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Tremor and Other Hyperkinetic Movements... 2024In a recent survey of 16,694 people receiving treatment for Restless Legs Syndrome (RLS), approximately 25% were treated with benzodiazepines either singly or in... (Review)
Review
UNLABELLED
In a recent survey of 16,694 people receiving treatment for Restless Legs Syndrome (RLS), approximately 25% were treated with benzodiazepines either singly or in combination with other RLS treatments. Because of the large number of people receiving benzodiazepines for treatment of RLS, we conducted a historical overview of the therapeutic role of benzodiazepines in RLS and its associated condition Periodic Limb Movements in Sleep (PLMS). We found 17 articles on the use of clonazepam in RLS, PLMS, or both, 3 on triazolam and PLMS, 1 on alprazolam and RLS, 1 on temazepam and PLMS, and 1 on nitrazepam and PLMS. The order of benefit of benzodiazepines from the summarized literature is Sleep>RLS>PLMS and arousals > PLMS. Most of the studies on clonazepam employed dosages of 0.5-2.0 mg. Dosages of 3 or 4 mg caused lethargy, somnolence and confusion. An epidemiological study on the therapy of RLS suggests that treatment of RLS with most types of RLS medications including benzodiazepines in combination with other RLS therapies lowers the future cardiovascular risk associated with RLS. The major effect of benzodiazepines is through potentiation of the effect of GABA on the GABA A receptor. Neuroimaging studies suggest that GABA is altered either positively or negatively in various brain regions in RLS and genetic studies suggest that there are alterations in the GABA receptor in RLS. These results suggest that medications with different GABAergic mechanisms such as tiagabine (Gabitril) or others should be investigated in RLS for their possible therapeutic benefit.
HIGHLIGHTS
Benzodiazepines are frequently used as therapy in Restless Legs Syndrome (RLS) and Periodic Limb Movements in Sleep. The order of benefit is Sleep>RLS>PLMS and arousals > PLMS. For clonazepam dosages of 0.5 mg-2.0 mg/day are most frequently employed. Benzodiazepines exert their therapeutic effect through GABA-ergic mechanisms.
Topics: Restless Legs Syndrome; Humans; Clonazepam; Benzodiazepines; Nocturnal Myoclonus Syndrome; History, 20th Century; History, 21st Century; Adult
PubMed: 38708125
DOI: 10.5334/tohm.824 -
Forensic Toxicology Apr 2024Toxicological analyses of biological samples play important roles in forensic and clinical investigations. Ingested drugs are excreted in urine as conjugates with...
PURPOSE
Toxicological analyses of biological samples play important roles in forensic and clinical investigations. Ingested drugs are excreted in urine as conjugates with endogenous substances such as glucuronic acid; hydrolyzing these conjugates improves the determination of target drugs by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In this study, we sought to improve the enzymatic hydrolysis of glucuronide conjugates of five psychoactive drugs (11-nor-9-carboxy-Δ-tetrahydrocannabinol, oxazepam, lorazepam, temazepam, and amitriptyline).
METHODS
The efficiency of enzymatic hydrolysis of glucuronide conjugates in urine was optimized by varying temperature, enzyme volume, and reaction time. The hydrolysis was performed directly on extraction columns. This analysis method using LC-MS/MS was applied to forensic autopsy samples after thorough validation.
RESULTS
We found that the recombinant β-glucuronidase B-One® quantitatively hydrolyzed these conjugates within 3 min at room temperature directly on extraction columns. This on-column method saved time and eliminated the loss of valuable samples during transfer to the extraction column. LC-MS/MS-based calibration curves processed with this method showed good linearity, with r values exceeding 0.998. The intra- and inter-day accuracies and precisions of the method were 93.0-109.7% and 0.8-8.8%, respectively. The recovery efficiencies were in the range of 56.1-104.5%. Matrix effects were between 78.9 and 126.9%.
CONCLUSIONS
We have established an LC-MS/MS method for five psychoactive drugs in urine after enzymatic hydrolysis of glucuronide conjugates directly on extraction columns. The method was successfully applied to forensic autopsy samples. The established method will have broad applications, including forensic and clinical toxicological investigations.
PubMed: 38557936
DOI: 10.1007/s11419-024-00685-1 -
Polymers Feb 2024In this research, a molecularly imprinted polymer (MIP) was synthesized by precipitation polymerization using oxazepam (OZ) as a template molecule and was subsequently...
In this research, a molecularly imprinted polymer (MIP) was synthesized by precipitation polymerization using oxazepam (OZ) as a template molecule and was subsequently applied as a selective sorbent for the extraction of diazepam (DZP) and its metabolites in urine samples using an SPE cartridge. OZ, temazepam (TZ), nordiazepam (NZ) and DZP were analyzed in the final extracts by high-performance liquid chromatography with diode array detection (HPLC-DAD). The SPE extraction steps were optimized, and the evaluation of an imprinting factor was carried out. The selectivity of the method for OZ versus structurally related benzodiazepines (BZDs), such as bromazepam (BRZ), tetrazepam (TTZ) and halazepam (HZ), was investigated. Under the optimum conditions, the proposed methodology provided good linearity in the range of 10-1500 ng/mL, with limit of detection values between 13.5 and 21.1 ng/mL and recovery levels for DZP and its metabolites from 89.0 to 93.9% (RSD ≤ 8%) at a concentration level of 1000 ng/mL. The proposed method exhibited good selectivity, precision and accuracy and was applied to the analysis of urine samples from a real case of DZP intake.
