Suicide due to cyclizine overdose.

Cyclizine is an antihistamine with sedative effect used to treat motion sickness. A few studies have reported on cyclizine abuse among teenagers, and cyclizine abuse has been reported among opioid dependants receiving methadone, with the combination having been reported to produce strong psychoactive effects. Few reports exist on the possible toxic effects of cyclizine, and it is regarded as a safe drug most often sold as a non-prescription/over-the-counter drug. Very few cases of fatalities resulting from cyclizine overdose can be found in the literature. We present a case where a 22-year-old female was found unconscious and intoxication with drugs and alcohol was suspected. Whole blood from the femoral vein, urine and stomach content were collected during autopsy and screened for drugs of abuse and medicinal drugs. GC-MS screening of the stomach contents revealed presence of cyclizine and meclozine. Cyclizine and meclozine concentrations in blood were determined using a UPLC-MS-MS method. Quantification of femoral blood revealed a high concentration of cyclizine (16 mg/L), a low concentration of meclozine (0.2 mg/L) and ethanol 0.16 g/dL. No other medicinal drugs or drugs of abuse were detected. We report on a case of suicide where cyclizine was found to be the principal drug and question the safety of this drug.

The pharmacokinetics and pharmacogenetics of the antiemetic cyclizine in palliative care patients.

CONTEXT: Cyclizine, an antihistaminic antiemetic, is commonly used in palliative care. Its pharmacokinetics have been poorly studied, and its metabolic pathway is unknown but may involve the genetically controlled cytochrome P450 2D6 (CYP2D6). If this is the case, the metabolic ratio of cyclizine to norcyclizine and efficacy/adverse effects may vary between patients according to their CYP2D6 genotype. OBJECTIVES: To deduce the pharmacokinetics and antiemetic/sedative effects of cyclizine and relate these and its metabolic ratio to the CYP2D6 genotype in palliative care patients. METHODS: Palliative care patients initiated on continuous cyclizine subcutaneous (SC) infusions had blood samples taken and efficacy/toxicity scores measured during the approach to steady state. Another group of patients at steady state receiving oral cyclizine had a single blood sample taken. Samples were analyzed to elucidate pharmacokinetic parameters and CYP2D6 genetics. RESULTS: SC dosing group: The median (interquartile range) cyclizine half-life, volume of distribution, and clearance were 13 (7-48) hours, 23 (12-30)L/kg, and 15 (11-26)mL/min/kg, respectively. Nausea and sedation scores were 3.0 (1.2-5.7) and 5.0 (2.6-8.1), respectively, overall and did not vary with genotype (P=0.76 and 0.11, respectively). The median overall metabolic ratio at steady state was 4.9 (3.8-9.2) and did vary with CYP2D6 genotype (P=0.02). Oral dosing group: The median metabolic ratio was 2.1 (1.5-2.9) and did not vary with CYP2D6 genotype (P=0.37). CONCLUSION: Palliative care patients have similar cyclizine pharmacokinetics to those reported in other patient groups. Cyclizine metabolism to norcyclizine may include CYP2D6 as the metabolic ratio varied with CYP2D6 genotype in the SC group.

Quantification of cyclizine and norcyclizine in human plasma by liquid chromatography-tandem mass spectrometry (LC-MS/MS).

A rapid and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed and validated for quantification of cyclizine and its main metabolite norcyclizine in human plasma. Samples were prepared by protein precipitation with acetonitrile and cinnarizine was used as internal standard (recovery >87%). The analytes were eluted from a C8 50 mm×2.0 mm analytical column using a linear gradient of methanol and 0.05% formic acid with a total analysis time of 4 min. Analytes were detected by MS/MS using electrospray ionisation in the positive mode with multiple reactions monitoring (MRM) of the precursor ion/product ion transitions 267.2/167.2 for cyclizine and 253.2/167.2 for norcyclizine. Matrix effects were negligible. Standard curves for cyclizine and norcyclizine were linear (r(2)≥0.996) over the range 2-200 ng/mL, with 2 ng/mL representing the lower limit of quantification. Relative standard deviations were <14% for intra- and inter-day precision and the accuracy was within ±8%. The assay was successfully applied to a clinical study.

Application of adsorptive voltammetry for the detection of sub-nano molar cyclizine in biological fluids and tablets using fast Fourier transform continuous cyclic voltammetry in a flowing system.

An easy and fast Fourier transform continuous cyclic voltammetric technique (FFTCV) for monitoring of ultra trace amounts of cyclizine in a flow-injection system has been introduced in this work. The potential waveform, which was applied continuously on an Au disk microelectrode (12.5 microm in radius) consisted of the potential steps for cleaning, accumulation and potential ramp. The proposed detection method has some advantages, the greatest of which are as follows: first, it is no longer necessary to remove oxygen from the analyte solution and second, this is a very fast and appropriate technique for determination of the drug compound in a wide variety of chromatographic analysis methods. The detection limit for cyclizine was 1.8 ng ml(-1). The relative standard deviation (RSD) of the proposed technique at 5.0 x 10(-7) was 2.0 for 10 runs. The influences of pH of eluent, accumulation potential, sweep rate, and accumulation time on the determination of the cyclizine were considered. The proposed method was applied to the determination of cyclizine in a pharmaceutical preparation.

An LC-MS-MS method for the determination of cyclizine in human serum.

