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PubMed2003

Distribution and binding parameters of GABAA receptors in the thalamic nuclei of Macaca mulatta and changes caused by lesioning in the globus pallidus and reticular thalamic nucleus.

Ascending output from the basal ganglia to the primate motor thalamus is carried by GABAergic nigro- and pallido-thalamic pathways, which interact with intrinsic thalamic GABAergic systems represented in primates by local circuit neurons and axons of the reticular thalamic nucleus. Disease-triggered pathological processes in the basal ganglia can compromise any of these pathways either directly or indirectly, yet the effects of basal ganglia lesioning on its thalamic afferent-receiving territories has not been studied in primates. Two GABA(A) receptor ligands, [(3)H]muscimol and [(3)H]flunitrazepam, were used to study the distribution and binding properties of the receptor in intact monkeys, those with kainic acid lesions in the globus pallidus, and those with ibotenic acid lesions in the reticular nucleus using quantitative autoradiographic technique on cryostat sections of fresh frozen brain tissue. In control monkeys the binding affinities for [(3)H]muscimol averaged 50 nM in the thalamic nuclei and 86 nM in the basal ganglia while the binding densities varied (maximum density of binding sites [Bmax] range of 99.4-1000.1 fmol/mg of tissue). Binding affinities and Bmax values for [(3)H]flunitrazepam averaged 2.02 nM and 81-113 fmol/mg of tissue, respectively. Addition of 100-microM GABA increased average affinity to 1.35 nM whereas Bmax values increased anywhere from 1-50% in different nuclei. Zolpidem (100 nM) decreased binding by 68-80%. Bmax values for both ligands were decreased at the two survival times in both medial and lateral globus pallidus implying involvement of both nuclei in the lesion. Statistically significant, 40% decrease (P=0.055) of Bmax for [(3)H]muscimol was observed in the ventral anterior nucleus pars densicellularis (VAdc, the main pallidal projection territory in the thalamus) 1 week after globus pallidus lesioning and a 36% decrease (P=0.017) 4 months post-lesioning. In contrast, [(3)H]flunitrazepam Bmax values in the VAdc of the same animals were increased by 23% (P=0.021) at 1 week and 28% (P=0.005) 4 months postlesion, respectively. One week after the reticular nucleus lesioning, the binding densities of [(3)H]muscimol and [(3)H]flunitrazepam were decreased in the thalamic nuclei receiving projections from the lesioned reticular nucleus sector by approximately 50% (P<0.05) and 10-33% (P<0.05), respectively. The results suggest that different GABA(A) receptor subtypes are associated with different GABAergic systems in the thalamus which react differently to deafferentation.

Animals↗
PubMed2001

Modulation of rate of onset and intensity of drug effects reduces abuse potential in healthy males.

Low, medium, and high doses of flunitrazepam were tested in three independent randomized, double-blind, balanced cross-over, placebo-controlled trials to study the influence of rate of onset of effects and dose administered on its acute effects. Three groups of 12 healthy male volunteers received six oral doses of placebo or flunitrazepam in slow and fast onset conditions as follows: six capsules of 0.16 mg (slow) and a single capsule of 0.8 mg (fast) in the low dose trial; six 0.25 mg (slow) and a single 1.25 mg (fast) capsules for medium dose; and six 0.4 mg (slow) and a single 2 mg (fast) capsule for high dose. At each dose level, slow or fast increasing flunitrazepam plasma concentrations lead to similar peak levels, but induced differential subjective and behavioral effects. In addition to objective and subjective sedation, flunitrazepam induced some pleasurable feelings, which were more intense in the fast than in the slow conditions. At the highest dose, unpleasant sedative effects surmounted positive effects, while at the lowest dose pleasurable effects were of low intensity. At the medium dose, the balance between pleasurable and unpleasant feelings resulted in euphorigenic effects, which were evident in the fast condition but were blunted in the slow condition.

Adolescent↗
PubMedDate not supplied

Drugs used in acquaintance rape.

