 at an inoculum of 10(6) cells/ml were 1/4 to 1/128 of those of AMPC and, in particular, the MICs of BRL 25000 were especially reduced against the organisms for which those of AMPC were more than 100 micrograms/ml. The pharmacokinetics of BRL 25000 were studied in 46 children at dose levels of 7.5 mg (8 fasting children, 7 non-fasting children), 10 mg/kg (4 fasting, 4 non-fasting), 15 mg/kg (4 fasting, 4 non-fasting), 20 mg/kg (8 fasting, 7 non-fasting). The peak serum concentrations in fasting children were marginally higher than those in non-fasting subjects. Values for AMPC and CVA from BRL 25000, dosed at 7.5, 10, 15 and 20 mg/kg to fasting children, 0.5-1 hour after dosing were 4.86 and 2.36 micrograms/ml, 5.20 and 1.69 micrograms/ml, 7.50 and 3.27 micrograms/ml, 9.38 and 6.30 micrograms/ml, respectively. In non-fasting subjects, corresponding values were 2.84 and 1.01 micrograms/ml, 4.53 and 2.10 micrograms/ml, 7.29 and 4.08 micrograms/ml, 6.83 and 2.96 micrograms/ml, respectively. The biological half-lives of AMPC and CVA, following the administration of BRL 25000, show no significant difference between the fasting and non-fasting states. Values for AMPC and CVA in fasting children were 0.85-1.15 hours and 0.64-1.03 hours, and in non-fasting children, 1.18-1.79 hours and 0.78-1.02 hours, respectively. The time to reach the peak serum concentration and half-lives were similar for AMPC and CVA when dosed as BRL 25000. Peak urinary concentrations for BRL 25000 (AMPC and CVA) at dose levels of 7.5, 10, 15, 20 mg/kg to fasting children were 681.8 and 148.2 micrograms/ml, 247.1 and 66.3 micrograms/ml, 484.2 and 149.1 micrograms/ml, 1,796.5 and 372.0 micrograms/ml, whilst in the non-fasting state the values were 496.3 and 83.2 micrograms/ml, 991.1 and 156.7 micrograms/ml, 2,397.5 and 460.7 micrograms/ml, 1, 896.3 and 323.4 micrograms/ml, respectively. The peak urinary concentration in the fasting state was observed at 0-2 hours after dosing, and in non-fasting individuals it occurred at 2-4 hours after dosing.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Experimental and clinical studies on BRL 25000 (clavulanic acid-amoxicillin) granules in the pediatric field]. 384 24

BRL 25000 (187.5 and 375 mg tablets), a formulation of CVA-K and AMPC in the ratio of 1:2, and AMPC (as control drug) were administered to healthy volunteers, aged 20 approximately 28 years and weighing 60 approximately 85 kg (68.8 kg, on average). Each drug was administered 3 times a day (after meals) for 5 days and the volunteers were separated into 3 groups of 4 subjects each. The effect on the fecal flora was studied before dosage, during administration (day 3 and 5) and day 3 and 5 after the administration course was completed. Studies were undertaken to isolate C. difficile on the last day of administration and 3 and 5 days after administration had ceased. Fecal concentrations and the susceptibility of the isolates to AMPC, CVA-K and BRL 25000 were measured. Side effects and laboratory findings were studied. The results obtained were as follows: 1. In BRL 25000 (187.5 mg X 3/day) group, the population of E. coli was on average, 1 X 10(6) approximately 9 X 10(6) cells/g feces before initiation of administration and it increased by 2 logarithms 3 and 5 days after initiation of administration. By 3 and 5 days after end of administration, the E. coli population was similar to the initial population. The population of Klebsiella sp. was 1 X 10(6) approximately 9 X 10(6) cells/g feces on average before commencement of dosage and it increased by 2 logarithms 3 days after initiation of administration but there was no consistent change in the Klebsiella sp. population thereafter. The Enterobacter sp., population was not consistent neither was the population of other Enterobacteriaceae. In total, the mean Enterobacteriaceae population was 1 X 10(7) approximately 9 X 10(7) cells/g feces before initiation of administration and increased by 2 logarithms 3 days after initiation of administration, and then returned to the initial level 5 days after end of administration. No consistent changes in population were noted for the other Gram-negative bacilli. The Staphylococcus sp. population was 1 X 10(6) approximately 9 X 10(6) cells/g feces on average before initiation of administration. This organism was detected in only 1 case 3 days after initiation of administration and in another 5 days after initiation of administration, thereafter, the population was similar to the initial population.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Effect of BRL 25000 (clavulanic acid-amoxicillin) on bacterial flora in human feces]. 384 25

