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Mephenytoin
Published in Stanley R. Resor, Henn Kutt, The Medical Treatment of Epilepsy, 2020
Because of the complexity of MHT biotransformation and nirvanol excretion mechanisms, with higher serum levels one will be faced with the potential for large increases in serum level with small dose increments. Doses in the range of 5 to 7 mg/kg in the patient with full induction of metabolism will tend to place the serum level in the middle of the therapeutically useful range in monotherapy. In the author’s case material a gradual downward drift of serum levels of MHT products over several weeks from the initial steady-state value has been observed. Similarly a lowering effect was seen caused by most other AEDs including CBZ, the various barbiturates, and benzodiazepines, while elevations occurred in the presence of MSM, ethosuximide, PAC, and occasionally nordiazepam. Some of these interactions can lead to dramatic increases in serum levels. Interactions affecting the binding to serum albumen are not clinically significant.
Pharmacokinetic determinants of clinical activity
Published in Adam Doble, Ian L Martin, David Nutt, Calming the Brain: Benzodiazepines and related drugs from laboratory to clinic, 2020
Adam Doble, Ian L Martin, David Nutt
Given that Nl-dealkylation is a major metabolic pathway for benzodiazepines, and that many clinically important benzodiazepines are N1-substituted, exposure to circulating N-dealkyl metabolites is high. This has important clinical implications, since these metabolites are both biologically active and slowly eliminated from the organism. One such metabolite is desmethyldiazepam. This is produced from many benzodiazepines, most importantly diazepam, but also halazepam, prazepam, oxazolam and others. Indeed, desmethyldiazepam (or nordazepam) is marketed as an anxiolytic in its own right in a number of countries, including Germany. Desmethyldiazepam probably contributes significantly to the biological activity of diazepam and other precursors, particularly after chronic administration, and at later times after single administration. The pharmacokinetic profiles of diazepam and desmethyldiazepam after single administration are illustrated in Figure 7.7. It can be seen that plasma levels of the metabolite actually overtake those of the parent drug during the second day after administration, and remain elevated for over a week, when all traces of diazepam in the organism have essentially disappeared. Desmethyldiazepam is itself slowly metabolised to oxazepam, which is then, as we have seen, rapidly removed from the organism by glucuronoconjugation and renal excretion.
Other Sleep Modulators
Published in Shojiro Inoué, Biology of Sleep Substances, 2020
On the other hand, De Blas and Sangameswaran97 and Sangameswaran et al.98 succeeded in detecting a known BZ, N-desmethyldiazepam (nordiazepam; see Figure 6), from bovine, human, and rat brains. It is uncertain whether the detected nordiazepam originated from the natural product of the brain itself or from the synthetic product contaminated during the experimental procedures. However, it is suggested that nordiazepam could be taken from the diet as such or in the form of a precursor that could be converted to nordiazepam in the animal body.
Sentanyl: a comparison of blood fentanyl concentrations and naloxone dosing after non-fatal overdose
Published in Clinical Toxicology, 2022
Alex J. Krotulski, Brittany P. Chapman, Sarah J. Marks, Sam T. Ontiveros, Katharine Devin-Holcombe, Melissa F. Fogarty, Hai Trieu, Barry K. Logan, Roland C. Merchant, Kavita M. Babu
Polydrug use was common. Ten participants’ (50.0%) blood samples showed markers of cocaine use (cocaine, benzoylecgonine, and/or cocaethylene) and methamphetamine use for one participant (5.0%). Buprenorphine (Suboxone®) was detected in one blood specimen (5.0%), while methadone and its metabolite were not found in any specimens. Acetylfentanyl was detected in two blood specimens (10.0%). Carfentanil was detected in the blood of one participant (5.0%). Benzodiazepines were detected in six participants (30.0%); one patient had nordiazepam detected in their specimen. Antidepressants were found in three (15.0%) specimens. Detailed testing results are in Table 2.