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To test the efficacy of venlafaxine at a dose of 18.75 mg/day on the reduction of behavioral problems such as irritability and hyperactivity/noncompliance in patients with intellectual disabilities and autism spectrum disorder (ASD). Our secondary hypothesis was that the usual doses of zuclopenthixol and/or clonazepam would decrease in the venlafaxine-treated group.In a randomized double-blind study, we compared six patients who received venlafaxine along with their usual treatment (zuclopenthixol and/or clonazepam) with seven patients who received placebo plus usual care. Irritability, hyperactivity/noncompliance, and overall clinical improvement were measured after 2 and 8 weeks, using validated clinical scales.Univariate analyses showed that the symptom of irritability improved in the entire sample (p = 0.023 after 2 weeks, p = 0.061 at study endpoint), although no difference was observed between the venlafaxine and placebo groups. No significant decrease in hyperactivity/noncompliance was observed during the study. At the end of the study, global improvement was observed in 33% of participants treated with venlafaxine and in 71% of participants in the placebo group (p = 0.29). The study found that decreased cumulative doses of clonazepam and zuclopenthixol were required for the venlafaxine group. Multivariate analyses (principal component analyses) with at least three combinations of variables showed that the two populations could be clearly separated (p b 0.05). Moreover, in all cases, the venlafaxine population had lower values for the Aberrant Behavior Checklist (ABC), Behavior Problems Inventory (BPI), and levels of urea with respect to the placebo group. In one case, a reduction in the dosage of clonazepam was also suggested. For an additional set of variables (ABC factor 2, BPI frequency of aggressive behaviors, hematic ammonia at Day 28, and zuclopenthixol and clonazepam intake), the separation between the two samples was statistically significant as was the Bartlett's test, but the Kaiser–Meyer–Olkin Measure of Sampling Adequacy was below the accepted threshold. This set of variables showed a reduction in the cumulative intake of both zuclopenthixol and clonazepam.Despite the small sample sizes, this study documented a statistically significant effect of venlafaxine. Moreover, we showed that lower doses of zuclopenthixol and clonazepam were needed in the venlafaxine group, although this difference was not statistically significant. This was confirmed by multivariate analyses, where this difference reached statistical significance when using a combination of variables involving zuclopenthixol. Larger-scale studies are recommended to better investigate the effectiveness of venlafaxine treatment in patients with intellectual disabilities and ASD.

In addition to the monographs which have been published in the past 7 years by the working group "Drug Monitoring” of the Swiss Society of Clinical Chemistry (SSCC) [1-6], new monographs have been written. The data presented in these monographs provide an overview of the information which is important for the request and interpretation of the results. Therefore, laboratory health professionals and the receivers of the reports are the targeted readers. In this series, antiretroviral drugs are presented for which drug concentrations are regularly determined (protease inhibitors, non-nucleoside reverse transcriptase inhibitors). To date, no clear evidence has been established that therapeutic drug monitoring of these drugs increases the success of the antiretroviral therapy. Nevertheless, many cases have demonstrated that the therapy can be guided with much more confidence and with good success if the drug concentrations are determined, especially if the patient has a combination therapy with many pharmacokinetically interfering compounds. First, information is given about pharmacology and pharmacokinetics of these drugs, such as protein binding, metabolic pathways with specific enzymes involved, elimination half-life time, elimination route(s) of the parent drug, as well as therapeutic and toxic concentrations. Moreover, indications for therapeutic drug monitoring are listed with important preanalytical information (time point of blood sampling and time to steady state since beginning or after change of posology). Furthermore, the stability of the drug and its metabolite(s) after blood sampling are described. For readers with a specific interest, references to important publications are given. The number of monographs will be further enlarged. The updated files are presented on the homepage of the SSCC (www.sscc.ch). We hope that these monographs are helpful for the better handling of therapeutic drug monitoring and we are looking forward to receiving comments from the readers

In 1995 the working group “Drug Monitoring” of the Swiss Society of Clinical Chemistry (SSCC) has already published a printed version of drug monographs, which are now newly compiled and presented in a standardised manner. The aim of these monographs is to give an overview on the most important informations that are necessary in order to request a drug analysis or is helpful to interpret the results. Therefore, the targeted audience are laboratory health professionals or the receivers of the reports. There is information provided on the indication for therapeutic drug monitoring, protein binding, metabolic pathways and enzymes involved, elimination half life time and elimination routes as well as information on therapeutic or toxic concentrations. Because preanalytical considerations are of particular importance for therapeutic drug monitoring, there is also information given at which time the determination of the drug concentration is reasonable and when steady-state concentrations are reached after changing the dose. Furthermore, the stability of the drug and its metabolite(s), respectively, after blood sampling is described. For readers with a specific interest, references to important publications are given. The number of the monographs will be continuously enlarged. The updated files are presented on the homepage of the SSCC (www.sscc.ch). We hope that these monographs are helpful for you handling therapeutic drug monitoring and look forward to comments of the audience.

We studied the relation between changes in pulmonary and systemic hemodynamics to those in the airway resistance, respiratory tissue mechanics, and thoracic gas volume (TGV) following acute hemorrhage and blood reinfusion in rats. Forced oscillation technique was used to measure airway resistance (Raw), respiratory tissue damping, and elastance at baseline and after stepwise 1-ml blood withdrawals up to 5 ml total, followed by stepwise reinfusion up to full restoration. Mean systemic (Pam) and pulmonary arterial pressures and suprarenal aortic blood flow were measured at each step. In supplemental animals, plethysmographic TGV, Pam, and respiratory mechanics measurements were performed. Blood volume loss (BVL) led to proportional decreases in Raw (66.5 ± 8.8 vs. 44.8 ± 9.0 cmH2O·s·l−1 with 5 ml, P < 0.001), Pam, and aortic blood flow. In contrast, tissue damping increased significantly (1,070 ± 91 vs. 1,235 ± 105 cmH2O/l, P = 0.009 with 5 ml BVL), whereas tissue elastance did not change significantly. TGV significantly increased with acute BVL (3.7 ± 0.2 vs. 4.2 ± 0.2 ml, P = 0.01). Stepwise reinfusions produced opposite changes in the above parameters, with Raw reaching a higher value than baseline ( P = 0.001) upon full volume restoration. Both adrenalin ( P = 0.015) and noradrenalin levels were elevated ( P = 0.010) after 5-ml blood withdrawal. Our data suggest that the decreases in Raw following BVL may be attributed to the following: 1) an increased TGV enhancing airway parenchymal tethering forces; and 2) an increase in circulating catecholamines. The apparent beneficial effect of a reduction in Raw in acute hemorrhagic shock is counteracted by an increase in dead space and the appearance of peripheral mechanical heterogeneities due to de-recruitment of the pulmonary vasculature.

