Psychiatric comorbidity and additional abuse of drugs in maintenance treatment with l- and d,l-methadone.

Sixty d,l- or l-methadone treated patients in maintenance therapy were interviewed for additional drug abuse and psychiatric comorbidity; 51.7% of the entire population had a comorbid Axis-I disorder, with a higher prevalence in females (P=0.05). Comorbid patients tended to have higher abuse of benzodiazepines, alcohol, cannabis, and cocaine, but not of heroin. They had received a significantly lower d,l- (P<0.05) and l-methadone dose than non-comorbid subjects. The duration of maintenance treatment showed an inverse relationship to frequency of additional heroin intake (P<0.01). Patients with additional heroin intake over the past 30 days had been treated with a significantly lower l-methadone dosage (P<0.05) than patients without. Axis-I comorbidity appears to be decreased when relatively higher dosages of d,l- (and l-methadone) are administered; comorbid individuals, however, were on significantly lower dosages. Finally, l-, but not d,l-methadone seems to be more effective in reducing additional heroin abuse.

The impact of newer antiepileptic drugs in the treatment of status epilepticus

Purpose: Newer antiepileptic drugs (AED) are increasingly prescribed, and seem to have a comparable efficacy as the classical AED in patients living with epilepsy; however, their impact on status epilepticus (SE) prognosis has received little attention. Method: In our prospective SE registry (2006-10) we assessed the use of newer AED (for this purpose: levetiracetam, pregabalin, topiramate, lacosamide) over time, and its relationship to outcome (return to clinical baseline conditions, new handicap, or death). We adjusted for recognized SE outcome predictors (Status Epilepticus Severity Score, STESS; potentially fatal etiology), and the use of >2 AED for a given SE episode. Result: Newer AED were used more often towards the end of the study period (42% versus 30% episodes), and more frequently in severe and difficult to treat episodes. However, after adjustment for SE etiology, STESS, and medication number, newer AED resulted independently related to reduced likelihood of return to baseline (p < 0.01), but not to increased mortality. STESS and etiology were robustly related to both outcomes (p < 0.01 for each), while prescription of >2 AED was only related to lower chance of return to baseline (p = 0.03). Conclusion: Despite increase in the use of newer AED, our findings suggest that SE prognosis has not been improved. This appears similar to recent analyses on patients with refractory epilepsy, and corroborates the hypothesis that SE prognosis is mainly determined by its biological background. Since newer AED are more expensive, prospective trials showing their superiority (at least regarding side effects) appear mandatory to justify their use in this setting.

Newer antiepileptic drugs in the treatment of status epilepticus: impact on prognosis

Background: Newer antiepileptic drugs (AED) are increasingly prescribed, and seem to have a comparable efficacy as the classical AED, but are better tolerated. Very scarce data exist regarding their prognostic impact in patients with status epilepticus (SE). We therefore analyzed the evolution of prescription of newer AED between 2006-2010 in our prospective SE database, and assessed their impact on SE prognosis.¦Methods: We found 327 SE episodes occurring in 271 adults. The use of older versus newer AED (levetiracetam, pregabalin, topiramate, lacosamide) and its relationship to outcome (return to clinical baseline conditions, new handicap, or death) were analyzed. Logistic regression models were applied to adjust for known SE outcome predictors.¦Results: We observed an increasing prescription of newer AED over time (30% of patients received them at the study beginning, vs. 42% towards the end). In univariate analyses, patients treated with newer AED had worse outcome than those treated with classical AED only (19% vs 9% for mortality; 33% vs 64% for return to baseline, p<0.001). After adjustment for etiology and SE severity, use of newer AED was independently related to a reduced likelihood of return to baseline (p<0.001), but not to increased mortality.¦Conclusion: This retrospective study shows an increase of the use of newer AED for SE treatment, but does not suggest an improved prognosis following their prescription. Also in view of their higher price, well-designed, prospective assessments analyzing their impact on efficacy and tolerability should be conducted before a widespread use in SE.

