De-risking in Tier I CNS safety assessments is the primary function of study design and technical training of laboratory staff observers.

Derisking is not a pharmaceutical industry strategy to reduce time, effort, or costs in drug development. Derisking strategies originated within the National Institutes of Health as a predicate to good science. There is a growing sentiment within drug development programs to diminish the importance of behavioral measures in toxicological studies and in the Tiered Safety assessment plans of the U.S. Regulatory Agencies and the International Commission on Harmonization. The validity and reliability of the Functional Observational Batter (FOB) is critically dependent on consistency and technical quality in each risk assessment plan. US Federal and International drug approval organizations have universally adopted the concept of principles of test construction rather than delineating specific behavioral assay endpoints for inclusion of the FOB in nonclinical safety protocols. The validity and reliability of behavioral observations in standardized neurotoxicity screening is critically dependent on the FOB developed by the Study Director with the Sponsor throughout all stages of testing.. The individual risk factors selected for observation to be included in the early Tier 1 safety program should be determined by the mechanism and mode of action of the test article. The results of Tier I testing are the basis for Tier II testing designs. Critical to the compliance with Good Laboratory Practices is the documentation of training of the operational staff scheduled to conduct all aspects of the established protocol.

Uncaria rhynchophylla and its Major Constituents on Central Nervous System: A Review on Their Pharmacological Actions.

BACKGROUND: Uncaria rhynchophylla (Miq.) Jacks (Rubinaceae), a common herbal medicine known as Gou-teng in Chinese, is commonly used in Chinese medicine practice for the treatment of convulsions, hypertension, epilepsy, eclampsia and other cerebral diseases. The major active components of U. rhynchophylla are alkaloids, terpenoids and flavonoids. The protective effects of U. rhynchophylla and its major components on central nervous system (CNS) have become a focus of research in recent decades. OBJECTIVE: The study aimed to systematically summarize the pharmacological activities of U. rhynchophylla and its major components on the CNS. METHODS: This review summarized the experimental findings from our laboratories, together with other literature data obtained through a comprehensive search of databases including the Pubmed and the Web of Science. RESULTS: U. rhynchophylla and its major components such as rhynchophylline and isorhynchophylline have been shown to have neuroprotective effects on Alzheimer's disease, Parkinson's disease, depression, cerebral ischaemia through a number of mechanisms including anti-oxidant, anti-inflammatory actions and regulation on neurotransmitters. CONCLUSION: U. rhynchophylla and its major components have multiple beneficial pharmacological effects on CNS. Further studies on U. rhynchophylla and its major components are warranted to fully illustrate the underlying molecular mechanisms, pharmacokinetics, and toxicological profiles of these naturally occurring compounds and their potential for clinical application.

Evaluation of the adjunctive effect of Xing Nao Jing Injection for viral encephalitis: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: To systematically evaluate the effect and safety of Xing Nao Jing (XNJ) injection as an add-on treatment on the treatment for viral encephalitis (VE). METHODS: Trials assessing the adjunctive effectiveness of XNJ injection for VE were searched from 4 electronic databases from inception to October 31, 2018. Two authors independently extracted data and assessed risk of bias. Statistical analyses were performed using RevMan 5.3 software. Meta-analysis and additional analysis were conducted if data permitted. Trial Sequential Analysis and Grading of Recommendations Assessment, Development and Evaluation (GRADE) were also performed. RESULTS: This review involved 23 trials and 1757 participants, all trials were assessed as having unclear risk of bias. Results from 5 meta-analyses, 13 subgroup meta-analyses, and the single studies showed that based on conventional therapy XNJ injection (0.4-0.6 mL/kg daily for children, 20 mL/day for adults) may have better effect on increasing the numbers of cured patients and decreasing the time of recovery of main symptoms for patients with viral encephalitis. Patients used combination of XNJ injection and conventional therapy had higher cured rate (risk ratio 1.61, 95% confidence interval 1.45-1.80, 19 trials, 1456 participants) and less mortality rate (risk ratio 0.26, 95% confidence interval 0.10-0.71, 9 trials, 595 participants). The average difference of time for fever, conscious, or convulsive recovery was average 2 hours shorter in combination group than in control. No difference was found between children and adults according to the subgroup analysis. Safety of the XNJ injection was failed to evaluate due to the insufficient evidence in this review. CONCLUSIONS: This review found "very low" quality evidence which showed the potential effectiveness of combination of XNJ injection and conventional therapies for VE. Considering the TSA results, conclusion could only be draw on effectiveness of the XNJ injection as add-on treatment for VE patients on increasing the cured rate. Firm conclusion on other outcome measures for effectiveness assessment or safety of XNJ injection could not be draw according to this review due to the insufficient evidence.

