[The development of the methods for the extraction, identification, and quantitative determination of alimemazine in the biological fluids from the laboratory animals under the acute poisoning conditions]. / Razrabotka metodik izolirovaniia, obnaruzheniia i kolichestvennogo opredeleniia alimemazina v biologicheskikh zhidkostiakh laboratornykh zhivotnykh pri ostrykh otravleniiakh.

There is the present-day tendency toward prescribing atypical neuroleptics for the management of neurologic and psychic disorders. Alimemazine appears to be very frequently used for this purpose due to the broad spectrum of its actions. At the same time, cases of alimemazine poisoning with the fatal outcome have been described. The objective of the present study was determine alimemazine in the biological fluids from the laboratory animals under the acute poisoning conditions. The experiments were carried with the use of the Wistar rats having 200 g body weight. Alimemazine was isolated from their biological fluids (blood plasma and urine) using the liquid-liquid extraction techniques developed specially for the purpose of this study. Alimemazine was extracted and quantitatively determined by HPLC and HPLC/MS. The method for the isolation of alimemazine from the urine and blood plasma is described. The results of the study give evidence that the maximum amount of the substance of interest can be extracted from the blood plasma within 1 hour after the administration of the toxic dose of alimemazine and within 2 hours after the administration of its therapeutic dose. The maximum amount of alimemazine in the urine is found within 3 hours after the administration of its therapeutic dose to the laboratory animals. It is concluded that the proposed methods for the extraction of alimemazine from the biological fluids can be included in the scheme of the chemical toxicological analysis of this substance.

Alimemazine poisoning as evidence of Munchausen syndrome by proxy: A pediatric case report.

Munchausen syndrome by proxy (MSBP), also known as fabricated or induced illness in a child by a caretaker, is a form of abuse where a caregiver deliberately produces or feigns illness in a person under his or her care, so that the proxy will receive medical care that gratifies the caregiver. The affected children are often hospitalized for long periods and endure repetitive, painful and expensive diagnostic attempts. We present an analytically confirmed case of MSBP by alimemazine. A 3-year-old boy was brought repetitively to a Pediatric Emergency Department by his mother because he presented limb tremors, dysarthria, obnubilation, and ataxia and generalized tonic-clonic seizures coinciding with intermittent fever. Neither the rest of the physical examination nor the complementary tests showed any significant alterations. MSBP was suspected and a routine systematic toxicological analysis in urine and blood was requested. Alimemazine was detected in all biological samples. The administration of this drug was never mentioned by the mother and the subsequent interview with her corroborated the suspicion of MSBP. Clinically, after separation from the mother, the child's neurological symptoms gradually improved until the complete disappearance of the cerebellar symptoms. Alimemazine was quantified in serum, urine, gastric content and cerebrospinal fluid samples by gas chromatography-mass spectrometry (maximum serum level was 0.42µg/ml). Hair quantification of alimemazine was performed by ultra-performance liquid chromatography-tandem mass spectrometry in different segments of hair. The results confirmed regular substance use during the at least eight last months (8.8, 14.7, 19.7 and 4.6ng/mg hair starting from most proximal segment). This patient represents the first case published with analytical data of alimemazine in blood, urine, gastric content, cerebrospinal fluid and hair, which allowed us to prove an acute and repetitive poisoning with alimemazine as evidence of MSBP.

A new method for quantitative determination of dimemorfan in human plasma using monolithic silica solid-phase extraction tips.

Dimemorfan was extracted from human plasma samples (100 µL) using MonoTip C(18) tips, which were packed with a C(18)-bonded monolithic silica gel attached to the inside of the tip. The samples, which contained dimemorfan and trimeprazine as an internal standard (IS), were mixed with 300 µL of distilled water and 50 µL of 1M glycine-sodium hydroxide buffer (pH 10). The mixture was extracted onto the C(18) phase of the tip by 20 sequential aspirating/dispensing cycles using a manual micropipettor. The analytes retained on the C(18) phase were then eluted with methanol by five sequential aspirating/dispensing cycles. The eluate was injected directly into a gas chromatograph and detected by a mass spectrometer with selected ion monitoring in positive electron ionization mode. An Equity-5 fused silica capillary column (30 m × 0.32 mm i.d., film thickness 0.25 µm) gave adequate separation of the dimemorfan, IS, and impurities. The recoveries of dimemorfan and the IS spiked into plasma were ≥83%. The regression equation for dimemorfan showed excellent linearity from 0.25 to 32.0 ng/100 µL of plasma, and the limit of detection was 0.125 ng/100 µL of plasma. The maximum intra-day and inter-day relative standard deviations were 13%, while accuracy ranged from 88% to 105%. Dimemorfan was stable for at least 12 h at 4°C, 4 weeks at -80°C, and three freeze-thaw cycles in plasma. This new method is expected to have application as a pretreatment for the rapid, simple, and quantitative determination of dimemorfan in plasma samples.

Determination of trimeprazine-facilitated sedation in children by hair analysis.

