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.     

Plasma and cerebrospinal fluid concentrations of indomethacin in humans

Summary Plasma and cerebrospinal fluid (CSF) concentrations of indomethacin have been determined in 52 patients hospitalized for nerve-root compression pain. Samples of blood and CSF were collected at the same time in each subject, 0.5 to 12 h after a single intramuscular injection of 50 mg indomethacin. Analgesic effect was assessed by the absolute and percentage variation in Huskisson's visual analogue scale between dosing and sampling.According to its high lipid solubility, indomethacin rapidly crossed the blood-brain barrier, being detected in CSF 0.5 h after administration. After attainment of equilibrium within 2 h, the CSF level exceeded the free plasma level. Since the drug was extensively bound to serum albumin (99.7±0.1%), this phenomenon may represent a slight degree of binding of indomethacin in CSF.The analgesic activity was not related to either the plasma or CSF concentration of indomethacin.Supported by a grant from Merck-Sharp and Dohme Chibret France     

Probenecid inhibition of methotrexate excretion from cerebrospinal fluid in dogs

Probenecid is known to inhibit the renal excretion of methotrexate (MTX) and the transport of organic anions by the choroid plexus of the brain. The effect of probenecid on the CSF clearance of MTX given by the intrathecal route was examined in anesthetized dogs. Plasma and CSF MTX levels were measured following intrathecal injection of 0.4 mg/kg MTX, with and without pretreatment with probenecid. In the absence of probenecid, the peak plasma MTX concentration of 3.18×10^–7±1.09×10^–7 M (mean±SD) was reached 5 hr after intrathecal injection. With probenecid pretreatment, the mean peak plasma MTX concentration was lower (2.09×10^–7+-0.98×10^–7 M) and plasma disappearance was prolonged. A biexponential decay of CSF MTX levels was observed over the duration of sampling. The half-life of the second exponential phase was 21 hr without probenecid pretreatment and was longer after probenecid pretreatment. These results provide strong evidence that probenecid inhibits transfer of MTX from CSF to plasma following intrathecal injection.This work was supported by NIGMS Grant GM22209 and the Oncology Research Donation Fund of the Children's Hospital at Stanford. Terrence Blaschke was the recipient of a Faculty Development Award in Clinical Pharmacology from the Pharmaceutical Manufacturers Association Foundation.     

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.     

Failure to influence the VIP level in the cerebrospinal fluid by transcutaneous nerve stimulation in humans

Low-frequency transcutaneous nerve stimulation (TNS) is known to produce a prolonged and widespread cutaneous vasodilatation. This is associated with a moderate but significant increase of 30-35% in the concentration of the vasoactive intestinal polypeptide (VIP) in the cubital vein plasma. A possible source of this increased plasma VIP following TNS is the central nervous system. This possibility is tested in the present experiment. The concentration of VIP in the cerebrospinal fluid (CSF) was determined by radioimmunoassay in 9 patients with no organic disease of the central nervous system, before and at various intervals (15, 30 and 45 min) after the onset of TNS. No significant change in the VIP level of the cerebrospinal fluid was encountered, although the stimulation evoked rises in finger temperature indicating effectiveness of the stimulation. It is concluded that the stimulation-induced increase in plasma VIP is due to release of VIP outside the brain.     