Cyclizine is a piperazine derivative with anti-emetic activity that is useful in the prevention and treatment of nausea and vomiting associated with motion sickness. A liquid chromatography-tandem mass spectrometry (LC-MS-MS) method is presented for the quantitation of cyclizine in serum. Sample pretreatment involved liquid-liquid extraction of 200 microl of serum with dichloromethane after the addition of 100 microl each of ammonium hydroxide and internal standard solutions. The extracts were analyzed by HPLC on a Luna C18 reversed-phase column and an ion-trap mass spectrometer with an electrospray interface. A limit of detection of 1 ng/ml was determined which allowed for the reliable measurement of cyclizine in the serum of human subjects. The method was found to be linear over the calibration range of 2.5-100 ng/ml. The applicability of this method was demonstrated by the analysis of serum obtained from a human volunteer following administration of a single 50 mg cyclizine hydrochloride tablet. The reported method was observed to have the necessary sensitivity, selectivity, precision and accuracy for monitoring cyclizine concentrations in human subjects following oral administration.

Sensitive high-performance liquid chromatographic determination of cyclizine and its demethylated metabolite, norcyclizine, in biological fluids using coulometric detection.

An accurate, sensitive, selective and reproducible high-performance liquid chromatographic method with coulometric detection for the determination of cyclizine and its inactive demethylated metabolite, norcyclizine, in biological fluids has been developed. The drugs were separated using a custom packed reversed-phase C18 analytical column and phosphate buffer (0.05 M, pH 3)-acetonitrile (7:3) as mobile phase. The dual electrode coulometric detector was operated in the "oxidative-screen" mode with the upstream electrode (detector 1) set at 0.55 V and the downstream electrode (detector 2) set at 0.90 V. Serum and urine samples were prepared for analysis by solid-phase extraction, followed by a simple phase-separation step. The limit of quantitation was 1 ng/ml for both cyclizine and norcyclizine in serum and urine.

Enantioselective pharmacokinetics of homochlorcyclizine: disposition of (+)- and (-)-homochlorcyclizine after intravenous and oral administration of racemic homochlorcyclizine to rats.

Concentrations of homochlorcyclizine enantiomers in blood, urine, and tissues of the liver, lung, kidney, brain, heart, spleen, intestine and stomach of rats after drug administration were determined by high-performance liquid chromatography on a chiral stationary phase. After intravenous administration (10 mg kg-1), homochlorcyclizine was rapidly distributed in many tissues, with the highest concentration in lung. No differences were found between enantiomers in blood concentrations. After oral administration (50 mg kg-1), the concentrations of the (+)-isomer in nearly all tissues were higher than those of the (-)-isomer. The AUC0-infinity values of the (+)- and (-)-isomers differed significantly. The absorption of racemic homochlorcyclizine from rat small intestine was not enantioselective. These results suggested that the different concentrations between enantiomers after oral administration were not caused by enantioselective absorption or distribution but rather by preferential first-pass metabolism of the (-)-isomer in the liver. The enantioselectivity of metabolism was also demonstrated by in-vitro experiments.

Enantioselective pharmacokinetics of homochlorcyclizine. II: Disposition and metabolism of (+)-, (-)- and racemic homochlorcyclizine after oral administration to man.

The pharmacokinetics of a single oral dose of 20 mg (+)-, (-)- and racemic homochlorcyclizine (HCZ) have been studied in humans. The formation of the quarternary ammonium-linked glucuronide was an important metabolic pathway, and the metabolic process was enantioselective as a result of differing urinary excretion rates of (+)-, (-)- and racemic glucuronide. There were significant differences between (+)-, (-)- and racemic HCZ in AUC (0-14 h) and plasma protein binding, but all HCZ enantiomers were slowly absorbed and eliminated (elimination half-lives about 11 h). The results shows help to establish a more efficient dosage regimen for HCZ therapy.

Fatality resulting from cyclizine overdose.

A case involving an overdose fatality of cyclizine is presented. Toxicological analysis revealed a cyclizine blood concentration of 80 micrograms/mL. The drug was quantified by gas chromatography/mass spectrometry (GC/MS). Qualitative analyses of urine and stomach contents were performed.

[Determination of dextromethorphan and its major metabolite dextrorphan by gas chromatography]. / Dosage du dextromethorphane et de son métabolite principal le dextrorphane par chromatographie gazeuse.

A gas chromatography assay has been developed for the determination of dextromethorphan and dextrorphan in human fluids. Drugs are extracted with chloroform-isopropanol-n-heptane (50/17/33, v/v) form alkalinized samples using cyclizine as an internal standard, analysed using a 3 p. cent OV-17 column, and detected by selective nitrogen detection. The lower detection limits are 0.4 and 0.7 micrograms/l for dextromethorphan and dextrorphan, respectively.

Blood and urine concentrations of cyclizine by nitrogen-phosphorus gas-liquid chromatography.

Gas-liquid chromatography with nitrogen-phosphorus detection was used to analyze blood and urine from a volunteer who ingested 50 mg of cyclizine hydrochloride. A peak blood cyclizine concentration of 69 ng/mL was observed 2 hr after drug administration, and the levels declined thereafter in a biphasic manner, with estimated half-lives of 7 and 24 hr for the early and late phases, respectively. The peak urine cyclizine concentration of 12.5 ng/mL was achieved at 4 hr after administration; only 0.01% of the dose was excreted in the 24 hr urine. Norcyclizine was not observed in blood or urine; however, the detectability of the method for this metabolite is poor relative to the parent drug.

Gas-liquid chromatographic determination of bupivacaine and lidocaine in plasma.

A modified gas-liquid chromatographic method for determining plasma concentrations of bupivacaine and lidocaine is described, with cyclizine as an internal standard. The extraction procedure requires no solvent evaporation, thus overcoming the problem of drug volatility. Concentrations as low as 0.1 mg/liter can be determined. The plasma sample is made alkaline and extracted into n-hexane, re-extracted into a small volume of an aqueous acid phase, and finally extracted into 50 microliter of methylene chloride after alkalinization. The final extract is assayed by gas chromatography on a 5% OV-17 column. The extraction scheme of the present method eliminates interferences by endogenous plasma constituents.