Postmortem Analysis of Benzodiazepines in Human Bone by Gas Chromatography-Mass Spectrometry.

A procedure based on gas chromatography-mass spectrometry was developed for the analysis of benzodiazepines (nordiazepam, oxazepam, lormetazepam, lorazepam, clonazepam, bromazepam and alprazolam) in postmortem human ribs. Powdered bone samples, including marrow remains inside, with the internal standard diazepam-d5 were subjected to enzymatic hydrolysis with 100 µL of ß-glucoronidase and were incubated in sodium hydroxide for 1 h in a 70°C oven. Samples underwent liquid phase extraction and ethyl acetate was used as eluent. Chromatography was performed on a fused silica capillary column and the selected-ion-monitoring mode was used for analytes determination. The method was validated in the range 0.1-0.5 ng/mg (depending on the benzodiazepine) to 100 ng/mg with average values of recovery, matrix effect and process efficiency ranged from 83.2 to 94.3%, from 97.3 to 102.1% and from 80.5 to 91.2%, respectively. The intra- and inter-day accuracy was <15%. The procedure was tested in rib specimens obtained during routine autopsies from 20 cases where these benzodiazepines were found in blood. Benzodiazepines were detected in the combined bone and marrow samples in 60% of cases. Lorazepam was detected in bone in the range of 0.3-0.7 ng/mg, nordiazepam at 1.3-4.2 ng/mg and oxazepam at 1.1-1.2 ng/mg. To our knowledge, this protocol for the simultaneous analysis of these benzodiazepines is the first performed and validated using human ribs.

Benzodiazepine abuse among athletes: Pain relief or just a weapon against insomnia? A clinical case study.

It is widely recognized that benzodiazepine abuse can potentially induce addiction. Benzodiazepine addiction among athletes is a new and growing phenomenon that we are encountering among our patients. We describe a case of lormetazepam addiction in a female competitive marathon runner. A 30-year-old female elite athlete developed lormetazepam addiction after increasing her daily benzodiazepine dosage in an attempt to achieve better sleep and enhanced performances during training. She was hospitalized for 7 days to undergo benzodiazepine detoxification. Her lormetazepam daily dosage on admission was 18 vials (20 ml × 18 = 360 ml). This report highlights the risk of athletes becoming addicted to benzodiazepines used to combat insomnia and pain. There is a need for clinical and epidemiological research to investigate the effects of this addiction, with a view to better protecting the health of athletes.

Benzodiazepines inhibit temperature-dependent L-[125I]triiodothyronine accumulation into human liver, human neuroblast, and rat pituitary cell lines.

L-T3 (T3) accumulates into cells in a temperature-dependent saturable manner through a purported iodothyronine membrane carrier protein. We report energy-dependent uptake of picomolar [125I]T3 into differentiated cell lines derived from human liver, human neuroblast, and rat pituitary malignancies. Furthermore, this cellular uptake is inhibited by classical and nonclassical benzodiazepine-type drugs (BZs); the apparent half-maximal inhibitory concentrations range from 50 nM to 50 microM, varying with drug and cell type. The site of this T3-BZ interaction was explored with cross-competitive radioligand binding to rat liver cell fractions. No interaction was seen in experiments cross-competing unlabeled T3 (10(-9)-10(-5) M) against [3H]Ro5 4864, a peripheral BZ receptor ligand, for binding sites in a crude rat liver mitochondrial fraction. As well, lormetazepam and triazolam, BZs that potently inhibit cellular uptake of [125I]T3, have no effect on [125I]T3 binding to rat liver nuclear sites. Studies of [3H]diazepam and [3H]Ro5 4864 show very little temperature-dependent uptake into HepG2 cells (less than 0.5% over 90 min) and no effect from coincubation of unlabeled T3 (1 microM). Thus, the possibility that BZs are substrates for the T3 carrier protein and are causing the reduced cellular hormonal accumulation via competitive uptake and dilution of the radiolabeled cellular T3 is unlikely. In summary, 1) drugs from the BZ class inhibit high affinity temperature-dependent cellular accumulation of thyroid hormone into cell lines from rat and human species; 2) the site of action of BZ inhibition does not involve direct antagonism of the T3 nuclear receptor, nor is it likely that the peripheral BZ receptor is the iodothyronine carrier. BZs could be interacting with the purported iodothyronine carrier protein itself to block uptake.

Effects of hypnotics on sleep and psychomotor performance. A double-blind randomised study of lormetazepam, midazolam and zopiclone.

Lormetazepam, midazolam and zopiclone were compared as night medication in patients scheduled for elective surgery the next morning. Sixty patients divided at random into three groups, received double-blind lormetazepam 1 mg, midazolam 15 mg or zopiclone 7.5 mg, by mouth at 2200 hours. The quality of sleep was assessed at 0700 hours from responses to a questionnaire, and psychomotor function by comparing paper and pencil (p-deletion) and Maddox Wing tests with reference values from the day before. The three hypnotics were equally effective as sleep medication for time until onset of sleep, duration of sleep and condition upon awakening, whereas zopiclone provided significantly fewer (p less than 0.05) spontaneous awakenings. The p-deletion test did not differ in any of the three groups from the reference values. The ocular imbalance test in all three groups was significantly different (p less than 0.01) from control. The lormetazepam group scored significantly better (p less than 0.05) than the zopiclone group. No side effects were seen.