Toxicological screening is the analysis of a biological specimen to detect and identify compounds in patients admitted to the hospital with acute intoxication of unknown origin. The screening of a wide range of toxicologically relevant compounds in biological samples is a serious challenge for clinical laboratories. The high selectivity and sensitivity of liquid chromatography coupled to mass spectrometry or tandem mass spectrometry technology provides an attractive alternative to the current methods. For these reasons, an increasing number of applications for multi-target screening or general screening of unknown compounds in biological matrices are being published. This paper is an overview of sample clean-up, chromatographic separation and mass spectrometry detection procedures which can be combined to obtain screening methods adapted to the constraints and needs of various laboratories, and none specifically in clinical toxicology. Currently the techniques are in the hands of specialists, principally in academic institutes. However, the evolution in technology should allow application of the techniques as a tool in toxicology laboratories and thus more widespread exploitation of their potential.

An exhaustive classification of matrix effects occurring when a sample preparation is performed prior to liquid-chromatography coupled to mass spectrometry (LC-MS) analyses was proposed. A total of eight different situations were identified allowing the recognition of the matrix effect typology via the calculation of four recovery values. A set of 198 compounds was used to evaluate matrix effects after solid phase extraction (SPE) from plasma or urine samples prior to LC-ESI-MS analysis. Matrix effect identification was achieved for all compounds and classified through an organization chart. Only 17% of the tested compounds did not present significant matrix effects.

In addition to the monographs which have been published recently by the working group “Drug Monitoring” of the Swiss Society of Clinical Chemistry (SSCC) [1, 2], new monographs have been written. The aim of these monographs is to provide an overview on the information which is important for the request and interpretation of the results. Therefore, the targeted readers are laboratory health professionals and the receivers of the reports. In this series, aminoglycoside as well as glycopeptide antibiotics are presented. In addition, two antimycotic drugs, which are regularly quantified in sera of intensive care patients, are described. Also, the monograph on mebendazole is shown. This drug is often used in high doses for the treatment of infections with Echinococcus multilocularis for which the measurement of drug concentrations in serum is recommended. Information on the indication for therapeutic drug monitoring (TDM), protein binding, metabolic pathways and enzymes involved, elimination half-life and elimination routes, and therapeutic or toxic concentrations is provided. Because pre-analytical considerations are of particular importance for therapeutic drug monitoring, there is also information given at which time the determination of the drug concentration is reasonable and when steady-state concentrations are reached after changing the dose. Furthermore, the stability of the drug and its metabolite(s) after blood sampling is described. For readers with a specific interest, references to important publications are provided. The number of the monographs will be continuously increased. The updated files are presented on the homepage of the SSCC (www.sscc.ch). We hope that these monographs are helpful for the better handling of therapeutic drug monitoring and we are looking forward to comments by the readers.

Objectives The aim of this work was to compare a validated liquid chromatography–mass spectrometry (LC–MS) method with the commercial enzyme multiplied immunoassay technique (EMIT) for cyclosporine and tacrolimus whole blood quantification. Design and methods Samples of transplant patients receiving cyclosporine ( n = 38) or tacrolimus ( n = 41) were analyzed successively by LC–MS and EMIT. Several statistical approaches for method comparison were evaluated and Passing–Bablok and Bland–Altman analyses chosen. Results Overestimations of the concentrations measured with EMIT compared to LC–MS were observed with means of 23% (range: 6% to 46%) for cyclosporine and 30% (range: − 3% to 73%) for tacrolimus. Conclusion The EMIT demonstrated significant positive biases due to cross-reactions with metabolites. This indicates that, in some clinical situations, a selective method such as LC–MS is preferable for therapeutic drug monitoring in transplant patients.

The expression on lymphocytes of P-glycoprotein, an efflux transporter encoded by the ABCB1 gene, might influence cyclosporine intracellular concentration.ABCB1 genotypes, cyclosporine intracellular and blood concentrations were determined in 64 stable renal, liver or lung transplant recipients.Cyclosporine intracellular concentration correlated moderately with blood concentration (r=0.30, P0.00005). The ABCB1 1199A carriers presented a 1.8-fold decreased cyclosporine intracellular concentration (P=0.04), whereas the 3435T carriers presented a 1.7-fold increase (P=0.02) as well as a 1.2-fold increased blood concentration (P=0.04). In contrast, ABCB1 61AG, 1236CT and 2677GT polymorphisms did not influence cyclosporine intracellular and blood concentrations.This is the first report demonstrating that ABCB1 polymorphisms influence cyclosporine intracellular concentration. Interestingly, its influence on intracellular concentration is significantly higher than on blood concentration (P0.002). This may therefore modulate cyclosporine immunosuppressive activity.

Emergence of psychotic thought has been related to a breakdown in left-hemisphere language dominance. Dopamine (DA) is implicated in both psychotic pathology and modulation of the semantic system. The present study explored whether controlled DA administration modulates basic language functions: (1) in general and/or (2) as a function of schizophrenia-associated thought. Forty healthy men performed a tachistoscopic lexical decision task. Participants' performance was also analyzed as a function of their positive (magical ideation, MI) and negative (physical anhedonia, PHYSAN) schizotypal features. Half of the subjects received 200 mg levodopa, the other half a placebo. Our findings showed that pharmacological treatment per se did not influence task performance, but influenced laterality patterns as a function of participants' schizotypal features. In the placebo, but not in the levodopa group, right hemisphere language contribution increased as a function of increasing MI scores. In the levodopa, but not in the placebo group, superior left hemisphere lexical decision performance was related to increasing PHYSAN scores. The findings from both substance groups suggest that in the healthy brain, a DA agonist restores left-hemispheric dominance for language by reducing right-hemispheric contribution with respect to a positive schizotypal trait and by increasing left-hemispheric specialization with respect to a negative schizotypal trait. We conjecture that the healthy brain compensates through intact neurochemical mechanisms an increased DA concentration, in particular for persons with elevated positive psychotic-like features.

