Elucidation of Degradation Behavior of Nitrazepam, a Benzodiazepine Drug, under Basic Conditions: Study on Degradability of Drugs in Stomach (IV).

This study investigates the stability of nitrazepam (NZP), a benzodiazepine drug, under basic conditions, since alkaline putrefactive amines and ammonia are produced once bodies are left to decompose for a long period postmortem after a murder involving NZP or an accidental overdose of NZP. The degradation of NZP in an aqueous alkaline solution was investigated by LC/photodiode array detector (PDA) where the NZP degradation product was isolated and purified by solid-phase extraction using Oasis® MCX, and its chemical structure was determined by LC/time-of-flight (TOF)-MS, NMR spectroscopy, and single-crystal X-ray crystallography. The results revealed that NZP was immediately degraded under basic conditions with 2-amino-5-nitrobenzophenone being an intermediate which further degraded to provide 2-hydroxy-5-nitrobenzophenone as the final degradation product. These results are expected to be useful in clinical chemistry and forensic science, such as the detection of drugs during postmortem examination and suspected addiction.

Nitrazepam and 7-aminonitrazepam studied at the macroscopic and microscopic electrified liquid-liquid interface.

Two benzodiazepine type drugs, that is, nitrazepam and 7-aminonitrazepam, were studied at the electrified liquid-liquid interface (eLLI). Both drugs are illicit and act sedative in the human body and moreover are used as date rape drugs. Existence of the diazepine ring in the concerned chemicals structure and one additional amine group (for 7-aminonitrazepam) allows for the molecular charging below their pKa values, and hence, both drugs can cross the eLLI interface upon application of the appropriate value of the Galvani potential difference. Chosen molecules were studied at the macroscopic eLLI formed in the four electrode cell and microscopic eLLI formed within a microtip defined as the single pore having 25 µm in diameter. Microscopic eLLI was formed using only a few µL of the organic and the aqueous phase with the help of a 3D printed cell. Parameters such as limit of detection and voltammetric detection sensitivity are derived from the experimental data. Developed methodology was used to detect nitrazepam in pharmaceutical formulation and both drugs (nitrazepam and 7-aminonitrazepam) in spiked biological fluids (urine and blood).

Genotype-phenotype correlations of STXBP1 pathogenic variants and the treatment choices for STXBP1-related disorders in China.

BACKGROUND: We aimed to analyze the genotype-phenotype correlations of STXBP1 pathogenic variants, prognostic factors and the treatment choices in a case-series of STXBP1-related disorders from China. METHODS: The clinical data and genetic results of the children diagnosed with STXBP1-related disorders at Xiangya hospital from 2011 to 2019 were collected retrospectively, and analyzed. We divided our patients into groups for comparison purposes: patients with missense variants and nonsense variants, patients who are seizure-free and not seizure-free, patients with mild to moderate intellectual disability (ID) and severe to profound global developmental delay (GDD). RESULTS: Nineteen patients were enrolled: 17 (89.5%) unrelated and 2 (10.5%) familial. Twelve (63.2%) were females. Developmental epileptic encephalopathy (DEE) was observed in 18 (94.7%) patients and ID alone in 1 (5.3%) individual. Thirteen patients (68.4%) had profound ID/GDD, 4 (23.53%) severe, 1 (5.9%) moderate and 1 (5.9%) mild. Three patients (15.8%) with profound ID died. A total of 19 variants were detected: pathogenic (n = 15) and likely pathogenic (n = 4). Seven were novel variants: c.664-1G>-, M486R, H245N, H498Pfs*44, L41R, L410del, and D90H. Of the 8 previous reported variants, 2 were recurrent: R406C and R292C. Anti-seizure medications were used in combinations, and 7 patients became seizure-free, and most of them achieved seizure freedom within the first 2 years of life irrespective of the type of the mutation. Effective medications for the seizure-free individuals included adrenocorticotropic (ACTH) and/or levetiracetam and/or phenobarbital and/or sodium valproate and/or topiramate and/or vigabatrin and/or nitrazepam. There was no correlation between the types of pathogenic variants and the phenotypes. CONCLUSION: Our case-series showed that there is no genotype-phenotype correlation in patients with STXBP1-related disorders. This study adds 7 novel variants which expand the spectrum of STXBP1-related disorders. Combinations of levetiracetam and/or sodium valproate and/or ACTH and/or phenobarbital and/or vigabatrin and/or topiramate and/or nitrazepam were more often associated with seizure freedom in our cohort within 2 years of life.

