Prevalence of levamisole and aminorex in patients tested positive for cocaine in a French University Hospital

Abstract

Context. The prevalence of levamisole in urine samples of subjects positive for cocaine in the US was estimated at 78% (95%confidence interval or CI: 73%–83%). However, levamisole was not quantified, and at the time of this report, aminorex was not known to be a possible metabolite of levamisole in human. Moreover no data are available in Europe. Objective. The aim of this study was to determine the prevalence and concentration of levamisole and aminorex in positive cocaine urine toxicology tests, and in serum samples of cocaine-positive subjects driving under the influence of drugs or forensic autopsies. Materials and methods. Consecutive urine toxicology samples tested positive for cocaine by immunoassay (EMIT, Siemens) from April to May 2014 at the toxicology laboratory of a French University Hospital, and blood samples of cocaine-positive subjects driving under the influence of drugs or forensic autopsies from April to December 2014 were analyzed by liquid chromatography–tandem mass spectrometry or LC–MS/MS (3200 QTrap, AB Sciex) to detect and quantify the presence of levamisole and aminorex. Results. Forty-two urine samples tested positive for cocaine in 39 patients (79.5% males) with a median age of 43 [range: 20–51] years. Toxicological analyses were mainly required by addictions care centers (n = 17; 40%) in the context of the routine management of addict patients. Cocaine concentrations were above the limit of quantification for 33 patients, with a median value of 228 [0–645,000] ng/ml. Levamisole was detected in 32 urine samples (76%) (median concentration: 1,430 ng/ml, range: 30–258,000). Aminorex was never detected. During the study period, levamisole was detected in 87.5% of cocaine-positive blood samples of the subjects driving under the influence of drugs or forensic autopsies. Discussion. In this prospective study, the prevalence of levamisole in cocaine-positive samples was 76%. Over this period, although clinical complications related to cocaine use were reported (agitation, road accident, and cardiac arrest), no complication specifically related to levamisole or aminorex was reported. Conclusion. Our results show a high prevalence of levamisole in samples of subjects positive for cocaine, close to the prevalence found in the US. This high prevalence raises issues with respect to well-identified health risks associated with regular consumption of levamisole.     

甘肃省环境空气中222Rn及其子体水平

为评价甘肃省环境空气啐²²²Rn及其子体对公众的危害,我们用活性炭方法测量了全省1213个不同类型建筑物室内和217个室外空气中的²²²Rn浓度,用热释光剂量计测量了312个室内和44个室外空气峙²²²Rn浓度。结果表明: 室内、外²²²Rn浓度均呈对数正态分布,全省室内加权平²²²Rn浓度为39.3Bq·m^-3,室外为22.2Bq·m^-3,室内和室外氡及其子体问的平衡因子分别为0.38和0.54,公众室内居留因子为0.77,室内和室外²²²Rn子体的平均平衡当量浓度分别为14.9Bq·m^-3和12.0Bq·m^-3,公众年平均有效剂量当量为1.31mSv.     

The effect of various cardenolides and bufadienolides with different cardiac activity on the 86Rubidium uptake of human erythrocytes

Summary The inhibitory effect of 23 cardiac glycosides, genins and derivatives on the ⁸⁶Rb-uptake of human erythrocytes was measured. Proscillaridin and its acetates, methyl ethers and -epoxide were the most active inhibitors of ⁸⁶Rb-uptake, followed by ouabain, digitoxin and digoxin. Inhibition induced by genins occurred at concentrations distinctly higher than with the glycosides. Substances with 3--configuration were less active than those with 3--configuration.The glycoside concentrations exerting half maximal inhibition of ⁸⁶Rb-uptake were correlated with the minimum lethal doses in guinea pigs (r=0.71) and cats (r=0.75).     

The time-course of changes in renal tissue composition during lysine vasopressin infusion in the rat

Summary The corticomedullary osmolal gradient, largely dissipated by sustained water-diuresis, was progressively repleted by continuous i.v. ADH infusion (lysine-vasopressin, 15 mU/min/100 g body weight) in conscious rats for up to 41/2 hr.A marked increase in sodium content was essentially complete by 1/2 hr in the papillary tip; smaller, but more progressive increases occurred in the papillary base and inner medulla. Increases in medullary urea content occurred mainly in the first 21/2 hr, especially in the papillary tip. A progressive decrease in water content of all medullary segments was preceded by a significant papillary tip increase at 1/2 hr.Papillary tip-urine osmotic equilibration was slowly achieved after about 21/2 hr. The small, but significant, tip-urinary urea concentration difference of water diuresis was more rapidly replaced by a substantial difference in the reverse direction.It is concluded that the changes can be explained, adequately, by ADH-induced modifications in water and urea permeabilities of distal nephron segments and, possibly, by changes in inner medullary blood flow; that the evidence of direct ADH stimulation of sodium transport is inconclusive; and that there was no evidence of active urea transport.     