Life-threatening opioid intoxication developed in a patient after he was given small doses of codeine for the treatment of a cough associated with bilateral pneumonia. Codeine is bioactivated by CYP2D6 into morphine, which then undergoes further glucuronidation. CYP2D6 genotyping showed that the patient had three or more functional alleles, a finding consistent with ultrarapid metabolism of codeine. We attribute the toxicity to this genotype, in combination with inhibition of CYP3A4 activity by other medications and a transient reduction in renal function.

Animals and men turn preferentially away from the hemisphere with the more active dopamine (DA) system. Consistent with the idea of a right-hemispheric hyperdopaminergia in schizophrenia, a leftsided turning bias was described for unmedicated psychotic patients. We investigated the modulating role of DA and schizophrenia-like thought on whole-body turns in a controlled double-blind study. The number of veers to either side when walking blindfolded straight ahead (20 meter) was assessed in 40 healthy righthanded men (20 men received levodopa, the remaining participants placebo). Side preferences were analyzed in terms of individuals' positive (Magical Ideation, MI) and negative (Physical Anhedonia, PhysAn) schizotypal features. In the placebo group, increasing MI scores were related to increasing left-sided veering and increasing PhysAn scores were related to increasing right-sided veering. In the levodopa group, this relationship between preferred veering side and type of schizotypy was reversed. The finding in the placebo group suggests an association between MI and a relative right-hemispheric hyperdopaminergia. Unexpectedly, levodopa did not enhance this veering bias, but reversed it, suggesting that psychosis-protective mechanisms exist in the healthy positive "schizotypic" brain. Also unexpectedly, levodopa made "anhedonics" veer like "magics" after placebo, suggesting that DA agonists suppress negative schizotypal symptoms.

Stereotyped behavior and left-sided orientation biases, associated with the dopamine (DA) system, were observed in populations of the schizophrenia spectrum disorders. We investigated whether heightened DA concentrations influence both side biases and stereotyped responding in a visuo-motor computer task, in which 90, 180, and 270 degrees rotated objects had to be brought into a target position. To account for the role of the schizophrenia spectrum, task performance was also analyzed as a function of healthy participants' high or low magical ideation (MI), a positive schizotypal feature. The first 36 participants (20 women) remained substance free. In a second sample, 20 men received levodopa and 20 men a placebo in a double-blind procedure. Results showed that high MI scorers responded more stereotyped than low MI scorers, without being specifically biased towards the left side. Rotation preferences toward one or the other side made high MI scorers less flexible for objects efficiently to be rotated into the opposite direction. This inflexibility may reflect impaired left hemisphere functioning. Unexpectedly, in the levodopa group, high MI scorers performed superior to low MI scorers. Since DA actions appear to follow an inverted U-shape function, the 'low' performing high MI scorers profited from the enhanced DA availability. Our observation in the levodopa group points to a dissociation between schizotypy and schizophrenia: while cognitive improvement in schizophrenia can occur after treatment with atypical neuroleptic agents, in our positive schizotypal participants a DA agonist resulted in improved task performance. This dissociation may point to protective neurochemical mechanisms preventing healthy schizotypes from developing full-blown psychotic symptoms.

Renal hemodynamic and tubular responses to salt in women using oral contraceptives.BackgroundThe use of oral contraceptives is associated with an increased risk of developing hypertension but the mechanisms of this hypertensive effect are not completely defined. The purpose of the present study was to assess prospectively the systemic and renal hemodynamic and tubular responses to salt in women taking oral contraceptives.MethodsTwenty seven young healthy normotensive women taking oral contraceptives containing monophasic combination of 30 μg ethynilestradiol and 150 μg desogestrel for>6 months were enrolled. All women were assigned at random to receive a low (40mmol/day) or a high (250mmol/day) sodium diet for 1 week on two consecutive menstrual cycles during the active oral contraceptive phase. At the end of each diet period, 24-hour ambulatory blood pressure, renal hemodynamics, sodium handling, and hormonal profile were measured.ResultsThe blood pressure response to salt on oral contraceptives was characterized by a salt-resistant pattern with a normal circadian rhythm. Salt loading results in an increase in glomerular filtration rate (GFR) (P < 0.05 vs. low salt), with no change in the renal plasma flow, thus leading to an increase in the filtration fraction (P < 0.05). At the tubular level, women on oral contraceptives responded to a low salt intake with a marked increased in proximal sodium conservation (P < 0.01 vs. high salt) and with an almost complete reabsorption of sodium reaching the distal tubule. After sodium loading, both the proximal and the distal reabsorption of sodium decreased significantly (P < 0.01).ConclusionThe use of oral contraceptives is not associated with an increased blood pressure response to salt in young normotensive women. However, oral contraceptives affect the renal hemodynamic response to salt, a high salt intake leading to an increase in GFR and filtration fraction. This effect is possibly mediated by the estrogen-induced activation of the renin-angiotensin system. Oral contraceptives also appear to increase the tubular responsiveness to changes in sodium intake. Taken together, these data point out evidence that synthetic sex steroids have a significant impact on renal function in women. The renal effects of oral contraceptives should be taken into account when managing young women with renal diseases.

BACKGROUND: Neuromuscular blocking agents may exert central nervous system effects when they reach the brain. This study assessed the concentrations and the time course of passage of vecuronium, atracurium, and its metabolite laudanosine in the cerebrospinal fluid (CSF) of patients undergoing intracranial aneurysm clipping. METHODS: Twenty-five patients with subarachnoid hemorrhage were randomly allocated to receive an intravenous infusion of vecuronium (n=13) or atracurium (n=12). Arterial blood and lumbar CSF were sampled before and 1, 2, 3, 4 and 8 h after the start of the relaxant infusion. The samples were analyzed by liquid chromatography-electrospray ionization mass spectrometry (vecuronium) and high-pressure liquid chromatography (atracurium and laudanosine). RESULTS: The data of 20 patients (10 in both groups) were analyzed. In 11 CSF samples from five patients atracurium was detected in concentrations from 10 to 50 ng/ml. Laudanosine was retrieved in all CSF samples at 1, 2, 3, 4 and 8 h; the highest CSF concentration of laudanosine occurred at 3 h [38 (18-63) ng/ml: median (range)]. Vecuronium was not found in any CSF sample. CONCLUSION: Significant concentrations of atracurium and laudanosine but not of vecuronium were detected in the CSF of patients during and immediately after intracranial aneurysm surgery.