PubMed: 38475318
DOI: 10.3390/polym16050635 -
The Analyst Feb 2024Pharmaceutical polymers and excipients represent interesting but often overlooked chemical classes in clinical exposure and bioanalytical research. These chemicals may...
High-abundance peaks and peak clusters associate with pharmaceutical polymers and excipients in urinary untargeted clinical metabolomics data: exploration of their origin and possible impact on label-free quantification.
Pharmaceutical polymers and excipients represent interesting but often overlooked chemical classes in clinical exposure and bioanalytical research. These chemicals may cause hypersensitivity reactions, they can be useful to confirm exposure to pharmaceuticals, and they may pose bioanalytical challenges, including ion suppression in liquid chromatography-mass spectrometry (LC-MS-)based workflows. In this work, we assessed these chemicals in light of a rather surprising finding presented in two previously published studies, namely that usage of cyclosporine A, an immunosuppressive drug which is known to be cleared through excretion in the bile, explained the largest amount of variance in principal component analysis of urinary LC-SWATH/MS small-molecule profiling data. Specifically, we examined the freely-accessible 24-hour urine metabolomics data of 570 kidney transplant recipients included in the TransplantLines Biobank and Cohort Study (NCT03272841). These data unveiled thousands of high-abundance polymer peaks in some samples, which were associated with the use of the macrogol (, polyethylene glycol) 3350 oral laxative agent. In addition, we found multiple clusters of high-abundance peaks which were linked to the exposure to two pharmaceutical excipients, namely short-chain polyethylene glycol (molecular weight <1000 Da) and polyethoxylated castor oil (also known as Kolliphor® EL or Cremophor® EL). Respectively, these excipients are used in temazepam capsules and cyclosporine A capsules, and the latter provides a plausible explanation for the rather surprising finding that instigated our work. Moreover, such explanation and our findings in general put emphasis on taking into consideration these and other pharmaceutical polymers and excipients when exploring, processing, and interpreting clinical small-molecule profiling data.
Topics: Humans; Excipients; Cyclosporine; Polymers; Cohort Studies; Polyethylene Glycols; Metabolomics
PubMed: 38251754
DOI: 10.1039/d3an01874a -
JMIR Formative Research Oct 2023Substance use disorder and associated deaths have increased in the United States, but methods for detecting and monitoring substance use using rapid and unbiased...
BACKGROUND
Substance use disorder and associated deaths have increased in the United States, but methods for detecting and monitoring substance use using rapid and unbiased techniques are lacking. Wastewater-based surveillance is a cost-effective method for monitoring community drug use. However, the examination of the results often focuses on descriptive analysis.
OBJECTIVE
The objective of this study was to explore community substance use in the United States by analyzing wastewater samples. Geographic differences and commonalities of substance use were explored.
METHODS
Wastewater was sampled across the United States (n=12). Selected drugs with misuse potential, prescriptions, and over-the-counter drugs and their metabolites were tested across geographic locations for 7 days. Methods used included wastewater assessment of substances and metabolites paired with machine learning, specifically discriminant analysis and cluster analysis, to explore similarities and differences in wastewater measures.
RESULTS
Geographic variations in the wastewater drug or metabolite levels were found. Results revealed a higher use of methamphetamine (z=-2.27, P=.02) and opioids-to-methadone ratios (oxycodone-to-methadone: z=-1.95, P=.05; hydrocodone-to-methadone: z=-1.95, P=.05) in states west of the Mississippi River compared to the east. Discriminant analysis suggested temazepam and methadone were significant predictors of geographical locations. Precision, sensitivity, specificity, and F-scores were 0.88, 1, 0.80, and 0.93, respectively. Finally, cluster analysis revealed similarities in substance use among communities.
CONCLUSIONS
These findings suggest that wastewater-based surveillance has the potential to become an effective form of surveillance for substance use. Further, advanced analytical techniques may help uncover geographical patterns and detect communities with similar needs for resources to address substance use disorders. Using automated analytics, these advanced surveillance techniques may help communities develop timely, tailored treatment and prevention efforts.
PubMed: 37883150
DOI: 10.2196/45353 -
BMC Pediatrics Sep 2023Evidence of drug-induced liver injury is abundant in adults but is lacking in children. Our aim was to identify suspected drug signals associated with pediatric liver...
BACKGROUND
Evidence of drug-induced liver injury is abundant in adults but is lacking in children. Our aim was to identify suspected drug signals associated with pediatric liver injury.
METHODS
Hepatic adverse events (HAEs) among children reported in the Food and Drug Administration Adverse Event Reporting System were analyzed. A descriptive analysis was performed to summarize pediatric HAEs, and a disproportionality analysis was conducted by evaluating reporting odds ratios (RORs) and proportional reporting ratios to detect suspected drugs.
