Distribution of enprofylline and theophylline between plasma and cerebrospinal fluid

Six patients undergoing diagnostic lumbar myelography were studied with respect to plasma and cerebrospinal fluid (CSF) concentrations of two xanthine drugs--enprofylline and theophylline. Three patients received enprofylline and three patients received theophylline, 200 mg t.i.d., and plasma and CSF were sampled on the morning of the third day of treatment. CSF plasma ratios averaged 0.095 with enprofylline (range of 0.094-0.097) and 0.36 with theophylline (range of 0.35-0.37). The different ratios of the two drugs contrast to their similar plasma protein binding, about 50%. Different lipophilicity or differences with regard to transport out of the CSF may explain the discrepancy.     

Paracetamol plasma and cerebrospinal fluid pharmacokinetics in children

Aims Paracetamol has a central action for both antipyresis and analgesia. Maximum temperature decrease and peak analgesia are reported at 1–2  h after peak plasma paracetamol concentration. We wished to determine the relationship between plasma and cerebrospinal fluid (CSF) pharmacokinetics in children.
Methods Concentration-time profiles in plasma and CSF after nasogastric paracetamol 40  mg  kg⁻¹ were measured in nine children who had indwelling ventricular drains. Estimation of population pharmacokinetic parameters was made using both a standard two-stage population approach (MKMODEL) and a nonlinear mixed effect model (NONMEM). Results were standardized to a 70  kg person using an allometric power model.
Results Both approaches gave similar estimates. NONMEM parameter estimates were clearance 10.2  l  h⁻¹ (CV 47%), volume of distribution 67.1  l (CV 58%) and absorption rate constant 0.77  h⁻¹ (CV 49%). Cerebrospinal fluid concentrations lagged behind those of plasma. The equilibration half time was 0.72  h (CV 117%). The CSF/plasma partition coefficient was 1.18 (CV 8%).
Conclusions Higher concentrations in the CSF probably reflect the lower free water volume of plasma. The CSF equilibration half time suggests that CSF kinetics approximate more closely to the effect compartment than plasma, but further time is required for paracetamol to exert its effects. Effect site concentrations equilibrate slowly with plasma. Paracetamol should be given 1–2  h before anticipated pain or fever in children.     

Bambuterol and terbutaline in human cerebrospinal fluid and plasma

Summary Concentrations in cerebrospinal fluid (CSF) and plasma of bambuterol and its active metabolite, the ₂-adrenoceptor agonist terbutaline, were measured in man after four once-daily doses of 30 mg bambuterol hydrochloride (Bambec^®). Nine patients scheduled for orthopaedic surgery under spinal anaesthesia completed the study.The concentrations of both substances were much lower in CSF than in plasma, the ratio CSF/plasma being 0.09 for bambuterol and 0.19 for terbutaline, at apparent steady state. While the rank order of the ratios was expected from the fractions of unbound bambuterol and terbutaline in plasma, their absolute values were only about 1/6 (bambuterol) and 1/4 (terbutaline) of those predicted from diffusion equilibria between plasma and CSF.Thus, the rates of transport of bambuterol and terbutaline from plasma into the central nervous system appear to be slow relative to transport out of the system, e.g. by outflow of CSF. The findings are in agreement with animal experiments and suggest that bambuterol and terbutaline are less likely than lipophilic ₂-adrenoceptor agonists to interact with central receptors.     

Disposition of ethmozine in cerebrospinal fluid and plasma of rabbits

The concentration-time profiles of ethmozine, a newly introduced anti-arrhythmic drug, in the cerebrospinal fluid (CSF) and plasma of six rabbits (New Zealand white rabbits of both sexes, 4.0-5.0 Kg) were studied after intravenous bolus administration. CSF samples at various intervals were obtained while the animal was lightly anaesthetized with intravenous thiopentone (40 mg Kg-1) and blood samples at other intervals were taken while the animal was conscious. Blood samples (1 ml) were collected from the implanted cannula of the ear artery while CSF samples (0.3 ml) were obtained from the cisterna magna. The plasma concentrations of ethmozine in six rabbits declined rapidly after intravenous injection for up to 30 min. then slowly over 12 h. Using non-compartmental analysis, the mean (+/- S.E.M.) elimination half-life, mean residence time, plasma clearance and volume of distribution at steady state were 13.9 +/- 9.2 h, 19.9 +/- 13.4 h, 2.3 Lh-1 and 26.8 +/- 7.9 L respectively. The mean CSF-plasma concentration ratios for ethmozine at 0.5, 1.0, 2.0, 4.0, 8.0 and 12.0 h were 0.17, 0.14, 0.16, 0.16, 0.23 and 0.22 respectively. The results suggest that ethmozine is able to penetrate into the CSF from the general circulation and this may be related to its adverse effects on the central nervous system.     

