A system-level approach to investigate alloxan-induced toxicity in microtubule-binding protein to lead type 2 diabetes mellitus.

Microtubule-associated protein tau (MAPT) is a key protein, which is mainly identified as an essential factor for microtubule dynamics and neuronal outgrowth. Though tau has several functions, regulation of insulin signaling is one among them to control type 2 diabetes. Abnormal expression of tau protein leads to hyperphosphorylation and is known as tauopathies. The presence of alloxan occurs in refined wheat flour, especially in various baking products such as parotta, a well-known South Indian dish. In this study, the reduced form of alloxan called dialuric acid can enter the beta cells of islets of Langerhans and binds MAPT to induce toxicity by hyperphosphorylating the tau protein, which ultimately causes destruction to pancreatic beta cells, and it leads to diabetes mellitus. Here, the toxic effects of dialuric acid targeting MAPT through in silico computational predictions have been investigated. The 3D structure of MAPT protein was constructed through I-Tasser, and it has been refined and validated by GalaxyRefine and PROCHECK. The structure of ligand was retrieved from PubChem. Molecular docking was accomplished by AutoDock 4.2 software, and the results indicate the strong binding affinity between dialuric acid and MAPT protein, and it showed a binding free energy (∆G) of - 3.72 kcal/mol. Dialuric acid binds with the active region SER 232 of MAPT whereby it hyperphosphorylates the protein to become toxic. Also, ADMET results strongly suggest that the compound dialuric acid possesses toxic property, and similarly, Ames test confirmed that it was found to be mutagenic. Thus, our results strongly revealed that dialuric acid was found to be toxic which could be able to damage the beta cells of the pancreas and abates insulin signaling, and finally, it leads to DM.

Trends and characteristics in barbiturate deaths Australia 2000-2019: a national retrospective study.

INTRODUCTION: There have been increasing reports documenting barbiturate-related deaths, despite routine prescribing for only relatively rare indications. The aims of the current study were to examine trends in barbiturate-related deaths in Australia from 2000 to 2019 and determine the case characteristics and circumstances of barbiturate-related deaths. METHODS: All barbiturate-related deaths identified in the Australian National Coronial Information System were examined. Information was collected on cause, manner, demographics, location, psychosocial factors, circumstances of deaths and toxicology. We examined these based on the age categories 18-44 years, 45-64 years and ≥65 years. RESULTS: We identified 511 cases. Mean age was 57.9 years (SD 20.2, range 18-100) and 56% were male. Intentional poisoning was the most common cause of death (87.5%) and was slightly higher in the oldest age group (92.1%) and lowest in the youngest age group (81.1%). Pentobarbitone was the most common barbiturate (75.7%) and pentobarbitone-related deaths increased from 0% in 2000 to 93.6% in 2017. There were notable differences between age categories, with the youngest age group recording more severe psychiatric histories. In contrast, the oldest age group were more likely to have severe physical health problems, such as cancer, chronic non-cancer pain, neurological conditions and significant cardiopulmonary morbidity. Euthanasia resources were commonly documented (33.9%), most frequently in the oldest age group (52.3%). CONCLUSION: Barbiturate-related deaths in Australia are increasing, particularly pentobarbitone-related deaths. Most deaths were intentional and involved adults across the lifespan. Younger people were more likely to have significant mental health problems, whilst the oldest age group were more likely to have severe physical health conditions.

Carcinogenicity Assessment of Daprodustat (GSK1278863), a Hypoxia-Inducible Factor (HIF)-Prolyl Hydroxylase Inhibitor.

