Disease relevance of Nordazepam

• A significant but weak linear correlation was found between the relative increase in the levels of diazepam, N-desmethyldiazepam and total benzodiazepine receptor ligands and the severity of hepatic encephalopathy [1].
• Signs of abstinence such as tremor, hot foot walking and twitches and jerks were more frequently observed in N-desmethyldiazepam-dependent dogs than in diazepam-dependent dogs as were decreases in food and water intake and in body weight [2].
• Dogs, surgically implanted with a chronic gastric fistula, were chronically dosed with N-desmethyldiazepam (32 mg/kg/day) in four divided doses to attain N-desmethyldiazepam plasma levels comparable to those observed in dogs dependent on diazepam (60 mg/kg/day) [2].
• Kinetics of drug action in disease states. XXV. Effect of experimental hypovolemia on the pharmacodynamics and pharmacokinetics of desmethyldiazepam [3].
• Drugs in this category have long-acting pharmacologically active metabolites (often desmethyldiazepam), accumulate extensively during multiple dosage, and may have impaired clearance in the elderly and those with liver disease [4].

Psychiatry related information on Nordazepam

• The percentage fall in serum levels of desmethyldiazepam in patients who experienced withdrawal symptoms after stopping diazepam was significantly greater in patients with no withdrawal symptoms [5].
• The effects on active social interaction of acute and chronic dosage with diazepam (1 mg/kg), desmethyldiazepam (2 mg/kg), and chlor-desmethyl-diazepam (0.125 mg/kg) were studied in pairs of mice [6].
• 3 There were no effects of nordiazepam (5 mg) on the duration (min) of sleep stages [7].
• Eight normal subjects were tested on a battery of subjective and psychological tests 12 hours after a hypnotic dose of chlordesmethyldiazepam (1 or 2 mg), amylobarbitone sodium (100 mg), and a placebo [8].
• 3 Potassium chlorazepate 15 mg, with its long-acting metabolite nordiazepam, would seem to be the drug of choice for insomnia secondary to anxiety [9].

High impact information on Nordazepam

• Concentrations of diazepam and its three pharmacologically active metabolites (desmethyldiazepam, temazepam, and oxazepam) were determined in multiple samples drawn during and after hospitalization [10].
• RESULTS: In white subjects omeprazole treatment decreased diazepam clearance by 38% +/- 4.4% and increased desmethyldiazepam area under the plasma concentration-time curve (AUC) by 42.4% +/- 7.0% [11].
• In addition, the plasma half-life of demethyldiazepam showed a statistically significant (p less than 0.001) difference between the extensive metabolizers (95.9 +/- 11.3 hours) and poor metabolizers (213.1 +/- 10.7 hours), and correlated with the log10 urinary excretion of 4-hydroxymephenytoin (rs = -0.615, p less than 0.01) [12].
• Microsomes prepared from livers of male and female rats of nine inbred and outbred strains and of male Sprague-Dawley rats pretreated with monooxygenase-inducing agents were used to study N-dealkylation of diazepam and temazepam and C3-hydroxylation of diazepam and nordazepam [13].
• However, the plasma half-life of demethyldiazepam was longer in poor metabolizers than in extensive metabolizers of mephenytoin (mean +/- SD: 161 +/- 37 and 116 +/- 29 hours, respectively; p less than 0.02) [14].

Chemical compound and disease context of Nordazepam

• This abstinence as measured by the NPAS score was more severe in diazepam- and halazepam-dependent than in nordiazepam-dependent dogs whereas the incidence of precipitated clonic seizures was greater in the diazepam- and nordiazepam-dependent than in the halazepam-dependent dogs [15].
• Effects of propranolol, atenolol, and chlordesmethyldiazepam on response to mental stress in patients with recent myocardial infarction [16].
• A combined high-performance liquid chromatography-based method was developed for the benzodiazepines midazolam, 1-hydroxymidazolam, 1-hydroxymidazolam glucuronide, diazepam, and nordiazepam and for the barbiturates thiopentone and pentobarbitone in serum or plasma of critically ill patients [17].
• Immediate memory was significantly impaired following the treatment with nordiazepam, chlordiazepoxide lactam, alcohol, and after the simultaneous administration of nordiazepam and chlordiazepoxide lactam with alcohol [18].

Biological context of Nordazepam

• The pharmacokinetics of the major metabolite desmethyldiazepam (DD) was investigated in four healthy individuals and four patients with hepatic dysfunction and compared to its parent compound D [19].
• Since AUCfree diazepam also rose in all (mean - 26.5 +/- 17.3%) and AUC of the metabolite N-desmethyldiazepam fell (mean = 50.5 +/- 11.7%, p < 0.01) there had been inhibition of hepatic intrinsic clearance of free drug [20].
• Diazepam and desmethyldiazepam are converted to their respective benzophenones by mineral acid hydrolysis [21].
• In 12 healthy volunteers the kinetics and neuropsychological actions of IV diazepam (DZ) (single dose) were studied with and without the presence of its main metabolite N-desmethyldiazepam (NDDZ) [22].
• Despite rapid uptake, the extent of CSF transfer of DZ and DMDZ was limited by plasma protein binding [23].