Hepsulfam distribution in blood,plasma and cerebrospinal fluid of baboons

Summary The alkylating agent Hepsulfam (Sulfamic acid 1,7-heptanediyl ester, NSC 329680) was developed as a more hydrophilic analog of busulfan. The objective of this study was to determine partitioning of hepsulfam between blood, plasma, and cerebrospinal fluid (CSF) in two female baboons following intravenous administration. Hepsulfam was administered at 11 mg/kg, and blood and CSF levels were determined by gas chromatography with electron capture detection. Blood levels were fairly constant btween animals (17–25 and 20–23 μg/ml) for six hours after administration, following peak levels of 43 and 33 μg/ml, respectively, for the two animals. Peak plasma levels of 35 and 36 μg/ml were achieved, and initial plasma half-lives in babbons were similar to those seen in other species, with at_1/2 α of 1 h. The plasma terminal half life of 0.2 h, estimated from limited sampling times, was shorter in baboons than in mice, dogs, or humans. Baboon CSF levels decreased from 1.7 to 0.3 μg/ml during 6h post infusion, and peak concentrations in CSF lagged behind plasma levels. CSF/plasma ratios ranged from 0.33 to 0.62 in one animal, whereas ratios of 0.2–0.25 were maintained in the other animal during the same period. Results from this study indicate hepsulfam will enter the CSF following intravenous administration, and the CSF/plasma ratios are lower than those obtained following oral busulfan administration.     

Distribution of beta-adrenoceptor blocking drugs into cerebrospinal fluid in rats

The distribution into cerebrospinal fluid (CSF) of five 3H- or 14C-labelled beta-adrenoceptor blocking drugs given intravenously was studied in urethane-anaesthetized rats. The doses (mg/kg) were: alprenolol 5, metoprolol 1, oxprenolol 5, pindolol 0.5, propranolol 0.1 and 5. Within 15 min. a marked fraction of the given radioactivity appeared in CSF with all substances. During the follow-up period of 315 min., only propranolol, independently of dose, caused high CSF/plasma ratios (0.54-0.73) of radioactivity. The other four beta-adrenoceptor blocking drugs caused levels of CSF radioactivity which were 0.05-0.28 of that in plasma and 0.05-0.14 of the calculated levels of activity in the whole body. Since propranolol is bound to plasma proteins to a higher degree than the other drugs studied, the penetration of the unbound fraction of propranolol into rat CSF is even more pronounced than what would be expected on the basis of CSF/plasma ratio measured.     

Doxepin and its metabolites in plasma and cerebrospinal fluid in depressed patients

Little information exists on the concentrations of antidepressants and their metabolites in CSF. We measured plasma and CSF levels of trans-doxepin (trans-DOX) and DOX metabolites in 12 depressed patients treated with DOX (250 mg/day) for 6 days. Spinal taps and blood samples were taken on day 7, 10 h after drug administration. Trans-DOX, cis-desmethyldoxepin (cis-DM-DOX), trans-desmethyldoxepin (trans-DM-DOX) and di-desmethyldoxepin (DDM-DOX) were analyzed in CSF and plasma samples by HPLC with column-switching. Although DOX was given as a mixture of 85% trans-DOX and 15% of the pharmacologically more active cis-DOX, we found similar amounts of cis-DM-DOX and trans-DM-DOX in plasma (59.8 ± 45.1 versus 72.0 ± 60.0 ng/ml; NS), suggesting that isomerization of DOX had taken place. Trans-DOX and DOX metabolites could be detected in CSF of most patients. Relatively low CSF concentrations of the active metabolite cis-DM-DOX were measured. Clinical efficacy, as assessed by HAMD scores, was not significantly related to plasma or CSF concentrations of trans-DOX or its metabolites. Trans-DOX and DOX metabolites were distributed differently between plasma and CSF. It is concluded that isomerization of DOX is not only relevant for neuronal uptake inhibition, but also for the transport of the metabolites. Received: 13 May 1996/Final version: 16 December 1996     

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.     

Toloxatone pharmacokinetics in the plasma and cerebrospinal fluid of the rabbit.