OBJECTIVE: To describe gamma-hydroxybutyrate (GHB), flunitrazepam, and ketamine and their purported uses to facilitate acquaintance rape. Patient presentation characteristics, treatment regimens, processes to detect the presence of the medications by toxicology screening, and methods to avoid exposure are discussed. DATA SOURCES: MEDLINE search from 1985 to 1998; additional references found within the articles; information obtained from the Internet. STUDY SELECTION: Clinical trials, reviews, and press releases concerning the use of GHB, flunitrazepam, and ketamine to facilitate acquaintance rape. Trials and reviews describing clinical effects, adverse effects, pharmacokinetics/pharmacodynamics, and usage trends were evaluated. Literature judged to be pertinent by the author was included in the discussion. DATA EXTRACTION/DATA SYNTHESIS: Reports of the use of GHB, flunitrazepam, and ketamine in acquaintance rape appear in the medical literature and lay press. Many health care professionals may not be familiar with these medications, and information about caring for patients under their influence is limited. Victims lose their ability to ward off attackers, develop amnesia, and are unreliable witnesses. Because symptoms caused by these agents mimic those of alcohol, not all victims are screened for their presence. Legislative efforts to further limit the use of or access to GHB, flunitrazepam, and ketamine have been initiated at the state and federal levels. Pharmacists should know the symptoms of exposure to the three agents; they should understand treatment regimens, methods to detect the presence of these and other drugs that may have been used in a sexual assault, and techniques individuals can use to avoid becoming victims of drug-assisted acquaintance rape. CONCLUSION: Because of their extensive drug knowledge and frequent access to patients, pharmacists are uniquely positioned to educate patients and other health care professionals about the dangers of acquaintance rape drugs and methods to reduce their risk of becoming victims.

Adjuvants, Anesthesia↗
PubMed2002

The bindings of [3H]muscimol and [3H]flunitrazapam are elevated in discrete brain regions of butorphanol-withdrawal rats.

We have investigated the effects of continuous infusion of butorphanol on the modulation of GABA(A) receptor binding. Butorphanol was infused continuously into intracerebroventricle (ICV) at a constant rate of 26 nmol/microl/h for 3 days, and the withdrawal from opioid was rendered 7 h after the cessation of infusion. The GABA(A) receptor bindings in rat brain slices were analyzed by quantitative autoradiography using [3H]muscimol and [3H]flunitrazepam. In the rats withdrawn from butorphanol, the levels of [3H]muscimol binding were significantly elevated in cortex, thalamus, and part of the hippocampus. The levels of [3H]flunitrazepam binding were elevated in almost all of brain regions including cortex, caudate putamen, thalamus, hippocampus, brainstem, and cerebellum in the rats withdrawn from butorphanol. The levels of binding of either [3H]muscimol or [3H]flunitrazepam were not changed in the rats tolerant to butorphanol. However, the activity of GABAergic neuron was not found to have been modulated by butorphanol withdrawal, because the level of glutamic acid decarboxylase was not changed markedly either in rats that were tolerant to or withdrawn from butorphanol by Western blot and immunohistochemical data. These results suggest that the withdrawal from butorphanol infusion markedly elevates the binding of [3H]muscimol and [3H]flunitrazepam throughout the brain in a region-specific manner, and that the regulatory mechanisms in butorphanol tolerance and withdrawal may be different.

Animals↗
PubMed1987

GABA and benzodiazepine receptors in the gerbil brain after transient ischemia: demonstration by quantitative receptor autoradiography.

Quantitative receptor autoradiography was used to measure the binding of gamma-aminobutyric acid (GABA) and benzodiazepine receptors after ischemia by means of transient occlusion of bilateral common carotid arteries in the gerbil. [3H]Muscimol was used to label the GABAA receptors and [3H]flunitrazepam to label central type benzodiazepine receptors. In the superolateral convexities of the frontal cortices, [3H]muscimol binding was increased in 60% of the animals killed 3 days after ischemia, and decreased in 67% of the animals killed 27 days after ischemia. Twenty-seven days after ischemia, [3H]flunitrazepam binding in the substantia nigra pars reticulata increased to 252% of the control, though the increase in [3H]muscimol binding was not significant. In the dorsolateral region of the caudate putamen, marked neuronal necrosis and depletion of both [3H]muscimol and [3H]flunitrazepam binding sites were observed 27 days after ischemia, the ventromedial region being left intact. In spite of the depletion of pyramidal cells in the CA1 region of the hippocampus, both [3H]muscimol and [3H]flunitrazepam binding sites were preserved 27 days after ischemia. Since our previous study revealed that adenosine A1 binding sites were depleted in the CA1 subfield of the hippocampus after ischemia correlating with neuronal damage, GABAA and benzodiazepine receptors may not be distributed predominantly on the pyramidal cells in the CA1 region.

