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ACS Omega Apr 2024Prebiotic genetic nucleotides (PGNs) often outcompete canonical alphabets in the formation of nucleotides and subsequent RNA oligomerization under early Earth...
Prebiotic genetic nucleotides (PGNs) often outcompete canonical alphabets in the formation of nucleotides and subsequent RNA oligomerization under early Earth conditions. This indicates that the early genetic code might have been dominated by pre-RNA that contained PGNs for information transfer and catalysis. Despite this, deciphering pre-RNAs' capacity to acquire function and delineating their evolutionary transition to a canonical RNA World has remained under-researched in the origins of life (OoL) field. We report the synthesis of a prebiotically relevant nucleotide (BaTP) containing the noncanonical nucleobase barbituric acid. We demonstrate the first instance of its enzymatic incorporation into an RNA, using a T7 RNA polymerase. BaTP's incorporation into baby spinach aptamer allowed it to retain its overall secondary structure and function. Finally, we also demonstrate faithful transfer of information from the pre-RNA-containing BaTP to DNA, using a high-fidelity RNA-dependent DNA polymerase, alluding to how selection pressures and complexities could have ensued during the molecular evolution of the early genetic code.
PubMed: 38680342
DOI: 10.1021/acsomega.3c09949 -
Tzu Chi Medical Journal 2024Sleep is an essential activity for the survival of mammals. Good sleep quality helps promote the performance of daily functions. In contrast, insufficient sleep reduces... (Review)
Review
Sleep is an essential activity for the survival of mammals. Good sleep quality helps promote the performance of daily functions. In contrast, insufficient sleep reduces the efficiency of daily activities, causes various chronic diseases like Alzheimer's disease, and increases the risk of having accidents. The GABAergic system is the primary inhibitory neurotransmitter system in the central nervous system. It transits the gamma-aminobutyric acid (GABA) neurotransmitter via GABA and GABA receptors to counterbalance excitatory neurotransmitters, such as glutamate, noradrenaline, serotonin, acetylcholine, orexin, and dopamine, which release and increase arousal activities during sleep. Several studies emphasized that dysfunction of the GABAergic system is related to insomnia, the most prevalent sleep-related disorder. The GABAergic system comprises the GABA neurotransmitter, GABA receptors, GABA synthesis, and degradation. Many studies have demonstrated that GABA levels correlate with sleep quality, suggesting that modulating the GABAergic system may be a promising therapeutic approach for insomnia. In this article, we highlight the significance of sleep, the classification and pathology of insomnia, and the impact of the GABAergic system changes on sleep. In addition, we also review the medications that target the GABAergic systems for insomnia, including benzodiazepines (BZDs), non-BZDs, barbiturates, GABA supplements, and Chinese herbal medicines.
PubMed: 38645778
DOI: 10.4103/tcmj.tcmj_243_23 -
International Journal of Molecular... Mar 2024Bile has emerged as an alternative matrix for toxicological investigation of drugs in suspected forensic cases of overdose in adults and intoxications in children....
Bile has emerged as an alternative matrix for toxicological investigation of drugs in suspected forensic cases of overdose in adults and intoxications in children. Toxicological investigation consists in screening and, subsequently, confirming the result with specific techniques, such as liquid chromatography with tandem mass spectrometry (LC-MS/MS). As there is no screening test on the market to test postmortem bile specimens, the novelty of this study was in investigating the applicability of a chemiluminescence immunoassay, designed for other matrices and available on the market, on bile and validate its use, testing the agreement with LC-MS/MS analysis. Bile specimens were obtained from 25 forensic cases of suspected death from overdose and intoxication. Sample preparation for bile screening consists simply in centrifugation and dilution. Confirmation analysis allows simultaneous identification of 108 drugs and was validated on bile. Kappa analysis assessed a perfect agreement (0.81-1) between the assays for benzodiazepines, methadone, opiates, cocaine, oxycodone, cannabinoids, buprenorphine and pregabalin; a substantial agreement (0.41-0.6) was reported for barbiturates. No agreement was assessed for amphetamines, due to an abundance of putrefactive amines in postmortem specimens. In conclusion, this fast and easy immunoassay could be used for initial screening of bile specimens, identifying presence of drugs, except amphetamines, with reliability.
Topics: Adult; Child; Humans; Bile; Chromatography, Liquid; Luminescence; Reproducibility of Results; Tandem Mass Spectrometry; Drug Overdose; Amphetamines
PubMed: 38612632
DOI: 10.3390/ijms25073825 -
Molecules (Basel, Switzerland) Mar 2024A systematic study has been conducted on barbiturate complexes of all five alkali metals, Li-Cs, prepared from metal carbonates or hydroxides in an aqueous solution...
