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PubMed2002

Sensitive method for the detection of 22 benzodiazepines by gas chromatography-ion trap tandem mass spectrometry.

A gas chromatography-ion trap tandem mass spectrometry method for simultaneous detection of 22 benzodiazepines is presented. Four operating modes were first optimized: the electron impact ionization and chemical ionization modes were compared on both underivatized and trimethylsilylated drugs. Results were compared in terms of sensitivity in MS-MS experiments. The trimethylsilylation of benzodiazepines including a protic functional group allows decreasing their detection threshold by a factor of 10-100. In terms of sensitivity, the comparison between both ionization modes shows that the most efficient one depends on the benzodiazepine considered. The use of an ion trap analyzer allows switching from an ionization mode to another one during the chromatographic process. It also provides a great selectivity owing to the MS-MS and multiple reaction monitoring acquisition modes. The detection thresholds are in the range 10-500 pg/microl for all the studied benzodiazepines but the three "triazolo" ones: estazolam, alprazolam and triazolam, have a detection threshold of 1 ng/microl. The applicability of the method on whole blood and urine extracts was demonstrated on an example implying five benzodiazepines among the most frequently encountered in forensic toxicology: nordazepam, oxazepam, bromazepam, flunitrazepam and prazepam.

Benzodiazepines↗
PubMed1997

Screening and identification of drugs in human hair by high-performance liquid chromatography-photodiode-array UV detection and gas chromatography-mass spectrometry after solid-phase extraction. A powerful tool in forensic medicine.

A method is described to screen for a wide range of pharmaceuticals in human hair. 75 mg of powdered hair are incubated (12 h at +56 degrees C) in 2 ml of distilled water (acidic compounds) or 0.1 M hydrochloric acid (neutral and basic compounds). A twin solid-phase extraction on C18 cartridges is used for the sample clean-up procedure. Acidic drugs are fixed at pH 2 and eluted with 1% ammoniacal methanol while neutral and basic drugs are retained on the column at pH 8.6 and eluted with methanol containing 0.5% acetic acid. The internal standard (I.S.) for the acidic extraction was bupivacaine while the I.S. for the basic extraction was prazepam. The separation of the drugs was performed using both the liquid and the gas chromatographic techniques whereas identification was achieved using photodiode array and mass spectrometric detection, respectively. The liquid chromatographic system gives an elution of the drugs following a multi step gradient from a Symmetry C8 (Waters) 5 microns column (250 x 4.6 mm I.D.) at +30 degrees C with acetonitrile-phosphate buffer (pH 3.8). Identification is achieved using the reference data (retention times and spectra) of 675 pharmaceuticals, toxicants and drugs of abuse stored in a personal library. The present method has been applied during 6 months in our laboratory. By establishing a victim's drug use history, it is a very powerful tool in forensic medicine. We illustrate the method with some real cases of police crime investigation.

Adult↗
PubMed1994

Confirmation of benzodiazepines in urine as trimethylsilyl derivatives using gas chromatography-mass spectrometry.

A confirmation procedure for the identification and quantitation of various benzodiazepines in urine is presented. The urine sample is first hydrolyzed enzymatically because of the glucuronide conjugation of some benzodiazepine metabolites, then extracted using bonded-phase columns. After elution into an organic solvent, the samples are evaporated, converted to the trimethylsilyl ether derivatives and analyzed by electron ionization GC-MS. Quantitation was performed using selected-ion monitoring for each benzodiazepine using prazepam as the internal standard. The method provides excellent linearity and sensitivity for the trimethylsilyl derivatives.

Benzodiazepines↗
PubMed1997

Screening for forensically relevant benzodiazepines in human hair by gas chromatography-negative ion chemical ionization-mass spectrometry.