Preferential inhibition of dizocilpine-induced hyperlocomotion by olanzapine

This study examined the putative inhibitory effect of the atypical antipsychotic, olanzapine, on dizocilpine (MK-801)-induced stereotypy and hyperlocomotion. Dizocilpine (0.1, 0.25 and 0.5 mg/kg) produced a dose-dependent increase in both stereotypy and hyperlocomotion. Pretreatment with olanzapine (0.25 and 0.5 mg/kg) inhibited the dizocilpine (0.5 mg/kg)-induced hyperlocomotion but not the stereotypy. At the higher doses (1, 2 and 4 mg/kg), olanzapine blocked both the stereotypy and hyperlocomotion induced by dizocilpine. Similarly, olanzapine, 0.25 and 0.5 mg/kg, did not inhibit apomorphine (3 mg/kg)-induced stereotypy, whereas the higher dose (1 mg/kg) blocked it. We also studied the effect of olanzapine on spontaneous locomotor activity and catalepsy. Olanzapine (0.25 and 0.5 mg/kg) did not induce a decrease in spontaneous locomotor activity but did so at the higher doses (1, 2 and 4 mg/kg). The lower doses (0.25, 0.5 and 1 mg/kg) did not induce catalepsy but higher doses (2 and 4 mg/kg) induced a significant catalepsy which lasted for more than 4 h. The results thus showed that, at lower doses, olanzapine selectively inhibited behaviours mediated by the mesolimbic/mesocortical system while at higher doses it inhibited behaviours mediated by both mesolimbic/mesocortical and nigrostriatal systems. Therefore, the minimal extrapyramidal side-effects produced by olanzapine at effective doses might be due to its preferential action at the mesolimbic/mesocortical area.     

The recovery of cerebrospinal fluid acetylcholinesterase activity in Alzheimer's disease patients after treatment with metrifonate

We investigated the relationship between peripheral and central cholinesterase (ChE) inhibition levels after chronic treatment of Alzheimer's disease (AD) patients with metrifonate (MTF). In a 6-month, double-blind, placebo-controlled trial in AD patients treated with a weekly 2.9 mg/kg MTF dose, we observed 17.15 +/- 23.43, 66.92 +/- 7.30 and 60.80 +/- 12.20% inhibition (n = 6) of cerebrospinal fluid (CSF) and red blood cell (RBC) acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BuChE), respectively. In another study, AD patients were treated with daily MTF to achieve RBC AChE inhibition levels of 85.90%. The CSF AChE inhibition was 67.93 +/- 13.69% (n = 3) at 3-4 h after the last treatment and 6.62 +/- 9.36% (n = 2) at 8 days after dosing. The recovery half time of CSF AChE was 2.21 +/- 1.22 days. These data show that CSF AChE recovers faster than the peripheral plasma and RBC enzymes. Under conditions of chronic weekly dosing with MTF, RBC AChE inhibition does not reflect CSF, and arguably, brain AChE inhibition. Our data do not support continuous central neuronal AChE inhibition as the mechanism for the long-term efficacy of metrifonate for the treatment of AD.     

Biliary excretion and cerebrospinal fluid partition of perfluorooctanoate and perfluorooctane sulfonate in humans

Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are detected in the environment and, more specifically, in wildlife and humans. The large variation in the reported biological half-lives for PFOA and PFOS has remained unexplored. In this study, we aimed to evaluate their partition from serum to bile and cerebrospinal fluid (CSF) in humans. Four pairs of serum and bile, and 7 pairs of serum and CSF were donated by patients. In considering biliary excretion, the median concentrations of PFOA and PFOS in serum samples were 3.8 and 23.2ng/mL, respectively, whereas those in bile samples were 1.0 and 27.9ng/mL, respectively. The median ratio of PFOS concentrations (bile/serum: 0.60) was significantly higher than that for PFOA, 0.21 (p<0.01). Biliary excretion rates for PFOA and PFOS in the present study subjects were estimated as 1.06 and 2.98mL/kg/day, respectively, which is significantly higher than serum clearances via urine in humans and might represent a major excretion route. Biliary reabsorption rates of PFOA and PFOS were estimated to be 0.89 and 0.97, respectively. In considering partition into the cerebrospinal fluid, the median concentrations of PFOA and PFOS in serum samples were 2.6 and 18.4ng/mL, respectively, whereas those in CSF samples were 0.06 and 0.10ng/mL, respectively. The median ratio of PFOS concentrations (CSF/serum: 9.1 (×10(-3))) was comparable to that of PFOA, 17.6 (×10(-3)), suggesting that PFOA and PFOS cannot pass through the blood-brain barrier freely. In conclusion, the biliary excretion of these compounds was comparable in both rats and humans and the long half-lives in humans might be attributable to low levels of excretion in urine and high biliary reabsorption rates.     