The pharmacokinetics of toloxatone (5 and 10 mg kg-1, i.v.) was studied in anaesthetized rabbits. There was a biexponential decline in plasma concentration with time. No differences were observed in the pharmacokinetic parameters with the increase of the dose. The terminal half-life was short (47.4 +/- 2.8 and 41.5 +/- 4.2 min for 5 and 10 mg kg-1, respectively). The total clearance was 79 +/- 18 mL min-1 after a dose of 5 mg kg-1 and 106 +/- 40 mL min-1 after a dose of 10 mg kg-1. The volume of distribution was 5.8 +/- 2.8 (5 mg kg-1) and 5.4 +/- 1.8 L (10 mg kg-1). The average percentage of toloxatone bound to plasma protein was 30% and was not affected by concentrations within the investigated range. In cerebrospinal fluid (CSF), the highest concentrations of toloxatone were obtained within 15 min after the end of the injection. The CSF level of toloxatone was equal to that of plasma unbound toloxatone and declined at a rate similar to toloxatone in plasma. These results suggest that the toloxatone passage through the blood-brain barrier may be completed by passive diffusion. In addition, the unbound plasma concentration would accurately reflect the toloxatone concentration in CSF and could be a useful tool for drug monitoring.     

Pharmacokinetics of tramadol in rat plasma and cerebrospinal fluid after intranasal administration

We have evaluated the potential of intranasal administration of tramadol. The pharmacokinetic behaviour of tramadol in rat plasma and cerebrospinal fluid (CSF) after intranasal administration was determined and compared with those after intravenous and oral administration. Serial plasma and CSF samples were collected for 6 h, and the drug concentrations were assayed by an HPLC-fluorescence method. The plasma absolute bioavailability values of tramadol after intranasal and oral administration were 73.8% and 32.4%, respectively, in conscious rats. The Cmax (maximum concentration) value after the intranasal dose was lower (P<0.05), and the MRT (mean retention time) was longer (P<0.05) than the values obtained after intravenous administration. A pharmacokinetic study of tramadol in plasma and CSF was undertaken in anaesthetized rats. The absolute bioavailability values in plasma and CSF after intranasal administration were 66.7% and 87.3%, respectively. The Cmax values in plasma and CSF after a nasal dose were lower (P<0.05) than after the intravenous dose. The values of Cmax and AUC0-->6 h in plasma and CSF after intranasal administration were higher than after the oral dose. The mean drug-targeting efficiency after intranasal administration was significantly greater than after the oral dose. In conclusion, intranasal administration of tramadol appeared to be a promising alternative to the traditional administration modes for this drug.     

Lead in cerebrospinal fluid and its relationship to plasma lead in humans

Lead levels in whole blood, plasma and cerebrospinal fluid (CSF) were determined in 18 patients suffering from Amyotrophic Lateral Sclerosis (ALS) and in 21 subjects hospitalized for neurological investigations. No significant differences were found for blood, plasma and CSF lead concentration between the ALS group and the other patient group. The plasma lead-CSF lead mean ratio was greater than 1 in both groups, while in subjects with a slight degree of blood-CSF barrier impairment a significant decrease of the ratio was demonstrated. A significant relationship between plasma lead and CSF lead levels (r = 0.405; p less than 0.01), but not between whole blood lead and CSF lead levels, was established. Lead levels in CSF were also age-related (r = 0.485; p less than 0.05) in the group of patients not suffering from ALS. In subjects with normal blood-brain barrier permeability, lead in plasma is a good indicator of CSF lead concentration.     

Pharmacokinetics of morphine in cerebrospinal fluid and plasma after epidural administration in man

The morphine concentration in serum as well as in cerebrospinal fluid (CSF) after epidural administration of 0.1 mg/kg morphine to 10 patients undergoing aortic abdominal surgery, was determined. Model independent pharmacokinetic parameters in serum and CSF i.e. mean residence time (MRT), clearance (Cl) and apparent volume of distribution were calculated from the concentration time curves using a non-linear square regression fitting programme. Peak concentration of morphine in serum (86 ng/ml) and in CSF (2610 ng/ml) was reached after 10 min respectively 40 min of epidural injection.     