A procedure is presented for the detection in human hair of forensically relevant benzodiazepines, i.e. nordiazepam, oxazepam, bromazepam, diazepam, lorazepam, flunitrazepam, alprazolam and triazolam. The method involves decontamination of hair with methylene chloride, pulverization in a ball mill, incubation of 50 mg powdered hair in Soerensen buffer (pH 7.6) in the presence of prazepam-d5 used as internal standard, liquid-liquid extraction with diethyl ether-chloroform (80:20, v/v) and gas chromatography-mass spectrometry using negative chemical ionization after derivatization with N,O-bis(trimethylsilyl)trifluoroacetamide plus 1% trimethylchlorosilane. The limits of detection for all benzodiazepines ranged from 1 to 20 pg/mg using a 50-mg hair sample. Coefficients of variation and extraction recoveries, ranging from 7.4 to 25.4% and 47.6 to 90%, respectively, were found suitable for a screening procedure. One hundred and fifteen samples were submitted to this screening procedure, and specimens tested positive for nordiazepam (0.20-18.87 ng/mg, n=42) and its major metabolite oxazepam (0.10-0.50 ng/mg, n=14), flunitrazepam (19-148 pg/mg, n=31), lorazepam (31-49 pg/mg, n=4) and alprazolam (0.3-1.24 ng/mg, n=2). Bromazepam, diazepam and triazolam were not detected.

Benzodiazepines↗
PubMed1998

High-performance liquid chromatographic determination of new 2,3-benzodiazepines.

A simple high-performance liquid chromatographic assay with ultraviolet detection at 254 nm for simultaneous determination of 2,3-benzodiazepine derivatives (2,3-BZ2 and 2,3-BZ2Me) and their metabolites in rat plasma is described. The procedure involves a fast extraction of the drugs from the buffered sample using methanol. The extract is evaporated to dryness at 45 degrees C and the residue is redissolved in methanol (twice). A 20-microl aliquot is injected into the liquid chromatograph and eluted with methanol-water (65:35, v/v) on a C18 reversed-phase column. At a flow-rate of 1.5 ml/min the detection time was 3.1 min for 2,3-BZ2, 5.06 min for 2,3-BZ2Me and 10.9 min for prazepam, used as internal standard for the quantification of the studied compounds. The method has been used to investigate the steady-state concentrations of two 2,3-benzodiazepine derivatives in Sprague-Dawley rat plasma.

Animals↗
PubMed2001

Determination of partial solubility parameters of five benzodiazepines in individual solvents.

Three and four component partial solubility parameters for diazepam, lorazepam, oxazepam, prazepam and temazepam were determined using the extended and expanded Hansen regression models. A comparison was made also with solubility parameters calculated by the group contribution method proposed by Van Krevelen. Although a limited number of solvents was used, the results from the present study indicate that the partial solubility parameters obtained from the experimental regression models clearly reflect the structural differences in these five structurally related molecules. High R(2)-values were observed in the regression models (0.932 < or =R(2)< or =0.984), except for lorazepam (0.606 < or =R(2)< or =0.825). This was attributed to difficulties in obtaining reliable values of the temperature and heat of fusion due to thermal decomposition of this compound. Introduction of the Flory-Huggins size correction parameter did not improve the R(2)- and F-values in any of the regression models used.

Algorithms↗
PubMed2003

Determination of midazolam and 1'-hydroxymidazolam by liquid chromatography-mass spectrometry in plasma of patients undergoing methadone maintenance treatment.

A rapid, sensitive and selective LC-MS method was developed for the simultaneous determination of midazolam (MDZ) and 1'-hydroxymidazolam (1'-OHMDZ) in plasma taken from 54 patients undergoing methadone maintenance therapy, most of whom were multidrug users. Samples spiked with prazepam, the internal standard, and were extracted into diethyl ether. Compounds were separated on a Phenomenex Luna C(18) column and a mobile phase of acetonitrile-ammonium acetate buffer (10 mM, pH 4.7) (52:48, v/v) at a flow-rate of 1 ml/min. The limit of detection was 0.65 and 0.68 (ng/ml) for MDZ and 1'-OHMDZ, respectively. Within-day relative standard deviations were less than 8%.

Adjuvants, Anesthesia↗
PubMed1999

Psychotropic drug prescription in a psychiatric university hospital.