A multi-perspective approach to performance anxiety in music students

AbstractPerforming publicly has become increasingly important in a variety of professions. This condition is associated with performance anxiety in almost all performers. Whereas some performers successfully cope with this anxiety, for others it represents a major problem and even threatens their career. Musicians and especially music students were shown to be particularly affected by performance anxiety.Therefore, the goal of this PhD thesis was to gain a better understanding of performance anxiety in university music students. More precisely, the first part of this thesis aimed at increasing knowledge on the occurrence, the experience, and the management of performance anxiety (Article 1). The second part aimed at investigating the hypothesis that there is an underlying hyperventilation problem in musicians with a high level of anxiety before a performance. This hypothesis was addressed in two ways: firstly, by investigating the association between the negative affective dimension of music performance anxiety (MPA) and self-perceived physiological symptoms that are known to co-occur with hyperventilation (Article 2) and secondly, by analyzing this association on the physiological level before a private (audience-free) and a public performance (Article 3). Article 4 places some key variables of Article 3 in a larger context by jointly analyzing the phases before, during, and after performing.The main results of the self-report data show (a) that stage fright is experienced as a problem by one-third of the surveyed students, (b) that the students express a considerable need for more help to better cope with it, and (c) that there is a positive association between negative feelings of MPA and the self-reported hyperventilation complaints before performing. This latter finding was confirmed on the physiological level in a tendency of particularly high performance-anxious musicians to hyperventilate. Furthermore, the psycho-physiological activation increased from a private to a public performance, and was higher during the performances than before or after them. The physiological activation was mainly independent of the MPA score. Finally, there was a low response coherence between the actual physiological activation and the self-reports on the instantaneous anxiety, tension, and perceived physiological activation.Given the high proportion of music students who consider stage fright as a problem and given the need for more help to better cope with it, a better understanding of this phenomenon and its inclusion in the educational process is fundamental to prevent future occupational problems. On the physiological level, breathing exercises might be a good means to decrease - but also to increase - the arousal associated with a public performance in order to meet an optimal level of arousal needed for a good performance.

Population PK-guided simulation study in children exposed to drugs in human milk

Risks of significant infant drug exposure through human milk arepoorly defined due to lack of large-scale PK data. We propose to useBayesian approach based on population PK (popPK)-guided modelingand simulation for risk prediction. As a proof-of-principle study, weexploited fluoxetine milk concentration data from 25 women. popPKparameters including milk-to-plasma ratio (MP ratio) were estimatedfrom the best model. The dose of fluoxetine the breastfed infant wouldreceive through mother's milk, and infant plasma concentrations wereestimated from 1000 simulated mother-infant pairs, using randomassignment of feeding times and milk volume. A conservative estimateof CYP2D6 activity of 20% of the allometrically-adjusted adult valuewas assumed. Derived model parameters, including MP ratio were consistentwith those reported in the literature. Visual predictive check andother model diagnostics showed no signs of model misspecifications.The model simulation predicted that infant exposure levels to fluoxetinevia mother's milk were below 10% of weight-adjusted maternal therapeuticdoses in >99% of simulated infants. Predicted median ratio ofinfant-mother serum levels at steady state was 0.093 (range 0.033-0.31),consistent with literature reported values (mean=0.07; range 0-0.59).Predicted incidence of relatively high infant-mother ratio (>0.2) ofsteady-state serum fluoxetine concentrations was <1.3%. Overall, ourpredictions are consistent with clinical observations. Our approach maybe valid for other drugs, allowing in silico prediction of infant drugexposure risks through human milk. We will discuss application of thisapproach to another drug used in lactating women.

Hyperventilation complaints in music performance anxiety among classical music students.

