Aminophylline in combination with caffeine citrate in neurodevelopmental treatment and follow-up of high-risk preterm infants using GMs assessment.

To explore the application effect of aminophylline combined with caffeine citrate and GMs in the evaluation of neurodevelopmental treatment and follow-up in high-risk preterm infants. A retrospective analysis of 66 high-risk preterm infants admitted to Hengshui People's Hospital from January 2020 to June 2021 was conducted. The children who received only conventional treatment were set as the control group, while those who received aminophylline and caffeine citrate on the basis of conventional treatment were set as the experimental group, 33 cases each group; GMs were used to evaluate the neurodevelopmental function of the children, and the treatment effect was analyzed. The normal proportion of GMs assessment results in the twisting phase and restless movement phase of the experimental group was superior to the control group (P<0.05); The proportion of children with normal neurodevelopment in the experimental group was significantly higher than that in the control group (P<0.05). Aminophylline in combination with caffeine citrate can help promote the neurodevelopment of children and improve their physical health using GMs assessment in the treatment and follow-up of high-risk preterm infants.

Assessment of Immunological Potential of Glial Restricted Progenitor Graft In Vivo-Is Immunosuppression Mandatory?

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease, causing motor neuron and skeletal muscle loss and death. One of the promising therapeutic approaches is stem cell graft application into the brain; however, an immune reaction against it creates serious limitations. This study aimed to research the efficiency of glial restricted progenitors (GRPs) grafted into murine CNS (central nervous system) in healthy models and the SOD1G93A ALS disease model. The cellular grafts were administered in semiallogenic and allogeneic settings. To investigate the models of immune reaction against grafted GRPs, we applied three immunosuppressive/immunomodulatory regimens: preimplantation factor (PiF); Tacrolimus; and CTLA-4, MR1 co-stimulatory blockade. We tracked the cells with bioluminescence imaging (BLI) in vivo to study their survival. The immune response character was evaluated with brain tissue assays and multiplex ELISA in serum and cerebrospinal fluid (CSF). The application of immunosuppressive drugs is disputable when considering cellular transplants into the immune-privileged site/brain. However, our data revealed that semiallogenic GRP graft might survive inside murine CNS without the necessity to apply any immunomodulation or immunosuppression, whereas, in the situation of allogeneic mouse setting, the combination of CTLA-4, MR1 blockade can be considered as the best immunosuppressive option.

Assessment of Toxicity of Nanoparticles Using Insects as Biological Models.

Nanomaterials have become increasingly important in medicine, manufacturing, and consumer products. A fundamental understanding of the effects of nanoparticles (NPs) and their interactions with biomolecules and organismal systems has yet to be achieved. In this chapter, we firstly provide a brief review of the interactions between nanoparticles and biological systems. We then provide an example by describing a novel method to assess the effects of NPs on biological systems, using insects as a model. Nanoparticles were injected into the central nervous system of the discoid cockroach (Blaberus discoidalis). It was found that insects became hyperactive compared to negative control (water injections). Our method could provide a generic method of assessing nanoparticles toxicity.

Assessment of ionizable, zwitterionic oximes as reactivating antidotal agents for organophosphate exposure.

Since the development in the 1950's of 2-PAM (Pralidoxime), an antidote that reactivates organophosphate conjugated acetylcholinesterase in target tissues upon pesticide or nerve agent exposure, improvements in antidotal therapy have largely involved congeneric pyridinium aldoximes. Despite seminal advances in detailing the structures of the cholinesterases as the primary target site, progress with small molecule antidotes has yet to define a superior agent. Two major limitations are immediately apparent. The first is the impacted space within the active center gorge, particularly when the active center serine at its base is conjugated with an organophosphate. The reactivating nucleophile will have to negotiate the tortuous gorge terrain to access the phosphorus atom with its most nucleophilic form or ionization state, the oximate anion. A second limitation stems from the antidote crossing the blood-brain barrier sufficiently rapidly, since it is well documented that central acetylcholinesterase inhibition gives rise to cardiovascular and respiratory compromise. The associated hypoxia then leads to a sequelae of events, including poor perfusion of the brain and periphery, along with muscle fasciculation, tremors and eventually seizures. We consider both the barriers confronting and further achievements necessary to enhance efficacy of antidotes.