A retrospective survey on drug prescription over a one-year period (1989) in 1083 patients (48.3% of whom were male) hospitalized in a psychiatric university hospital in Switzerland and a 35-day prospective study (1992) on the prescription of "as needed" (prn) medication in a closed and an open ward were carried out. Their aim was to establish a basis for a monitoring of prescription habits and for pharmacoeconomic considerations. In the retrospective study, 48.3% of the patients were male. The mean duration of hospitalization of the patients was 47.0 +/- 68.1 days (mean +/- s.d.). Only 11 out of the 1083 patients (1%) were without psychotropic medication. The mean (+/- SD) number of drugs/day the patients were prescribed was 4.6 +/- 2.8, including 3.2 +/- 1.7 psychotropic drugs. Patients suffering from schizophrenia (67 d) or from unipolar depression (67.4 d) were hospitalized for the longest periods. Antipsychotics (67.5% of the patients) were the most frequently prescribed psychotropic drugs, followed by anxiolytics (42.2%), antidepressants (28.3%), hypnotics (31.4%) and mood stabilizers (7.1%). Antiparkinsonian agents accounted for 4.6% of all prescriptions. Levomepromazine, haloperidol (30.9% of all patients) and clotiapine were the most often prescribed neuroleptics, and clozapine was administered to only 6.4% of all patients. Among the antidepressants, maprotiline (11.9% of all patients) was more frequently prescribed than the classical tricyclic antidepressant amitriptyline, while the only available SSRI fluvoxamine and MAO inhibitors were rarely used. The most frequently prescribed anxiolytics were clorazepate (28.2% of all patients), lorazepam, bromazepam, and prazepam. Among the hypnotic drugs, chloral hydrate (11.5%) was more frequently administered than the first-ranking benzodiazepine flunitrazepam (7.8%). In the prospective study, 97% and 77% of the patients (n = 55) of the closed (n = 29) and of the open ward, respectively, were prescribed "as needed" (prn) drugs. However, only 71 and 80%, respectively, of these patients finally received the drug. The frequency of prescription was 34.9% for neuroleptics, 15.1% for anxiolytic drugs, 8.2% for non-benzodiazepine hypnotics and only 2.1% for benzodiazepine hypnotics. The most frequently prescribed neuroleptic drug was clotiapine (18% of all patients), but finally, only 29% of the prescribed doses were administered. Studies of this type are biased by the fact that local habits of prescription do not allow generalisation of the findings. Such surveys should be carried out more frequently and simultaneously in different centers. Critical comparisons could help to optimize treatment.

Adult↗
PubMedDate not supplied

Simultaneous HPLC analysis of the hypnotic benzodiazepines nitrazepam, estazolam, flunitrazepam, and triazolam in plasma.

A new analytical methodology was developed for simultaneous high-performance liquid chromatographic quantitation of nitrazepam, estazolam, flunitrazepam, and triazolam in plasma. After addition of the internal standard nor-prazepam, biological samples and calibration standards were extracted at basic pH into diethyl ether-methylene chloride (2:1, v/v). The reconstituted extract was separated on a reversed-phase Nova Pak C18 column with acidic buffer (6mM)-acetonitrile-methanol (64:23:13, v/v) as mobile phase. The detection was performed at 242 nm. Within-run and day-to-day precision values were about 2-8%. The method is thus sensitive and reproducible for use in clinical and experimental toxicokinetic studies.

Chromatography, High Pressure Liquid↗
PubMed2001

Improved solid-phase extraction method for systematic toxicological analysis in biological fluids.

A method for the simultaneous qualitative and quantitative determination of drugs of abuse (opiates, cocaine, or amphetamines) and prescribed drugs (tricyclic antidepressants, phenotiazines, benzodiazepines, etc.) in biological fluids--blood, urine, bile, and gastric contents--was developed. This procedure involves solid-phase extraction with Bond-Elut Certify columns followed by analysis by gas chromatography-nitrogen-phosphorus detection (GC-NPD) and confirmation by gas chromatography-mass spectrometry (GC-MS), after derivatization, when necessary. Pretreatment was performed on all samples: sonication for 15 min plus enzymatic hydrolysis with beta-glucuronidase in urine. With respect to the internal standards, nalorphine and trihexylamine were used for basic substances, allobarbital for acidic drugs, and prazepam for benzodiazepines. Acidic and basic compounds were extracted from different aliquots of samples at different pH levels: 6-6.5 for the acidic and neutral and 8-8.5 for the basic and the benzodiazepines. Several areas of experimental design were considered in the process of method optimization. These included internal standards, pH, sonication, flow rate and washing solvents. It was found that systematic analysis could be reliably performed using optimized extraction conditions. The recovery rates for the compounds tested were always higher than 61.02%.