Objective: Despite the importance of respiration and hyperventilation in anxiety disorders, research on breathing disturbances associated with hyperventilation is rare in the field of music performance anxiety (MPA, also known as stage fright). The only comparable study in this area reported a positive correlation between negative feelings of MPA and hyperventilation complaints during performance. The goals of this study were (a) to extend these previous findings to the period before performance, (b) to test whether a positive correlation also exists between hyperventilation complaints and the experience of stage fright as a problem, (c) to investigate instrument-specific symptom reporting, and (d) to confirm gender differences in negative feelings of MPA and hyperventilation complaints reported in other studies. Methods: We assessed 169 university students of classical music with a questionnaire comprising: the State-Trait Anxiety Inventory for negative feelings of MPA, the Nijmegen Questionnaire for hyperventilation complaints, and a single item for the experience of stage fright as a problem. Results: We found a significant positive correlation between hyperventilation complaints and negative feelings of MPA before performance and a significant positive correlation between hyperventilation complaints and the experience of stage fright as a problem. Wind musicians/singers reported a significantly higher frequency of respiratory symptoms than other musicians. Furthermore, women scored significantly higher on hyperventilation complaints and negative feelings of MPA. Conclusion: These results further the findings of previous reports by suggesting that breathing disturbances associated with hyperventilation may play a role in MPA prior to going on stage. Experimental studies are needed to confirm whether hyperventilation complaints associated with negative feelings of MPA manifest themselves at the physiological level. (C) 2010 Elsevier Inc. All rights reserved.

Simultaneous determination of antidementia drugs in human plasma: Procedure transfer from HPLC-MS to UPLC-MS/MS.

A previously developed high performance liquid chromatography mass spectrometry (HPLC-MS) procedure for the simultaneous determination of antidementia drugs, including donepezil, galantamine, memantine, rivastigmine and its metabolite NAP 226-90, was transferred to an ultra performance liquid chromatography system coupled to a tandem mass spectrometer (UPLC-MS/MS). The drugs and their internal standards ([(2)H(7)]-donepezil, [(13)C,(2)H(3)]-galantamine, [(13)C(2),(2)H(6)]-memantine, [(2)H(6)]-rivastigmine) were extracted from 250μL human plasma by protein precipitation with acetonitrile. Chromatographic separation was achieved on a reverse phase column (BEH C18 2.1mm×50mm; 1.7μm) with a gradient elution of an ammonium acetate buffer at pH 9.3 and acetonitrile at a flow rate of 0.4mL/min and an overall run time of 4.5min. The analytes were detected on a tandem quadrupole mass spectrometer operated in positive electrospray ionization mode, and quantification was performed using multiple reaction monitoring. The method was validated according to the recommendations of international guidelines over a calibration range of 1-300ng/mL for donepezil, galantamine and memantine, and 0.2-50ng/mL for rivastimgine and NAP 226-90. The trueness (86-108%), repeatability (0.8-8.3%), intermediate precision (2.3-10.9%) and selectivity of the method were found to be satisfactory. Matrix effects variability was inferior to 15% for the analytes and inferior to 5% after correction by internal standards. A method comparison was performed with patients' samples showing similar results between the HPLC-MS and UPLC-MS/MS procedures. Thus, this validated UPLC-MS/MS method allows to reduce the required amount of plasma, to use a simplified sample preparation, and to obtain a higher sensitivity and specificity with a much shortened run-time.

First nationwide study on driving under the influence of drugs in Switzerland.