Daprodustat (GSK1278863) is a hypoxia-inducible factor (HIF)-prolyl hydroxylase (PHD) inhibitor in development for treatment of anemia of chronic kidney disease. Daprodustat's biological activity simulates components of the natural response to hypoxia; inhibition of PHDs results in HIF stabilization and modulation of HIF-controlled gene products, including erythropoietin. The carcinogenic potential of daprodustat was evaluated in 2-year carcinogenicity studies in Sprague-Dawley rats and CD-1 mice, where once-daily doses were administered. The mouse study also included evaluation of daprodustat's 3 major circulating human metabolites. There were no neoplastic findings that were considered treatment related in either study. Exaggerated pharmacology resulted in significantly increased red cell mass and subsequent multiorgan congestion and secondary non-neoplastic effects in both species, similar to those observed in chronic toxicity studies. In rats, these included aortic thrombosis and an exacerbation of spontaneous rodent cardiomyopathy, which contributed to a statistically significant decrease in survival in high-dose males (group terminated in week 94). Survival was not impacted in mice at any dose. Systemic exposures (area under the plasma concentration-time curve) to daprodustat at the high doses in rats and mice exceed predicted maximal human clinical exposure by ≥143-fold. These results suggest that daprodustat and metabolites do not pose a carcinogenic risk at clinical doses.

Identification of a pyrimidinetrione derivative as the potent DprE1 inhibitor by structure-based virtual ligand screening.

Despite the increasing need of new antituberculosis drugs, the number of agents approved for the market has fallen to an all-time low. In response to the emerging drug resistance followed, structurally unique chemical entities will be highlighted. decaprenylphosphoryl-ß-d-ribose oxidase (DprE1) participating in the biosynthesis of mycobacterium cell wall is a highly vulnerable and validated antituberculosis target. On the basis of it, a systematic strategy was applied to identify a high-quality lead compound (compound 50) that inhibits the essential enzyme DprE1, thus blocking the synthesis of the mycobacterial cell wall to kill M. tuberculosis in vitro and in vivo. Correspondingly, the rational design and synthetic strategy for compound 50 was reported. Notably, the compound 50 has been confirmed to be no toxicity. Altogether, our data suggest the compound 50 targeting DprE1 is a promising candidate for the tuberculosis (TB) therapy.

[The development of the method for enzymatic hydrolysis for the extraction of toxic substances from the hair samples]. / Razrabotka metodiki fermentativnogo gidroliza dlia izolirovaniia toksichnykh veshchestv iz obraztsov volos.

The objective of the present study was to develop and validate the method for the extraction of toxic substances from the hair samples as exemplified by enzymatic hydrolysis of barbituric acid derivatives. The experiments were carried out with the use of laboratory animals (white female rats and albino guinea pigs) that had been daily given a phenobarbital solution per os during 4 months preceding the study. The hairs obtained from the experimental animals were subjected to acid hydrolysis with a 6 mole hydrochloric acid and enzymatic hydrolysis with the use of chymopsin, trypsin, chymotrypsin, and papain solutions. The analysis of the extracted materials was performed by means of gas chromatography with mass-selective detection. The application of the proposed method for enzymatic hydrolysis produced the better results than acid hydrolysis. This technique was validated. The results of the study made possible the comparative characteristic of the effectiveness of acid and enzymatic hydrolysis.

Comparison of umbilical cord tissue and meconium for the confirmation of in utero drug exposure.

OBJECTIVES: Drug screening in neonates is traditionally performed using meconium, but cord tissue has been proposed as an alternative specimen. This study compares the detection of drugs in a large number of paired meconium and umbilical cord tissue samples from subjects at risk of in utero drug exposure. DESIGN AND METHODS: Physician-ordered toxicology results and clinical information were collected in a retrospective review of subject medical records. All toxicology testing was performed by a national reference laboratory using a combination of immunoassays and chromatography-mass spectrometry. The comparison was limited to drugs present in both cord and meconium panels. RESULTS: Overall agreement between cord and meconium ranged from 76% (cannabinoids) to 100% (barbiturates), but Cohen's kappa was <65% for 5 of the 6 drug classes we studied. Considering meconium as the gold standard, cord was less sensitive for the detection of 5 of the 6 drug classes, and for the detection of all 5 individual opioids. For 3 of the 5 individual opioids, the concentration of drug measured in meconium did not correlate well with qualitative detection in cord. CONCLUSIONS: This study reveals different sensitivities of drug detection in umbilical cord tissue and meconium. For the drugs studied here, meconium provides greater sensitivity, and is likely to remain the specimen of choice when sensitivity is of greatest importance. These results can help clinicians, laboratorians, and epidemiologists to (1) select the most appropriate test to confirm a suspected drug exposure and (2) interpret discordant results when testing is performed in multiple matrices.