MICs of BRL 25000, a combination of a newly developed beta-lactamase inhibitor CVA and AMPC in the ratio of 1 to 2, were determined against a number of bacterial strains and compared with those of AMPC, CVA, CEX and CCL. The 98 bacterial strains tested included 2-S. aureus, 23-H. influenzae, 25-E. coli, 22-K. pneumoniae and 26-P. mirabilis. In pharmacokinetic studies, BRL 25000 medium granules were administered to groups of 3 male subjects, aged between 7 years 8 months and 9 years 5 months, at doses of 10, 15 and 20 mg/kg, 2 hours after a meal. The resultant serum and urine concentrations and drug recoveries were measured. Furthermore, BRL 25000 was administered to a total 43 patients (2-pharyngitis, 8-tonsillitis, 3-bronchitis, 2-pneumonia and 28-urinary tract infection) whom clinically evaluable. An average daily dosage of 45.3 mg/kg was given, in 3 or 4 divided doses, for a period of 8 days on average. Clinical and bacteriological effects as well as side effects were studied. In the microbiological studies on 98 clinical strains, including beta-lactamase negative bacteria, BRL 25000 showed MICs against the Gram-positive cocci (2-S. aureus) superior to the other 4 drugs at inoculum sizes of 10(8) and 10(6) cells/ml. For the Gram-negative bacilli, against H. influenzae at inoculum sizes of 10(8) and 10(6) cells/ml, BRL 25000 was inferior in the small MIC range but superior in the large MIC range to AMPC, and was superior to the other 3 drugs. Against E. coli at an inoculum of 10(8) cells/ml, BRL 25000 showed antibacterial activity next to AMPC and CCL whilst at an inoculum of 10(6) cells/ml, it was inferior in the small MIC range but superior in the large MIC range to AMPC and CEX and was inferior to CCL but superior to CVA. Against K. pneumoniae at an inoculum of 10(8) cells/ml, BRL 25000 was equal to AMPC, CVA and CEX but inferior to CCL, whilst at an inoculum of 10(6) cells/ml, it was inferior to CCL but superior to the other 3 drugs. Against P. mirabilis at inoculum sizes of 10(8) and 10(6) cells/ml, BRL 25000 was inferior in the small MIC range but equal or superior in the large MIC range to AMPC, and was superior to CVA and CEX.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Experimental and clinical trials of BRL 25000 (clavulanic acid-amoxicillin) granules in the field of pediatrics]. 389 76

The authors have carried out laboratory and clinical studies on the BRL 25000 granule (containing 2 parts amoxicillin and 1 part clavulanic acid). The antibacterial activity of BRL 25000 against 29 clinically isolated strains of S. aureus, 30 E. coli and 30 K. pneumoniae were measured by the agar dilution method using an inoculum size of 10(6) cells/ml. beta-Lactamase production was detected by the Nitrocefin method. The MICs of BRL 25000 against S. aureus ranged from 0.2 approximately 12.5 micrograms/ml, with the majority of strains being inhibited by 1.56 micrograms/ml or less. Seven beta-lactamase producing strains of S. aureus were all inhibited by less than 12.5 micrograms/ml. The range against E. coli was 1.56 approximately 100 micrograms/ml, with the majority inhibited by 6.25 micrograms/ml or less. Fifteen beta-lactamase producing strains of E. coli were inhibited by 6.25 approximately 100 micrograms/ml and the majority by 25 micrograms/ml or less. All strains of K. pneumoniae were beta-lactamase producers and the MIC distribution against K. pneumoniae was 1.56 approximately 50 micrograms/ml, with a majority inhibited by 3.13 micrograms/ml or less, 96% of strains, were inhibited by less than 6.25 micrograms/ml. Against K. pneumoniae, BRL 25000 showed a 8 to 16-fold superiority when compared with AMPC. In a pharmacokinetic study, BRL 25000 granules were orally administered to children in the fasting state at single doses of 7.5 mg/kg and 20 mg/kg. The peak serum levels of AMPC were 6.13 and 6.94 micrograms/ml approximately 1 hour after administration and decreased with half-lives of 1.08 and 0.97 hours, respectively. The corresponding serum levels of CVA were 1.16 and 1.90 micrograms/ml at 1 hour after administration, with half-lives of 0.99 and 0.87 hour, respectively. In clinical studies, the BRL 25000 granule was effective in 39 cases of bacterial infection out of a total of 41 treated. Side effects were limited to 2 cases of diarrhea and minor changes in laboratory findings were elevation of serum GOT (1 case), elevation of serum GPT (1 case), and eosinophilia (2 cases).
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PMID:[Laboratory and clinical studies of BRL 25000 (clavulanic acid-amoxicillin) granules in the pediatric field]. 400 52

We have previously shown that treatment with selective kappa-opioid receptor agonist BRL 52537 hydrochloride [(+/-)-1-(3,4-dichlorophenyl) acetyl-2-(1-pyrrolidinyl) methylpiperidine] (1) has a long therapeutic window for providing ischemic neuroprotection and (2) attenuates ischemia-evoked nitric oxide (NO) production in vivo in rats. Neuronally derived NO has been shown to be deleterious in the male, but not in the female, rodent model of focal ischemic stroke. We sought to determine if the agent fails to protect ischemic brain when neuronal NO synthase (nNOS) is genetically deleted in male, but not female, mice. Halothane-anesthetized adult male and female nNOS null mutants (nNOS(-/-)) and the genetically matched wildtype (WT) strain were subjected to transient (2 h) middle cerebral artery occlusion by the intraluminal filament technique. Vehicle or BRL 52537 treatment with continuous intravenous infusion was instituted at the onset of reperfusion and continued for 22 h. In WT male mice, infarct volumes measured at 72 h of reperfusion were robustly decreased with BRL 52537 treatment. In contrast, BRL 52537 did not decrease infarct volume in male nNOS(-/-) mice. BRL 52537 had no effect in the WT or nNOS(-/-) female mice. These data support that BRL 52537's mechanism of neuroprotection in vivo is through attenuation of nNOS activity and ischemia-evoked NO production. Neuroprotective effects of BRL 52537 are lost in the male when nNOS is not present; therefore, BRL 52537 likely acts upstream from NO generation and its subsequent neurotoxicity.
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PMID:Neuroprotective effect of selective kappa opioid receptor agonist is gender specific and linked to reduced neuronal nitric oxide. 1604 24

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