Multivariable analysis of total cholesterol levels in male Swiss Armed Forces conscripts 2006-2012 (N = 174,872).

BACKGROUND: Cholesterol is an important contributor to morbidity and mortality risks due to its association with obesity, cardiovascular disease, and cancer. A system of mandatory military conscription is a useful tool for disease-risk monitoring in a given male population. Swiss military conscription data are representative for more than 90% of a given male birth cohort (with Swiss citizenship). The medical examination also includes voluntary laboratory testing, for which approximately 65% of the young men present at conscription give consent. METHODS: Here we present the temporal and subgroup analyses of total serum cholesterol levels (TCL) among Swiss conscripts from 2006 to 2012 (N = 174,872; mean age = 19.75 years). The voluntary blood samples were tested by a central laboratory (Viollier AG) with identical measurement standards and strict quality control. To test differences in TCL by socioeconomic occupational status, sports test performance, Body Mass Index (BMI), age, and place of residence of the conscripts we used a multivariable regression model with TCL as dependent variable. RESULTS: Mean TCL decreased significantly, by 0.125 mmol/l (95% CI 0.108-0.142, p < 0.001) from 4.225 mmol/l (95% CI 4.210-4.240) in 2006 to 4.100 mmol/l (95% CI 4.091-4.109) in 2012. Similarly, the prevalence of conscripts with an elevated TCL ≥ 5.17 mmol/l decreased from ≥ 10.2% prior to 2011 to 6.9% in 2011 and 8.2% in 2012. Multivariate regression showed an association between elevated TCL and lower socioeconomic occupational status, lower sports test performance, higher BMI, higher age, and area of residence. There was no longer a significant increase in mean TCL among the three grades of obesity (BMI ≥ 30.0 kg/m2) as defined by the WHO. Within the BMI categories of normal weight and overweight, TCL was stratified by sports performance (better sports performance = lower TCL). CONCLUSION: Decreasing TCL in 2011 and 2012 fits the known pattern of conscripted persons' stabilizing BMI and sports test performance of the conscripts in recent years. However, small temporal drifts within the laboratory analyses cannot be ruled out as confounding factors. In conclusion, identifying subgroups with unfavorable lipid profiles will contribute to the continuing success of intensified public health programs.

Therapeutic drug monitoring of once daily aminoglycoside dosing: comparison of two methods and investigation of the optimal blood sampling strategy.

PURPOSE: Therapeutic drug monitoring of patients receiving once daily aminoglycoside therapy can be performed using pharmacokinetic (PK) formulas or Bayesian calculations. While these methods produced comparable results, their performance has never been checked against full PK profiles. We performed a PK study in order to compare both methods and to determine the best time-points to estimate AUC0-24 and peak concentrations (C max). METHODS: We obtained full PK profiles in 14 patients receiving a once daily aminoglycoside therapy. PK parameters were calculated with PKSolver using non-compartmental methods. The calculated PK parameters were then compared with parameters estimated using an algorithm based on two serum concentrations (two-point method) or the software TCIWorks (Bayesian method). RESULTS: For tobramycin and gentamicin, AUC0-24 and C max could be reliably estimated using a first serum concentration obtained at 1 h and a second one between 8 and 10 h after start of the infusion. The two-point and the Bayesian method produced similar results. For amikacin, AUC0-24 could reliably be estimated by both methods. C max was underestimated by 10-20% by the two-point method and by up to 30% with a large variation by the Bayesian method. CONCLUSIONS: The ideal time-points for therapeutic drug monitoring of once daily administered aminoglycosides are 1 h after start of a 30-min infusion for the first time-point and 8-10 h after start of the infusion for the second time-point. Duration of the infusion and accurate registration of the time-points of blood drawing are essential for obtaining precise predictions.

Effects of the α2-adrenergic agonist clonidine on the pharmacodynamics and pharmacokinetics of 3,4-methylenedioxymethamphetamine in healthy volunteers.

The mechanism of action of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) involves the carrier-mediated and potentially vesicular release of monoamines. We assessed the effects of the sympatholytic α2-adrenergic receptor agonist clonidine (150 µg p.o.), which inhibits the neuronal vesicular release of norepinephrine, on the cardiovascular and psychotropic response to MDMA (125 mg p.o.) in 16 healthy subjects. The study used a randomized, double-blind, placebo-controlled crossover design with four experimental sessions. The administration of clonidine 1 h before MDMA reduced the MDMA-induced increases in plasma norepinephrine concentrations and blood pressure but only to the extent that clonidine lowered norepinephrine levels and blood pressure compared with placebo. Thus, no interaction was found between the cardiovascular effects of the two drugs. Clonidine did not affect the psychotropic effects or pharmacokinetics of MDMA. The lack of an interaction of the effects of clonidine and MDMA indicates that vesicular release of norepinephrine, which is inhibited by clonidine, does not critically contribute to the effects of MDMA in humans. Although clonidine may be used in the treatment of stimulant-induced hypertensive reactions, the present findings do not support a role for α2-adrenergic receptor agonists in the prevention of psychostimulant dependence.