Morphine and morphine-6-glucuronide in the plasma and cerebrospinal fluid of children

AIMS: To measure morphine and morphine-6-glucuronide in the plasma and cerebrospinal fluid of children following a single intravenous dose of morphine. METHODS: Twenty-nine paired samples of cerebrospinal fluid and plasma were collected from children with leukaemia undergoing therapeutic lumbar puncture. An intravenous dose of morphine was administered at selected intervals before the procedure. Concentrations of morphine and morphine-6-glucuronide (M6G) were measured in each sample. Morphine was measured using a specific radioimmunoassay (r.i.a.) and M6G was measured using a novel enzyme-linked immunosorbent assay (ELISA). RESULTS: The ELISA for measuring M6G was highly sensitive. The intra-and interassay variations were less than 15%. Using a two-compartment model for plasma morphine, the area under the curve to infinity (AUC, 7143 ng ml-1 min), volume of distribution (3.6 l kg-1 ) and elimination half-life (88 min) were comparable with those reported in adults. Clearance (35 ml min-1 ) was higher than that in adults. Morphine-6-glucuronide was readily synthesized by the children in this study. The elimination half-life (321 min) and AUC (35507 ng ml-1 min) of plasma M6G were much greater than those of morphine. CONCLUSIONS: Extensive metabolism of morphine to M6G in children with cancer has been demonstrated. These data provide further evidence to support the importance of M6G accumulation after multiple doses. There was no evidence that morphine passed more easily into the CSF of children than adults.     

大鼠血浆和脑脊液中甲氨蝶呤浓度测定及其应用

目的　建立测定大鼠血浆和脑脊液中甲氨蝶呤(MTX)浓度的HPLC法,为脑内靶向制剂及其在动物体内药动学研究提供方法学。方法　采用高效液相色谱-紫外检测法,用C18键合硅胶柱,流动相为甲醇- 0 . 0 5mol·L-1醋酸铵缓冲液(2 3∶77,pH =6 ) ,检测波长313nm。血浆样品沉淀蛋白后取上清液进样,脑脊液样品离心后直接进样。本法应用于MTX纳米粒给药后大鼠血浆、脑脊液中药物浓度测定。结果　该法专属性好,最低检测浓度为16 μg·L-1,血浆和脑脊液样品检测线性、精密度、回收率等指标均符合生物样品分析标准,在应用中取得良好效果。结论　本法可用于测定大鼠血浆和脑脊液中MTX的浓度。     

Pharmacokinetics of hydroxyurea in plasma and cerebrospinal fluid of HIV-1-infected patients

Hydroxyurea has been shown to potentiate the activity of the antiretroviral nucleoside analogs. A significant complication of AIDS is invasion of the virus into the CNS, resulting in HIV-associated dementia (HAD). Because of the polar nature of these nucleosides and the presence of efflux pumps in the blood-brain barrier, only low CNS drug concentrations are achieved. Introduction of hydroxyurea into the CNS may therefore increase the antiviral activity of these drugs. This study evaluates the accessibility of hydroxyurea to the CNS following oral drug administration. Twelve HIV patients received 800 mg, 1000 mg, or 1200 mg oral hydroxyurea. Cerebrospinal fluid (CSF) and plasma drug concentrations were measured over 8 hours and simultaneously fitted to a pharmacokinetic model. It was determined that CSF hydroxyurea concentrations, corresponding to those found to increase antiretroviral nucleoside activity in vitro, were achieved.     

中国西部地区脑脊液细菌分布及耐药性分析

目的 了解2016—2017年中国西部脑脊液分离菌的分布及耐药性。方法 中国西部10家医院脑脊液分离株,按统一 方案用纸片扩散法或自动化仪器进行抗菌药物敏感性试验,按CLSI(美国临床实验室标准化协会)2016年版标准判断结果。结果 10家医院2016—2017年脑脊液标本分离细菌1234株,其中革兰阳性菌697株,占56.5%,革兰阴性菌537株,占43.5%。最常见的 分离菌依次为凝固酶阴性葡萄球菌、鲍曼不动杆菌、肺炎克雷伯菌、屎肠球菌、大肠埃希菌、粪肠球菌、肺炎链球菌、醋酸钙 不动杆菌、铜绿假单胞菌和金黄色葡萄球菌。脑脊液标本中MRSA和MRCNS的检出率分别为27.9%和66.7%,未发现对万古霉 素、替考拉宁和利奈唑胺耐药菌株;粪肠球菌和屎肠球菌对万古霉素的耐药率分别为2.2%和1.6%;大肠埃希菌、肺炎克雷伯菌 中产超广谱β-内酰胺酶(ESBL)菌株的检出率分别为64.2%和58.1%,肺炎克雷伯菌对碳青霉烯类抗生素的耐药率(22.2%~23.6%) 高于大肠埃希菌(3.6%~4.4%),铜绿假单胞菌对碳青霉烯类的耐药率45%以上,鲍曼不动杆菌对碳青霉烯类的耐药率高达85%以 上。结论 脑脊液分离株对常用抗菌药物耐药性严重,碳青霉烯耐药革兰阴性菌的出现和增多,给脑脊液感染的治疗带来极大 挑战,应合理使用抗菌药物,加强医院感染控制,抑制耐药菌的传播。     