Treatment of adjustment disorders: a comparative evaluation.

With the aim of assessing four forms of therapy with adjustment-disordered outpatients, we randomly assigned 70 subjects to the following treatments: supportive psychotherapy (psychoanalytically oriented), viloxazine (an antidepressant), lormetazepam (a benzodiazepine), and S-adenosylmethionine (a methyl donor with antidepressive properties). A further group of 15 subjects received a placebo, orally administered. The trial lasted 4 wk. None of the treatments had clearly superior effects over others on scores on the Zung Self-rating Depression Scale. All produced a significant improvement. However, groups given S-adenosylmethionine and supportive psychotherapy had the highest mean scores.

A double-blind comparison between nitrazepam, lorazepam, lormetazepam and placebo as preoperative night sedatives.

Benzodiazepines are used as hypnotics to reduce anxiety and give a good night's sleep on the night prior to surgery. In a double-blind procedure, patients were given either lorazepam (2 mg or 4 mg), lormetazepam (1 mg or 2 mg), nitrazepam 10 mg or placebo. Measures were taken of sleep, anxiety, memory and after-effects. There was no evidence that the drugs reduced anxiety, nor evidence of amnesia. Quality and length of sleep was shown to be better for nitrazepam (P less than 0.05), lorazepam 2 mg (P less than 0.05) and lorazepam 4 mg (P less than 0.01), compared with placebo. However, significantly higher ratings of clumsiness and confusion as after-effects were found with nitrazepam (P less than 0.05), and clumsiness (P less than 0.005), slurred speech and blurred vision (P less than 0.01), sleepiness, nausea, weakness and confusion (P less than 0.05) with lorazepam 4 mg. It was concluded that lorazepam 2 mg produced the greatest net benefit.

Controlled comparison of a new sublingual lormetazepam formulation and i.v. diazepam in outpatient minor oral surgery.

In a randomized, double-blind, parallel groups study, 40 patients undergoing surgical removal of impacted 3rd molar teeth received either sublingual lormetazepam 2.5 mg (n = 20) in a new cellulose wafer formulation followed at 35 min by i.v. saline; or sublingual placebo followed at 35 min by i.v. diazepam 10 mg (Diazemuls). Rapid onset of sedation was seen after sublingual lormetazepam, while the course and duration of postoperative sedation, measured using standard psychometric tests, was similar following both treatments. Surgeons' ratings indicated that sublingual lormetazepam was comparable to i.v. diazepam but patients' ratings indicated greater satisfaction with and preference for i.v. diazepam. Significant anterograde amnesia was found following both treatments. Both treatments were tolerated well, with no significant cardiovascular complications. These results indicate that sublingual lormetazepam may have a role in anaesthesia as a premedicant and for conscious sedation.

A new lormetazepam galenical formulation for sublingual premedication.

This study reports a double-blind evaluation of a new formulation of lormetazepam for sublingual administration, given as a premedicant in 48 female patients undergoing minor gynecological procedures. Both patient's and nurse's assessments for anxiety and sedation were recorded at different times. Anxiolysis and sedation were present 30 minutes after administration of the drug as reported by the patient with a peak effect at 45 minutes. Nurses reported significant differences in sedation only, but already present at 30 minutes after premedication. The memory test showed no persistent effect of the benzodiazepine one day after surgery.

[Effect and side effects of oral morphine, lormetazepam and placebos as premedication]. / Die Wirkung und Nebenwirkung oralen Morphins, Lormetazepams und Plazebos zur Prämedikation.

In 60 patients undergoing a curettage in thiopentone induced inhalation anaesthesia with enflurane and N2O/O2 = 2:1, the effects of oral premedication (2 h before anaesthesia) with 30 mg morphine (MST 30) (n = 21), 1 mg lormetazepam (Noctamid) (n = 19) and placebo (n = 21) on psychological (anxiety, depression and asthenia), physiological (blood pressure, heart and respiratory rate) and pain parameters (visual analogue scale, analgesic consumption) were investigated. The study design was single blind, randomized. Before premedication the three groups did not differ in one parameter and so were comparable. MST 30 had a significantly better anxiolytic, Lormetazepam a significantly better antidepressive effect than the compared substance. There were no differences in blood pressure and heart rate. In contrast to lormetazepam and placebo after MST 30 there was no increase in the respiratory rate which can be explained by the anxiolytic stress reducing effect. There was no difference in peri- and intraoperative pain parameters, probably due to the type of surgery. Nausea and vomiting occurred more frequently after MST 30, but there was no significance. A higher rate was probably prevented by the application of transdermal scopolamine the day before surgery. The indication of analgesics (opiates) for premedication is discussed taking the controversy into account. The results of this study show that oral morphine (MST 30) has an anxiolytic effect, one of the most important effects a premedication should have. Further studies should investigate in which types of surgery the analgesic effect of MST 30 is peri- and intraoperatively relevant, so that advantages compared to e.g. Flunitrazepam, Midazolam or Lormetazepam in a higher dosage could be expected.