In Switzerland, a two-tier system based on impairment by any psychoactive substances which affect the capacity to drive safely and zero tolerance for certain illicit drugs came into force on 1 January 2005. According to the new legislation, the offender is sanctioned if Delta(9)-tetrahydrocannabinol THC is >or=1.5ng/ml or amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyethylamphetamine (MDEA), cocaine, free morphine are >or=15ng/ml in whole blood (confidence interval+/-30%). For all other psychoactive substances, impairment must be proven in applying the so-called "three pillars expertise". At the same time the legal blood alcohol concentration (BAC) limit for driving was lowered from 0.80 to 0.50g/kg. The purpose of this study was to analyze the prevalence of drugs in the first year after the introduction of the revision of the Swiss Traffic Law in the population of drivers suspected of driving under the influence of drugs (DUID). A database was developed to collect the data from all DUID cases submitted by the police or the Justice to the eight Swiss authorized laboratories between January and December 2005. Data collected were anonymous and included the age, gender, date and time of the event, the type of vehicle, the circumstances, the sampling time and the results of all the performed toxicological analyses. The focus was explicitly on DUID; cases of drivers who were suspected to be under the influence of ethanol only were not considered. The final study population included 4794 DUID offenders (4243 males, 543 females). The mean age of all drivers was 31+/-12 years (range 14-92 years). One or more psychoactive drugs were detected in 89% of all analyzed blood samples. In 11% (N=530) of the samples, neither alcohol nor drugs were present. The most frequently encountered drugs in whole blood were cannabinoids (48% of total number of cases), ethanol (35%), cocaine (25%), opiates (10%), amphetamines (7%), benzodiazepines (6%) and methadone (5%). Other medicinal drugs such as antidepressants and benzodiazepine-like were detected less frequently. Poly-drug use was prevalent but it may be underestimated because the laboratories do not always analyze all drugs in a blood sample. This first Swiss study points out that DUID is a serious problem on the roads in Switzerland. Further investigations will show if this situation has changed in the following years.

Changes over time in risk factors for cardiovascular disease and use of lipid-lowering drugs in HIV-infected individuals and impact on myocardial infarction.

BACKGROUND: Because of the known relationship between exposure to combination antiretroviral therapy and cardiovascular disease (CVD), it has become increasingly important to intervene against risk of CVD in human immunodeficiency virus (HIV)-infected patients. We evaluated changes in risk factors for CVD and the use of lipid-lowering therapy in HIV-infected individuals and assessed the impact of any changes on the incidence of myocardial infarction. METHODS: The Data Collection on Adverse Events of Anti-HIV Drugs Study is a collaboration of 11 cohorts of HIV-infected patients that included follow-up for 33,389 HIV-infected patients from December 1999 through February 2006. RESULTS: The proportion of patients at high risk of CVD increased from 35.3% during 1999-2000 to 41.3% during 2005-2006. Of 28,985 patients, 2801 (9.7%) initiated lipid-lowering therapy; initiation of lipid-lowering therapy was more common for those with abnormal lipid values and those with traditional risk factors for CVD (male sex, older age, higher body mass index [calculated as the weight in kilograms divided by the square of the height in meters], family and personal history of CVD, and diabetes mellitus). After controlling for these, use of lipid-lowering drugs became relatively less common over time. The incidence of myocardial infarction (0.32 cases per 100 person-years [PY]; 95% confidence interval [CI], 0.29-0.35 cases per 100 PY) appeared to remain stable. However, after controlling for changes in risk factors for CVD, the rate decreased over time (relative rate in 2003 [compared with 1999-2000], 0.73 cases per 100 PY [95% CI, 0.50-1.05 cases per 100 PY]; in 2004, 0.64 cases per 100 PY [95% CI, 0.44-0.94 cases per 100 PY]; in 2005-2006, 0.36 cases per 100 PY [95% CI, 0.24-0.56 cases per 100 PY]). Further adjustment for lipid levels attenuated the relative rates towards unity (relative rate in 2003 [compared with 1999-2000], 1.06 cases per 100 PY [95% CI, 0.63-1.77 cases per 100 PY]; in 2004, 1.02 cases per 100 PY [95% CI, 0.61-1.71 cases per 100 PY]; in 2005-2006, 0.63 cases per 100 PY [95% CI, 0.36-1.09 cases per 100 PY]). CONCLUSIONS: Although the CVD risk profile among patients in the Data Collection on Adverse Events of Anti-HIV Drugs Study has decreased since 1999, rates have remained relatively stable, possibly as a result of a more aggressive approach towards managing the risk of CVD.