Animals↗
PubMed1986

The gamma-aminobutyrate/benzodiazepine receptor from pig brain. Purification and characterization of the receptor complex from cerebral cortex and cerebellum.

The gamma-aminobutyrate/benzodiazepine-receptor complex has been purified from a Triton X-100 extract of crude synaptic membranes from pig cerebral cortex and cerebellum by a combination of affinity and ion-exchange chromatography. [3H]Flunitrazepam binding activity was purified 2200-fold from cortex with an overall yield of 2%. The dissociation constants for the binding of [3H]muscimol and [3H]flunitrazepam to the receptor complex were 14 +/- 3 nM and 14 +/- 2 nM respectively. The ratio of [3H]muscimol to [3H]flunitrazepam binding sites was in the range 2.2-2.8. There appeared to be no selective inactivation of either binding site during the purification procedure. Sodium dodecyl sulphate/polyacrylamide-gel electrophoresis revealed two major polypeptides of Mr 49 000 and 55 000 from both cortex and cerebellum. When the receptor from cortex was photoaffinity labelled with [3H]flunitrazepam, radioactivity was incorporated predominantly into the Mr-49 000 polypeptide, although some radioactivity was detectable in the Mr-55 000 band. The cerebellar receptor was photoaffinity labelled on the 49 000-Mr polypeptide but not on the polypeptide of Mr 55 000. In addition, some radioactivity was detected in a minor polypeptide of Mr 43 000. When purified in the presence of 3-[(3-cholamidopropyl)dimethylammonio]propanesulphonate the same major polypeptide components (Mr 49 000 and 55 000) were isolated, but the receptor now retained its ability to be modulated by secobarbital and by the anaesthetic propanidid.

Animals↗
PubMed1984

In vitro effect of benzodiazepines on polymorphonuclear leukocyte oxidative activity.

The effect of three benzodiazepine compounds, diazepam, flunitrazepam, and clorazepate, on oxidative activity of human polymorphonuclear leukocyte (PMN) was investigated. The oxidative activity of zymosan-stimulated PMN in the presence of three concentrations (10, 20, and 40 micrograms/ml) of these compounds was measured polarographically. In addition, zymosan-stimulated nitroblue tetrazolium (NBT) reduction was measured in the presence of various concentrations of flunitrazepam. All three compounds inhibited oxygen consumption of the PMN. The extent of inhibition was linear with respect to log-concentrations; oxygen consumption was reduced 50% for concentrations of diazepam, flunitrazepam, and clorazepate of 13 micrograms/ml, 56 micrograms/ml, and 285 micrograms/ml, respectively. In addition 30% and 100% inhibition of NBT reduction by flunitrazepam were observed at respective concentrations of 10 micrograms/ml and 60 micrograms/ml. The clinical relevance of these findings remains to be determined.

Anti-Anxiety Agents↗
PubMed1994

Presence of endogenous inhibitors of benzodiazepine binding in developing chick optic lobe.

An endogenous inhibitor of benzodiazepine receptor binding was removed from synaptic membranes of developing chick optic lobe by an exhaustive buffer washing procedure. This treatment increased [3.H]flunitrazepam binding at all stages of development, although this effect was greater at early stages (embryonic day 14-16). Scatchard analysis performed on exhaustively washed membranes at embryonic day 16 and postnatal day 15 revealed the presence of a single population of flunitrazepam binding sites with apparent dissociation constants (Kd) of 1.99 +/- 0.11 and 3.28 +/- 0.10 nM and a maximal number of binding sites (Bmax) of 1.07 +/- 0.08 and 1.22 +/- 0.11 pmol mg-1 protein, respectively. At both stages of development, the addition of inhibitory material, present in the supernatants obtained after the washing procedure, reduced the affinity of recognition sites for [3H]flunitrazepam with Kd of 4.92 +/- 0.13 and 5.62 +/- 0.12 nM, respectively while their Bmax values remained unchanged. These studies demonstrate the presence of an endogenous material in developing chick optic lobe which competitively inhibits [3H]flunitrazepam binding to its receptor site.

Animals↗
PubMed1990

Three-dimensional comparison of peripheral benzodiazepine binding and histological findings in rat brain tumor.