Acetylcholine release in cerebrospinal fluid by ouabain

Ouabain increased the acetylcholine and potassium levels in the effluent collected from cisterna magna in cats anaesthetized and with the cerebral ventricles perfused with artificial cerebrospinal fluid. These effects were not modified by tetrodotoxin.     

Pharmacological significance of acetylcholinesterase inhibition by tetrahydroaminoacridine

Tetrahydroaminoacridine (THA; Tacrine) is a potent, non-competitive inhibitor of the neuronal enzyme acetylcholinesterase (AChE) and, consequently, a potent modulator of central cholinergic function. The compound reportedly improves the memory deficits of Alzheimer's dementia. Experiments were run with purified bovine caudate AChE to examine the kinetic properties of THA-AChE interaction within the scheme of multiple binding sites on the enzyme and a proposed "map" of the enzyme surface. The kinetic analyses were also designed to determine whether chemical modification of peripheral anionic sites on AChE may provide insight into mechanism for selective pharmacological alteration of cholinergic function in the brain. The studies demonstrated that THA is a reversible, non-competitive inhibitor with an I50 of 160 +/- 10 nM. THA bound primarily at a hydrophobic area outside of the catalytic sites, and binding of THA enhanced the effect of Ca2+ binding to a separate group of "accelerator" sites. Experiments with Al3+ demonstrated non-competitive inhibitor effects that were additive with THA inhibition and consistent with a model suggesting interaction of THA and Al3+ at the enzyme surface. In vitro enzyme inhibition studies also provide evidence for THA "protection" of the catalytic site against inhibition by the high-affinity phosphorylating agent, DFP (isoflurophate).     

The effect of chlorpromazine on the concentration of acetylcholinesterase in the cerebrospinal fluid of rabbits.

Following administration of chlorpromazine (4 mg/kg i.v.), there was an increase of up to 5-fold in the concentration of acetylcholinesterase in rabbit cerebrospinal fluid sampled from the cisterna magna but not in cerebrospinal fluid from a lateral ventricle. The pattern of multiple molecular forms and specific activity of acetylcholinesterase in cerebrospinal fluid did not resemble that of blood plasma and so a breakdown of the blood-cerebrospinal fluid barrier can be excluded. The concentration of lactate dehydrogenase in cisternal cerebrospinal fluid did not change, hence a non-specific increase in permeability of cell membranes seems unlikely. Prior administration of atropine sulphate (3 mg/kg i.v.), but not the same dose of atropine methylnitrate, prevented the effect of chlorpromazine.The possibility that the rise in the concentration of acetylcholinesterase was the result of increased activity of central neurons containing this enzyme is discussed.     

Co-administration of memantine has no effect on the in vitro or ex vivo determined acetylcholinesterase inhibition of rivastigmine in the rat brain