The Sensitivity of Structure to Ionic Radius and Reaction Stoichiometry: A Crystallographic Study of Metal Coordination and Hydrogen Bonding in Barbiturate Complexes of All Five Alkali Metals Li-Cs.
A systematic study has been conducted on barbiturate complexes of all five alkali metals, Li-Cs, prepared from metal carbonates or hydroxides in an aqueous solution without other potential ligands present, varying the stoichiometric ratio of metal ion to barbituric acid (BAH). Eight polymeric coordination compounds (two each for Na, K, and Rb and one each for Li and Cs) have been characterised by single-crystal X-ray diffraction. All contain some combination of barbiturate anion BA (necessarily in a 1:1 ratio with the metal cation M), barbituric acid, and water. All organic species and water molecules are coordinated to the metal centres via oxygen atoms as either terminal or bridging ligands. Coordination numbers range from 4 (for the Li complex) to 8 (for the Cs complex). Extensive hydrogen bonding plays a significant role in all the crystal structures, almost all of which include pairs of N-H···O hydrogen bonds linking BA and/or BAH components into ribbons extending in one dimension. Factors influencing the structure adopted by each compound include cation size and reaction stoichiometry as well as hydrogen bonding.
PubMed: 38611775
DOI: 10.3390/molecules29071495 -
Molecules (Basel, Switzerland) Mar 2024The plant-derived toxin ricin is classified as a type 2 ribosome-inactivating protein (RIP) and currently lacks effective clinical antidotes. The toxicity of ricin is...
The plant-derived toxin ricin is classified as a type 2 ribosome-inactivating protein (RIP) and currently lacks effective clinical antidotes. The toxicity of ricin is mainly due to its ricin toxin A chain (RTA), which has become an important target for drug development. Previous studies have identified two essential binding pockets in the active site of RTA, but most existing inhibitors only target one of these pockets. In this study, we used computer-aided virtual screening to identify a compound called RSMI-29, which potentially interacts with both active pockets of RTA. We found that RSMI-29 can directly bind to RTA and effectively attenuate protein synthesis inhibition and rRNA depurination induced by RTA or ricin, thereby inhibiting their cytotoxic effects on cells in vitro. Moreover, RSMI-29 significantly reduced ricin-mediated damage to the liver, spleen, intestine, and lungs in mice, demonstrating its detoxification effect against ricin in vivo. RSMI-29 also exhibited excellent drug-like properties, featuring a typical structural moiety of known sulfonamides and barbiturates. These findings suggest that RSMI-29 is a novel small-molecule inhibitor that specifically targets ricin toxin A chain, providing a potential therapeutic option for ricin intoxication.
Topics: Animals; Mice; Ricin; Ribosome Inactivating Proteins, Type 2; Drug Development; Hydrolases; Liver
PubMed: 38611715
DOI: 10.3390/molecules29071435 -
Frontiers in Chemistry 2024A sustainable methodology for the synthesis of pyrano [2,3-] pyrimidine scaffolds have been developed, employing the Knoevenagel-Michael tandem cyclocondensation...
A sustainable methodology for the synthesis of pyrano [2,3-] pyrimidine scaffolds have been developed, employing the Knoevenagel-Michael tandem cyclocondensation reaction of barbituric acid/1,3-dimethylbarbituric acid, malononitrile, and aryl aldehydes. This study elucidates the advancement of a sustainable and environmentally conscious approach to synthesizing this category of chemical compounds. In the present investigation, a novel photosensitizer comprising proflavine (PFH) bio-photocatalyst was employed in an aqueous medium, subjected to air atmosphere at room temperature, and stimulated by a blue-light-emitting diode (LED) to harness renewable energy. The fundamental objective of this initiative is to utilize a photosensitizer (PS) biocatalyst that has been recently developed, can be conveniently acquired, and is priced affordably. The proflavine (PFH) photocatalyst, demonstrates the ability to initiate photoinduced-electron transfer (PET) through exposure to visible light. This property endows the photocatalyst with a practical and efficient method of achieving high effectiveness, energy efficiency, and environmentally friendly outcomes. The current research endeavor has the objective of examining the turnover number (TON) and turnover frequency (TOF) pertaining to pyrano [2,3-] pyrimidine scaffolds. Moreover, it has been validated that cyclization at the gram-scale is a feasible approach that can be employed in various industrial settings.