Effectiveness and safety of Injinoryung-San-Gagambang (Yinchen Wuling powder) decoction on stroke patients with elevated serum liver enzymes: Three case reports.

RATIONALE: Injinoryung-San-Gagambang (IJORS) effectively improves hepatic dysfunction caused by polypharmacy in stroke patients. PATIENT CONCERNS: We present 3 cases of hepatic dysfunction caused by polypharmacy, one of which was a 51-year-old man with cerebellum infarction and pneumonia as a complication of stroke. He took multiple medications because of baseline diseases. After recurrence of pneumonia, his laboratory tests showed abnormal aminotransferase levels. Another patient was an 81-year-old woman with cerebral infarction at the right-middle cerebral artery. She was also taking >5 medications. Her laboratory tests conducted on admission showed abnormally elevated aminotransferase levels. The last patient was 77-year-old man with cerebral infarction at the left-middle cerebral artery. He also had an abdominal aneurysm, a thoracic aortic aneurysm, and a myocardial infarction. After taking multiple medications including healthy functional foods, his laboratory tests showed abnormally elevated aminotransferase levels. DIAGNOSIS: Diagnosis is conducted with the result of laboratory test including blood count, chemistry test. INTERVENTIONS: All 3 patients received the same herbal treatment (IJORS decoction) for 1 to 3 weeks. OUTCOMES: All 3 patients' abnormal serum aminotransferase level were significantly improved by IJORS decoction treatment while keeping other medicines. LESSONS: IJORS can be considered as an effective treatment for hepatic dysfunction induced by numerous medications in stroke patients.

Tau-Centric Multitarget Approach for Alzheimer's Disease: Development of First-in-Class Dual Glycogen Synthase Kinase 3ß and Tau-Aggregation Inhibitors.

Several findings propose the altered tau protein network as an important target for Alzheimer's disease (AD). Particularly, two points of pharmacological intervention can be envisaged: inhibition of phosphorylating tau kinase GSK-3ß and tau aggregation process. On the basis of this consideration and on our interest in multitarget paradigms in AD, we report on the discovery of 2,4-thiazolidinedione derivatives endowed with such a profile. 28 and 30 displayed micromolar IC50 values toward GSK-3ß, together with the capacity of inhibiting AcPHF6 aggregation of 60% and 80% at 10 µM, respectively. In addition, they showed PAMPA-BBB permeability, together with a suitable cellular safety profile. 30 also displayed inhibition of both K18 and full-length tau aggregations. Finally, both compounds were able to improve cell viability in an okadaic acid-induced neurodegeneration cell model. To the best of our knowledge, 28 and 30 are the first balanced, nontoxic, dual-acting compounds hitting tau cascade at two different hubs.

Use of melatonin versus valproic acid in prophylaxis of migraine patients: A double-blind randomized clinical trial.