Adverse reactions of fluoroquinolones to central nervous system and rational drug use in nursing care.

.Fluoroquinolones are a kind of synthetic drugs commonly used in clinical treatment. They have good broad-spectrum antimicrobial properties. They are not only convenient to administer, but also have remarkable therapeutic effects. In this paper, we selected 70 patients with adverse reactions of central nervous system during the use of fluoroquinolones as the research object. We reviewed and analyzed the basic data, main manifestations and outcomes of adverse reactions, and summarized the influencing factors. The results showed that dizziness, irritability and insomnia were the main symptoms in 42 patients with mild adverse reactions. In 28 patients with moderate to severe adverse reactions, neuropsychiatric symptoms such as restlessness, depression, nervous excitation, phonism and hallucination were found. 54 patients were able to recover after stopping the medication. The remaining 16 patients were treated with drugs, and the effective rate was 87.5%. By analyzing the related factors, it can be seen that elderly patients over 60 years old, intravenous administration, combination of drugs and past history of neurological diseases are the main factors leading to adverse reactions of the central nervous system. In this survey, there were 7 kinds of adverse drug reactions, of which 31 cases (44.28%) were caused by levofloxacin. Therefore, fluoroquinolones have adverse effects on the central nervous system in the course of treatment, and the occurrence of adverse reactions is related to patients' age, route of administration, drug combination and past history of illness. It is important to grasp the above factors and make rational use of drugs.

Neuroprotective effects of PACAP against paraquat-induced oxidative stress in the Drosophila central nervous system.

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder that can arise after long-term exposure to environmental oxidative stressors, such as the herbicide paraquat (PQ). Here we investigated the potential neuroprotective action of vertebrate pituitary adenylate cyclase-activating polypeptide (PACAP) against PQ in Drosophila. We found that pre-treatment with this neuropeptide applied to the ventral nerve cord (VNC) at low doses markedly extended the survival of wild-type decapitated flies exposed to neurotoxic levels of PQ or dopamine (DA). In contrast and interestingly, application of a PACAP receptor antagonist, PACAP-6-38, had opposite effects, significantly decreasing the resistance of flies to PQ. PACAP also reduced PQ-induced caspase activation and reactive oxygen species (ROS) accumulation in the VNC. We then searched for the endogenous neuropeptide receptor potentially involved in PACAP-mediated neuroprotection in Drosophila. Knocking down the gene encoding the receptor Han/PDFR of the neuropeptide pigment-dispersing factor (PDF) in all neurons conferred to flies higher resistance to PQ, whereas PDFR downregulation restricted to PDF or DA neurons did not increase PQ resistance, but remarkably suppressed the neuroprotective action of PACAP. Further experiments performed with Pdf and Pdfr-deficient mutant strains confirmed that PDF and its receptor are required for PACAP-mediated neuroprotection in flies. We also provide evidence using split-green fluorescent protein (split-GFP) reconstitution that PDF neurons make synaptic contacts onto DA neurons in the abdominal VNC. Our results therefore suggest that the protective action of PACAP against PQ-induced defects in the Drosophila nervous system involves the modulation of PDFR signaling in a small number of interconnected neurons.

Relative equivalence of CNS safety (FOB) assessment outcomes in male and female Wistar-Han and Sprague-Dawley rats.

In 2006 the National Toxicology Program (NTP) of the FDA shifted to the preferred use of Wistar-Han rats from the more commonly used Sprague-Dawley (SD) strain - and industry followed. While European laboratories preferred the Wistar-Han line, there was a paucity of relevant historical control data in many US research institutions for the new "industry standard" rat strain. In 2010 the NTP reversed its decision and shifted back to SD rats because of reproductive issues with the Wistar strain. For post hoc comparative analyses, we report minimal practical differences in Functional Observational Battery (FOB) data from a large sample of male and female Wistar-Han and SD rats. In summarizing data from the preclinical safety evaluations of the CNS effects of new drugs using the FOB, it is crucial to understand the value of not only how the functional expression of drug effects in the rat are predictive of the human response, but also how and why they differ. What we can predict from the behavioral and physiological response of the designated test system to drug administration is the foundation of "generalizability" to the human's response. Here, we conclude that the use of either SD or WH rat strains in standard CNS safety studies provide equivalent supportive data for CNS safety assessment required for IND approval under the harmonized guidelines.