Formulation of biofungicides based on Streptomyces caeruleatus strain ZL-2 spores and efficacy against Rhizoctonia solani damping-off of tomato seedlings.

This work aims at exploring an antagonistic actinobacterial strain isolated from the roots of Ziziphus lotus in bioformulation processes and the biocontrol of Rhizoctonia solani damping-off of tomato seedlings. The strain Streptomyces caeruleatus ZL-2 was investigated for the principal in vitro biocontrol mechanisms and then formulated in three different biofungicides: wettable talcum powder (WTP), sodium alginate propagules (SAP) and clay sodium alginate propagules (CAP). Compared to a marketed control products (Serenade® and Acil 060FS®), the formulated biofungicides were investigated against the R. solani damping-off of tomato cv. Aïcha seedlings. The strain ZL-2 produced chitinases, cellulases, ß-1,3-glucanases, cyanhydric acid and siderophores. It also showed strong antagonistic effect on the mycelial growth of R. solani. Bioautographic and HPLC analysis revealed the production of a single or several co-migrating antifungal compounds. The biofungicide WTP presented an attractive biocontrol effect by significantly reducing the disease severity index (DSI) compared to untreated seeds. No significant differences were obtained compared to the chemical treatment with Acil 060FS®. The viability of spores and biocontrol efficacy of the WTP were confirmed after 1-year storage. Strain ZL-2 has never been reported in the bioformulation of active biofungicides against Rhizoctonia solani damping-off and this work opens up very attractive prospects in the fields of biocontrol and crop improvement.

Quetiapine Add-On Therapy May Improve Persistent Sleep Disturbances in Patients with PTSD on Stabile Combined SSRI and Benzodiazepine Combination: A One-Group Pretest-Posttest Study.

BACKGROUND: To assess potential benefits of quetiapine for persistent sleep disturbances in patients with posttraumatic stress disorder (PTSD) on stable combined SSRI and benzodiazepine therapy, who previously failed to respond to various benzodiazepine and non-benzodiazepine hypnotic adjuvant treatment as well as to first-generation antipsychotic add-on treatment. SUBJECTS AND METHODS: Fifty-two male PTSD outpatients on stable combination treatment with SSRI and benzodiazepines, with persistent sleep disturbances not responding to prescription of zolpidem, flurazepam, nitrazepam, promazine, and levopromazine, were assessed for sleep disturbances improvements after prescription of quetiapine in the evening. Each patient met both ICD-10 and DSM-IV criteria for PTSD. Psychiatric comorbidity and premorbidity were excluded using the Mini-International Neuropsychiatric Interview (MINI). Improvement on the CAPS recurrent distressing dream item, reduction in the amount of time needed to fall asleep, prolongation of sleep duration, and reduction in average number of arousals per night in the last 7 days before the assessment period were used as efficacy measures. RESULTS: All sleep-related parameters improved significantly at the end of a five-week follow-up: sleep duration increased by one hour (p<0.001), sleep latency decreased by 52.5 minutes (p<0.001), median number of arousals per night decreased from two to one (p<0.001), CAPS recurrent distressing dream item median decreased from five to four (p<0.001), and the number of patients dissatisfied with their sleep quality and quantity decreased from 45 to two (p<0.001). CONCLUSION: Quetiapine prescribed in the evening may be successful therapy for persistent sleep disturbances in patients with PTSD and generally good response to an SSRI and benzodiazepine combination, who previously failed to respond to some of the usual hypnotic medication or addition of first-generation antipsychotics: zolpidem, flurazepam, nitrazepam, promazine, and levopromazine.

Vortex-assisted dispersive liquid-liquid microextraction-gas chromatography (VADLLME-GC) determination of residual ketamine, nimetazepam, and xylazine from drug-spiked beverages appearing in liquid, droplet, and dry forms.