Whilst augmented renal clearance (ARC) is associated with reduced β-lactam plasma concentrations, its impact on clinical outcomes is unclear. This single-centre prospective, observational, cohort study included non-pregnant, critically ill patients aged 18-60 years with presumed severe infection treated with imipenem, meropenem, piperacillin/tazobactam or cefepime and with creatinine clearance (CL(Cr)) ≥60 mL/min. Peak, intermediate and trough levels of β-lactams were drawn on Days 1-3 and 5. Concentrations were deemed 'subthreshold' if they did not meet EUCAST-defined non-species-related breakpoints. Primary and secondary endpoints were clinical response 28 days after inclusion, and ARC prevalence (CL(Cr)≥130 mL/min) and subthreshold and undetectable concentrations, respectively. Logistic regression was used to evaluate associations between ARC, antibiotic concentrations and clinical failure. From 2010 to 2013, 100 patients were enrolled (mean age, 45 years; median CL(Cr) at inclusion, 144.1 mL/min). ARC was present in 64 (64%) of the patients. Most patients received imipenem/cilastatin (54%). Moreover, 86% and 27% of patients had at least one subthreshold or undetectable trough level, respectively. Among imipenem and piperacillin trough levels, 77% and 61% were subthreshold, respectively, but intermediate levels of both antibiotics were largely above threshold. ARC strongly predicted undetectable trough concentrations (OR=3.3, 95% CI 1.11-9.94). A link between ARC and clinical failure (18/98; 18%) was not observed. ARC and subthreshold β-lactam antibiotic concentrations were widespread but were not associated with clinical failure. Larger studies are necessary to determine whether standard dosing regimens in the presence of ARC impact negatively on clinical outcome and antibiotic resistance.

Background: Plasma free metanephrines are a more reliable analyte to measure than catecholamines for the biochemical diagnosis of pheochromocytomas. We hypothesized that the long persistence of total (sulfate-conjugated plus free) metanephrines in the blood might have a significant diagnostic value. Methods: We measured plasma concentrations of catecholamines and total metanephrines (sulfate-conjugated plus free forms) by HPLC with amperometric detection, and neuropeptide Y (NPY) by an amplified ELISA in seven patients before and after removal of their pheochromocytomas. The results for catecholamine, total metanephrines, and NPY in each patient were analyzed for up to 120 min, starting from the time of tumor vessel clamping. The persistence of analytes was quantified as the area under the concentration–time curve over 120 min. Results: On the basis of the upper reference limit for each variable, plasma free norepinephrine (NE) and epinephrine (E) concentrations were increased preoperatively in at least one sample in seven and six patients, respectively. Total normetanephrine (NMN) and metanephrine (MN) were increased in all samples in seven and six patients, respectively. NPY was increased 2- to 465-fold. After removal of the tumor, MN and NMN showed a higher average relative increase above the upper limit of the reference interval than NE and E (P = 0.05), whereas NPY was intermediate. The persistence of increased values was significantly shorter for catecholamines than for metanephrines. The half-life estimated by nonlinear regression was 12.3 ± 7.8 min for NPY. Significant correlations were observed among NE, E, NMN, MN, and NPY concentrations, but parent markers (E and MN or NE and NMN) did not appear significantly intercorrelated. Conclusions: A larger increase and a longer persistence of total metanephrines (reflecting predominantly sulfo-conjugated metanephrines) than catecholamines and NPY in plasma may contribute to their greater diagnostic accuracy in pheochromocytoma.

Background: Current interest in the role of functional foods in weight control has focused on plant ingredients capable of interfering with the sympathoadrenal system. Objective: We investigated whether a green tea extract, by virtue of its high content of caffeine and catechin polyphenols, could increase 24-h energy expenditure (EE) and fat oxidation in humans. Design: Twenty-four-hour EE, the respiratory quotient (RQ), and the urinary excretion of nitrogen and catecholamines were measured in a respiratory chamber in 10 healthy men. On 3 separate occasions, subjects were randomly assigned among 3 treatments: green tea extract (50 mg caffeine and 90 mg epigallocatechin gallate), caffeine (50 mg), and placebo, which they ingested at breakfast, lunch, and dinner. Results: Relative to placebo, treatment with the green tea extract resulted in a significant increase in 24-h EE (4%; P < 0.01) and a significant decrease in 24-h RQ (from 0.88 to 0.85; P < 0.001) without any change in urinary nitrogen. Twenty-four-hour urinary norepinephrine excretion was higher during treatment with the green tea extract than with the placebo (40%, P < 0.05). Treatment with caffeine in amounts equivalent to those found in the green tea extract had no effect on EE and RQ nor on urinary nitrogen or catecholamines. Conclusions: Green tea has thermogenic properties and promotes fat oxidation beyond that explained by its caffeine content per se. The green tea extract may play a role in the control of body composition via sympathetic activation of thermogenesis, fat oxidation, or both.

The purpose of this investigation was the evaluation of Bioadhesive Ophthalmic Drug Inserts (BODI) for prolonged release of gentamicin sulfate (GS) in tears. The BODIs (length 5.0 mm, diameter 2.0 mm, weight 20.5 mg, average GS content 5.0 mg) were prepared by extrusion of a mixture based on hydroxypropylcellulose (HPC), ethylcellulose (EC) and carbomer. Two methods were tested to prolong the release of GS in tears: (1) preliminary treatment of GS and (2) use of a less hydrophilic polymer than HPC, hydroxypropylmethylcellulose (HPMC), as a vehicle constituent. The preliminary treatment consisted of the formation of a GS/cellulose acetate phthalate (CAP) solid dispersion (ratio GS/CAP: 10/6) made in acetonic medium, and in the coating of GS/EC granules (GS/EC ratio: 10/0.5) with an aqueous dispersion of CAP, to form a GS/EC/CAP coprecipitate (GS/EC/CAP ratio: 10/0.5/6). Inserts containing GS/CAP solid dispersion, GS/EC/CAP coprecipitate and HPMC resulted in improved time of efficacy (t(eff)) (43.8, 23.3, and 33.1 h, respectively), when compared to inserts containing GS without preliminary treatment (t(eff) = 11.9 h). A high irritation level was observed for inserts containing the GS/EC/CAP and HPMC. A relation between t(eff) and irritation score was established, emphasizing the importance of irritability as a factor during the evaluation of the potential of these systems.