The effect of clonidine on perioperative blood coagulation.

STUDY OBJECTIVE: To evaluate the influence of perioperative stress protection by clonidine on blood coagulation. DESIGN: Prospective, randomized, double-blinded, placebo-controlled clinical trial. SETTING: University hospital. PATIENTS: 50 patients scheduled for elective gynecoabdominal surgery. INTERVENTIONS AND MEASUREMENTS: Patients were randomly assigned to control (placebo) or clonidine group (single intravenous clonidine dose; 4 microg/kg(-1) or 3 microg/kg(-1) for age >65 years). Three measurement time points were defined: before administration of placebo/clonidine and anesthesia induction, (t1; baseline measurement); after surgery, before emergence of anesthesia (t2); and at the first postoperative day, 24 hours after anesthesia induction (t3). Blood coagulation was analyzed at all time points measuring international normalized ratio, platelets, thrombin-antithrombin complex, von Willebrand factor, soluble thrombomodulin, d-dimers, plasminogen activator inhibitor 1, and Thrombelastograph analysis. MAIN RESULTS: In the postoperative period (t2, t3), hypercoagulability was present in all patients compared with baseline measurements (t1) but without differences between the control and clonidine group. Regarding hematologic, laboratory blood coagulation, and Thrombelastograph parameters, there was no statistically and clinically relevant difference throughout the study period between the 2 groups. No hemodynamic adverse events of clonidine were observed in the perioperative period. Until day of discharge, no thrombotic or thromboembolic events were reported in both groups. CONCLUSIONS: Preoperative administration of a single dose of clonidine has no effect on perioperative blood coagulation.

Acute cocaine-related health problems in patients presenting to an urban emergency department in Switzerland: a case series.

BACKGROUND: Emergency departments may be a useful information source to describe the demographics and clinical characteristics of patients with acute cocaine-related medical problems. We therefore conducted a retrospective analysis of 165 acute, laboratory-confirmed cocaine intoxications admitted to an urban emergency department in Switzerland between January 2007 and March 2011. RESULTS: A total of 165 patients with a mean age of 32 years were included. Most patients were male (73%) and unemployed (65%). Only a minority (16%) had abused cocaine alone while 84% of the patients had used at least one additional substance, most commonly ethanol (41%), opioids (38%), or cannabis (36%) as confirmed by their detection in blood samples. The most frequently reported symptoms were chest pain (21%), palpitations (19%), anxiety (36%) and restlessness (36%). Psychiatric symptoms were present in 64%. Hypertension and tachycardia were observed in 53% and 44% of the patients, respectively. Severe poisonings only occurred in patients with multiple substance intoxication (15%). Severe intoxications were non-significantly more frequent with injected drug use compared to nasal, oral, or inhalational drug use. Severe complications included acute myocardial infarction (2 cases), stroke (one case), and seizures (3 cases). Most patients (75%) were discharged home within 24 h after admission. A psychiatric evaluation in the ED was performed in 24% of the patients and 19% were referred to a psychiatric clinic. CONCLUSIONS: Patients with acute cocaine intoxication often used cocaine together with ethanol and opioids and presented with sympathomimetic toxicity and/or psychiatric disorders. Severe acute toxicity was more frequent with multiple substance use. Toxicity was typically short-lasting but psychiatric evaluation and referral was often needed.

Pharmacokinetics and pharmacodynamics of recombinant human angiotensin-converting enzyme 2 in healthy human subjects.