Presently, investigations of drug-facilitated crimes (DFCs) rely on the detection of substances extracted from biological samples following intake by the victim. However, such detection requires rapid sampling and analysis prior to metabolism and elimination of the drugs from the body. In cases of suspected DFCs, drug-spiked beverage samples, whether in liquid, droplet, or even dried form, can be tested for the presence of spike drugs and used as evidence for the occurrence of DFCs. This study aimed to quantitatively determine three sedative-hypnotics (ketamine, nimetazepam, and xylazine) from drug-spiked beverages using a vortex-assisted dispersive liquid-liquid microextraction-gas chromatography (VADLLME-GC) approach. In this study, a GC method was first developed and validated, followed by the optimization of the VADLLME protocol, which was then applied to quantify the target substances in simulated forensic case scenarios. The developed GC method was selective, sensitive (limit of detection: 0.08 µg/ml [ketamine]; 0.16 µg/ml [nimetazepam]; 0.08 µg/ml [xylazine]), linear (R2 > 0.99), precise (%RSD <7.2%), and accurate (% recovery: 92.8%-103.5%). Higher recoveries were achieved for the three drugs from beverage samples in liquid form (51%-97%) as compared to droplet (48%-96%) and dried (44%-93%) residues. The recovery was not hindered by very low volumes of spiked beverage and dried residues. In conclusion, the developed VADLLME-GC method successfully recovered ketamine, nimetazepam, and xylazine from spiked beverages that are likely to be encountered during forensic investigation of DFCs.

The Risk of Preoperative Central Nervous System-Acting Medications on Delirium Following Hip or Knee Surgery: A Matched Case-Control Study.

INTRODUCTION: Medicines acting on the central nervous system can increase the risk of postoperative delirium, but the specific medicines associated with greatest risk remain unclear. OBJECTIVES: We aimed to examine the risk of individual central nervous system-acting medicines used preoperatively on delirium after hip or knee surgery. METHODS: A matched case-control study was conducted using data from the Australian Government Department of Veterans' Affairs. We included people aged 65 years or older who had knee or hip surgery between 2000 and 2019. People with hip or knee surgery who developed postoperative delirium were cases and controls were people with hip or knee surgery but who did not develop postoperative delirium. Use of medicines including anxiolytics, sedatives, and hypnotics, opioid analgesics and antidepressants prior to surgery was compared between cases and controls. RESULTS: A total of 2614 patient cases with postoperative delirium were matched by same sex, age (±2 years), and year of admission (±2 years) with 7842 controls without postoperative delirium. Cases were more likely to be exposed to nitrazepam (odds ratio [OR] = 1.81, 95% confidence interval [CI] 1.24-2.64), sertraline (OR = 1.50, 95% CI 1.20-1.87), mirtazapine (OR = 1.38, 95% CI 1.11-1.74), venlafaxine (OR = 1.42, 95% CI 1.02-1.98), citalopram (OR = 1.54, 95% CI 1.19-1.99), escitalopram (OR = 1.42, 95% CI 1.06-1.89) or fluvoxamine (OR = 5.01, 95% CI 2.15-11.68) prior to surgery than controls. At the class level, exposure to benzodiazepines (OR = 1.20, 95% CI 1.05-1.37) and antidepressants (OR = 1.64, 95% CI 1.47-1.83) prior to surgery was significantly higher in cases than in controls. The numbers needed to treat to harm for one additional delirium case were 43 for sertraline, 40 for citalopram, 57 for mirtazapine and 26 for nitrazepam. Whereas, the numbers needed to treat to harm were found to be 20 for sertraline, 17 for citalopram, 19 for mirtazapine and 10 for nitrazepam in the 85 years or older age group, indicating that the harmful effect of these medicines is pronounced as age advances. CONCLUSIONS: People who developed delirium following hip or knee surgery were more likely to be exposed to nitrazepam, sertraline, mirtazapine, venlafaxine, citalopram, escitalopram or fluvoxamine at the time of admission for surgery. Planning to reduce use of these medicines well prior to surgery may decrease the risk of postoperative delirium.