Background Although neuromuscular blocking agents do not cross the blood-brain barrier, they may penetrate the central nervous system under particular circumstances and eventually cause neurotoxic consequences. Methods The effects of neuromuscular blocking agents on excitatory and inhibitory transmission in area CA1 of rat hippocampal slices were investigated using extracellular and intracellular recording techniques. Results Application of atracurium in the perfusion medium resulted in a dose-dependent enhancement of excitatory synaptic responses averaging 48.7 +/- 4.3% at a concentration of 10 nM. This effect was correlated with an increase in the size of the presynaptic fiber volley. Laudanosine, but not pancuronium bromide or vecuronium bromide, produced similar changes. In addition, atracurium and laudanosine blocked inhibitory transmission and reduced intracellularly recorded gamma-aminobutyric acidA receptor-mediated potentials. These effects were observed only at concentrations >1 microM and were not reproduced by pancuronium bromide and vecuronium bromide. Conclusions Atracurium and its metabolite, laudanosine, contrary to pancuronium bromide and vecuronium bromide, produce two distinct effects on hippocampal slices. They enhance excitatory transmission and neuronal excitability and they block inhibitory gamma-aminobutyric acidA-mediated synaptic responses.

In the case of external ophthalmic infections, repeated instillations of antibiotics are required to reach therapeutic level, above the minimal inhibitory concentration (MIC). An additional administration of a corticosteroid is often needed, in order to limit the precorneal damages caused by the infection. However, repeated administration of a corticosteroid can increase intraocular pressure and thus lead to glaucoma. To overcome the disadvantages of separated and repeated instillations of two products and to avoid the side effects of dexamethasone, a soluble insert containing gentamicin sulfate and dexamethasone phosphate was developed. The new system ensures the concomitant release of the two drugs during the first 10 h of treatment, followed by an adequate concentration of gentamicin sulfate, above the MIC of 4.0 microgram ml-1, during 50 h, due to a combination of gentamicin sulfate with cellulose acetate phthalate, which reduces the solubility of gentamicin.

OBJECTIVE: To assess the safety, efficacy and plasma drug levels of the combination of ritonavir plus saquinavir for the treatment of advanced HIV infection. DESIGN: Multicentre pilot study. PATIENTS: Eighteen protease inhibitor-naive patients, with intolerance or contraindication to reverse transcriptase inhibitors, a median CD4 cell count of 12 x 10(6)/l (range, 1-50 x 10(6)/l), and a median HIV viraemia of 5.25 log10 copies/ml (range, 4.00-6.13 log10 copies/ml). METHODS: Patients received 600 mg twice daily of both ritonavir and saquinavir. Viraemia was measured at baseline and at weeks 5, 9 and 13. Response was defined as a drop of viraemia of more than 1 log10 at week 5. Plasma drug levels were determined after at least 3 weeks of combined treatment: samples were collected before and 1, 2, and 4 h after the morning ingestion of both drugs. The protease gene was sequenced at baseline and under treatment. RESULTS: Among the 16 patients evaluable at week 5, 11 were responders, and among these patients, six remained responders at week 13 (two with undetectable viraemia). Study discontinuations were due to side-effects (n = 4), patient choice (n = 3), protocol violation (n = 1) and death (n = 1). Responders had higher drug levels than non-responders (P < 0.01 for saquinavir, P = 0.04 for ritonavir). In two non-responders, development of multiple new mutations at positions 10, 20, 48, 82, 84 and 90 was observed after 5-13 weeks. CONCLUSION: The response to ritonavir plus saquinavir in advanced HIV infection is unpredictable. A minority of patients respond with disappearance of HIV viraemia. In other patients, rapid cumulative emergence of protease mutations conferring resistance to treatment cannot always be prevented by good compliance and relatively high plasma drug levels.

Evaluate a new LC-MS/MS screening method for drugs and drugs of abuse as an alternative to the existing methods used in clinical toxicology laboratories.The work was divided in two parts. The first part was dedicated to the technical development and evaluation of the method for which a set of 97 drugs and relevant metabolites was used to perform a complete investigation of matrix effects and lower limit of identification (LOI). The second part was a comparison of identified drugs between LC-MS/MS and Remedi® instrument on clinical serum samples.The method offers good performance allowing an automatic peak detection and compound identification. The limit of identification is equivalent to 50 μg/L for the majority of the studied compounds. The process efficiency (PE) is higher than 70% for 65% of the evaluated compounds. Thus, a sufficient detection capability in terms of limit of detection for identification and PE satisfied the expected performance.The described methodology allows the identification of the main drugs incriminated in intoxications within a quite short analysis time. The separation of most of the analytes is performed in 15 min. The procedure is sufficiently sensitive and selective.

The diversity of experimental workflows involving LC-MS/MS and the extended range of mass spectrometers tend to produce extremely variable spectra. Variability reduces the accuracy of compound identification produced by commonly available software for a spectral library search. We introduce here a new algorithm that successfully matches MS/MS spectra generated by a range of instruments, acquired under different conditions. Our algorithm called X-Rank first sorts peak intensities of a spectrum and second establishes a correlation between two sorted spectra. X-Rank then computes the probability that a rank from an experimental spectrum matches a rank from a reference library spectrum. In a training step, characteristic parameter values are generated for a given data set. We compared the efficiency of the X-Rank algorithm with the dot-product algorithm implemented by MS Search from the National Institute of Standards and Technology (NIST) on two test sets produced with different instruments. Overall the X-Rank algorithm accurately discriminates correct from wrong matches and detects more correct substances than the MS Search. Furthermore, X-Rank could correctly identify and top rank eight chemical compounds in a commercially available test mix. This confirms the ability of the algorithm to perform both a straight single-platform identification and a cross-platform library search in comparison to other tools. It also opens the possibility for efficient general unknown screening (GUS) against large compound libraries.

Reverse iontophoresis across the skin is a potentially useful alternative for non-invasive clinical and therapeutic drug monitoring. In this work, the reverse iontophoretic extraction of 17 amino acids was studied in vivo in healthy volunteers. Charged amino acids were primarily extracted towards the electrode of opposite polarity, while zwitterionic species were extracted, more or less equally, to both anode and cathode, suggesting that the net charge on the skin, under the conditions of the experiment, was close to zero. The significant presence of a 'skin reservoir' of several amino acids, presumably originating from the barrier's so-called 'natural moisturizing factor', was deduced from the results. While this phenomenon had been observed in an earlier in vitro investigation, the levels of certain amino acids (including serine and glycine) in the skin were found to be much higher in vivo. Hence, while the results of this study confirm the feasibility of extracting some amino acids at physiologically relevant levels in vivo, the objective of achieving a correlation between iontophoretically extracted fluxes and blood plasma levels may not be a practically realisable goal in all cases.