PubMed: 38595702
DOI: 10.3389/fchem.2024.1304850 -
BMC Pregnancy and Childbirth Apr 2024Infants who are born from mothers with substance use disorder might suffer from neonatal abstinence syndrome (NAS) and need treatment with medicines. One of these... (Randomized Controlled Trial)
Randomized Controlled Trial
Comparison of the effect of phenobarbital & levetiracetam in the treatment of neonatal abstinence syndrome (NAS) as adjuvant treatment in neonates admitted to the neonatal intensive care unit: a randomized clinical trial.
BACKGROUND
Infants who are born from mothers with substance use disorder might suffer from neonatal abstinence syndrome (NAS) and need treatment with medicines. One of these medicines is phenobarbital, which may cause side effects in long-term consumption. Alternative drugs can be used to reduce these side effects. This study seeks the comparison of the effects of phenobarbital & levetiracetam as adjuvant therapy in neonatal abstinence syndrome.
METHODS
This randomized clinical trial was performed in one year from May 2021 until May 2022. The neonates who were born from mothers with substance use disorder and had neonatal abstinence syndrome in Afzalipoor Hospital of Kerman were studied. The treatment started with morphine initially and every four hours the infants were checked. The infants who were diagnosed with uncontrolled symptoms After obtaining informed consent from the parents were randomly divided into two groups and treated with secondary drugs, either phenobarbital or levetiracetam.
RESULTS
Based on the obtained results, it was clear that there was no significant difference between the hospitalization time of the two infant groups under therapy (phenobarbital: 18.59 days versus Levetiracetam 18.24 days) (P-value = 0.512). Also, there was no significant difference between both groups in terms of the frequency of re-hospitalization during the first week after discharge, the occurrence of complications, and third treatment line prescription (P-value = 0.644).
CONCLUSIONS
Based on the obtained results, like hospitalization duration time (P-value = 0.512) it seems that levetiracetam can be used to substitute phenobarbital in treating neonatal abstinence syndrome.
TRIAL REGISTRATION
The current study has been registered in the Iran registry of clinical trials website (fa.irct.ir) on the date 25/2/2022 with registration no. IRCT20211218053444N2.
Topics: Infant, Newborn; Infant; Female; Humans; Neonatal Abstinence Syndrome; Levetiracetam; Intensive Care Units, Neonatal; Phenobarbital; Hospitalization; Substance-Related Disorders; Plant Extracts
PubMed: 38580935
DOI: 10.1186/s12884-024-06433-y -
PloS One 2024This retrospective cohort study described the obstetric and neonatal outcomes, antiseizure medication (ASM) use, and types of seizures in pregnant women with epilepsy...
This retrospective cohort study described the obstetric and neonatal outcomes, antiseizure medication (ASM) use, and types of seizures in pregnant women with epilepsy (PWWE). Data collected from the medical records of 224 PWWE aged < 40 years with controlled or refractory seizures and 492 pregnant women without epilepsy (PWNE) control group from high-risk maternity hospitals in Alagoas between 2008 and 2021 were included in this study. The obstetric and neonatal outcomes observed in PWWE were pregnancy-related hypertension (PrH) (18.4%), oligohydramnios (10.3%), stillbirth (6.4%), vaginal bleeding (6%), preeclampsia (4.7%), and polyhydramnios (3%). There was a greater likelihood of PrH in PWWE with generalized tonic-clonic seizures (GTCS) and that of maternal intensive care unit (ICU) admissions in those with GTCS and status epilepticus, and phenytoin and lamotrigine use. PWWE with GTCS had a higher risk of stillbirth and premature delivery. PWWE with status epilepticus were treated with lamotrigine. Phenobarbital (PB) with diazepam were commonly used in GTCS and status epilepticus. Total 14% patients did not use ASM, while 50.2% used monotherapy and 35.8% used polytherapy. Total 60.9% of patients used PB and 25.2% used carbamazepine. This study described the association between the adverse obstetric and neonatal outcomes and severe seizure types in PWWE.
Topics: Infant, Newborn; Female; Humans; Pregnancy; Lamotrigine; Pregnant Women; Retrospective Studies; Stillbirth; Brazil; Anticonvulsants; Seizures; Epilepsy; Phenobarbital; Status Epilepticus
PubMed: 38558080
DOI: 10.1371/journal.pone.0291190 -
The Journal of Veterinary Medical... May 2024Euthanasia agents should rapidly induce death and loss of consciousness without causing pain or distress. Various methods exist for the euthanasia of laboratory animals,...