Adsorption↗
PubMedDate not supplied

Simultaneous determination of viloxazine, venlafaxine, imipramine, desipramine, sertraline, and amoxapine in whole blood: comparison of two extraction/cleanup procedures for capillary gas chromatography with nitrogen-phosphorus detection.

A comparative study for the simultaneous gas chromatographic (GC) resolution and detection of the six antidepressants viloxazine, venlafaxine, imipramine, desipramine, sertraline, and amoxapine in whole blood at concentration levels of 100-2000 ng/mL was developed. Two extraction/cleanup analytical procedures were compared regarding their recovery, precision, sensitivity and matrix purification efficiency. The first procedure consists of the employment of Chem Elut columns (diatomaceous earth) and is based on the principle of liquid-solid absorption extraction that is closely related to conventional liquid-liquid extraction. The second focuses on the use of Bond Elut Certify columns and a mixed SPE, reversed-phase and cation-exchange sorbent, more recently developed for the market. Each procedure required 2.0 mL of whole blood extraction and injection into a capillary GC equipped with a nitrogen-phosphorus detector. Mepivacaine was used as the extraction standard (surrogate), and prazepam was used as the chromatographic standard. No interferences were found, and the time for the chromatographic analysis was 16 min for one sample. Recoveries of the compounds using Chem Elut columns at 500 ng/mL were in the range of 28-74% with intra-assay and interassay precisions of less than 7% and 19%, respectively. Limits of detection (LOD) and quantitation (LOQ) ranged from 39 to 153 ng/mL and from 128 to 504 ng/mL, respectively. Recoveries of the compounds using Bond Elut Certify columns at 500 ng/mL were in the range of 64-86% with intra-assay and interassay precisions of less than 4% and 10%, respectively. LODs and LOQs ranged from 21 to 100 ng/mL and from 70 to 330 ng/mL, respectively. An excellent linearity was observed with both procedures from the LOQs up to 2000 ng/mL. The use of the reversed-phase and cation-exchange sorbent Bond Elut Certify showed advantages compared with Chem Elut columns for the screening of these antidepressants such as higher recoveries, cleaner extracts, better sensitivity, better precision, and less solvent consumption and disposal.

Antidepressive Agents↗
PubMedDate not supplied

Evaluation of EMIT-TOX Enzyme Immunoassay for the analysis of benzodiazepines in serum: usefulness and limitations in an emergency laboratory.

The EMIT-TOX Enzyme Immunoassay for benzodiazepines was evaluated. Reproducibility, linearity, accuracy, sensitivity, and interferences were tested and found to be in good agreement with the manufacturer's specifications. Furthermore, the reactivity of 15 benzodiazepines were studied. According their differential reactivity, the 15 benzodiazepines can be classified into three groups: good reactivity similar to diazepam (potassium clorazepate, prazepam, estazolam, medazepam, flunitrazepam, nitrazepam); medium reactivity (clobazam, clonazepam, bromazepam, chlordiazepoxide, triazolam); and low reactivity (oxazepam, ethyl loflazepate, lorazepam). A possible structure/reactivity relationship is discussed. It is concluded that this kit is well adapted for the rapid detection of most benzodiazepines, but in no way can the EMIT technique permit quantitative results without clinical information.

Anti-Anxiety Agents↗
PubMed2004

Distribution of diazepam and nordiazepam between plasma and whole blood and the influence of hematocrit.