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The present study was conducted to examine the haemodynamic and endocrine effects of clonidine, given as sole preanaesthetic medication, in neurosurgical patients. Nineteen patients of ASA physical status I and II, subjected to craniotomy, randomly received po premedication of either clonidine (300 micrograms, n = 9) or placebo (n = 10). Blood pressure and heart rate were monitored continuously, while arterial blood samples were collected at specific times, from induction of anaesthesia to recovery, for the measurement of plasma concentrations of epinephrine, norepinephrine, cortisol, aldosterone, and glucose. Clonidine treatment led to a decrease in mean arterial blood pressure (MABP), heart rate (HR), and plasma cortisol and aldosterone concentrations throughout the study, compared with placebo (P less than 0.05). Clonidine, however, did not prevent increases in MABP (16 +/- 5 mmHg, mean +/- SE, P less than 0.05) and HR (18 +/- 4 bpm, P less than 0.05) during induction of anaesthesia, which was comparable to the placebo group. Plasma catecholamine concentrations did not differ between the two groups. Plasma glucose concentrations increased in both groups at the end of the study (P less than 0.05), but were lower in clonidine-treated patients (P less than 0.05). Though statistically significant, the observed inhibitory haemodynamic and endocrine effects of clonidine seem to be of minor clinical importance. As the action of clonidine on cerebral blood flow regulation is not well known, we see no advantage in the preanaesthetic administration of clonidine to neurosurgical patients with normal cardiovascular status.

Reverse iontophoresis across the skin has been investigated as alternative, non-invasive method for clinical and therapeutic drug monitoring. This research investigated the reverse iontophoretic extraction of 19 amino acids present at clinically relevant levels in the subdermal compartment of an in vitro diffusion cell. Over a simulated, systemic concentration range of 0-500 microM, the extraction of amino acids was linear. Charged amino acids were extracted towards the electrode of opposite polarity, while zwitterionic species were extracted to both anode and cathode with the latter predominating. The reverse iontophoretic extraction flux was a linear function of amino acid isoelectric point, reflecting the different contributions of electromigration and electroosmosis to electrotransport. Overall, the results confirm the feasibility of monitoring amino acids at clinically relevant levels and provide an incentive for in vivo research to further explore the clinical potential of reverse iontophoresis for the non-invasive monitoring of amino acids.

The calcineurin inhibitor cyclosporine is removed from lymphocytes by the drug efflux transporter P-glycoprotein (P-gp) encoded by the ABCB1 gene for which several single nucleotide polymorphisms (SNPs) have been identified. Of a total of 87 healthy volunteers genotyped for ABCB1 G2677T/A and C3435T SNPs, 10 GG-CC and 9 TT-TT individuals were selected and received a single oral dose of cyclosporine. Peripheral blood mononuclear cell (PBMC) ABCB1 mRNA expression, P-gp activity in CD4(+) and CD8(+) cells and the 24h cyclosporine pharmacokinetics in PBMCs and whole blood were determined. No correlation was observed between cyclosporine PBMC and whole blood levels (AUC(0-24), Spearman, r(S)=0.09, p=0.71). Intraindividual PBMC and whole blood levels followed parallel profiles that did not significantly differ with respect to t(max) (Wilcoxon, p=0.53) and t((1/2)) (p=0.49). Significant negative correlations between cyclosporine t((1/2)) in PBMCs and P-gp activity in CD4(+) (r(S)=-0.82, p=0.007) and CD8(+) (r(S)=-0.72, p=0.03) were observed among TT-TT subjects. Similarly, a negative correlation was detected in the GG-CC group between P-gp activity in CD4(+) and cyclosporine PBMC AUC(0-24) (r(S)=-0.69, p=0.03), as well as PBMC to whole blood AUC(0-24) ratio (r(S)=-0.60, p=0.07). Tested ABCB1 genotypes had no influence on cyclosporine pharmacokinetic parameters in PBMCs and whole blood. The haplotypes investigated were neither significantly correlated with PBMC ABCB1 mRNA expression nor with P-gp activity in CD4(+) and CD8(+). In conclusion, cyclosporine PBMC pharmacokinetics was influenced by P-gp activity and cyclosporine whole blood concentrations did not predict PBMC drug levels, suggesting that despite values in the therapeutic range, some subjects could have inadequate intracellular drug levels.

Objectives The aim of this work was to develop a selective method for the simultaneous quantification of cyclosporine, tacrolimus, sirolimus and everolimus in whole blood. Design and methods An automated on-line solid-phase extraction system coupled with liquid chromatography–mass spectrometry (LC–MS) was used. After a simple protein precipitation, the supernatant was load on a C8 column with a mobile phase composed of MeOH/H 2 O (5/95 v/v), supplemented with formic acid 0.02% and sodium formate 1 μM. After column-switching, the analytes were transferred in the back-flush mode on a C18 column with MeOH/H 2 O (65/35). The valve was then commuted to its initial position and the chromatographic separation was performed with a gradient of MeOH/H 2 O (65/35–95/5). The sodium adducts [M+Na] + were monitored for quantification with an electrospray ionization-single quadrupole MS. Results The LC–MS assay was fully validated on a concentration range of 2.5–30 ng/mL for tacrolimus, sirolimus and everolimus and of 50–1500 ng/mL for cyclosporine, allowing a quantification of cyclosporine 2 h post-dose without sample dilution. Trueness, repeatability and intermediate precision were found to be satisfactory. Conclusion This method provided a selective, rapid and automated procedure that can be easily used for routine quantification of immunosuppressive drugs in most clinical laboratories.

As a potential alternative to cyclosporine A (CsA) monitoring in whole blood, a sensitive and selective method was developed for quantifying this immunosuppressive drug in human peripheral blood mononuclear cells (PBMCs) by liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS). PBMCs were isolated from whole blood by density gradient centrifugation. After purification, cell counts were performed to express CsA amounts per single cell. The pelleted cells were then lysed and CsA was extracted with methanol (MeOH) containing 27-demethoxy-sirolimus as internal standard. After evaporation of the supernatant under nitrogen, the residue was reconstituted in MeOH, further diluted with water and injected onto a column-switching unit. On-line solid-phase extraction was performed using a C8 column with an acidic aqueous mobile phase containing 5% MeOH. The analytes were transferred in the back-flush mode on a C18 column with 65% MeOH and the chromatographic separation performed with a MeOH gradient (65-90%). The detection was carried out with a single quadrupole analyzer and the sodium adducts [M+Na](+) were monitored for quantification. This sensitive method was fully validated in the range of 5-400 ng/mL. This allowed the measurement of very small CsA amounts present in cells up to 0.5 fg/PBMC in clinical samples. Trueness (95.0-113.2%), repeatability (5.1-9.9%) and intermediate precision (7.0-14.7%) were found to be satisfactory. This method represents a new potential tool for therapeutic drug monitoring of CsA and could be used in clinical conditions if the utility of intracellular measurements is confirmed in prospective clinical trials.