Effectiveness and Safety of Nitrazepam in Children with Resistant West Syndrome.

OBJECTIVES: To study the effectiveness, tolerability, and safety of oral nitrazepam in children with resistant West syndrome (WS). METHODS: This prospective observational study was conducted at a tertiary care hospital in North India from January 2019 to October 2020. Children with WS resistant to standard therapy were enrolled within 7 d of initiation of nitrazepam and prospectively followed-up for cessation of spasms and adverse events. RESULTS: Forty-one children with resistant WS initiated on nitrazepam therapy were evaluated. The median age at onset of spasms was 6 mo (Q1, Q3: 4, 8). There was a preponderance of male gender (71%) and structural causes (78%). More than half of the enrolled children had failed four or more antiseizure medications (ASM) for epileptic spasms. The study participants had a long lead-time-to-treatment (LTTT) for the initial standard therapy (median: 2 mo; Q1, Q3: 1, 5) and nitrazepam (median: 11 mo; Q1, Q3: 8, 16). Nitrazepam was instituted as monotherapy in 7 (17%) children and as an adjunct in the rest. Twenty-one (51%) children achieved persistent cessation of epileptic spasms. However, the electroclinical response was observed in 17 (42%) children. Drowsiness, sialorrhea, and decreased appetite were the most commonly observed adverse events. Most adverse events were mild to moderate in severity and did not require dose reduction or change of medication. There was no significant difference between the responders and nonresponders in terms of LTTT, age at onset, or etiology. CONCLUSIONS: Nitrazepam is a safe and feasible treatment alternative in children with resistant WS resulting in persistent cessation of spasms and electroclinical response in nearly half of patients.

Incorporation of five common hypnotics into hair after a single dose and application to a forensic case of drug facilitated crimes.

In order to obtain fundamental information on the disposition of hypnotics into hair after a single oral dose the quantitative hair analysis of triazolam (TZ), etizolam (EZ), flunitrazepam (FNZ), nitrazepam (NZ) and zolpidem (ZP) have been performed using a validated LC-MS/MS procedure. Hair specimens (straight, black) were collected from three subjects about one month and three months after a single 0.25 mg dose of TZ, 1 mg of EZ, 2 mg of FNZ, 5 mg of NZ and 10 mg of ZP tartrate. The subjects ingested just one out of five different hypnotics on each day, each of five days in turn. All ingested hypnotics have been detected in hair from each subject both one month and three months after intake, and their concentrations were in the range of 0.023-0.043 pg/hair strand (0.077-0.36 pg/mg) for TZ, 0.11-0.63 pg/hair strand (0.44-5.2 pg/mg) for EZ, 0.14-2.6 pg/hair strand (0.56-22 pg/mg) for FNZ, 0.33-1.7 pg/hair strand (1.3-17 pg/mg) for NZ and 20-40 pg/hair strand (120-270 pg/mg) for ZP. For FNZ and NZ, not only the parent drugs but also their metabolites, 7-amino-FNZ and 7-amino-NZ, were detected in the range of 2.3-9.2 pg/hair strand (9.2-82 pg/mg) and 2.4-9.1 pg/hair strand (8.0-55 pg/mg), respectively. The calculated incorporation ratios into hair against the dose were found to exhibit similarity between the four benzodiazepines. This finding suggests the ability to apply these quantitative data to approximately estimating the amounts of other benzodiazepines, which have similar chemical structures, in hair although it should be noted that the amounts of drugs in hair varies considerably depending on the hair color. On the other hand, the incorporation ratio of ZP showed 15-29 times higher than that of TZ, indicating that lipophilic ZP was more likely to incorporate into hair than benzodiazepines. In addition, the application of the present data to a drug-facilitated sexual assault was shown.

Elucidation of Degradation Behavior of Nitrazepam and Other Benzodiazepines in Artificial Gastric Juice: Study on Degradability of Drugs in Stomach (II).