不同纯度和浓度橙皮苷对大鼠在体肠吸收比较研究

目的:比较研究不同纯度和浓度的橙皮苷在大鼠体肠吸收情况,初步探讨橙皮苷的吸收机理.方法:运用大鼠在体肠灌流模型,收集灌流流出液,并采用HPLC测定橙皮苷和酚红在灌流液中的浓度,对橙皮苷吸收特性进行研究.结果与结论:橙皮苷在大鼠肠道的吸收常数Ka随浓度的升高而显著降低(P<0.01),但纯度升高时Ka降低不显著(P>0.05);橙皮苷提取物中的共存成分可增加其吸收,吸收方式现可排除被动吸收,但有仍待于进一步研究.     

Fatal poisoning with verapamil

The toxicologic findings in a case of fatal poisoning with verapamil (Isoptin^®) are presented. For isolation of verapamil the biologic material was subjected to protein precipitation. The aqueous solutions were acidified with hydrochloric acid, prepurified by extraction with ether, and subsequently the basic drug verapamil was isolated by ion pair extraction with chloroform. Quantitative determination of verapamil was carried out by gas chromatography using a nitrogen specific flame ionization detector. The following concentrations of verapamil were measured: liver 5500 ng/g, kidney 2000 ng/g, blood 590 ng/g, urine 250 ng/g, gastric contents 3 mg (total). During examination by the police it was claimed by a witness that two tablets of Isoptin^® had been taken before death.After application of a therapeutic dose of Isoptin^® peak concentrations of 11 and 30 ng/g of blood cells and of 30 and 65 ng/g of plasma were measured in two healthy subjects; the latter figures corresponded well to previous findings of other authors, who investigated plasma concentrations of verapamil after therapeutic administration. In the case presented here, the blood concentration of 590 ng/g clearly demonstrated that an extreme overdose must have been taken before death.

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Zusammenfassung Es werden die Ergebnisse der toxikologischen Untersuchung bei einer tödlichen Vergiftung mit Verapamil (Isoptin^®) dargestellt. Die biologischen Materialien wurden wie folgt aufgearbeitet: Nach Eiweißfällung wurden die wäßrigen Lösungen mit Salzsäure angesäuert und durch Ätherextraktion vorgereinigt. Anschließend wurde das basische Verapamil durch Ionenpaarextraktion mit Chloroform isoliert. Die quantitative Bestimmung erfolgte durch Gaschromatographie mit Hilfe eines Stickstoff-spezifischen Flammenionisationsdetektors. Folgende Konzentrationen an Verapamil wurden bestimmt: Leber 5500 ng/g, Niere 2000 ng/g, Blut 590 ng/g, Urin 250 ng/g, Mageninhalt 3 mg (gesamt).Während der polizeilichen Vernehmung sagte ein Zeuge aus, daß vor dem Tod zwei Tabletten Isoptin eingenommen wurden.Nach Gabe einer therapeutischen Dosis Isoptin^® fanden sich bei zwei gesunden Versuchspersonen Maximalkonzentrationen von 11 und 30 ng/g Blutzellen und von 30 und 65 ng/g Blutplasma; die letzteren Zahlen stimmen gut überein mit Versuchsergebnissen anderer Autoren über die Plasmaspiegel nach therapeutischer Verapamilgabe. Die Blutkonzentration von 590 ng/g im vorliegenden Fall zeigt dagegen eindeutig, daß vor dem Tod Verapamil in extremer Überdosierung zur Anwendung gelangt sein muß.

     

Perphenazine concentrations in human whole blood

Perphenazine (PPZ) (Trilafon^®) has been studied in human whole blood under therapeutic conditions. By means of a new specific and highly sensitive gas Chromatographic method, concentrations of 0.2 g PPZ/l whole blood could be assayed with a sufficient degree of accuracy. In acutely psychotic patients the PPZ levels were studied after administration in three different ways: A) as single doses of PPZ given intramuscularly, B) as multiple doses of PPZ given orally, and C) as single doses of PPZ enanthate given intramuscularly. The highest PPZ concentration, 7.4 g/l, was measured in experiment C. Neurological side effects were registered, and their relation to blood concentrations of PPZ are briefly discussed.