Anatomical context of Nordazepam

• Postmortem analysis of fetal tissue concentrations showed accumulation of NDZ in heart and lungs [24].
• DZ and its metabolite N-demethyldiazepam (NDZ) were constantly present in umbilical cord plasma at concentrations comparable to the mother's shortly after drug administration [24].
• Metabolism of diazepam was studied in vitro to identify the forms of cytochrome P450 (CYP) responsible for N-demethylation (nordazepam formation) and 3-hydroxylation (temazepam formation), using liver microsomes obtained from extensive (EM) and poor metabolizers (PM) for S-mephenytoin 4'-hydroxylation [25].
• Plasma, erythrocyte, and saliva diazepam and N-desmethyldiazepam concentrations did not correlate with the impairment of psychomotor skills over time [26].
• Concentrations of DZ and its major metabolite desmethyldiazepam (DMDZ) were simultaneously measured in plasma and cisternal cerebrospinal fluid (CSF) for up to 8 h after the dose by electron-capture gas-liquid chromatography [23].

Associations of Nordazepam with other chemical compounds

• Metabolites of PZ were separated by normal phase high performance liquid chromatography and the relative amounts of major metabolites were found to be N-desalkylprazepam (also known as N-desmethyldiazepam and nordiazepam) greater than 3-hydroxy-PZ (3-OH-PZ) greater than oxazepam [27].
• Propranolol prolonged diazepam elimination t1/2 (58 and 49 hr), reduced its clearance (0.20 and 0.24 ml/min/kg), and increased the 168-hr AUC for desmethyldiazepam, the major metabolite of diazepam (5.63 and 4.81 micrograms/ml . hr) [28].
• Plasma levels of N-desmethyldiazepam in subjects receiving both single and chronic doses of chlordiazepoxide were determined by an EC-GC method with a limit of sensitivity of 10 ng/ml using 2-ml samples and by a radioimmunoassay procedure which had a limit of sensitivity of 20 ng/ml using a 0.1-ml sample [29].
• A double-blind randomised placebo-controlled study was conducted in healthy male volunteers to determine the effects of sertraline on the pharmacokinetics of diazepam and its primary metabolite, N-demethyldiazepam [30].
• Halazepam as a precursor of desmethyldiazepam: quantitation by electron-capture gas-liquid chromatography [31].

Gene context of Nordazepam

• 5. Our results suggest that in the human liver, the metabolism of diazepam to nordiazepam is mediated by CYP3A4, which has been reported as the most abundant P450 form in human liver as well as 2C19, which has been reported as a polymorphic enzyme [32].
• The formations of their metabolites, 4'-hydroxymephenytoin (4'-OH-MP), demethyldiazepam, and 5-hydroxyomeprazole (5-OH-OP) are CYP2C19 genotype dependent [33].
• Although endozepine peaks 1 and 2 had HPLC retention profiles similar to those of nordiazepam and diazepam, respectively, gas chromatography-mass spectrometry as well as high-performance TLC revealed biologically insignificant amounts of diazepam (less than 0.02 pg/g) and nordiazepam (less than 0.02 pg/g) in the purified material [34].
• Diazepam and N-desmethyldiazepam concentrations in saliva, plasma and CSF [35].
• The MAbs to 1A1, 1A2, 2A6, 2D6, and 2E1 did not inhibit TMZ or nordiazepam formation; this indicates their noninvolvement in DZ metabolism [36].

Analytical, diagnostic and therapeutic context of Nordazepam

• High correlations (r = 0.98; P less than .001) were obtained between the "diazepam equivalents" measured in plasma with the radioreceptor assay and the levels of diazepam and nordiazepam obtained by gas-liquid chromatography [37].
• Both isocratic and gradient-elution HPLC indicated that this inhibitory activity was localized in 3-8 peaks with retention times corresponding to deschlorodiazepam, deschlorolorazepam, lorazepam, oxazepam, diazepam, and N-desmethyldiazepam [38].
• Serum diazepam and desmethyldiazepam concentrations were measured by electron-capture gas-liquid chromatography in samples drawn up to 72 hr after injection [39].
• The results of this three-period randomized complete crossover study showed a trend of initially slower absorption and lower peak nordiazepam plasma levels when administered with the antacid suspension [40].
• Evaluation of an enzyme immunoassay for determining diazepam and nordiazepam in serum and urine [41].

References