Degradation of vicine, convicine and their aglycones during fermentation of faba bean flour.

In spite of its positive repercussions on nutrition and environment, faba bean still remains an underutilized crop due to the presence of some undesired compounds. The pyrimidine glycosides vicine and convicine are precursors of the aglycones divicine and isouramil, the main factors of favism, a genetic condition which may lead to severe hemolysis after faba bean ingestion. The reduction of vicine and convicine has been targeted in several studies but little is known about their degradation. In this study, the hydrolysis kinetics of vicine and convicine and their derivatives during fermentation with L. plantarum DPPMAB24W was investigated. In particular, a specific HPLC method coupled to ESI-MS and MS/MS analysis, including the evaluation procedure of the results, was set up as the analytical approach to monitor the compounds. The degradation of the pyrimidine glycosides in the fermented flour was complete after 48 h of incubation and the aglycone derivatives could not be detected in any of the samples. The toxicity of the fermented faba bean was established through ex-vivo assays on human blood, confirming the experimental findings. Results indicate that mild and cost effective bioprocessing techniques can be applied to detoxify faba bean also for industrial applications.

PPL catalyzed four-component PASE synthesis of 5-monosubstituted barbiturates: Structure and pharmacological properties.

Enzymatic four-component reactions are very rare although three-component enzymatic promiscuous reactions are widely reported. Herein, we report an efficient PASE protocol for the synthesis of potentially lipophilic zwitterionic 5-monosubstituted barbiturates by four component reaction of mixture of ethyl acetoacetate, hydrazine hydrate, aldehyde and barbituric acid in ethanol at room temperature. Seven different lipases were screened for their promiscuous activity towards the synthesis of 5-monosubstituted barbiturates and the lipase from porcine pancreas (PPL) found to give optimum efficiency. The zwitterionic 5-monosubstituted barbiturates with pyrazolyl ring showed promising pharmacological activity upon screening for antibacterial and apoptotic properties.

Insomnio y muerte de Marilyn Monroe. Parte I: Insomnio / No disponible

Objetivo: Conocer la historia clínica del insomnio de Marilyn Monroe (MM) y de quiénes, y con qué criterio, cuidaron del mismo. Material y métodos: Empleo de información gráfica (documentos y fotografías) de origen contrastado, testimonios directos de testigos verificables y valoración de conflictos de intereses. Resultados: MM daba importancia al sueño nocturno para presentar un buen aspecto en su trabajo. Desarrolló insomnio durante su ascenso a la fama en el contexto de un problema de pánico escénico y su adicción a barbitúricos pudo iniciarse por la facilidad para obtenerlos. Se interesó por el psicoanálisis como vía de autoconocimiento personal y mejora interpretativa. Sus psiquiatras basaron su tratamiento en el psicoanálisis freudiano y un uso intensivo de fármacos, sobre todo barbitúricos, pero esta estrategia fracasó. La relación médico-paciente con su último psiquiatra, el Dr. Greenson, fue particularmente anómala. En sus últimos meses de vida, MM fue tratada con cerca de una docena de psicofármacos, sobre todo barbitúricos, pero también otros hipnóticos y ocasionalmente anfetaminas. Discusión: Los fármacos complicaron la evolución del insomnio de MM y ejercieron un efecto negativo sobre su salud general y su comportamiento, situación que suelen ignorar los diversos diagnósticos psiquiátricos que se le otorgan. Dada la falta de control médico, la presencia de intereses espurios, y una paciente que creía tener bajo un control razonable su consumo de fármacos, la aparición de una complicación grave sólo era cuestión de tiempo(AU)

