The penetration of cefoperazone into the cerebrospinal fluid in patients on acute or chronic stage

Cefoperazone (CPZ) was administered to 10 patients with cerebrovascular disturbances at acute and chronic phases to investigate its passage into the cerebrospinal fluid. The antibiotic was administered at dosages of 1 g and 2 g to patients in the acute phase to examine the dose-dependency. The results obtained are summarized as follows: 1. Serum concentrations Peak values of CPZ were 46.9 +/- 4.42 microgram/ml in acute phase patients in 1 g dosage group (acute group 1), 253.1 +/- 63.2 micrograms/ml in acute phase patients in 2 g dosage group (acute group 2), and 197.9 +/- 15.7 micrograms/ml in chronic phase patients in 2 g dosage group (chronic group 2) at 1 hour after CPZ administration. Concentrations of CPZ varied about 5-fold between the 1 g dosage group and the 2 g dosage groups. The acute group 2 showed generally higher values of CPZ concentrations than the chronic group 2. 2. Cerebrospinal fluid concentrations. Peak values were 0.96 +/- 0.30 microgram/ml (at 3 hours) in acute group 1, 4.55 +/- 3.41 micrograms/ml (at 1 hour, except 1 case) in acute group 2, and 1.29 +/- 1.28 micrograms/ml (at 1 hour) in chronic group 2. Acute group 2 showed generally higher values than chronic group 2. 3. CPZ was considered useful for the prevention of postoperative infections in the field of brain surgery.     

Penetration of cefotaxime into human cerebrospinal fluid

The penetration of cefotaxime (CTX) into the cerebrospinal fluid (CSF) was monitored to evaluate the prophylactic efficacy of the drug against post-craniotomy infections. Doses ranged from 1 to 2 g were administered to patients with subarachnoid hemorrhage due to the rupture of cerebral aneurysm, traumatic cerebral contusion, or subdural edema accompanied by intracerebral hemorrhage, by intravenous drip infusion over a period of 30 or 60 minutes. CTX readily entered the CSF with concentrations exceeding MICs against the major pathogens occurring after craniotomy. CTX proved to be effective in the prevention of post-craniotomy infections in noninflammatory situations, especially after surgery in the case of cerebral traumas or subarachnoid hemorrhage.     

Fluconazole penetration into cerebrospinal fluid in humans

One hour after intravenous doses of 50 mg/d fluconazole for 6 days or 100 mg/d for seven days to healthy subjects, the cerebrospinal fluid concentrations of fluconazole were 1.26 mg/L and 2.74 mg/L, respectively. These values were approximately 52% and 62% those of serum. Four patients with an initial clinical diagnosis of meningitis also had significant concentrations of fluconazole in the cerebrospinal fluid.     

Clinical evaluation of cefuzonam in pediatrics and a study on the penetration into cerebrospinal fluid

Studies were carried out on the penetration of cefuzonam (L-105, CZON), a new synthetic cephalosporin antibiotic, into cerebrospinal fluid, and on the clinical efficacy against bacterial infections. The results are summarized as follows: Concentrations of CZON in cerebrospinal fluid at 1 hour after intravenous administration of 100 mg/kg in cases of furunculosis of the external canal, encephalitis and mumps meningitis were 0.56 micrograms/ml, 1.44 micrograms/ml and 0.33 micrograms/ml, respectively. Concentrations of CZON in cerebrospinal fluid at 1 hour after intravenous administration of 100 mg/kg in 3 cases of purulent meningitis were 2.80-6.40 micrograms/ml at the acute stage and 0.56-1.45 micrograms/ml even at the recovering stage. Sensitivities of clinically isolated strains to CZON were determined and expressed as MIC. MICs of CZON on Haemophilus influenzae, Escherichia coli, Proteus mirabilis and Klebsiella pneumoniae were similar to MIC's of cefmenoxime (CMX), and lower than those of cefoperazone (CPZ), cefmetazole (CMZ), cefatiam (CTM) and Cefazolin (CEZ). The MIC of CZON on Staphylococcus aureus was similar to those of CEZ, CMZ and CTM, and lower than those of CMX and CPZ. Clinical responses of CZON were good in 2 cases of purulent meningitis, good in 2 cases of pyothorax, excellent in 1 case of septicemia, excellent in 3 cases of urinary tract infections, excellent in 7 cases and good in 3 cases out of 10 cases of pneumonia. Clinical responses of other diseases were excellent in 4 cases of bronchitis, good in 1 case of furunculosis of the external canal, excellent in 1 case of tonsillitis. No side effects nor abnormal laboratory findings were observed except 2 cases of mild diarrhea out of 24 cases.     