Experiments were undertaken to determine the in vivo utility of the mixed benzodiazepine ligand [3H]flunitrazepam and the selective peripheral benzodiazepine ligand [3H]PK 11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide] to outline the borders of rat C6 glial tumors in three dimensions. Intravenous injection of [3H]flunitrazepam resulted in a tumor/cortex ratio of radioactive densities between 2.7 and 1.5 within the first 60 minutes after injection. [3H]PK 11195 demonstrated a higher tumor/cortex ratio (5.3) than [3H]flunitrazepam. For three-dimensional studies, images were generated from thionin-stained histological sections and autoradiograms. The mixed type benzodiazepine ligand [3H]flunitrazepam was superior in showing some of the normal anatomical structures surrounding the tumor, whereas [3H]PK 11195, a specific peripheral ligand, demonstrated higher tumor/brain contrast and superior topographical correlation between histological and autoradiographic images. Implications of peripheral benzodiazepine receptor ligands for positron emission tomography are discussed.

Animals↗
PubMed1980

Decreased benzodiazepine receptor density in rat cerebellum following neurotoxic doses of phenytoin.

The effect of acute and chronic administration of phenytoin on [3H]flunitrazepam binding was examined in the rat cerebellum. There was no significant effect of phenytoin on [3H]flunitrazepam binding in the rat cerebellum 1 and 6 h after a single i.p. injection of 200 mg/kg of phenytoin. However, after 14 days and 28 days of chronic phenytoin administration, significant decreases in [3H]flunitrazepam receptor density were observed, with no changes in apparent affinity constants in the rat cerebellum. This effect of phenytoin was dose-dependent, as lower doses of phenytoin (100 mg/kg/day) for 14 or 28 days produced no alterations in [3H]flunitrazepam binding the the rat cerebellum. Light-microscopic examination of the rat cerebellum treated with 200 mg/kg/day of phenytoin for 14 days showed degeneration of the Purkinje cells, with edematous Bergmann astrocytes. These data provide evidence for the neuronal localization of benzodiazepine receptors on cerebellar Purkinje cells.

Animals↗
PubMed1983

Characterization of the solubilized GABA and benzodiazepine receptors from various regions of bovine brain.

GABA and benzodiazepine receptors were solubilized from bovine cerebral cortex, cerebellum, and hippocampus and then partially purified by gel filtration and characterized. The apparent molecular weights of all these receptors were determined to be 600,000-650,000 by gel filtration, the sedimentation coefficients being 11.0-11.3 S by sucrose density gradient centrifugation. [3H]Muscimol was bound to two classes of sites in fractions from all three regions, and [3H]flunitrazepam bound to one class of sites. A comparison of the ratios of Bmax for flunitrazepam binding to Bmax for muscimol binding revealed that the fractions from the hippocampus exhibited a much higher ratio of benzodiazepine binding sites than were detected in fractions from the cortex and cerebellum. GABA agonist and antagonist inhibited [3H]muscimol binding to the fractions from these regions, at similar concentrations. Benzodiazepine agonists and antagonists also inhibited [3H]flunitrazepam binding in these three fractions, with similar potency. CL 218,872, however, inhibited [3H]flunitrazepam binding in the cerebellar fraction with the lowest IC50 value and that in th hippocampal fraction with the highest IC50 value. Hill coefficients for CL 218,872 inhibition were 0.98, 0.64, and 0.58 for cerebellum, cortex, and hippocampus, respectively.

Animals↗
PubMed1984

Benzodiazepine receptor binding following amygdala-kindled convulsions: differing results in washed and unwashed brain membranes.

The binding of [3H]flunitrazepam and [3H]RO5-4864 was measured in unwashed brain homogenates and in extensively washed brain membranes from amygdala-kindled and "yoked" control rats sacrificed 2 weeks following the sixth stage 5 convulsion. In unwashed homogenates, [3H]flunitrazepam binding was reduced in both the hypothalamus and ipsilateral right cortex of kindled rats (unchanged in other areas). In washed brain membranes, [3H]flunitrazepam binding was unaltered in these regions; it was bilaterally elevated, however, in both the amygdala and hippocampus (unchanged in other areas). In washed membranes, the in vitro addition of gamma-aminobutyric acid enhanced [3H]flunitrazepam binding to a similar extent in kindled and control membranes. These data indicate that the type of benzodiazepine binding abnormality observed after kindling depends on the type of tissue preparation employed in the assay procedure.