Probabilistic cumulative dietary risk assessment of pesticide residues in foods for the German population based on food monitoring data from 2009 to 2014.

Cumulative dietary risks for the German population owing to pesticide residues in foods were assessed using food monitoring and consumption data. Based on grouping principles for cumulative assessment groups (CAG) as defined by the European Food Safety Authority, probabilistic modelling gave cumulative long- and short-term dietary exposures relevant to the nervous and thyroid system. Compound specific toxicological reference values were considered to assess the total margins of exposure (MoEs) for each CAG, allowing an assessment of the cumulative dietary consumer risk. For the German population, no public health concerns were identified for 6 of 11 CAGs. For three CAGs high uncertainties remained, since MoEs were less than the usually required threshold of 100 for the upper confidence interval of the modelling uncertainty. For two CAGs relevant to the nervous and thyroid system, possible health risks cannot be excluded with the selected approach. Most potent risk drivers were chlorpyrifos and the group of dithiocarbamates (expressed as propineb). For regulatory decisions on possible cumulative dietary health risks the limitations of the published approaches and the absence of harmonized data sources for robust refinements have to be considered. Future research to reduce this high uncertainty is considered necessary in this area.

A 28-day Sub-acute Genotoxic and Behavioural Assessment of Garcinielliptone FC.

Garcinielliptone FC (GFC) is a polyisoprenylated benzophenone isolated from Platonia insignis Mart (Clusiaceae) with promising anticonvulsant properties. However, its safe use and other effects on the central nervous system require assessment. This study assessed the toxicological effects of GFC using the comet assay and the micronucleus test in mice treated for 28 days. A behavioural model was employed to detect possible injuries on the central nervous system. Mice treated with GFC (2, 10 and 20 mg/kg; i.p.) daily for 28 days were submitted to rotarod test, open-field test and tail suspension test (TST). After the behaviour tasks, biological samples were assessed to evaluate genotoxic and mutagenic effects using the comet assay and the micronucleus test. Garcinielliptone FC did not impair the performance of the animals in the rotarod and open-field tests, with no antidepressant-like effect in TST. No genotoxic effects in blood and cerebral cortex were observable in the comet assay; however, there was a significant increase in index and frequency of damage in liver after treatment with GFC 20 mg/kg. Garcinielliptone FC did not increase micronucleus frequency in bone marrow. At the tested doses, GFC was not toxic to the CNS and did not induce genotoxic damage to blood or bone narrow cells. DNA damage to liver tissue was caused only by the highest dose, although no mutagenic potential was observed.

Abuse liability assessment for biologic drugs - All molecules are not created equal.

The development of novel drug candidates involves the thorough evaluation of potential efficacy and safety. To facilitate the safety assessment in light of global increases in prescription drug misuse/abuse, health authorities have developed guidance documents which provide a framework for evaluating the abuse liability of candidate therapeutics. The guidances do not distinguish between small molecules and biologics/biotherapeutics; however, there are key differences between these classes of therapeutics which are important drivers of concern for abuse. An analysis of these properties, including ability to distribute to the central nervous system, pharmacokinetic properties (e.g., half-life and metabolism), potential for off-target binding, and the physiochemical characteristics of biologic drug products suggests that the potential for abuse of a biologic is limited. Many marketed antibodies and recombinant proteins have been associated with adverse effects such as headache and dizziness. However, biologics have not historically engendered the rapid-onset psychoactive effects typically present for drugs of abuse, thus further underscoring their low risk for abuse potential. The factors to be taken into consideration before conducting nonclinical abuse liability studies with biologics are described herein; importantly, the aggregate assessment of these factors leads to the conclusion that abuse liability studies are unlikely to be necessary for this class of therapeutics.