Rivastigmine, a cholinesterase inhibitor, is successfully used for the symptomatic therapy of Alzheimer's disease (AD) in the clinic. The drug has a very low potential for drug-drug interactions, as has been demonstrated within large clinical trials. Memantine, recently approved by the FDA for the treatment of moderate to severe AD, acts as a low affinity, non-competitive NMDA-antagonist, on a completely different neurotransmitter system, the glutamatergic system. Given the different sites of action, the possibility to combine a cholinergic with a glutamatergic intervention as potentially superior AD therapy has recently been proposed. In vitro studies have demonstrated that memantine, when added to reversible AChE inhibitors, such as tacrine, donepezil or galantamine, did not interfere with the inhibitory action of any of these drugs. The results from the present study provide evidence that rivastigmine as a pseudo-irreversible (or slow-reversible) AChE inhibitor shares this property described for reversible inhibitors, since memantine (1-100 microM), irrespective of whether given prior to or after rivastigmine did not influence rivastigmine's AChE inhibition in vitro. A similar observation was also made under in vivo conditions (ex vivo measurements): following a 21 day chronic, oral administration of 6 micromol/kg rivastigmine alone or of a combination of rivastigmine plus memantine (6 micromol/kg p.o. of either of the two compounds), an identical degree of AChE inhibition was observed. The concentrations of rivastigmine, its metabolite NAP 226-90 and memantine were measured in the brain of the same animals. Following an equimolar oral dose (6 micromol/kg) of both compounds, the brain level of memantine exceeded that of rivastigmine + metabolite, by a factor of around 30, when measured 2 h after the final dosing, irrespective of the duration of treatment (acute, for 3 or 21 days). This indicates that neither of the two drugs showed accumulation but also, and more importantly, that memantine does not modulate the prime therapeutic action of rivastigmine (AChE inhibition) in vitro or in vivo. Clinical trials using a combination of both drugs will provide a final proof of whether a combination therapy would lead to an increased efficacy in AD patients.     

Preferential inhibition of 5-lipoxygenase activity by manoalide

Treatment of human polymorphonuclear leukocytes (PMNLs) with micromolar concentrations of the anti-inflammatory drug manoalide inhibited production of leukotriene B4 (LTB4) and LTC4/LTD4 in response to the calcium ionophore A23187. In an attempt to further define the mechanism(s) of action of this agent, we have examined its interaction with several lipoxygenase enzymes. In RBL-1 cells, manoalide inhibited 5-lipoxygenase (5-LO) activity with an approximate IC50 of 0.3 microM. This was equipotent in our system with the known lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA). Manoalide was virtually inactive, however, against 12-lipoxygenase activity in both human platelets and mouse epidermis, with little inhibition seen at concentrations up to 100 microM. Manoalide showed some activity against soybean lipoxygenase, although it was 30- to 50-fold less potent than as an inhibitor of the 5-lipoxygenase enzyme. These data indicate that manoalide is a selective 5-LO inhibitor and suggest the possibility that its anti-inflammatory actions may be due, at least in part, to inhibition of leukotriene synthesis.     

The distribution of sulfamerazin between plasma, cerebrospinal fluid, and bile in humans

The concentration-time curves of sulfamerazin were determined in plasma, cerebrospinal fluid (c.s.f.) and bile in two groups of patients (ventricle drainage and Kerr's T-tube drain). In plasma, a half-life of 13.6 hours as well as an invasion and evasion constant of 0.145 hours -1 and 0.051 hours -1, resepectively, were observed. The distribution of half-life times showed a bimodal behavior in these patients. The unbound part of sulfamerazin was 12% and the acetylated products 14%. Unlike plasma in c.s.f. and bile the influx is delayed up to steady state. The decreases of concentration in all three compartments are the same. The concentration ratio of sulfamerazin between C.S.F. and bile and plasma water amounted to 1 and 2.5, respectively. Of the given dose of sulfamerzin, 0.87% was eliminated by bile within 24 hours. The therapeutic conclusions are discussed with regard to the bimodal distribution of half-lives, the minimal inhibition concentrations and the unbound part in the plasma.     