Amygdala↗
PubMed1987

Photoaffinity labeling of benzodiazepine receptor proteins with the partial inverse agonist [3H]Ro 15-4513: a biochemical and autoradiographic study.

Photolabeling of the benzodiazepine receptor, which to date has been done with benzodiazepine agonists such as flunitrazepam, can also be achieved with Ro 15-4513, a partial inverse agonist of the benzodiazepine receptor. [3H]Ro 15-4513 specifically and irreversibly labeled a protein with an apparent molecular weight of 51,000 (P51) in cerebellum and at least two proteins with apparent molecular weights of 51,000 (P51) and 55,000 (P55) in hippocampus. Photolabeling was inhibited by 10 microM diazepam but not by 10 microM Ro 5-4864. The BZ1 receptor-selective ligands CL 218872 and beta-carboline-3-carboxylate ethyl ester preferentially inhibited irreversible binding of [3H]Ro 15-4513 to protein P51. Not only these biochemical results but also the distribution and density of [3H]Ro 15-4513 binding sites in rat brain sections were similar to the findings with [3H]flunitrazepam. Thus, the binding sites for agonists and inverse agonists appear to be located on the same proteins. In contrast, whereas [3H]flunitrazepam is known to label only 25% of the benzodiazepine binding sites in brain membranes, all binding sites are photolabeled by [3H]Ro 15-4513. Thus, all benzodiazepine receptor sites are associated with photolabeled proteins with apparent molecular weights of 51,000 and/or 55,000. In cerebellum, an additional protein (MW 57,000) unrelated to the benzodiazepine receptor was labeled by [3H]Ro 15-4513 but not by [3H]flunitrazepam. In brain sections, this component contributed to higher labeling by [3H]Ro 15-4513 in the granular than the molecular layer.

Affinity Labels↗
PubMed1986

Aspects of driving after hypnotic therapy with particular reference to temazepam.

In a double-blind study, 32 outpatients with sleep disorders received oral doses of temazepam 20 mg (n = 16) or flunitrazepam 2 mg (n = 16) once a night for 7 days. On the morning after the first and seventh doses, patients completed psychomotor tests and a real driving test on the road over a 25 km course. The road test included a 1 km straight stretch driven at constant speed. In the car, various parameters were automatically recorded every second for approximately 60 minutes. These included angular velocity of steering, lateral acceleration and velocity. An optimization quotient, a measure of the efficiency of information processing in the driver-vehicle-road interaction, was derived from these parameters. An observer recorded driving performance by scoring standardized tasks. After a single dose of temazepam, the improvement in driver performance as shown by a decreased optimization quotient was significantly different to the deterioration seen after flunitrazepam (p less than 0.05). After the seventh dose, this trend was still apparent but was not statistically significant. After both one and seven doses, the angular velocity of steering was significantly decreased in the temazepam group compared with an increase after flunitrazepam (p less than 0.001). Over the straight, this deterioration in steering ability in the flunitrazepam group was apparent after one dose and reached statistical significance compared with temazepam after seven doses (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Anxiety Agents↗
PubMed1999

Long-term alterations in benzodiazepine, muscarinic and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor density following continuous cocaine administration.

Animal models of clinical phenomena, such as stimulant-induced psychosis have focused primarily on persisting alterations that develop in brain after chronic stimulant administration. The present study utilized autoradiographic measures to examine changes in the density of benzodiazepine ([3H] flunitrazepam), muscarinic ([3H] quinuclidinyl benzilate), and non-NMDA glutamatergic (3H alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid: AMPA) receptor binding in rats 21 days following two exposures to cocaine administered continuously for 5 days via subcutaneous pellets. A marked, selective increase in [3H] flunitrazepam binding in both the lateral and medial habenula nucleus was observed. Reduced [3H] quinuclidinyl benzilate binding was observed in various brain areas, including large decreases in the anterior cingulate cortex and ventral thalamus. A reduction in [3H]AMPA binding was observed in the ventral striatum and was suggested in the nucleus accumbens. [3H] Flunitrazepam binding was also examined 12 hr following a single 5 day cocaine exposure to determine if the long-term habenular changes were evident at acute withdrawal. No alterations in [3H] flunitrazepam binding were observed in the habenula or any other structure analyzed at this time point. The relation of these results to persisting alterations in mesocorticolimbic pathways and previous findings of cocaine-induced degeneration in lateral habenula circuitry is discussed.