Clinical evaluation of flomoxef in pediatrics and a study on the penetration into cerebrospinal fluid

The transfer to cerebrospinal fluid of a new oxacephem antibiotic flomoxef (FMOX, 6315-S) and its clinical efficacy against bacterial infections were investigated. 1. In 3 cases of purulent meningitis, cerebrospinal fluid concentrations of FMOX after one shot intravenous injection of 100 mg/kg during the acute stage of infections were 5.12-6.32 micrograms/ml and ratios of FMOX in cerebrospinal fluid in serum were about 5%. During the recovery stage, cerebrospinal fluid concentrations were about 3.8 micrograms/ml and cerebrospinal fluid/serum ratios were about 3.5%. 2. In 1 case of purulent meningitis, the treatment with FMOX was clinically effective but this case was classified as "unevaluable" because other drug was used concomitantly. FMOX was rated effective in other 2 cases of purulent meningitis. Of 9 cases of pneumonia, FMOX was rated very effective in 8 cases and it was rated only effective in the other. Of 4 cases of bronchitis, the drug was rated very effective in 3 cases and only effective in the other. FMOX was rated very effective against 2 cases of tonsillitis, also. 3. As side effects, thrombocytosis was observed in 3 of 20 cases examined. All cases, however, were deemed unrelated to the FMOX treatment and the side effect was only transient as are often found in courses of recovery from infections.     

Clinical evaluation of cefpirome in pediatrics and a study on the penetration into cerebrospinal fluid

Cefpirome (CPR, HR 810), a new cephem antibiotic, was investigated for its penetration into cerebrospinal fluid (CSF), and its clinical efficacy against bacterial infections. 1. CSF concentrations of CPR following intravenous injection was investigated in 2 patients with purulent meningitis. In one of them, the concentrations were 2.11 micrograms/ml and 1.31 micrograms/ml on 3 and 8 days, respectively, after start of administration. In the other patient, they were 24.2 micrograms/ml, and 1.35 micrograms/ml on 2 days and 7 days after administration, respectively. 2. Antibacterial activities of CPR against clinical isolates, Escherichia coli, Haemophilus influenzae, Staphylococcus aureus and Streptococcus pneumoniae, except those against Pseudomonas aeruginosa, were clearly superior to those of ceftazidime. 3. Clinical efficacies evaluated in 15 patients were "excellent" in 9, "good" in 5 and "unknown" in 1. The overall efficacy rate was 93.0%. 4. Clinical efficacies were "excellent" in 1 patient with bacteremia, "excellent" in 6 and "good" in one of 7 patients with pneumonia, and "good" in both of the 2 patients with purulent meningitis. Clinical efficacies against other diseases were "excellent" or "good", in 1 patient with pyothorax, 1 patient with purulent lymphadenitis, and 2 patients with facial cellulitis. In 1 patient with biliary tract infection, the results of treatment with CPR were "unknown" due to insufficient clinical data. 5. No adverse reactions were observed except in 1 patient who showed an increase in platelet count.     

Pharmacokinetics of cefotaxime and its desacetyl metabolite in plasma and in cerebrospinal fluid

The aim of the study was to investigate the pharmacokinetic modelling of Cefotaxime (CTX) and its main metabolite Desacetyl Cefotaxime (DCTX) which has a less antibacterial activity than the CTX. After intravenous administration of 1g of CTX to 26 patients, the plasma concentrations determined by HPLC showed that the pharmacokinetics of CTX and transformation to DCTX can be described with an open five-compartment model. The implications of this are discussed from the clinical point of view.     

Tryptophan levels in human cerebrospinal fluid after acute and chronic ethanol consumption

The essential amino acid tryptophan was measured in human cerebrospinal fluid by a fluorometric high-performance liquid chromatographic method. Acute ethanol consumption (80 g) by healthy volunteers lead to a decrease in tryptophan levels during intoxication. After intoxication no difference from base levels was evident. Following ingestion of a higher dose (120 g) the mean levels of tryptophan remained unchanged. Alcoholics were found to have elevated tryptophan levels in the cerebrospinal fluid as compared to healthy subjects even after abstention from ethanol for several weeks.     

The passage of cloxacillin into cerebrospinal fluid in the absence of meningitis.

1. Eleven patients undergoing lumbar discectomy received cloxacillin by continuous i.v. infusion, starting before the operation. During the operation several blood samples and one CSF sample were taken. 2. Mean rate constants describing the passive transfer of drug from plasma to CSF (kp) and the largely active transfer in the opposite direction (kCSF) were estimated. 3. In some subjects the CSF albumin quotient, defined as the ratio between the albumin concentration in CSF and in plasma times 1000, was slightly elevated (up to 23) which caused a significant increase in the value of kp. 4. The estimate of mean kp for healthy individuals was 0.065 h-1, which corresponds to a half-life of 10 h. The estimate of mean kCSF was 2.10 h-1. This predicts a steady-state CSF drug concentration which is 3% of the unbound plasma drug concentration. 5. There was a significant lag between the time courses of plasma and CSF drug concentrations, presumably reflecting the time for drug to move from the choroid plexus to the lumbar sampling site. 6. Four other patients received cloxacillin for prophylactic or therapeutic reasons by continuous i.v. infusion. In three of those patients the albumin quotient was normal or slightly elevated and the steady-state CCSF/Cu ratio was similar to the predicted normal value. 7. These findings indicate that eradicating staphylococci from CSF in cases of meningitis with a low degree of inflammation may be difficult.     