The binding of drugs to plasma proteins is important to consider when concentrations in whole blood (eg, in forensic toxicology) are compared with therapeutic and toxic concentrations based on the analysis of plasma or serum. The plasma to whole blood distribution of diazepam (D) and its major metabolite nordiazepam (ND) was investigated under in vitro and ex vivo conditions. Studies in vitro were done by spiking whole blood with D and ND to give concentrations ranging from 0.1 to 1.0 microg/g. Venous blood was also obtained from hospital blood donors (n = 66) after informed consent. The hematocrit, hemoglobin, and water content of blood specimens were determined by routine procedures before D and ND were added to produce target concentrations of approximately 0.5 microg/g for each substance. The ex vivo work was done with blood specimens from hospital outpatients who were being medicated with D. Concentrations of D and ND were determined in body fluids by capillary column gas chromatography after adding prazepam as internal standard and solvent extraction with butyl acetate. The method limit of quantitation was 0.03 microg/g for both D and ND. The concentrations of D and ND were highest in plasma and lowest in erythrocytes. The plasma/blood (P/B) distribution ratios did not depend on drug concentration between 0.1 and 1.0 microg/g. The mean P/B ratios were 1.79:1 for D and 1.69:1 for ND when hematocrit was 45%. Furthermore, the P/B ratio for D (y) was positively correlated with blood hematocrit (x) and the regression equation was y = 0.636 + 0.025x (r = 0.86, P < 0.001). A similar strong association was found between the P/B ratio and hematocrit for ND (r = 0.79). P/B ratios of D and ND, blood hematocrit, hemoglobin, and the water content differed between sexes (P < 0.001). The overall mean P/B ratios for D and ND were 1.69 +/- 0.097 (+/- SD) and 1.62 +/- 0.08 (P < 0.001, n = 66) respectively when the mean hematocrit was 42.9 +/- 3.4 (+/- SD). For forensic purposes, it would be better to forgo making any conversion of a drug concentration measured in whole blood to that expected in plasma or serum; instead, therapeutic and toxic concentrations should be established for the actual specimens received.

Adult↗
PubMed1998

Anticonvulsant properties of 1,4-benzodiazepine derivatives in amygdaloid-kindled seizures and their chemical structure-related anticonvulsant action.

The effects of 14 different 1,4-benzodiazepines on amygdaloid-kindled seizures and their chemical structure-related anticonvulsive actions were studied. The prophylactic effects of 1, 4-benzodiazepines on amygdaloid-kindled seizures were also examined. Male Wistar strain rats were used in this study. Rats were anesthetized with pentobarbital sodium (35 mg/kg i.p.) and bipolar electrodes were implanted into the right amygdala. The stimulating parameters were 1 ms pulse duration, 60 Hz frequency and a 1 s duration at an intensity just sufficient to induce afterdischarge (AD). All the 1,4-benzodiazepines depressed both seizure stage and AD duration of amygdaloid-kindled seizures. Of the 1, 4-benzodiazepines, prazepam, flutoprazepam and flurazepam with a long alkyl chain at position 1 were less effective than the drugs having a hydrogen or methyl group at the same position. Nitrazepam, nimetazepam, flunitrazepam and clonazepam which have a nitro group at position 7 showed more potent antiepileptic activity than the drugs with a chloro group. Certain 1,4-benzodiazepines caused inhibition of the development of amygdaloid-kindled seizures. The existence of a hydrogen or methyl group at position 1 and a nitro group at position 7 is important for exhibiting potent anticonvulsant activity in amygdaloid-kindled seizures. Introduction of an oxygen group at position 2 is also necessary for high activity. 1,4-benzodiazepines had not only therapeutic but also prophylactic effects on amygdaloid-kindled seizures.

Amygdala↗
PubMed1982

Antagonism of caffeine-facilitated conflict-induced behavior by depressants in cats.

Cats trained in 4-6 weeks to obtain a reward (food pellet) were made 'neurotic' by a randomly occurring air blast at the reward box. Previous studies have shown that d-amphetamine facilitates development of 'neurotic' (conflict-induced) behavior. Caffeine, another stimulant, was examined to determine how it affects positive reinforcement behavior, induction of 'neurosis' and its interaction with depressants. Caffeine, given orally, induced stereotyped behavior, facilitated development of the 'neurotic' behavior and disrupted the feeding cycle. Chlorpromazine, pentobarbital, diazepam, prazepam and fluazepam delayed the onset of the caffeine-facilitated conflict behavior. Phenobarbital antagonized the caffeine effect. Studies of conflict-induced behavior in the cat appear to be useful for the investigation of drug interactions and for the detection of side effects of drugs that are not ordinarily considered to have effects on the central nervous system.

Animals↗
PubMed1992

Effect of benzodiazepines on tryptophan binding to rat hepatic nuclei.