DUI offenders may have multiple health and social problems - doctors play a central role in monitoring the use of medications affecting the central nervous system.

While the overall number of driving under the influence (DUI) cases has reduced, the proportion of drivers under the influence of medications or illicit drugs has increased. In studies based on Finnish register data sets, the factors involved in DUI have been examined with the conclusion that drunk driving may be an indication of multiple health or social problems. According to several measures, DUI offenders who had used medications, especially benzodiazepines, were ill and disadvantaged. Doctors play a central role in reducing the number of DUI cases, e.g. by treating substance abuse problems and by monitoring the use of drugs which affect the central nervous system. It is possible that a DUI offender has accumulated a number of different problems at the same time, which is why the treatment of DUI offenders should pay attention to a comprehensive mapping of the situation and the use of multidisciplinary cooperation.

Assessing the predictive value of the rodent neurofunctional assessment for commonly reported adverse events in phase I clinical trials.

Central Nervous System (CNS)-related safety concerns are major contributors to delays and failure during the development of new candidate drugs (CDs). CNS-related safety data on 141 small molecule CDs from five pharmaceutical companies were analyzed to identify the concordance between rodent multi-parameter neurofunctional assessments (Functional Observational Battery: FOB, or Irwin test: IT) and the five most common adverse events (AEs) in Phase I clinical trials, namely headache, nausea, dizziness, fatigue/somnolence and pain. In the context of this analysis, the FOB/IT did not predict the occurrence of these particular AEs in man. For AEs such as headache, nausea, dizziness and pain the results are perhaps unsurprising, as the FOB/IT were not originally designed to predict these AEs. More unexpected was that the FOB/IT are not adequate for predicting 'somnolence/fatigue' nonclinically. In drug development, these five most prevalent AEs are rarely responsible for delaying or stopping further progression of CDs. More serious AEs that might stop CD development occurred at too low an incidence rate in our clinical dataset to enable translational analysis.

Monitoring and Assessment of Neuropsychological Outcomes as a Standard of Care in Pediatric Oncology.

Central nervous system cancers or exposure to CNS-directed therapies increase risk for neuropsychological deficits. There are no accepted guidelines for assessment of neuropsychological functioning in this population. A multifaceted literature search was conducted and relevant literature reviewed to inform the guidelines. Studies of neuropsychological outcomes are widely documented in the pediatric oncology literature. There is strong evidence of need for neuropsychological assessment, but insufficient evidence to guide the timing of assessment, nor to recommend specific interventions. Children with brain tumors and others at high risk for neuropsychological deficits should be monitored and assessed for neuropsychological deficits.

Histopathological, ultrastructural, and immunohistochemical assessment of hippocampus structures of rats exposed to TCDD and high doses of tocopherol and acetylsalicylic acid.

The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on central nervous system consists of changing expression of estrogen receptors, whereas the result of chronic inflammatory reaction caused by dioxin is occurrence of destructive changes in various organs connected with disturbed metabolism of connective tissue and damage of cells. The aim of the study was to determine the effect of dioxins on function, ultrastructure, and cytological and histological structure of hippocampus, particularly on expression of estrogen receptors in central nervous system as well as to define protective influence of tocopherol (TCP) and acetylsalicylic acid (ASA) on the decrease in activity of proinflammatory effects in central nervous system. It was shown that TCDD contributes to destructive and inflammatory changes along with demyelization of myelin sheaths and atrophy of estrogen receptors in hippocampus. Dioxin contributes to atrophy of estrogen receptors in hippocampus, in which also destructive and inflammatory changes were found along with demyelination of myelin sheaths. Histopathological and ultrastructural image of hippocampus areas in rats, in which both TCP and ASA were used, is characterized by poorly expressed degenerative changes and smaller inflammatory reactivity. Using both TCP and ASA has a protective effect on functions of central nervous system.