RESULTS
Here, 14,143 pediatric cases were reported, specifically 49.6% in males, 45.1% in females, and 5.2% unknown. Most patients (68.8%) were 6-18 years old. Hospitalization ranked first among definite outcomes (7,207 cases, 37.2%). In total, 264 disproportionate drug signals were identified. The top 10 drugs by the number of reports were paracetamol (1,365; ROR, 3.6; 95% confidence interval (CI), 3.4-3.8), methotrexate (878; ROR, 2.5; 95% CI, 2.3-2.7), vincristine (649; ROR, 3.0; 95% CI, 2.8-3.3), valproic acid (511; ROR, 3.2; 95% CI, 2.9-3.6), cyclophosphamide (490; ROR, 2.4; 95% CI, 2.2-2.6), tacrolimus (427; ROR, 2.4; 95% CI, 2.2-2.7), prednisone (416; ROR, 2.1; 95% CI, 1.9-2.3), prednisolone (401; ROR, 2.3; 95% CI, 2.1-2.5), etoposide (378; ROR, 2.3; 95% CI, 2.1-2.6), and cytarabine (344; ROR, 2.8; 95% CI, 2.5-3.2). After excluding validated hepatotoxic drugs, six were newly detected, specifically acetylcysteine, thiopental, temazepam, nefopam, primaquine, and pyrimethamine.
CONCLUSIONS
The hepatotoxic risk associated with 264 signals needs to be noted in practice. The causality of hepatotoxicity and mechanism among new signals should be verified with preclinical and clinical studies.
Topics: Male; Adult; Female; United States; Humans; Child; Adolescent; Pharmaceutical Preparations; Adverse Drug Reaction Reporting Systems; United States Food and Drug Administration; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Liver
PubMed: 37770847
DOI: 10.1186/s12887-023-04097-9 -
Healthcare (Basel, Switzerland) Aug 2023Despite the well-established treatment effectiveness of exercise, cognitive behavioral therapy for insomnia (CBT-I), and pharmacotherapy on improving sleep, there have... (Review)
Review
Effectiveness of Exercise, Cognitive Behavioral Therapy, and Pharmacotherapy on Improving Sleep in Adults with Chronic Insomnia: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.
Despite the well-established treatment effectiveness of exercise, cognitive behavioral therapy for insomnia (CBT-I), and pharmacotherapy on improving sleep, there have been no studies to compare their long-term effectiveness, which is of clinical importance for sustainable management of chronic insomnia. This study compared the long-term effectiveness of these three interventions on improving sleep in adults with chronic insomnia. MEDLINE, PsycINFO, Embase, and SPORTDiscus were searched for eligible reports. Trials that investigated the long-term effectiveness of these three interventions on improving sleep were included. The post-intervention follow-up of the trial had to be ≥6 months to be eligible. The primary outcome was the long-term effectiveness of the three interventions on improving sleep. Treatment effectiveness was the secondary outcome. A random-effects network meta-analysis was carried out using a frequentist approach. Thirteen trials were included in the study. After an average post-intervention follow-up period of 10.3 months, both exercise (SMD, -0.29; 95% CI, -0.57 to -0.01) and CBT-I (-0.48; -0.68 to -0.28) showed superior long-term effectiveness on improving sleep compared with control. Temazepam was the only included pharmacotherapy, which demonstrated superior treatment effectiveness (-0.80; -1.25 to -0.36) but not long-term effectiveness (0.19; -0.32 to 0.69) compared with control. The findings support the use of both exercise and CBT-I for long-term management of chronic insomnia, while temazepam may be used for short-term treatment.
PubMed: 37570447
DOI: 10.3390/healthcare11152207 -
Toxics Jul 2023There has been a significant increase in sodium azide intoxications since the 1980s. Intoxications caused by sodium azide are becoming increasingly prevalent in the...
There has been a significant increase in sodium azide intoxications since the 1980s. Intoxications caused by sodium azide are becoming increasingly prevalent in the Netherlands as a result of its promotion for the purpose of self-euthanasia. The mechanism of toxicity is not completely understood but is dose-dependent. The presented case describes a suicide by sodium azide of a young woman (26 years old) with a history of depression and suicide attempts. The decedent was found in the presence of prescription medicine, including temazepam, domperidone in combination with omeprazole, and the chemical preservative sodium azide. Quantitative toxicology screening of whole blood revealed the presence of 70 µg/L temazepam (toxic range > 1000 µg/L) and 28 mg/L sodium azide (fatal range: 2.6-262 mg/L). Whole blood qualitative analysis revealed the presence of temazepam, temazepam-glucuronide, olanzapine, n-desmethylolanzapine, and acetaminophen. In circles promoting sodium azide, it is recommended to use sodium azide in combination with medications targeting sodium azide's negative effects, such as analgesics, antiemetics, and anti-anxiety drugs. The medicines recovered at the body's location, as well as the results of the toxicology screens, were consistent with the recommendations of self-euthanasia using sodium azide.
PubMed: 37505573
DOI: 10.3390/toxics11070608