Euthanasia agents should rapidly induce death and loss of consciousness without causing pain or distress. Various methods exist for the euthanasia of laboratory animals, and injectable anesthetics, particularly barbiturate derivatives, are widely used due to the rapid onset of unconsciousness induced by these agents. Moreover, pharmaceutical-grade drugs should be used to eliminate undesirable side effects as much as possible. However, in Japan, the sale of pharmaceutical-grade pentobarbital sodium (PB) ended in 2019, and that of secobarbital sodium (SB) ended in 2023, leading to a demand for new pharmaceutical-grade injectable euthanasia drugs. This study evaluates thiamylal sodium (TM), a barbiturate derivative that is available domestically, as a euthanasia agent for mice. The results showed that when administered at dosages of 200 mg/kg or more, TM exhibited effects equivalent to those of PB and SB. In addition, the impact of TM administration on hematological characteristics was examined. In female mice administered TM, decreased blood chloride and calcium levels and increased aspartate aminotransferase and alanine aminotransferase levels, which are markers of liver damage, were observed. These findings suggest that high concentrations of TM may affect renal and liver function. This study revealed that TM is effective as a euthanasia agent at dosages of 200 mg/kg or more. However, considering the potential risks of renal and liver damage due to TM administration, it may be preferable to use alternative euthanasia drugs when these risks could affect the objectives or outcomes of the research.
Topics: Animals; Female; Euthanasia, Animal; Mice; Male; Pentobarbital
PubMed: 38556347
DOI: 10.1292/jvms.24-0041 -
JAMA Network Open Mar 2024Young children are ingesting illicit drugs at increased rates, but it is unknown what the associated child protection system (CPS) responses are when a child tests...
IMPORTANCE
Young children are ingesting illicit drugs at increased rates, but it is unknown what the associated child protection system (CPS) responses are when a child tests positive.
OBJECTIVE
To document the child protection system involvement and the characteristics of children who test positive for illicit substances.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective cross-sectional study linked medical discharge and child protection system administrative data. The setting was Rady Children's Hospital San Diego, a free-standing pediatric hospital in California. Participants included all emergency department and inpatient medical encounters involving children aged 12 years or younger with a positive urine drug test between 2016 and 2021. Statistical analysis was performed from February 2023 to January 2024.
EXPOSURE
Drug type, including amphetamines, barbiturates, benzodiazepines, cannabis, cocaine, fentanyl, opiates, and phencyclidine.
MAIN MEASURES AND OUTCOMES
CPS responses associated with the medical encounter including reports, substantiations, case openings, and out-of-home placements.
RESULTS
A total of 511 emergency department and inpatient medical encounters involving children had a positive drug test (262 [51.3%] were female; 309 [60.5%] were age 6 years or younger; fewer than 10 [<3.0%] were American Indian or Alaska Native; 252 [49.3%] were Hispanic [any race], 20 [3.9%] were non-Hispanic Asian, 56 [11.0%] were non-Hispanic Black, 143 [28.0%] were non-Hispanic White, 36 [7.0%] had other or unknown race and ethnicity; 233 [43.6%] had a CPS report prior to the medical encounter). Following the positive screen, 244 (47.7%) were reported to child protection, and 61 (11.9%) were placed out-of-home within 30 days. Mean (SD) quarterly counts of encounters with positive drug tests doubled after the COVID-19 pandemic onset (32.9 [9.8]) compared with prior to the pandemic onset (16.5 [4.7]); for encounters positive for cannabis, mean (SD) quarterly counts were 3 times as high after the pandemic onset than prior (16.6 [4.7] vs 5.7 [2.9]). Encounters for children under age 1 were significantly more likely to have associated child protection reports (relative risk [RR], 2.91 [95% CI, 2.21-3.83]) and child protection case openings (RR, 1.71 [95% CI, 1.07-2.72]) than encounters involving older children.
CONCLUSIONS AND RELEVANCE
In this cross-sectional study of emergency department and inpatient medical encounters, less than half of children with positive urine drug screens were reported to CPS; out-of-home placements were uncommon. With increased encounters for positive drug tests, it is unclear what services these children and families are receiving.
Topics: Child; Humans; Female; Adolescent; Child, Preschool; Male; Cross-Sectional Studies; Pandemics; Retrospective Studies; Urine; Urinalysis; Cannabinoid Receptor Agonists; Cannabis; Hallucinogens
PubMed: 38512254
DOI: 10.1001/jamanetworkopen.2024.3133