High performance liquid chromatographic determination of moxalactam in human plasma and cerebrospinal fluid

Summary A sensitive and reproducible method for the measurement of moxalactam in plasma and cerebrospinal fluid is described. Plasma proteins were removed by precipitation with ice-cold methanol at pH 5.6 and centrifugation. The supernatant was analysed by HPLC on a µ-Bondapack/phenyl column, with a mobile phase of acetonitrile/water/PIC Reagent A (20/80/1), and detection at 280 nm. The calibration curve was linear for plasma concentrations from 10 µg/ml to 60 µg/ml. Reproducibility was 4.7% (coefficient of variation) for within-day analysis and 13.8% for day-to-day analysis. Plasma concentrations in 9 moxalactam-treated patients with severe infections ranged from 0.9 µg/ml to 409 µg/ml. Individual pharmacokinetic parameters were calculated using a personal computer. In selected cases moxalactam concentrations were also determined in cerebrospinal fluid and tracheal aspirates.     

The pharmacokinetics of isoniazid and hydrazine metabolite in plasma and cerebrospinal fluid of rabbits

The pharmacokinetics of isoniazid (INH) and hydrazine metabolite (HYD) in plasma and cerebrospinal fluid (CSF) of ten rabbits was studied after separate intravenous (i.v.) and oral (p.o.) administration in a crossover study. The concentrations of INH and HYD in the biological fluids were determined by high performance liquid chromatography (HPLC). There was no difference in the area under plasma concentration-time curves, indicating that oral absorption was complete. The mean apparent volume of distribution after i.v. (3.02 +/- 0.55 L) was smaller (p less than 0.01) than that after p.o. (4.29 +/- 1.25 L) dosing. The elimination t1/2 of INH in CSF was longer (p less than 0.005) than that in plasma after either route of administration. There was no significant barrier to the penetration of INH into the CSF from the general circulation. The HYD plasma concentrations were similar after either route. HYD was eliminated at a slower rate (Ke = 0.17 h-1) than INH (Ke = 0.59 h-1). There was prolonged exposure of the body to HYD (greater than 6 h - above 0.1 micrograms/ml).     

Distribution of valproate across the interface between blood and cerebrospinal fluid.

The entry of valproate into cerebrospinal fluid (CSF) was studied in dogs anaesthetized with pentobarbital and relaxed by suxamethonium. Steady-state concentrations of the rather strong acid (pK_a 4.56) in CSF were reached within 1 hr, they corresponded exactly to the concentration of free drug in serum. Probenecid considerably enhanced the rate of entry into CSF as well as the ratio between CSF and serum concentrations of valproate. An increase in the ratio between valproate concentrations in CSF and the concentration of free drug in serum could also be induced by a strong acidosis (pH 6.9–7.2 in blood). Neither probenecid nor acidosis had an influence on the binding of valproate to serum proteins. Phenylbutazone displaced valproate from its protein binding and gave rise to higher concentrations in CSF. The results suggest a transport of valproate into and out of CSF, probably by the monocarboxylic acid system. Diffusion should only play a minor role.     

Regulation of leptin distribution between plasma and cerebrospinal fluid by cholecystokinin receptors

Cholecystokinin (CCK) is a postprandial hormone that elicits a satiating effect and regulates feeding behaviour. CCK has been shown to enhance the effect of leptin in several experimental paradigms. The goal of this work was to characterize the effect of endogenous CCK on plasma leptin content by using CCK receptor antagonists. Therefore, we administered SR-27897, a selective CCK1 receptor antagonist, and L-365260, a selective CCK2 receptor antagonist, to fed and food-deprived rats and determined plasma leptin concentration by enzyme immunoassay. Plasma insulin and glucose concentration as well as food intake were also determined. Under our conditions, SR-27897 increased plasma concentration of leptin both in fed and food-deprived rats. It also increased food intake as well as plasma concentration of insulin in fed animals. L-365260 increased plasma leptin concentration only in fed rats. In animals receiving exogenous leptin, CCK-8 increased the ratio between the concentration of leptin in cerebrospinal fluid and plasma. These results show that CCK receptor antagonists increases plasma concentration of leptin and suggest that endogenous CCK may facilitate the uptake of plasma leptin to the cerebrospinal fluid.