The degradation behavior of eight benzodiazepines (BZPs): alprazolam, etizolam, diazepam, triazolam, nitrazepam (NZP), flunitrazepam (FNZ), bromazepam, and lorazepam, in artificial gastric juice was monitored by a LC/photodiode array detector (PDA) to estimate their pharmacokinetics in the stomach. For drugs that were degradable, such physicochemical parameters as reaction rate constant were measured to evaluate the effect of storage conditions on drug degradability, such as whether the degradation proceeds faster by increasing storage temperature, or whether the degradation reaction is reversible by adjusting pH. As a result, it was confirmed that although the eight BZPs degraded in artificial gastric juice, most of them could be restored when pH was increased, and the restoration rates differed depending on the pH and the type of BZP. As for NZP, an Arrhenius plot was drawn to obtain the physicochemical parameters, such as activation energy and activation entropy involved in the degradation reaction, and the reaction kinetics was discussed. In addition, two substances were confirmed as the degradation products of NZP in artificial gastric juice: one was a reversible degradation product (A) (intermediate) and the other was an irreversible degradation product (B) (final degradation product). The intermediate was identified as 2-amino-N-(2-benzoyl-4-nitrophenyl)-acetamide, and the final degradation product was 2-amino-5-nitrobenzophenone. Therefore, when detecting NZP in human stomach contents, such as during judicial dissection, it would be prudent to target NZP as well as the intermediate (A) and the final degradation product (B).

Caracterización de la prescripción de ansiolíticos en adultos mayores institucionalizados en un hogar de ancianos / Characterization of the prescription of anxiolytics in institutionalized older adults in the nursing home

El objetivo de este estudio fue caracterizar la prescripción de los medicamentos ansiolíticos utilizados en población de adultos mayores institucionalizados en el hogar de ancianos de Pinar del Río durante el año 2017.Se realizó un estudio descriptivo transversal, con recogida de datos retrospectiva, sobre prescripción de medicamentos ansiolíticos en la población de adultos mayores institucionalizados en el hogar de ancianos, se analizó la forma de utilización de los medicamentos, su indicación y prescripción con elementos de esquema terapéutico y factores que condicionan los hábitos de prescripción. Se trabajó con el universo (U= 98) de estudio el cual estuvo conformado por el total de pacientes institucionalizados, que estaban consumiendo ansiolíticos. Se revisaron las historias clínicas individuales y se confeccionó un modelo de recolección de datos.El medicamento más consumido por los adultos mayores fue el nitrazepam (41,8 %), siendo este a su vez el más consumido por el sexo masculino, no así para el femenino que resultó ser el clorodiazepóxido (64,6 %), el grupo de edad que más predominó fue el de 60-69 años, asimismo los viudos y el nivel educacional primario, el 79,5 % de los ancianos consume otros medicamentos que poseen interacción farmacocinética. El profesional que más indicó fue el médico de familia, la prescripción e intervalos entre dosis fue adecuada, la prescripción se consideró no racional.La prescripción de ansiolíticos en la población objeto de estudio, disminuye a medida que aumenta la edad, los más consumidores son los del sexo masculino y los institucionalizados por abandono familiar, esto apunta a la necesidad de continuar trabajando desde el nivel primario de atención dado que es de donde proceden estos ancianos.

The objective of this study was to characterize the prescription of anxiolytic medications used in the institutionalized elderly population at the Pinar del Río Nursing Home during 2017.A cross-sectional descriptive study was carried out, with retrospective data collection, on the prescription of anxiolytic medications in the population of institutionalized older adults in the Nursing Home, the form of use of the medications, their indication and prescription with elements of the therapeutic scheme was analyzed and factors that condition prescription habits. We worked with the universe (U = 98) of the study, which was made up of the total number of institutionalized patients who were consuming anxiolytics. Individual medical records were reviewed and a data collection model was created.The drug most consumed by older adults was nitrazepam (41.8%), this in turn being the most consumed by males, not so for females, which turned out to be chlorodiazepoxide (64.6%), the group The most prevalent age group was 60-69 years, likewise widowers and primary educational level, 79.5% of the elderly consume other drugs that have pharmacokinetic interaction. The professional who indicated the most was the family doctor, the prescription and intervals between doses were adequate, the prescription was considered non-rational.The prescription of anxiolytics in the population under study decreases as age increases, the most consumers are those of the male sex and those institutionalized due to family abandonment, this points to the need to continue working from the primary level of care since that is where these elders come from.