Trimeprazine or alimemazine is largely used as an antipruritic agent, but it is also used for insomnia, cough, and oral premedication in pediatric day surgery. The first cases involving repetitive sedation linked to the use of trimeprazine as a drug-facilitated crime and subsequent impairment of two children are reported. Because of the long delay between the alleged crime and clinical examination, collection of blood or urine was of little value. This is the reason why the laboratory developed an original approach based on hair testing by liquid chromatography-tandem mass spectrometry. A strand of hair from each child was sampled about 2 months after the first suspicion of administration and was cut into small segments. After cutting into small pieces, 20 mg of hair was incubated overnight in a phosphate buffer (pH 8.4). The aqueous phase was extracted by 5 mL of a mixture of diethyl ether/methylene chloride (80:20) in presence of diazepam-d(5) used as the internal standard (IS). Hair extract was separated on a XTerra MS C18 column using a gradient of acetonitrile and formate buffer. Detection was based on two daughter ions: transitions m/z 299.3 to 299.0 and 100.0 and m/z 289.9 to 154.0 for trimeprazine and the IS, respectively. In the hair of the two subjects, trimeprazine was detected at concentrations in the range 23 to 339 pg/mg. The stepmother, who was the perpetrator in both cases, did not challenge the use of trimeprazine as a sedative drug.

Acute fatal poisoning with cyamemazine.

A case of fatal poisoning with cyamemazine is presented. The cyamemazine was identified in post-mortem blood using a specific gas chromatographic/mass spectrometry method. The autopsy blood concentration of cyamemazine was 1800 ng/ml. Chronic use of cyamemazine was demonstrated by the presence of the drug in hair. Two other drugs were also detected (bromazepam and trimeprazine). We think that this current blood concentration (1800 ng/ml) is a fatal blood concentration because of the negativity of the other parameters, but careful interpretation of analytical findings are important, the possibility that this death was a consequence of the toxicity of combined drugs could not be excluded. Not many therapeutics and toxic levels were previously reported in overdosage cases in which cyamemazine was involved. We consider that this concentration is only of guidance value for a fatal cyamemazine poisoning.

In vitro and in vivo study of the antithyroid side effects of trimeprazine.

Trimeprazine (TMP), a phenothiazine used as antipsychotic drug, was previously shown to induce a decrease in thyroid hormone serum levels in rats. Different mechanisms might be involved, mainly (i) a central mechanism, involving a reduction of thyroid-stimulating hormone (TSH) secretion; (ii) a peripheral mechanism, acting upon the synthesis of thyroid hormones, by inhibition of thyroperoxidase (TPO) or trapping of molecular iodine present in the thyroid gland. These different hypotheses were investigated in the present study, using in vitro and in vivo experiments. In vitro studies concerned TMP and its three main metabolites: trimeprazine sulphoxide (TSO), N-desmethyl trimeprazine (NDT), and 3-hydroxy-trimeprazine (3-OHT). TMP and TSO expressed a high affinity for iodine in vitro, contrary to NDT, which did not complex iodine. Only 3-OHT inhibited TPO in vitro. Administration of 5 mg/kg TMP ip twice daily for 11 days to Wistar rats induced a decrease of free triiodothyronine and free thyroxine (fT(3) and fT(4)) and a trend toward an increase of TSH serum levels. Thyroid concentrations of TMP, NDT, and TSO were significantly higher than serum levels, while 3-OHT was never detected. An iodine-supplemented diet administered to a group of rats treated with TMP significantly increased the thyroid concentration of TMP and TSO, but not that of NDT, while it did not affect the concentrations observed in serum and other organs. The increase in plasma TSH is not consistent with the central mechanism hypothesis, and the absence of TPO inhibition by TMP, TSO, and NDT contradicts the TPO inhibition hypothesis. On the contrary, three findings support the hypothesis of iodine trapping through formation of a complex with TMP and TSO: these molecules complex iodine in vitro, they accumulate in the thyroid, and their thyroid concentration is increased when the rats are fed an iodine-supplemented diet.

Fly larvae: a new toxicological method of investigation in forensic medicine.

Toxicological analyses on a putrefied cadaver are sometimes difficult to achieve because of the absence of blood and urine. In this study, maggots, living material, are proposed as a new medium of investigation in forensic medicine. Five drugs (triazolam, oxazepam, phenobarbital, alimemazine, and clomipramine) were identified and assayed in some tissues of a putrefied cadaver and in the maggots found on and in the body.

On-line recovery of trimeprazine enantiomers following chiral separation by reversed-phase high-performance liquid chromatography using a beta-cyclodextrin-containing mobile phase.

A procedure is described which allows the on-line recovery of enantiomers following semi-preparative chiral separation by RP-HPLC using beta-cyclodextrin in the mobile phase. By this method, the phenothiazine antihistamine trimeprazine (I) was resolved into its antipodes at greater than 95% optical purity at a throughput of more than 1 mg of each enantiomer per hour, using 4 mm i.d. columns. The recovered trimeprazine was found to be free from cyclodextrin.