Efficacy of lorazepam and lormetazepam as intravenous premedicants for anesthesia and surgery.

Lorazepam 4 mg and lormetazepam 2 mg were compared as intravenous premedicants by assessing their effects on the level of consciousness and anxiety, sensory and motor functions, neuromuscular function and vital parameters in sixty surgical patients in a randomized study. Lormetazepam exerted a marked sedative-hypnotic effect maximal at 10 min. Lorazepam had a slower onset of action with a peak effect at 40 min on the different neurobehavioral functions but seemed to induce a longer duration of sedation and a more consistently obtunded awareness of perisurgical events than lormetazepam. Sensory functions were similarly affected by both drugs. Motor function was significantly more impaired by lormetazepam than by lorazepam (P 0.05). Both drugs significantly decreased anxiety for at least 60 min after premedication. Important changes of muscle tone were noticed with lormetazepam at 10 to 30 min resulting in upper airway obstruction in some patients. All hemodynamic changes remained clinically acceptable in both groups and no side effects were seen. The clinical anesthesiologists rated the quality of premedication as unsatisfactory in 7% of the patients treated with lorazepam and in 27% of those receiving lormetazepam. Together with its milder neurobehavioral effects and highly effective anxiolytic action, these factors favor the use of lorazepam for anesthetic premedication despite a relatively slow onset of action.

[Hemodynamic changes following the injection of lormetazepam under premedication and anesthesia conditions in coronary surgery patients]. / Hämodynamische Veränderungen nach Injektion von Lormetazepam unter Prämedikations- und Narkosebedingungen bei koronarchirurgischen Patienten.

Lormetazepam, a new short-acting benzodiazepine, was studied in 30 patients undergoing coronary artery bypass grafting (10 patients before induction of anaesthesia, 8 patients before extracorporeal circulation, 12 patients during extracorporeal circulation). Before induction of anaesthesia lormetazepam caused only a small reduction in CI, heart rate and a moderate hypoventilation. During anaesthesia (fentanyl, pancuronium bromide, ventilation with N2O/O2 1: 1) there was a decrease in CI (26%), SI (18%), HR (5,7%), dp/dt (15%) and an increase in TSR (25%) and TPR (32%); Part, PAP, PCWP and PRA remained unchanged. There was a small decrease in myocardial oxygen consumption. During ECC lormetazepam increased the arterial perfusion pressure (20%); the priming volume of the oxygenator decreased by 48% at the same time, indicating venous pooling.

[Premedication with flunitrazepam, lormetazepam or pethidine-promethazine. Psychometric study of subjective conditions]. / Praemedikation mit Flunitrazepam, Lormetazepam oder Pethidin-Promethazin. Psychometrische Untersuchung der subjektiven Befindlichkeit.

In the course of a clinical study oral administration of two different diazepine derivatives as well as i.m. injection of pethidine and promethazine have been explored with a view to their anxiolytic, sedating and hypnotic action. The study involved 128 patients, randomized into four groups. Group 1 received flunitrazepam 1,5-2 mg p.o. only the evening before operation to group 2 flunitrazepam 1,5-2 p.o. was administered the evening before and the morning of the operation, group 3 were given lormetazepam 2-2,5 mg p.o. at the same time as group 2, in group 4 nitrazepam, 5 mg p.o. the evening before operation and pethidine, 50-100 mg combined with promethazine, 25 mg was given i.m. 60 min before surgery. In group 1 anxiolytic and sedating effect of flunitrazepam were not persistent enough to provide the patient with adequate premedication until the onset of surgery. Intensive sedation and fatigue as well as minimum recollection were observed under medication 2, however, increase in anxiety and depression as well as deterioration of mood were not prevented. Under medication 3 patients felt less exhausted and fatigued than under medication 2, but likewise anxiety and depression increased in the course of the operating day. Group 4 emerged as the last effective premedication both with regard to sleep during the previous night and the conditions of the day of the operation itself.

Histamine release in anaesthesia and surgery. premedication with H1- and H2-receptor antagonists: indications, benefits and possible problems.

Our clinical and experimental studies have so far demonstrated, that the drugs used in anaesthesia; such as hypnotics, sedatives, narcotics or muscle relaxants, release histamine. The intravenous short acting anaesthetic etomidate has not shown either in experimental studies or in clinical use for 10 years any anaphylactoid reaction. The benzodiazepines are another group of drugs which appear not to release high amounts of histamine. Accurate studies on volunteers as well as on patients on the application of H1- and H2-receptor antagonists have demonstrated an effective inhibition of the anaphylactoid reaction. We suggest that in case of a history of allergy H1- and H2-receptor antagonists should be administered as a prophylactic premedication.