Objective: To understand Marilyn Monroe’s (MM) insomnia clinical history, and how and by whom it was managed. Materials and method: Use of graphic information (documents and photographs) from verified sources, direct accounts from reliable witnesses, and assessment of conflicts of interest. Results: MM valued nocturnal sleep as a way to keep her good looks at work. She developed insomnia during her raise to fame in the context of stage fright, and might have become addicted to barbiturates because she had an easy access to them. She became interested in psychoanalysis as a way of self-knowledge and acting improvement. Her psychiatrists based their treatment in Freudian psychoanalysis and an intensive use of drugs, mostly barbiturates, but this approach failed. The doctor-patient relationship with her last psychiatrist, Dr. Greenson, was particularly anomalous. During the last months of her life, MM was prescribed close to a dozen different psychoactive drugs, mostly barbiturates, but also other hypnotic drugs, and occasionally amphetamines. Discussion: Drugs complicated the course of MM’s insomnia and had a negative effect on her general health and behaviour, a situation that is usually ignored by the various psychiatric diagnoses given to her. Due to a lack of real medical control, the presence of spurious interests, and a patient who thought she had reasonable control on her drug intake, a severe problem was just a matter of time(AU)

Respiratory depression in rats induced by alcohol and barbiturate and rescue by ampakine CX717.

Barbiturate use in conjunction with alcohol can result in severe respiratory depression and overdose deaths. The mechanisms underlying the additive/synergistic actions were unresolved. Current management of ethanol-barbiturate-induced apnea is limited to ventilatory and circulatory support coupled with drug elimination. Based on recent preclinical and clinical studies of opiate-induced respiratory depression, we hypothesized that ampakine compounds may provide a treatment for other types of drug-induced respiratory depression. The actions of alcohol, pentobarbital, bicuculline, and the ampakine CX717, alone and in combination, were measured via 1) ventral root recordings from newborn rat brain stem-spinal cord preparations and 2) plethysmographic recordings from unrestrained newborn and adult rats. We found that ethanol caused a modest suppression of respiratory drive in vitro (50 mM) and in vivo (2 g/kg ip). Pentobarbital induced an ∼50% reduction in respiratory frequency in vitro (50 µM) and in vivo (28 mg/kg for pups and 56 mg/kg for adult rats ip). However, severe life-threatening apnea was induced by the combination of the agents in vitro and in vivo via activation of GABA(A) receptors, which was exacerbated by hypoxic (8% O(2)) conditions. Administration of the ampakine CX717 alleviated a significant component of the respiratory depression in vitro (50-150 µM) and in vivo (30 mg/kg ip). Bicuculline also alleviated ethanol-/pentobarbital-induced respiratory depression but caused seizure activity, whereas CX717 did not. These data demonstrated that ethanol and pentobarbital together caused severe respiratory depression, including lethal apnea, via synergistic actions that blunt chemoreceptive responses to hypoxia and hypercapnia and suppress central respiratory rhythmogenesis. The ampakine CX717 markedly reduced the severity of respiratory depression.

Synthesis and evaluation of chromenyl barbiturates and thiobarbiturates as potential antitubercular agents.

A novel series of barbiturate and thiobarbiturate analogs of 2-benzoyl-3-methyl-5-oxo-5H-furo[3,2-g]chromene-6-carbaldehydes (3a-g and 4a-d, respectively) and 6-methyl-4,8-dioxo-4,8-dihydropyrano[3,2-g]chromenes (7a-c), were synthesized and evaluated for their antitubercular activities against Mycobacterium tuberculosis H37RV, and cytotoxicity (CC(50)) in the VERO cell MABA assay. The results indicate that the furanochromene series of compounds (3a-g and 4a-d) showed only weak to moderate antitubercular activity. However, the pyranochromene analog 7b showed good antitubercular activity (IC(90): 5.9µg/mL) and cytotoxicity (CC(50): 14.27µg/mL). The antitubercular activity of 7b was superior to the antituberculosis drug, pyrazinamide (PZA; IC(90): >20µg/mL). Analog 7b was considered to be a lead compound for subsequent structural optimization.

Mixture toxicity of SN2-reactive soft electrophiles: 1. Evaluation of mixtures containing α-halogenated acetonitriles.