Concomitant administration of intravenous drugs in the ICU: evaluation of physico-chemical compatibilities

Background and objective: Patients in the ICU often get many intravenous (iv) drugs at the same time. Even with three-lumen central venous catheters, the administration of more than one drug in the same iv line (IVL) is frequently necessary. The objective of this study was to observe how nurses managed to administer these many medications and to evaluate the proportion of two-drugs associations (TDA) that are compatible or not, based on known compatibility data. Design: Observational prospective study over 4 consecutive months. All patients receiving simultaneously more than one drugs in the same IVL (Y-site injection or mixed in the same container) were included. For each patient, all iv drugs were recorded, as well as concentration, infusion solution, location on the IVL system, time, rate and duration of administration. For each association of two or more drugs, compatibility of each drug was checked with each other. Compatibilities between these pairs of drugs were assessed using published data (mainly Trissel LA. Handbook on Injectable Drugs and Trissel's Tables of Physical Compatibility) and visual tests performed in our quality control laboratory. Setting: 34 beds university hospital adult ICU. Main outcome measures: Percentage of compatibilities and incompatibilities between drugs administered in the same IVL. Results: We observed 1,913 associations of drugs administered together in the same IVL, 783 implying only two drugs. The average number of drugs per IVL was 3.1 ± 0.8 (range: 2-9). 83.2% of the drugs were given by continuous infusion, 14.3% by intermittent infusion and 2.5% in bolus. The associations observed allowed to form 8,421 pairs of drugs (71.7% drug-drug and 28.3% drug-solute). According to literature data, 80.2% of the association were considered as compatible and 4.4% incompatible. 15.4% were not interpretable because of different conditions between local practices and those described in the literature (drug concentration, solute, etc.) or because of a lack of data. After laboratory tests performed on the most used drugs (furosemide, KH2PO4, morphine HCl, etc.), the proportion of compatible TDA raised to 85.7%, the incompatible stayed at 4.6% and only 9.7% remain unknown or not interpretable. Conclusions: Nurses managed the administration of iv medications quite well, as only less than 5% of observed TDA were considered as incompatible. But the 10% of TDA with unavailable compatibility data should have been avoided too, since the consequences of their concomitant administration cannot be predictable. For practical reasons, drugs were analysed only by pairs, which constitutes the main limit of this work. The average number of drugs in the same association being three, laboratory tests are currently performed to evaluate some of the most observed three-drugs associations.

Resistance of Candida spp. to antifungal drugs in the ICU: where are we now?

Current increases in antifungal drug resistance in Candida spp. and clinical treatment failures are of concern, as invasive candidiasis is a significant cause of mortality in intensive care units (ICUs). This trend reflects the large and expanding use of newer broad-spectrum antifungal agents, such as triazoles and echinocandins. In this review, we firstly present an overview of the mechanisms of action of the drugs and of resistance in pathogenic yeasts, subsequently focusing on recent changes in the epidemiology of antifungal resistance in ICU. Then, we emphasize the clinical impacts of these current trends. The emergence of clinical treatment failures due to resistant isolates is described. We also consider the clinical usefulness of recent advances in the interpretation of antifungal susceptibility testing and in molecular detection of the mutations underlying acquired resistance. We pay particular attention to practical issues relating to ICU patient management, taking into account the growing threat of antifungal drug resistance.

Newer antiepileptic drugs in the treatment of status epilepticus: Impact on prognosis.

Newer antiepileptic drugs (AEDs) are increasingly prescribed and seem to have a comparable efficacy as the classical AEDs; however, their impact on status epilepticus (SE) prognosis has received little attention. In our prospective SE database (2006-2010), we assessed the use of older versus newer AEDs (levetiracetam, pregabalin, topiramate, lacosamide) over time and its relationship to outcome (return to clinical baseline conditions, new handicap, or death). Newer AEDs were used more often toward the end of the study period (42% of episodes versus 30%). After adjustment for SE etiology, SE severity score, and number of compounds needed to terminate SE, newer AEDs were independently related to a reduced likelihood of return to baseline (p<0.001) but not to increased mortality. These findings seem in line with recent findings on refractory epilepsy. Also, in view of the higher price of the newer AEDs, well-designed, prospective assessments analyzing the impact of newer AEDs on efficacy and tolerability in patients with SE appear mandatory.