Maestro of the SereNADe: SLC25A51 Orchestrates Mitochondrial NAD.

Recently, three groups, Girardi et al., Kory et al., and Luongo et al., independently identified solute carrier (SLC) 25A51 as the long-sought, major mitochondrial NAD+ transporter in mammalian cells. These studies not only deorphan an uncharacterized transporter of the SLC25A family, but also shed light on other aspects of NAD+ biology.

Oral S-ketamine effective after deep brain stimulation in severe treatment-resistant depression and extensive comorbidities.

This case report describes successful maintenance treatment with oral S-ketamine in a patient with severe depression, who previously was resistant to electroconvulsive therapy and deep brain stimulation, and who also had comorbid psychotic and obsessive compulsive symptoms.

Subunit-Specific Photocontrol of Glycine Receptors by Azobenzene-Nitrazepam Photoswitcher.

Photopharmacology is a unique approach that through a combination of photochemistry methods and advanced life science techniques allows the study and control of specific biological processes, ranging from intracellular pathways to brain circuits. Recently, a first photochromic channel blocker of anion-selective GABAA receptors, the azobenzene-nitrazepam-based photochromic compound (Azo-NZ1), has been described. In the present study, using patch-clamp technique in heterologous system and in mice brain slices, site-directed mutagenesis and molecular modeling we provide evidence of the interaction of Azo-NZ1 with glycine receptors (GlyRs) and determine the molecular basis of this interaction. Glycinergic synaptic neurotransmission determines an important inhibitory drive in the vertebrate nervous system and plays a crucial role in the control of neuronal circuits in the spinal cord and brain stem. GlyRs are involved in locomotion, pain sensation, breathing, and auditory function, as well as in the development of such disorders as hyperekplexia, epilepsy, and autism. Here, we demonstrate that Azo-NZ1 blocks in a UV-dependent manner the activity of α2 GlyRs (GlyR2), while being barely active on α1 GlyRs (GlyR1). The site of Azo-NZ1 action is in the chloride-selective pore of GlyR at the 2' position of transmembrane helix 2 and amino acids forming this site determine the difference in Azo-NZ1 blocking activity between GlyR2 and GlyR1. This subunit-specific modulation is also shown on motoneurons of brainstem slices from neonatal mice that switch during development from expressing "fetal" GlyR2 to "adult" GlyR1 receptors.

A molecularly imprinted polymer based chemiluminescence array sensor for one-step determination of phenothiazines and benzodiazepines in pig urine.

The residues of phenothiazines and benzodiazepines in foods of animal origin are dangerous to consumers. For inspection of their abuses, this study for the first time reported on the use of a chemiluminescence array sensor for the simultaneous determination of four phenothiazines and five benzodiazepines in pig urine. Two molecularly imprinted polymers were coated in different wells of a conventional 96-well microtiter plate as the recognition reagents. After sample loading, the absorbed analytes were initiated directly by using an imidazole enhanced bis(2,4,6-trichlorophenyl)oxalate-hydrogen peroxide system to emit light. The assay process consisted of only one sample-loading step prior to data acquisition, so one test was finished within 10 min. The limits of detection for the nine drugs in the pig urine were in a range of 0.1 to 0.6 pg/mL, and the recoveries from the fortified blank urine samples were in a range of 80.3 to 95%. Furthermore, the sensor could be reused six times. Therefore, this sensor could be used as a simple, rapid, sensitive and reusable tool for routine screening for residues of phenothiazines and benzodiazepines in pig urine.

Identification of enzymes responsible for nitrazepam metabolism and toxicity in human.