Animals↗
PubMed1999

Mutagenesis of the rat alpha1 subunit of the gamma-aminobutyric acid(A) receptor reveals the importance of residue 101 in determining the allosteric effects of benzodiazepine site ligands.

The gamma-aminobutyric acid(A) (GABA(A)) receptor contains a binding site (or sites) for benzodiazepines and related ligands. Previous studies have shown that the residue occupying position 101 (rat numbering) of the alpha subunit is particularly important in determining how some of these compounds interact with the receptor. We have made multiple substitutions (F, Y, K, Q, and E) of the histidine at this position of the rat alpha1 subunit and coexpressed the mutant subunits with beta2 and gamma2 subunits in Xenopus oocytes. The effects of flunitrazepam, Ro15-1788, and Ro15-4513 on GABA-gated currents were then examined using electrophysiological techniques. Three substitutions (F, Y, and Q) had little effect on the ability of flunitrazepam to potentiate GABA-induced currents and had relatively modest effects on the EC(50) value of the flunitrazepam response. Other mutations (K and E) resulted in drastic reduction of flunitrazepam recognition. All substitutions also affected the EC(50) values for Ro15-1788 and Ro15-4513, and some led to dramatic changes in their efficacy. For example, H101Y, H101K, and H101Q produced receptors at which Ro15-1788 acted as a partial agonist (maximum potentiation of 164, 159, and 130%, respectively), whereas Ro15-4513 acted as a partial agonist at H101F, H101K, and H101E (potentiation of 122, 138, and 110%, respectively) and an antagonist at H101Y and H101Q. These results indicate that the characteristics of the residue at position 101 of the alpha1 subunit play a crucial role in determining the efficacy of benzodiazepine-site ligands.

Allosteric Regulation↗
PubMed1990

Interaction of zonisamide with benzodiazepine and GABA receptors in rat brain.

The effects of zonisamide on [3H]flunitrazepam binding and [3H]muscimol binding were studied in Sprague-Dawley rat brain. Specific [3H]flunitrazepam bound was decreased to 64.6 +/- 5.6% (mean +/- SD, n = 5, p < 0.002) and 91.9 +/- 4.0% (p < 0.005) by the addition of 10(-3) M and 10(-4) M zonisamide, respectively. Scatchard plot analysis of [3H]flunitrazepam binding with 10(-3) M of zonisamide revealed an increased Kd value with no change in Bmax. No inhibitory effect of zonisamide was seen on the enhancement of specific [3H]flunitrazepam binding by GABA. As for the effects on GABA receptors, specific [3H]muscimol bound was decreased to 27.7 +/- 10.4% (mean +/- SD, n = 4, p < 0.005) and 68.3 +/- 3.7% (mean +/- SD, n = 4, p < 0.005) by the addition of 10(-3) M and 10(-4) M zonisamide, respectively. Since therapeutic serum level of zonisamide are around 10(-4) M, these results suggest that zonisamide neuropharmacologically interacts with the GABA/benzodiazepine receptor ionophore complex in a manner similar to phenytoin.

Animals↗
PubMed1992

Detection of benzodiazepine intake in therapeutic doses by immunoanalysis of urine: two techniques evaluated and modified for improved performance.

We evaluated the EMIT (enzyme-multiplied immuno technique) and FPIA (fluorescence polarization immunoassay) urine screening systems for detection of benzodiazepine intake. Healthy male volunteers were given single oral therapeutic doses of alprazolam (2 mg), chlordiazepoxide (25 mg), flunitrazepam (1 mg), lorazepam (3.75 mg), nitrazepam (5 mg), and triazolam (0.25 mg), after which urine was collected for the next 32 h. The EMIT method failed to detect the intake of flunitrazepam, lorazepam, and nitrazepam. FPIA did not detect the intake of chlordiazepoxide, flunitrazepam, lorazepam, nitrazepam, and triazolam. Modification of the EMIT method to include enzymatic hydrolysis did not significantly alter the results obtained with this method. A modification of the FPIA method to include enzymatic hydrolysis and a lower cutoff value improved the results considerably, so that we reliably detected all studied substances but flunitrazepam. We conclude that (a) both EMIT and FPIA techniques, when used as intended by the manufacturers, are unreliable for the detection of intake of therapeutic doses of these benzodiazepines, and (b) the described modification of the FPIA should provide a much improved tool for detection of benzodiazepine intake.

Adult↗