This study evaluates whether or not some of the benzodiazepines would influence the binding of L-tryptophan to rat hepatic nuclei or nuclear envelopes. Previous publications have indicated that binding of L-tryptophan to hepatic nuclear envelope proteins was saturable, stereospecific, and of high affinity. In this study, we investigated whether some of the benzodiazepines would influence L-tryptophan binding to rat hepatic nuclei or nuclear envelopes as assayed by in vitro L-(5-3H) tryptophan binding. Our results indicate that the addition of chlordiazepoxide, diazepam, prazepam, flurazepam, nordazepam, N-desalkylflurazepam, temazepam, oxazepam, lorazepam, or 4-chlorodiazepam has little influence on the L-(5-3H) tryptophan binding to hepatic nuclei in vitro. However, the addition of demoxepam, the N-desalkylated compound of chlordiazepoxide, caused marked competition with 3H-tryptophan binding to hepatic nuclei in vitro. When chlordiazepoxide (1 mg/100 g body weight) is administered intraperitoneally 20 min before killing, the isolated hepatic nuclei reveal decreased specific L-tryptophan binding compared to controls. Also, rats pretreated with chlordiazepoxide intraperitoneally before tube-feeding L-tryptophan revealed diminished tryptophan-induced hepatic nuclear RNA efflux and protein synthesis. Our results suggest that chlordiazepoxide, possibly by itself or through a metabolite, can act to affect hepatic nuclear binding of L-tryptophan and to inhibit the stimulatory effect of L-tryptophan on hepatic protein synthesis.

Animals↗
PubMedDate not supplied

Changing patterns of psychotropic drug use in the elderly: a five-year update.

Psychotropic drug use was evaluated in 2022 ambulatory elderly subjects in 1978-80 and again in 1984-86. Use of hypnotic drugs declined from 8.5 percent (n = 3234) in 1978-80 to 6.3 percent (n = 2681) in 1984-86 (p less than 0.01). Use of the long-acting hypnotic flurazepam decreased (p less than 0.01) and use of two short-acting drugs, triazolam and temazepam, increased. Prescribing of long half-life benzodiazepines, such as diazepam (p less than 0.01) and chlordiazepoxide, clorazepate, halazepam, and prazepam as a group (p less than 0.01) decreased as well as the use of nearly all products containing barbiturates (p less than 0.01).

Aged↗
PubMed1994

Acute renal failure and neurotoxicity following oral acyclovir.

OBJECTIVE: To report a case of acute renal failure and neurotoxicity following administration of oral acyclovir. DATA SOURCES: Medical record of the patient, case reports identified by MEDLINE. DATA EXTRACTION: Data were abstracted from relevant published data by Johnson and reviewed by the remaining authors. CASE SUMMARY: A 69-year-old woman was diagnosed with herpes zoster and oral acyclovir was prescribed by her local physician. After approximately two days the patient was taken to the emergency department of a local hospital with signs of acute confusion and acute renal failure. Medications included oxycodone/acetaminophen, alprazolam, prazepam, and digoxin. Pertinent laboratory abnormalities included serum digoxin 4.1 mumol/L, white blood cell count 17.6 x 10(9)/L, blood urea nitrogen (BUN) 24 mmol/L of urea, and serum creatinine 305 mumol/L (patient baseline is 11 mmol/L of urea and 91.5 serum creatinine mumol/L, respectively). Because of increasing lethargy and a focal seizure, she was transferred to our institution. Despite an extensive workup, no organic cause of her altered mental status and acute renal failure was identified. Four days after discontinuation of the acyclovir, without specific intervention, the patient's mental status improved and her BUN and serum creatinine concentrations had decreased to 21 mmol/L of urea and 190.6 mumol/L, respectively. On day 5, the patient was alert and oriented to name, place, year, and month. On day 9, her renal function and mental status had returned to baseline and she was discharged. CONCLUSIONS: Acute renal failure and neurotoxicity are usually associated with intravenous acyclovir. The temporal relationship between the initiation of oral acyclovir therapy and the onset of adverse events, supported by published data of a few similar cases, strongly implicate oral acyclovir as the cause of this patient's acute renal failure and neurotoxicity. This case suggests that elderly patients with mild increased serum creatinine concentrations may be at increased risk and should be monitored closely for signs and symptoms of acute renal failure and neurotoxicity.

Acute Kidney Injury↗