In addition to the monographs which were published last year by the working group "Drug Monitoring" of the Swiss Society of Clinical Chemistry (SSCC) [1], new monographs have been written. The aim of these monographs is to give an overview of the most important information necessary for ordering a drug analysis or interpreting the results. Therefore, the targeted readers comprise laboratory health professionals and all receivers of laboratory reports. There is information provided on the indication for therapeutic drug monitoring, protein binding, metabolic pathways and enzymes involved, elimination half-life and elimination routes, and on therapeutic or toxic concentrations. Preanalytical considerations are of particular importance for therapeutic drug monitoring. Therefore, information is provided regarding a reasonable timing for the determination of drug concentrations as well as steady-state concentrations after changing the dose. Furthermore, the stability of the drug and its metabolite(s) after blood sampling is described. For readers with a specific interest in drug analysis, references to important publications are given. The number of monographs will be continuously enlarged. The updated files are presented on the homepage of the SSCC (www.sscc.ch).

Desorption electrospray ionization mass spectrometry (DESI-MS) was used as a simple and rapid way to analyze drug tablets and powders without sample preparation. Experiments were performed with a home-made DESI source coupled to a triple-quadrupole linear-ion trap (QqQ(LIT)) mass spectrometer. Twenty-one commercial drugs as well as some illicit Ecstasy tablets and powders were analyzed. MS spectra almost exclusively showed the protonated or deprotonated ion of the drug after directing the pneumatically assisted electrospray onto the tablet's surface. With some tablets, inhomogeneity of the surface resulted in different spectra depending on the spot analyzed, thus showing that DESI could be used for imaging. Directly triggered MS/MS spectra were used for confirmatory analysis, with analysis times often below 10 s per tablet. For illicit Ecstasy tablets, DESI-MS, GC/MS and LC/MS analyses provided similar qualitative results for the main analytes. With MS/MS spectra library comparison or exact mass measurements, this technique could become very powerful for the rapid analysis of unknown tablets and shows the great potential of desorption techniques as an alternative to solution-based analysis.

Spontaneous eye blink rate (SBR) is thought to be a biological marker for cerebral dopamine (DA) activity. Accordingly, positive psychotic symptoms have been found to be associated with an increased SBR and negative psychotic symptoms with a decreased SBR. However, modulations of the DA system in patient populations also result from prior neuroleptic treatment. Here, we tested the possible relationship between SBR and positive and negative schizotypal thought. To test the direct influence of DA on SBR in general and as a function of schizotypy, half of a sample of 40 healthy men received levodopa and the other half placebo in a double-blind procedure. SBR did not differ between substance groups suggesting that a pharmacologically induced DA increase in healthy individuals does not generally increase SBR. However, in the levodopa group, increasing SBR correlated with increasing negative schizotypy scores, while no relationship was found between SBR and (1) negative schizotypy in the placebo group, or (2) positive schizotypy in either substance group. We conjecture that a pre-existing hypodopaminergic state in high negative schizotypy scorers, made these individuals susceptible to an increased DA concentration, as it has been observed in Parkinson’s disease. Furthermore, the absence of any relationship in the placebo group might suggest that variations in DA concentration as a function of schizotypy are too subtle to influence SBR. Finally, the lack of any association of SBR with positive schizotypy might indicate that SBR and positive schizotypy are mediated by functionally distinct neural circuits

The recent development of multilayered bags has minimized ascorbic acid oxidation in parenteral nutrition (PN) admixtures. However, the gas-barrier property of multilayered bags depends on their plastic material. This study compared ascorbic acid stability in different multilayered bags under experimental conditions.Oxygen permeability of a newly developed 6-layered bag (6-L) was compared with a highly mechanical-resistant 3-layered bag (3-L(R)) and a highly flexible 3-layered bag (3-L(F)) using gas chromatography. Ascorbic acid stability was assessed by iodine titration in bags filled with 2.5 L H(2)O and 40 g carbohydrates after setting residual O(2) content ator =1 oror =5 ppm. The effect of storage at 4 degrees C, 21 degrees C, and 40 degrees C on ascorbic acid stability was assessed over 48 hours in a complete PN admixture (ie, 330 g carbohydrates, 100 g lipids, 96 g amino acids and trace elements) using high-pressure liquid chromatography.Oxygen permeability was markedly reduced in 6-L bags (0.5 mL O(2) /m(2)/d) compared with 3-L(R) (150 mL O(2) /m(2)/d) and 3-L(R) (1500 mL O(2)/m(2)/d). Accordingly, ascorbic acid was more stable in 6-L bags (half-life [T(1/2)] = 16 days up to 40 degrees C) than in 3-L(R) (T(1/2) = 9 days at 4 degrees C, 47 hours at 21 degrees C and 29 hours at 40 degrees C) and 3-L(F) (T(1/2) = 15 hours at 4 degrees C, 10 hours at 21 degrees C, and 6 hours at 40 degrees C). During the first 6 hours after PN admixture compounding, an additive ascorbic acid loss of 4.6 +/- 0.5 mg/L/ppm O(2) occurred because of residual O(2) in the bag.The new combination of plastic layers and careful O(2) monitoring during the filling process allowed near to complete prevention of ascorbic acid degradation in multilayered PN bags during 48 hours, regardless of the storage temperature.