Regional effects of donepezil and rivastigmine on cortical acetylcholinesterase activity in Alzheimer's disease

Donepezil and rivastigmine are acetylcholinesterase (AChE) inhibitors used to improve cholinergic neurotransmission and cognitive function in Alzheimer's disease (AD). This study examined direct effects of these drugs on AChE activity in the frontal, temporal, and parietal cortices in AD. Six AD patients were scanned with positron emission tomography before and after 3 months of treatment with donepezil (10 mg/day), and five AD patients were scanned before and after 3 to 5 months of treatment with rivastigmine (9 mg/day). Healthy unmedicated controls were imaged twice to evaluate the reproducibility of the method. A specific AChE tracer, [methyl-11C]N-methyl-piperidyl-4-acetate, and a 3D positron emission tomography system with MRI coregistration were used for imaging. Treatment with donepezil reduced the AChE activity (k3 values) in the AD brain by 39% in the frontal (p < 0.001, Bonferroni corrected), 29% in the temporal (p = 0.02, corrected) and 28% in the parietal cortex (p = 0.05, corrected). The corresponding levels of inhibition for rivastigmine were 37% (p = 0.003, corrected), 28% (p = 0.03, uncorrected) and 28% (p = 0.05, corrected). When the treatment groups were combined, the level of AChE inhibition was significantly greater in the frontal cortex compared to the temporal cortex (p = 0.03, corrected). The test-retest analysis with healthy subjects indicated good reproducibility for the method, with a nonsignificant 0% to 7% intrasubject variability between scans. The present study provides first evidence for the effect of rivastigmine on cortical AChE activity. Our results indicate that the pooled effects of donepezil and rivastigmine on brain AChE are greater in the frontal cortex compared to the temporal cortex in AD. This regional difference is probably related to the prominent temporoparietal reduction of AChE in AD. We hypothesize that the clinical improvement in behavioral and attentional symptoms of AD due to AChE inhibitors is associated with the frontal AChE inhibition.     

Acute changes in cerebrospinal fluid 5-HIAA following oral paroxetine challenge in healthy humans.

A number of studies have reported decreased human lumbar cerebrospinal fluid (CSF) concentrations of the major serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), following chronic administration of selective serotonin reuptake inhibitors (SSRIs). This decrease has been thought to be a consequence of elevated extracellular serotonin and to be mediated through terminal autoreceptor feedback inhibition of serotonin turnover. We wished to study the previously unexamined acute effects of SSRI administration on human CSF 5-HIAA. A serial lumbar puncture (LP) procedure was used to collect CSF samples before and after a single oral 40 mg dose of the SSRI paroxetine (PAR) or matching placebo in eight healthy adult humans in a randomized, double-blind fashion. CSF 5-HIAA concentrations did not change following placebo, but showed a statistically significant 27% mean increase 3 h following PAR. Our findings stand in contrast to the decreases reported for CSF 5-HIAA after chronic SSRI treatment in humans and the decreases seen in brain extracellular 5-HIAA after acute or chronic administration of SSRIs to animals.     

HPLC法测定脑脊液中去甲万古霉素的浓度

目的 :建立HPLC法测定人脑脊液中去甲万古霉素浓度。方法 :采用ODS hypersilC1 8柱 ,甲醇 0 0 5mol/L KH2PO4(1 6∶84,pH =5 0 )为流动相 ,检测波长 2 80nm ,以替硝唑为内标对去甲万古霉素进行定量测定。结果 :脑脊液中去甲万古霉素在 1～ 6 0mg/ml范围内浓度与峰面积具良好线性 (r =0 9993) ,平均回收率为 98 70 %&#177; 2 6 5 % ,日内及日间RSD分别为 1 73%～ 1 95 %和 3 6 2～ 6 78%。     

The inhibition of acetylcholinesterase and pseudocholinesterase by cimetidine

Cimetidine inhibited cholinesterases from human blood serum, erythrocytes, brain and gastric mucosa in a dose-dependent manner. The median inhibitory concentrations ranged between 7.0 x 10(-4) mol/l and 2.1 x 10(-3) mol/l. The inhibition was of competitive type, the inhibitory constant of acetylcholinesterases in erythrocytes were found to be 8.5 x 10(-5) mol/l and of pseudocholinesterases in serum 8.5 x 10(-4) mol/l. A significance of our findings may be the explanation of side effects seen in cimetidine overdosage.