The concept of multiple modes of toxic action denotes that an individual chemical can induce two or more toxic effects within the same series of concentrations, for example, reactive toxicity and narcosis. It appears that such toxicity confounds the ability to develop precise predictions of mixture toxicity and makes it more difficult to clearly link a dose-additive combined effect to agents in the mixture having a single common mechanism of toxic action. This initial study of a three-part series begins to examine this issue in greater detail by testing three α-halogenated acetonitriles: (1) in sham combinations, (2) in true combinations, and (3) with a nonreactive nonpolar narcotic. Iodo-, bromo-, and chloro-derivatives of acetonitrile were selected for testing based on their electro(nucleo)philic reactivity, via the S(N)2 mechanism, and their time-dependent toxicity individually. Reactivity of each agent was assessed in tests with the model nucleophile glutathione (GSH). Each acetonitrile was reactive with GSH, but the nonpolar narcotic 3-methyl-2-butanone was not. In addition, toxicity of the agents alone and in mixtures was assessed using the Microtox(®) acute toxicity test at three time points: 15, 30, and 45 min of exposure. Each of the three agents alone had time-dependent toxicity values of about 100%, making it likely that most of the toxicity of these agents, at these times, was due to reactivity. In contrast, the nonpolar narcotic agent lacked time-dependent toxicity. In mixture testing, sham combinations of each acetonitrile showed a combined effect consistent with predicted effects for dose-addition at each time point, as did the sham combination of the nonpolar narcotic. Mixture toxicity results for true acetonitrile combinations were also consistent with dose-addition, but the acetonitrile-nonpolar narcotic combinations were generally not consistent with either the dose-addition or independence models of combined effect. Based on current understanding of mixture toxicity, these results were expected and provide a foundation for the second and third studies in the series.

Biodegradability of kraft mill TCF biobleaching effluents: application of enzymatic laccase-mediator system.

The great amount of pollutants released from kraft pulp processes, mainly from cooking and bleaching stages, is one of the most relevant environmental problems in this type of industry. New bleaching sequences are being studied based on the use of oxidative enzymes from fungal cultures. In this study, the bleaching systems consisting of Laccase and different mediators such as 1-hydroxybenzotriazole, violuric acid, syringaldehyde and methyl syringate in the bleaching sequence of Eucalyptus globulus kraft pulp were applied. The main objective of this study is to evaluate the aerobic and anaerobic biodegradability and toxicity to Vibrium fischeri of generated L-stage and total bleaching sequence effluents. The highest levels of aerobic and anaerobic degradation of the generated effluents were achieved for treatments with laccase plus violuric acid, with 80% of aerobic degradation and 68% of anaerobic biodegradation. V. fischeri toxicity was remarkably reduced for all the effluents after aerobic degradation.

Novel substituted (Z)-5-((N-benzyl-1H-indol-3-yl)methylene)imidazolidine-2,4-diones and 5-((N-benzyl-1H-indol-3-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones as potent radio-sensitizing agents.

A series of (Z)-5-((N-benzyl-1H-indol-3-yl)methylene)imidazolidine-2,4-dione (9a-9m) and 5-((N-benzyl-1H-indol-3-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-trione (10a-10i) derivatives that incorporate a variety of aromatic substituents in both the indole and N-benzyl moieties have been synthesized. These analogs were evaluated for their radiosensitization activity against the HT-29 cell line. Three analogs, 10a, 10b, and 10c were identified as the most potent radiosensitizing agents.

Use of a point-of-care urine drug test in a dog to assist in diagnosing barbiturate toxicosis secondary to ingestion of a euthanized carcass.

OBJECTIVE: To describe a case of barbiturate toxicosis in a dog secondary to ingestion of a previously buried euthanized goat carcass and to discuss the utility of urine drug testing in diagnosing barbiturate toxicosis. CASE SUMMARY: A 6-year-old neutered male Border Collie was presented to a university veterinary teaching hospital for evaluation of ataxia and acute collapse. Past pertinent history included Addison's disease that had been managed for 1 year. A companion dog was seen 12 hours earlier chewing on the partially decomposed head of a goat that had been euthanized 47 days previously and buried on the owner's property. The dog was laterally recumbent, unresponsive to stimuli, and hypothermic on physical examination. Initial blood work revealed hyponatremia and hyperkalemia, with a Na/K ratio of 18.5. The dog was volume resuscitated and received an injection of dexamethasone sodium phosphate due to a suspected Addisonian crisis. Despite this treatment, the dog remained laterally recumbent and unresponsive to stimuli. A urine drug screen was performed and was positive for barbiturates. A diagnosis of barbiturate toxicosis secondary to ingestion of a euthanized goat carcass was made. The dog was treated supportively over 12 hours with IV fluids and activated charcoal. The dog was able to walk 11 hours after presentation and was subsequently discharged from the hospital. NEW OR UNIQUE INFORMATION PROVIDED: Urine drug testing is a fast, easy, and point-of-care test that may be useful in dogs to assist in the diagnosis of barbiturate intoxication. Proper disposal of euthanized animals is necessary to prevent toxicosis and possible death of companion animals and wildlife.