The diffusion of pirprofen into the cerebrospinal fluid in man

Summary We have measured the concentrations of pirprofen at various times in plasma and cerebrospinal fluid (CSF) samples, drawn during diagnostic myelography from 28 patients affected by sciatica.After intramuscular injection of 400 mg plasma concentrations of pirprofen reached a peak in 60 min then fell slowly. In contrast, the CSF concentration rose until 12 h and then fell. Pirprofen rapidly crossed the blood-brain barrier and was detectable in CSF at 15–30 min after injection.These results support the suggested hypothesis of a central analgesic action of pirprofen along with the known peripheral one. A new sensitive HPLC method was developed for measuring the concentration of pirprofen in the CSF.     

Clinical evaluation on aztreonam in pediatric field and fundamental study on its penetration into cerebrospinal fluid

The penetration of aztreonam (AZT), a new synthetic monobactam, into cerebrospinal fluid (CSF) and the clinical studies for bacterial infections were carried out. The following results were obtained. The concentrations of AZT in CSF were less than 0.31 microgram/ml and 0.42 microgram/ml, respectively, at 1 hour after intravenous administration of 34 mg/kg and 71 mg/kg in 2 cases of aseptic meningitis at the acute stage. The concentration of AZT in CSF was 6.9 micrograms/ml at 1 hour after intravenous administration of 100 mg/kg in 1 case of purulent meningitis at the acute stage and was 0.62-0.98 micrograms/ml even at the recovering stage. At each stage, its concentration was more than the minimum inhibitory concentration of E. coli (0.10, less than 0.05 microgram/ml; at inoculum size of 10(8), 10(6) cells/ml). Clinical efficacy of AZT was good in 2 cases of purulent meningitis, excellent in 1 case of septicemia, excellent in 5 cases of urinary tract infection, excellent in 1 case and good in 3 cases out of 4 cases of gastroenteritis, excellent in 4 cases and poor in 2 cases out of 6 cases of pneumonia and bronchitis, excellent in 2 cases and good in 1 case out of 3 cases of tonsillitis. No side effects and no abnormal laboratory findings were observed except 1 case of mild diarrhea out of 21 cases.     

腰池置管持续引流治疗脑脊液漏及颅内感染

目的分析腰穿置管持续引流术对脑脊液漏的治疗效果。方法均采用于腰3～4间隙处穿刺置入引流管持续引流脑脊液。结果 46例脑脊液漏患者,经持续腰池置管引流10～12 d,除2例全身衰竭死亡外,余44例均治愈出院。结论对于脑脊液漏者,经腰池置管持续引流术是易行,简便的治疗方法,不仅减少临床工作量,减轻患者痛苦,而且对提高疾病治疗的彻底性有重要意义。     

Does dexamethasone affect ceftriaxone [corrected] penetration into cerebrospinal fluid in adult bacterial meningitis

Trough cerebrospinal fluid (CSF) ceftriaxone concentrations were measured daily to investigate the effect of dexamethasone on ceftriaxone penetration into CSF in adult patients with acute bacterial meningitis. Patients were divided into two groups in this double blind randomized study. In group 1 (n=6) patients were given ceftriaxone with dexamethasone whereas in group 2 (n=6) patients were only administered ceftriaxone. Plasma and CSF samples were collected at 24, 48, 72, 96 and 264 h following the study treatments. The trough CSF ceftriaxone concentrations were measured using high performance liquid chromatography (HPLC) and microbiological assay. CSF ceftriaxone concentrations were 3.21 mg/l at 24 h in group 1 and 4.85 mg/l at the same time in group 2 by HPLC. Although microbiological assay results were lower than HPLC the trough CSF ceftriaxone concentrations in dexamethasone group were at least 10(3) times higher than the minimum inhibitory concentrations of the susceptible strains. It was concluded that the ceftriaxone concentration in CSF was adequate and ceftriaxone penetration was not significantly affected by concomitant dexamethasone use in adult patients with acute bacterial meningitis.     

