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A simple and rapid method based on drop-to-drop solvent microextraction (DDSME) coupled with gas chromatography/mass spectrometry (GC/MS) has been successfully applied for the pharmacokinetic studies of trimeprazine in 8 microL of urine and blood samples of rats. Several factors that influenced the extraction efficiency of DDSME, such as selection of organic solvent, extraction time, exposure volume of organic phase, addition of salt and pH, were optimized. Linearity was obtained over the concentration ranges of 0.2-10, 0.25-7.0 and 0.5-6.0 microg/mL with correlation coefficients of 0.998, 0.996 and 0.993 in deionized water, urine and blood samples of rats, respectively. The limits of detection (LODs) of trimeprazine were 0.05, 0.06 and 0.1 microg/mL in deionized water, urine and blood samples. The concentrations of trimeprazine obtained in urine and blood samples of rats were 0.21-1.25 and 2.72-0.22 microg/mL, respectively, after a single intravenous administration of this drug. The enrichment factors and LOD values obtained by DDSME coupled to GC/MS were compared with those of hollow fiber liquid-phase microextraction (HF-LPME) combined with GC/MS. We believe that this novel approach can be very useful in clinical application since only one microdrop of biological samples was required to perform the pharmacokinetic studies from rats, so the sample pretreatments for animal experiments can be very easy too.

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Flumazenil is a competitive antagonist with specific action at the central benzodiazepine receptor. It is used when benzodiazepine intoxication is suspected. Its use has also been reported in cannabis intoxication, chloral hydrate overdose, hepatic encephalopathy, and alcohol intoxication. We report the case of a 7-month-old male infant with a depressed level of consciousness after intentional intoxication of antihistamines, whose mental status fully recovered after administration of flumazenil. To our knowledge, this is the first case in children where flumazenil has been reported to reverse antihistamine-induced coma.

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Alimemazine, a phenothiazine derivative with the properties of antihistamines, was determined by a selective high-performance liquid chromatographic technique in blood and tissues from a postmortem case. The blood concentration of alimemazine was 6.52 micrograms/mL. The brain was the major site of drug deposition, and tissue distribution is discussed in light of the existing literature.

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Fourteen phenothiazine derivatives were tested for their detection by gas chromatography (GC) with surface ionization detection (SID). The sensitivity of GC-SID was highest with trimeprazine and levomepromazine, which contain aliphatic tertiary amino side chains, and lowest with thiethylperazine and thioproperazine, which contain sulphur residues. Chlorpromazine, trimeprazine and promazine showed excellent linearity between the SID response and the drug amount in the range 0.25-3.0 pmol on-column. Their detection limits were as low as ca. 5-10 pg (15-30 fmol) on-column (250-500 pg per ml of body fluid). A detailed procedure for isolation of phenothiazines from human whole blood and urine using Sep-Pak C18 cartridges, before the GC with SID, is also presented. The recoveries of the drugs (100 pmol), which were added to 1 ml of whole blood or urine, were more than 79%. The baselines remained steady as the column temperature was increased.

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The pharmacokinetics of trimeprazine (alimemazine) were studied over 24 hr in six children after a recommended preanaesthetic oral dose of 3 mg.kg-1. The degree of sedation before anaesthesia was evaluated. Median maximal venous blood drug concentration was 0.357 mumols.1(-1), 1-2 hr after oral ingestion, half-life 6.8 hr and AUC0-infinity h 2.758 mumols.1(-1) hr. Assuming 100 per cent bioavailability, blood clearance was estimated to median 3.7 1.kg-1.hr-1. Trimeprazine concentrations in cerebrospinal fluid (CSF) and in venous blood were compared in three other children, measured by gas chromatography. No trimeprazine was detected in the cerebrospinal fluid. We found a rough correlation between preanaesthetic sedation and blood trimeprazine concentrations. The kinetic parameters showed substantial interindividual differences, and accordingly, major interindividual variations in drug response might be anticipated even on standardized dosage regimens.

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Preoperative and postoperative sedation, postoperative analgesia and vomiting were assessed following four different oral premedications in 143 children aged 1-10 years, weighing 10-30 kg, and undergoing elective adenotonsillectomy or inguinal surgery. Diazepam, diazepam combined with droperidol, trimeprazine and trimeprazine combined with droperidol were compared in a double-blind trial in conjunction with a standardised inhalational anaesthetic technique employing an intraoperative narcotic. Trimeprazine produced significantly more preoperative sedation (P less than 0.001) and was associated with enhanced postoperative analgesia (P less than 0.01). The incidence of postoperative vomiting was significantly less in the group receiving trimeprazine (P less than 0.001). The addition of droperidol to diazepam and trimeprazine only marginally improved the performance of those drugs but significantly prolonged postoperative recovery times. This was more marked when droperidol was combined with trimeprazine.

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Antisera to trimeprazine were raised in New Zealand white rabbits to an immunogen synthesized by covalent linkage of bovine serum albumin to N-(2-carboxyethyl)desmethyltrimeprazine. By use of an antiserum, a radioimmunoassay for trimeprazine was developed that is able to quantitate 0.38 ng/ml-1 in a 200 microliter plasma sample with a coefficient of variation of approximately 12%. The antiserum did not cross-react with the supposedly pharmacologically inactive metabolite trimeprazine sulfoxide; however, the cross-reactivity with the supposedly active metabolite N-desmethyltrimeprazine is significant (49%). The radioimmunoassay was able to measure the drug and/or N-desalkyl metabolites in plasma samples obtained as late as 24 hr following administration of a single oral dose (10mg) of trimeprazine tartrate. Analysis of the same plasma samples by a published high-performance liquid chromatographic procedure gave values much lower than those obtained by the radioimmunoassay, indicating the N-desalkyl metabolites are produced significantly after trimeprazine oral administration.

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HPLC procedures with electrochemical or ultraviolet detection were developed in order to analyze plasma samples from patients and volunteers who had received antipsychotic drugs. Procedures were described for the determination of chlorpromazine and trimeprazine in human plasma. The described procedures for chlorpromazine and trimeprazine demonstrated sufficient sensitivity for their use in pharmacokinetic studies following low single oral doses of these agents. The HPLC-EC procedures for chlorpromazine and trimeprazine were compared with GC-MS and radioimmunoassay procedures, respectively.

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