Nitrazepam (NZP) is a hypnotic agent that rarely causes liver injuries in humans and teratogenicity in rodents. In humans, NZP is primarily metabolized to 7-aminonitrazepam (ANZP) by reduction and subsequently to 7-acetylamino nitrazepam (AANZP) by acetylation. ANZP can be regenerated from AANZP by hydrolysis in rodents, but it is still unclear whether this reaction occurs in humans. In rodents, AANZP may be associated with teratogenicity, while in humans, it is known that drug-induced liver injuries may be caused by NZP reactive metabolite(s). In this study, we attempted to identify the enzymes responsible for NZP metabolism to obtain a basic understanding of this process and the associated metabolite toxicities. We found that the NZP reductase activity in human liver cytosol (HLC) was higher than that in human liver microsomes (HLM). We purified the responsible enzyme(s) from HLC and found that the NZP reductase was aldehyde oxidase 1 (AOX1). The role of AOX1 was confirmed by an observed increase in the NZP reductase activity upon addition of N1-methylnicotinamide, an electron donor of AOX1, as well as inhibition of this activity in HLC in the presence of AOX1 inhibitors. ANZP was acetylated to form AANZP by N-acetyltransferase (NAT) 2. An experiment using recombinant esterases in an inhibition study using HLM revealed that AANZP is hydrolyzed by arylacetamide deacetylase (AADAC) in the human liver. N-Hydroxylamino NZP, which is suspected to be a reactive metabolite, was detected as a conjugate with N-acetyl-l-cysteine through NZP reduction and ANZP hydroxylation reactions. In the latter reaction, the conjugate was readily formed by recombinant CYP3A4 among the various P450 isoforms tested. In sum, we found that AOX1, NAT2, AADAC, and CYP3A4 are the determinants for the pharmacokinetics of NZP and that they confer interindividual variability in sensitivity to NZP side effects.

Health risk appraisal in older people 7: long-acting benzodiazepine use in community-dwelling older adults in London: is it related to physical or psychological factors?

Aim To investigate whether the use of long-acting benzodiazepines, in individuals aged 65 and over is mediated by physical or psychological factors. BACKGROUND: Long-acting benzodiazepine consumption among older people has implications for mortality, morbidity and cost-effective prescribing. Two models explain benzodiazepine use in this age group, one linked to physical illness and disability and one to psychological factors. METHODS: Secondary analysis of baseline data from a study of 1059 community-dwelling non-disabled people aged 65 years and over recruited from three general practices in London. For this analysis, use of long-acting benzodiazepines was defined as any self-reported use of diazepam or nitrazepam in the last four weeks. Associations between demographic factors, health service use, and physical and psychological characteristics and benzodiazepine use were investigated. Findings The prevalence of benzodiazepine use in this sample was 3.3% (35/1059). In univariate analyses, benzodiazepine use was associated with female gender, low income, high consultation rates, physical factors (medication for arthritis or joint pain, polypharmacy, difficulties in instrumental activities of daily living, recent pain) and psychological factors (poor self-perceived health, social isolation, and symptoms of anxiety or agitation). In a multivariate logistic regression analysis only two factors retained statistically significant independent associations with benzodiazepine use: receiving only the state pension (OR=4.0, 95% CI: 1.70, 9.80) and pain in the past four weeks (OR=3.79, 95% CI: 1.36, 10.54).

Structure-based design and synthesis of imidazo[1,2-a]pyridine derivatives as novel and potent Nek2 inhibitors with in vitro and in vivo antitumor activities.

We present herein the discovery and development of novel and potent Nek2 inhibitors with distinctive in vitro and in vivo antitumor activity based on an imidazo[1,2-a]pyridine scaffold. Our studies identified a nonlinear SAR for activity against both Nek2 and cancer cells. Bioisostere and structure-based design techniques were employed to identify compounds 42c (MBM-17, IC50 = 3.0 nM) and 42g (MBM-55, IC50 = 1.0 nM), which displayed low nanomolar activity and excellent selectivity for Nek2. Both compounds effectively inhibited the proliferation of cancer cells by inducing cell cycle arrest and apoptosis. Importantly, the salts form of these two compounds (MBM-17S and MBM-55S) significantly suppressed tumor growth in vivo without apparent toxicity based on appearance and changes in body weight. In summary, MBM-17 and MBM-55 displayed the potential for substantial therapeutic application in cancer treatment.