The passage of flunitrazepam into cerebrospinal fluid in man

The passage of flunitrazepam into cerebrospinal fluid (CSF) was studied in 23 surgical patients (group 1), after a single 0.02 mg/kg intravenous injection, in 9 otherwise healthy patients undergoing neurological examination (group 2), after a single 2 mg oral dose, and in 9 chronically-ill neurological patients (group 3), after 2 to 4 successive 2 mg oral doses. Flunitrazepam in plasma and the CSF was determined by gas chromatography and its plasma protein binding by equilibrium dialysis. Uptake of flunitrazepam into human CSF was found to very fast: even 5 min. after intravenous injection the drug level in the CSF was 2.8% of the corresponding plasma concentration. CSF levels increased up to 77 min. after intravenous injection. In group 2 the mean percentage level in the CSF was 23.5 +/- 13.0 (S.D.) and in group 3 it was 16.7 +/- 3.1. In group 1, 22.9+/- 8.0% of flunitrazepam was not bound to plasma protein, in group 2, 12.1 +/- 8.3% and, in group 3, 30.3 +/- 14.1%. Groups 1 and 2 (P less than 0.01) and 2 and 3 (P less than 0.01) differ significantly from each other. In groups 2 and 3 there was no significant correlation between the percentage not bound to protein and CSF levels of flunitrazepam. The uptake of flunitrazepam by CSF provides an explanation for its rapid drug effects. Its binding to plasma protein is affected by disease and, possible, by other drugs.     

The partitioning of cimetidine into canine cerebrospinal fluid

The pharmacokinetics and cerebrospinal fluid (CSF) partitioning of cimetidine were studied in the dog. Four healthy male mongrel dogs were given a 22 mg/kg iv dose of cimetidine. The dogs demonstrated metabolic and pharmacokinetic characteristics similar to human volunteers, as the total body clearance of cimetidine averaged 7.5 ml/min/kg in the dog as compared to 7.7 ml/min/kg in humans. Autopsy tissue concentrations were similar to those measured in humans. There were no statistical differences between dogs and humans in any pharmacokinetic parameters. Cimetidine sulfoxide was the major metabolite in the dog, similar to that in humans. Cimetidine CSF partitioning, as determined by the ratio of cimetidine CSF:serum area under the curve was 0.125 +/- 0.03. Cimetidine appears to enter the CSF by passive diffusion, and is removed by passive diffusion, CSF bulk flow, and possibly by an active transport process. We conclude that the dog is an appropriate animal to investigate cimetidine pharmacokinetics and is a suitable model for examining the CSF uptake of H2-antagonists.     

原发性颅内肿瘤患者的临床及脑脊液细胞学检查

目的探讨原发性颅内肿瘤患者的临床和脑脊液细胞学检查在肿瘤定性诊断中的应用价值。方法对13例原发性颅内肿瘤患者的脑室、腰椎穿刺引流的脑脊液进行细胞学检查。结果手术前由脑室、腰椎穿刺引流行脑脊液检查确诊的颅内肿瘤患者分别占44．4％和50．0％。结论脑脊液细胞学检查可作为术前颅内肿瘤影像学定性诊断的重要补充，亦可作为病理学诊断的手段之一。     

Pharmacokinetics,cerebrospinal fluid penetration,and metabolism of piroxantrone in the Rhesus monkey

Summary Piroxantrone is an anthrapyrazole derivative with broad anti-tumor activityin vitro and less cardiac toxicity than the anthracyclines. The metabolic pathways and central nervous system penetration of piroxantrone have not been determined. In this study we examined the pharmacokinetic behavior of piroxantrone in plasma and cerebrospinal fluid in a non-human primate model. In addition, a urinary metabolite of piroxantrone was isolated and its cytotoxicity evaluatedin vitro. The disappearance of piroxantrone from plasma after an intravenous dose of 150 mg/m² given over 60 minutes was biexponential with mean t_1/2 alpha of 1.0 minutes and a mean t_1/2 beta of 180 minutes. The mean area under the curve was 220 M·min and the clearance was 1420 ml/min/m². Piroxantrone was not detectable in the cerebrospinal fluid.Piroxantrone and three other compounds not present in pre-treatment samples were detected in urine. The major urinary metabolite was isolated. Its cytotoxicity against MOLT-4 cellsin vitro was at least one log less than that of piroxantrone. In addition, one of the other compounds detected in urine was determined to be a glucuronide conjugation product of the major metabolite.The results of this study may be useful in the interpretation of the activity and toxicity of piroxantrone in clinical trials.     

Penetration of cefmetazole and netilmicin into the cerebrospinal fluid

1. Cefmetazole (CMZ) and netilmicin (NTL) were administered by one-shot intravenous and intramuscular injection, respectively, and measurements were made on their concentrations in the serum as well in the cerebrospinal fluid (CSF) which was collected using a drainage tube inserted into the cisterna basalis after the operation of ruptured cerebral aneurysm. 2. Concentrations of CMZ and NTL in the CSF changed nearly in parallel to those in the serum. 3. A one-shot intravenous injection of these drugs seemed to achieve their high concentrations in the CSF, though high concentrations may not last very long.