Central nervous system effects of the second-generation antihistamines marketed in Japan--review of inter-drug differences using the proportional impairment ratio (PIR)-.

BACKGROUND: Second-generation antihistamines (AHs) have, in general, fewer sedative effects than the first-generation. However, important inter-drug differences remain in the degree of cognitive and/or psychomotor impairment. The extent to which a particular compound causes disruption can be conveniently compared, to all other AHs, using the Proportional Impairment Ratio (PIR). Although the PIR can differentiate the relative impairment caused by individual drugs, there is no indication of the reliability of the ratios obtained. OBJECTIVE: To calculate the PIRs -together with 95% confidence intervals (CIs), as an index of reliability- and compare AHs currently, or soon to be, available in Japan, with respect to their intrinsic capacity to cause impairment. METHODS: Results from studies of cetirizine, desloratadine, ebastine, fexofenadine, levocetirizine, loratadine, mequitazine, and olopatadine were included in the PIR calculations. All data utilised came from crossover studies in healthy volunteers which were randomised and placebo and positive-internal controlled. Existing databases from studies reporting the sedative effects of AHs on objective (speed, accuracy, memory) and subjective (feeling) psychometrics were augmented, via results from suitable studies published after the previous reviews. The null value for a PIR was one. RESULTS: A total of 45 studies were finally included for this review. Of the AHs assessed, fexofenadine, ebastine, and levocetirizine showed a PIR for objective tests of 0. However, only fexofenadine (PIR = 0.49) had an upper limit of the 95% CI of less than 1. Fexofenadine, levocetirizine, desloratadine, olopatadine, loratadine, and mequitazine all had a PIR for subjective ratings of 0, but the upper limits of the 95% CIs were all in excess of 1, although fexofenadine (PIR = 2.57) was the lowest. CONCLUSIONS: The results show that there are differences between second-generation AHs in the extent of sedation produced. However, subjective ratings indicate that patients may not necessarily be aware of this.

A compilation of research working groups on drug utilisation across Europe.

BACKGROUND: The assessment of the benefit-risk of medicines needs careful consideration concerning their patterns of utilization. Systems for the monitoring of medicines consumption have been established in many European countries, and several international groups have identified and described them. No other compilation of European working groups has been published. As part of the PROTECT project, as a first step in searching for European data sources on the consumption of five selected groups of medicines, we aimed to identify and describe the main characteristics of the existing collaborative European working groups. FINDINGS: Google and bibliographic searches (PubMed) of articles containing information on databases and other sources of drug consumption data were conducted. For each working group the main characteristics were recorded.Nineteen selected groups were identified, focusing on: a) general drug utilisation (DU) research (EuroDURG, CNC, ISPE'S SIG-DUR, EURO-MED-STAT, PIPERSKA Group, NorPEN, ENCePP, DURQUIM), b) specific DU research: b.1) antimicrobial drugs (ARPAC, ESAC, ARPEC, ESGAP, HAPPY AUDIT), b.2) cardiovascular disease (ARITMO, EUROASPIRE), b.3) paediatrics (TEDDY), and b.4) mental health/central nervous system effects (ESEMeD, DRUID, TUPP/EUPoMMe). Information on their aims, methods and activities is presented. CONCLUSIONS: We assembled and updated information on European working groups in DU research and in the utilisation of five selected groups of drugs for the PROTECT project. This information should be useful for academic researchers, regulatory and health authorities, and pharmaceutical companies conducting and interpreting post-authorisation and safety studies. European health authorities should encourage national research and collaborations in this important field for public health.

Bioactivity assessment and toxicity of crocin: a comprehensive review.