Purpose. Transdermal iontophoresis was investigated as a noninvasive tool for drug monitoring and pharmacokinetic profiling. Lithium, a frequently monitored drug, was used as a model. The objectives were a) to demonstrate the linear dependence of the iontophoretic extraction flux of lithium on the subdermal concentration of the drug, b) to evaluate the capacity of iontophoresis to monitor sudden changes in the subdermal level, c) to investigate the utility of reverse iontophoresis as a tool in pharmacokinetic studies, and d) to examine the validity of an internal standard calibration procedure to render the method completely noninvasive. Methods. Transdermal, iontophoretic extraction was performed in vitro using dermatomed pig-ear skin. The subdermal solution consisted of a physiological buffer containing lithium chloride at concentrations in the therapeutic range and two putative internal standards, sodium and potassium, at fixed physiological levels. The subdermal concentration of lithium was changed either in a stepwise fashion or by simulating one of two pharmacokinetic profiles. Results. Lithium was extracted via electromigration to the cathode. A excellent correlation between subdermal lithium concentration and iontophoretic extraction flux was observed. Iontophoresis tracked sudden concentration changes and followed kinetic profiles. In addition, the effective elimination rate constant could be directly, and noninvasively, estimated from the extraction flux data. Conclusions. Reverse iontophoresis is a potentially useful and noninvasive tool for lithium monitoring

Locomotion depends on an intact dopamine system. This system seems to be functionally asymmetric, as evidenced by an asymmetric turning preference. Using a double-blind procedure, the effect of levodopa on the number of veers when walking blindfolded along a straight line (20 m) in the middle of a corridor was tested in 40 healthy dextral men. One group received 200 mg levodopa, while the other group received placebo. We found that (1). subjects veered less after levodopa than after placebo, and (2). improved straight-walking tendency was most prominent for the levodopa group which veered less often to the right side than the placebo group. These findings imply that spatial orientation skills improved under levodopa. We conjecture that a task-dependent dopamine demand during our task was satisfied by levodopa supplementation, and over-proportionately so by the right hemisphere.

Objective: We investigated the metabolic, hemodynamic, and inflammatory responses of pharmacological and physical therapies aimed at reducing body temperature in febrile critically ill patients. Design and setting: Open-label, randomized trial in a surgical ICU in a tertiary university hospital. Patients: Thirty analgosedated, mechanically ventilated patients with a temperature of 38.5°C or higher were randomized to receive either intravenous metamizol, intravenous propacetamol, or external cooling. Measurements and results: Body temperature and metabolic and hemodynamic variables were recorded at baseline and during the following 4h. Cytokine concentrations were assessed before and 4 and 12h after the initiation of antipyresis. Body temperature decreased significantly in all treatment groups. For a 1°C temperature decrease, the energy expenditure index increased by 5% with external cooling and decreased by 7% and 8% in the metamizol and propacetamol groups, respectively. Metamizol induced a significant decrease in mean arterial pressure and urine output compared to baseline and to the other two groups. C-reactive protein increased over time, but compared to the other groups it was significantly lower in patients receiving metamizol after 4h. Cytokine concentrations were not different among the three groups or over time, although interleukin 6 tended to decrease over time in the metamizol group. Conclusions: Metamizol, propacetamol, and external cooling equally reduced temperature. Considering the undesirable hemodynamic effects, metamizol should not be considered the first antipyretic choice in unstable patients. Propacetamol or external cooling should be preferred, although the latter should be avoided in patients unlikely to tolerate the increased metabolic demand induced by external cooling

After transfer of diabetic patients from porcine to human insulin, many reports emerged supporting an increased hypoglycemia unawareness. Several studies were then undertaken in both diabetic and healthy adults to investigate counterregulatory hormone responses to both porcine and human insulin-induced hypoglycemia as a possible underlying cause for this different hypoglycemia awareness. Most studies demonstrated similar neuroendocrine responses to both insulin species in adults. However, no such studies have ever been performed in healthy children. We undertook a double-blinded study of counterregulatory hormone responses to both porcine and human insulin-induced hypoglycemia in 17 short normal children randomly assigned to two groups, one receiving human and the other porcine insulin. We found similar responses of growth hormone, cortisol, epinephrine, norepinephrine and dopamine to both porcine insulin- and human insulin- induced hypoglycemia. Interestingly, we observed a significantly higher glucagon secretion when hypoglycemia was induced by human insulin. In conclusion, human insulin induces a higher glucagon secretion in healthy children than porcine insulin. Evidently, this observation cannot be extrapolated to diabetic patients. This study, however, further underlines the importance of performing investigations in children, since results found in adults differ from those observed in children.

Serotonin excretion was investigated in the nausea and vomiting associated with hyperemesis gravidarum. Urinary hydroxyindoleacetic acid was measured in 13 gravid women with hyperemesis gravidarum, 10 gravid women without nausea and vomiting, and 10 nongravid women of similar age not taking contraceptive pills. No significant difference in the urinary excretion of hydroxyindoleacetic acid was found among the groups. Hyperemesis gravidarum is not associated with an increase of serotonin secretion.

Toxicological screening is the analysis of biological samples to detect and identify unknown compounds. The high selectivity and sensitivity of liquid chromatography (LC) coupled to mass spectrometry (MS) or tandem mass spectrometry (MS/MS) technology provide an attractive alternative to the current methods (LC-UV, GC/MS, etc.). For these reasons, an increasing number of applications are being published. This paper is a brief overview of LC-MS(/MS) screening methods developed for clinical toxicology in recent years. Various sample treatments, chromatographic separations and detection by mass spectrometry can be combined to obtain screening methods adapted to the constraints and needs of clinical toxicology laboratories. Currently the techniques are in the hands of specialists, mainly in academic institutions. However, the evolution in technology should allow application of these techniques as a tool in toxicology laboratories, thus allowing a more widespread exploitation of their potential.

Background. Nausea and vomiting associated with cisplatin chemotherapy is a source of major morbidity that remains difficult to control. Acute phase (0-24 hours after induction of chemotherapy) nausea and vomiting parallels plasma serotonin release, which explains the effectiveness of 5HT3 antagonists; serotonin release in the delayed phase (24–48 hours after induction), during which consistent antiemetic control remains elusive, has not been investigated. The effect of propofol, a recent addition to the antiemetic armamentarium, on this serotonin release has not been studied. Methods. Ten women with nausea and vomiting refractory to ondansetron and dexamethasone prophylaxis in their first cisplatin chemotherapy cycle were studied. Serial urinary 5-hydroxyindoleacetic acid (5-HIAA) levels were determined during a 48-hour period in 30 subsequent cycles, conducted under ondansetron/dexamethasone prophylaxis together with a propofol infusion. Results. There was a significant urinary 5-HIAA peak 6 hours after induction of chemotherapy, with no peaks thereafter. Propofol did not inhibit serotonin release. Conclusions. Cisplatin chemotherapy is associated with serotonin release in the acute phase. There is no serotonin release during the delayed phase. Thus the use of 5HT3 antagonists for delayed-phase nausea and vomiting would appear questionable.