BACKGROUND AND OBJECTIVES: Angiotensin-converting enzyme 2 (ACE2) converts angiotensin II (Ang1-8) to angiotensin 1-7 (Ang1-7), a functional antagonist of Ang1-8, with vasodilatory, antiproliferative, antiangiogenic, and anti-inflammatory properties. In conditions with an unbalanced renin-angiotensin-aldosterone system with elevated Ang1-8, administration of ACE2 has shown promising effects in a variety of animal models. Enhancing ACE2 activity by exogenous administration of ACE2 might also be beneficial in human diseases with pathologically elevated Ang1-8. As a first step we performed a first-in-man study to determine pharmacokinetics, pharmacodynamics, safety, and tolerability of recombinant ACE2 in healthy volunteers. METHODS: Recombinant human ACE2 (rhACE2) was administered intravenously to healthy human subjects in a randomized, double-blind, placebo-controlled, single-dose, dose-escalation study followed by an open-label multiple-dose study. ACE2 concentrations were determined by quantifying ACE2 activity and ACE2 content in plasma samples. Concentrations of the angiotensin system effector peptides Ang1-8, Ang1-7, and Ang1-5 were determined using a liquid chromatography-tandem mass spectrometry method. RESULTS: Single rhACE2 doses of 100-1,200 µg/kg caused a dose-dependent increase of systemic exposure with biphasic elimination and a dose-independent terminal half-life of 10 h. In all single-dose cohorts, Ang1-8 decreased within 30 min postinfusion, angiotensin 1-7 (Ang1-7) either increased (100 and 200 µg/kg doses), decreased, or remained unchanged (400-1,200 µg/kg doses), whereas angiotensin 1-5 (Ang1-5) transiently increased for all doses investigated. With the exception of the lowest rhACE2 dose, the decrease in Ang1-8 levels lasted for at least 24 h. Repeated dosing (400 µg/kg for 3 or 6 days) caused only minimal accumulation of ACE2, and Ang1-8 levels were suppressed over the whole application period. CONCLUSIONS: Administration of rhACE2 was well tolerated by healthy human subjects. Exposure was dose dependent with a dose-independent terminal elimination half-life in the range of 10 h. Despite marked changes in angiotensin system peptide concentrations, cardiovascular effects were absent, suggesting the presence of effective compensatory mechanisms in healthy volunteers.

Severe toxicity due to injected but not oral or nasal abuse of methylphenidate tablets.

BACKGROUND: Non-medical use of methylphenidate is increasing. Little is known about potential acute medical complications associated with recreational use of methylphenidate. STUDY AIM: To identify medical problems associated with methylphenidate abuse. METHODS: Retrospective case series of methylphenidate abuse cases presenting to an inner city emergency department. RESULTS: We identified 14 cases of methylphenidate abuse between 2003 and 2010. Ten of these patients abused methylphenidate alone while four co-ingested other drugs, mainly alcohol. The route of ingestion was oral in nine patients, nasal in one and intravascular in four. Severe toxicity was exclusively observed in users who injected the drug. Two cases involved accidental intra-arterial injection and resulted in tissue necrosis leading to the amputation of a forearm and of fingertips, respectively. Clinical findings in the non-serious cases included mild to moderate symptoms and signs of sympathetic nervous stimulation such as agitation, tachycardia, hypertension, anxiety, hallucination, headache, tremor and dizziness. Nine of the fourteen patients were taking methylphenidate as a prescribed drug. Eight patients were former or current multiple substance abusers. CONCLUSION: Methylphenidate misuse is not a significant burden for emergency departments in Switzerland. Oral and nasal administration of methylphenidate did not result in severe toxicity. However, injection of crushed methylphenidate pills lead to serious local toxicity. Most patients with methylphenidate abuse had a prescription for the drug indicating deviation from medical use. A history of multiple substance use may be a risk factor for non-medical use of methylphenidate.

Retrospective analysis of stimulant abuse cases reported to the Swiss Toxicological Information Centre during 1997-2009.

STUDY AIM: To describe characteristics of stimulant abuse and toxicity. METHOD: We conducted a retrospective analysis of cases of exposure to cocaine, amphetamines (amphetamine, methamphetamine, and 3,4-methylenedioxymethamphetamine [MDMA]) and methylphenidate reported to the Swiss Toxicological Information Centre between 1997 and 2009. RESULTS: There were 667 reports for cocaine, 147 for amphetamine, 41 for methamphetamine, 433 for MDMA, and 122 for methylphenidate. Detailed outcome data were available in 546 (39%) of all reported cases. Exposure to amphetamine or MDMA commonly resulted in mild to moderate toxicity, but severe toxicity was seen in approximately 15% of reported cocaine and MDMA exposures with a known medical outcome. Frequently observed clinical signs and symptoms included tachycardia, arterial hypertension, nausea, agitation, and panic. Amphetamine and MDMA exposures were seen in a younger population and were mainly reported at weekends, while cocaine users were older and exposures occurred proportionally more frequently on weekdays. Parenteral drug use and co-use of heroin was more frequent in cocaine users than in those using other stimulants. There has been an increase in reports of non-medical use of methylphenidate in recent years, indicating a need for further studies of abuse of prescription stimulants. CONCLUSION: Stimulant abuse is associated with major toxicity in approximately 15% of reported cases with a known medical outcome. Amphetamine and MDMA users differed from cocaine users in terms of user characteristics, time of use and medical complications. Non-medical use of prescription stimulants such as methylphenidate needs attention.