Since ancient times, saffron, the dried stigma of the plant Crocus sativus L. has been extensively used as a spice and food colorant; in folk medicine it has been reputed to be efficacious for the alleviation and treatment of ailments. In addition to the three founded major constituents including crocin, picrocrocin and safranal, presence of carotenoids, carbohydrates, proteins, anthocyanins, vitamins and minerals provide valuable insights into the health benefits and nutritional value of saffron. Of the carotenoids present in saffron, highly water-soluble crocin (mono and diglycosyl esters of a polyene dicarboxylic acid, named crocetin) is responsible for the majority of its color, and appears to possess various health-promoting properties, as an antioxidant, antitumor, memory enhancer, antidepressant, anxiolytic and aphrodisiac. It is also worth noting that the crocin principle of saffron exhibited high efficacy along with no major toxicity in experimental models. We would be remiss to not consider the great potential of saffron and crocin, which benefits the cuisine and health of human life throughout the world. The present study provides a comprehensive and updated report of empirical investigations on bioactivities and biological characteristics of crocin.

A nonclinical safety assessment of MnTE-2-PyP, a manganese porphyrin.

Manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP or BMX-010; CASRN 219818-60-7) is a manganese porphyrin compound developed as a potential drug substance for use as a radioprotective and for the ex vivo treatment of cells, tissues, and organs intended for transplantation. In preparation for an investigational new drug filing, a full good laboratory practice nonclinical safety assessment was conducted in order to evaluate the safety of MnTE-2-PyP and included the performance of in vitro genotoxicity studies, local tissue tolerance evaluation, safety pharmacology core battery studies, and single- and repeat-dose intravenous (iv) toxicity studies in mice and monkeys. The MnTE-2-PyP was determined not to be genotoxic or hemolytic, did not demonstrate flocculation or elicit adverse pharmacologic effects on respiration, the central nervous system (CNS), and had limited transitory effects on the cardiovascular system only at levels well above the therapeutic target dose. The intended iv clinical solution did not cause venous irritation in rabbits. The no observed adverse effect level (NOAEL) in mice was determined to be 10 mg/kg/day after 18 consecutive days of bolus iv dosing once daily in the morning. The NOAEL in monkeys after 14 days of bolus iv dosing in the morning was determined to be 5 mg/kg/day. At doses relevant to clinical use in humans, neither study revealed any indication of any specific target organ toxicity, including the classic heme porphyrin kidney, liver, CNS, or cardiac toxicities, or manganese toxicity. Mortality seen shortly after dosing in individual animals at higher doses was not accompanied by any organ or clinical pathology indications, suggesting a functional pharmacological-mediated effect. Based on the results of these studies, a conservative safe initial starting clinical dose of 5.0 mg (0.083 mg/kg in a 60 kg adult) was proposed for the initiation of human trials. Because of patent life issues, use of MnTE-2-PyP as a transplantation aid or radioprotective agent is not currently being pursued past the preclinical stages. It serves as a model for the clinical development of this class of drugs.

Neuromapping techniques in drug discovery: pharmacological MRI for the assessment of novel antipsychotics.

INTRODUCTION: Treatment of psychiatric and neurological diseases represents a substantial unmet medical need, but the development of novel, effective and safe drugs is proving difficult. While substantial improvement over existing pharmacological agents is expected from new molecular targets emerging in the genomic era, the validation and exploitation of novel mechanisms of action is a lengthy and costly process. The use of neuroimaging techniques, and more specifically of functional and pharmacological magnetic resonance imaging (MRI), has been advocated as a powerful approach to this problem, providing translational biomarkers for the objective assessment of drug activity on brain function, and possibly surrogate markers of clinical response. AREAS COVERED: The authors review the recent application of functional and pharmacological MRI (phMRI) in the study of novel treatments of psychosis based on glutamatergic mechanisms. Furthermore, they review contribution of functional imaging in the target validation and early assessment of drugs exploiting glutamatergic mechanisms as an example of potentially impactful exploitation of neuroimaging methods in drug discovery. EXPERT OPINION: While functional neuroimaging methods may provide useful markers of drug activity and response to treatment, their translational potential, that is, their use to bridge animal and human investigations is seldom exploited. The application of phMRI in the study of novel antipsychotics based on glutamatergic mechanisms represents an example of functional neuroimaging as a powerful means to link preclinical and clinical research, thus providing a paradigm that may help expedite progression into the clinical phase of novel mechanisms for the treatment of psychiatric and neurological diseases.