Intensification of ammonium diffusion from rat gastrointestinal tract during acute barbiturate intoxication.

In rats with acute sodium thiopental intoxication, ammonium concentration in the caecal contents was at the lower boundary of control values, while accumulation of ammonium in lavage solution injected intraperitoneally was 50-70% accelerated. Blood ammonium level did not change 3 h after sodium thiopental injection in a dose inducing sopor, but increased 3-fold during coma modeling. Intragastric administration of gentamicin (antibiotic poorly absorbed from the gastrointestinal tract) 2-fold reduced ammonium concentration in the caecal contents and prevented hyperammoniemia during induction of barbiturate coma. Hence, increased permeability of the gastrointestinal wall for ammonium promotes the development of hyperammoniemia in rats during induction of barbiturate coma.

PASS: identification of probable targets and mechanisms of toxicity.

Toxicity of chemical compound is a complex phenomenon that may be caused by its interaction with different targets in the organism. Two distinct types of toxicity can be broadly specified: the first one is caused by the strong compound's interaction with a single target (e.g. AChE inhibition); while the second one is caused by the moderate compound's interaction with many various targets. Computer program PASS predicts about 2500 kinds of biological activities based on the structural formula of chemical compounds. Prediction is based on the robust analysis of structure-activity relationships for about 60,000 biologically active compounds. Mean accuracy exceeds 90% in leave-one-out cross-validation. In addition to some kinds of adverse effects and specific toxicity (e.g. carcinogenicity, mutagenicity, etc.), PASS predicts approximately 2000 kinds of biological activities at the molecular level, that providing an estimated profile of compound's action in biological space. Such profiles can be used to recognize the most probable targets, interaction with which might be a reason of compound's toxicity. Applications of PASS predictions for analysis of probable targets and mechanisms of toxicity are discussed.

Synthesis and anticonvulsant activity of some potential thiazolidinonyl 2-oxo/thiobarbituric acids.

A series of 5-[(N-substituted benzylidenylimino)amino]-2-oxo/thiobarbituric acids (3a-3h) have been synthesized by the condensation of 5-hydrazino-2-oxo/thiobarbituric acids (2a-2b) with various aromatic aldehydes. Cycloaddition of thioglycolic acid to 3a-3h, yielded 5-[(2'-substituted phenyl-4'-oxothiazolidin-3'-yl)amino]-2-oxo/thiobarbituric acids (4a-4h). All these compounds were screened, in vivo, for their anticonvulsant activity and acute toxicity studies. Compounds 4f and 4g were found to be most potent compounds of this series and were compared with the reference drugs, phenytoin sodium, lamotrigine and sodium valproate. The structures of these compounds have been established by IR, 1H NMR and mass spectroscopic data.

Vigilância toxicológica: comprovação do uso de álcool e drogas através de testes toxicológicos / Toxicological surveillance: evidence of alcohol and drugs by toxicological tests

O objetivo deste livro é ser uma fonte de informação para profissionais que têm que lidar com testes toxicológicos para comprovação do uso de álcool e drogas, no seu dia-a-dia, auxiliando-os na escolha dos mesmos e nos critérios para sua aplicação...

QSAR of chemical polarizability and nerve toxicity. 2.

Polarizability is a property of molecules that has long been of interest to scientists from a variety of viewpoints. However, in the area of the QSAR of chemical-biological interactions, it has received little attention. Recently we have shown that one can use the simple summation of the valence electrons (H = 1, C = 4, O = 6, etc.) in a molecule as a measure of its polarizability. We have found this parameter to correlate nerve toxicity of a wide variety of chemicals acting on nerves of frogs, rabbits, cockroaches, and humans.