BACKGROUND: Melatonin is known to be effective in curing migraine. OBJECTIVE: This study aimed to investigate the therapeutic effect of melatonin versus sodium valproate in the prophylaxis of chronic migraine. METHODS: This randomized, double-blind, placebo-controlled clinical trial included patients with chronic migraine who were divided into three equal sized groups, and baseline therapy with nortriptyline (10-25 mg) and propranolol (20-40 mg) was used. Patients in groups A, B, and C were adjunctively treated daily with 3 mg melatonin, 200 mg sodium valproate, and a placebo, respectively. The patients underwent treatment for 2 months and follow-up was done at baseline (baseline), first (I) and second month (II). Attack frequency (AF), attack duration, attack severity, Migraine Disability Assessment (MIDAS) score (within 3 months in two steps), analgesic intake, and drug side effects between the groups and during follow-up were compared. RESULTS: The mean of monthly AF (melatonin: baseline: 4.2, I: 3.1, II: 2.5, p = 0.018; valproate: baseline: 4.3, I: 3.1, II: 2.3, p = 0.001; placebo: baseline: 4.1, I: 3.8, II: 3.8 p = 0.211), attack duration (hr) (melatonin: baseline: 19.8, I: 10.1, II: 8.7, p < 0.001; valproate: baseline: 19.5, I: 10.2, II: 8.8, p < 0.001; placebo: baseline: 19.6, I: 15.4, II: 14.1, p = 0.271), attack severity (melatonin: baseline: 7.3, I: 5.4, II: 3.5, p < 0.001; valproate: baseline: 7.4, I: 5.3, II: 3.4, p = 0.000; placebo: baseline: 7.3, I: 6.4, II: 6, p = 0.321), and MIDAS score (melatonin: baseline: 15.2, II: 8.9, p = 0.005; valproate: baseline: 16.1, II: 8.3, p = 0.001; placebo: baseline: 16, II: 12.1, p = 0.44), were significantly reduced in the melatonin and sodium valproate groups, but not in the placebo groups. Adverse events were reported in 11 patients (10.47%): 2 (5.71%) during melatonin treatment, 8 (22.85%) during valproate, and 1 (2.85%) during placebo. CONCLUSION: The adjuvant treatment with melatonin was found to be superior to the placebo and had the same clinical efficacy as sodium valproate, but with higher tolerability. Melatonin may prove to be an efficient substitute for sodium valproate, as a chronic migraine prophylaxis.

Intrastriatal injection of botulinum neurotoxin-A is not cytotoxic in rat brain - A histological and stereological analysis.

Parkinson's disease (PD) is caused by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta, resulting in a deficiency of dopamine in the striatum and an increased release of acetylcholine by tonically active interneurons. Botulinum neurotoxin-A (BoNT-A) is well known for blocking transmitter release by cholinergic presynaptic terminals. Treating striatal hypercholinism by local application of BoNT-A could be a possible new local therapy option of PD. In previous studies of our group, we analyzed the effect of BoNT-A injection into the CPu of 6-OHDA lesioned hemiparkinsonian rats. Our studies showed that BoNT-A application in hemiparkinson rat model is capable of abolishing apomorphine induced rotations for approximately 3 months. Regularly occurring axonal swellings in the BoNT-A infiltrated striata were also discovered, which we named BoNT-A induced varicosities (BiVs). Résumé: Here we investigated the long-term effect of the injection of 1ng BoNT-A into the right CPu of naive Wistar rats on the number of ChAT-ir interneurons as well as on the numeric density and the volumetric size of the BiVs in the CPu. Significant differences in the number of ChAT-ir neurons between the right BoNT-A treated CPu and the left untreated CPu were not detected up to 12 month post BoNT-A injection. The numeric density of BiVs in the treated CPu reached a maximum 3 months after BoNT-A treatment and decreased afterwards, whereas the volume of single BiVs increased steadily throughout the whole time course of the experiment.

A tool to utilize adverse effect profiles to identify brain-active medications for repurposing.

BACKGROUND: To shorten the time required to bring new treatments to clinics, recent efforts have focused on repurposing existing Food and Drug Administration (FDA)-approved drugs with established safety data for new indications. We hypothesized that adverse effect profiles might aid in prioritizing compounds for investigation in central nervous system (CNS) applications by providing an indication of their abilities to cross the blood-brain barrier. METHODS: Data were drawn from an investigation of similarity of adverse effect profiles, utilizing pre- and post-marketing data. A panel of known CNS-active drugs was utilized to estimate aggregate similarity profiles for all other FDA drugs in the database. Permutations were used to test whether similarities for any given drug exceeded that expected under the null hypothesis. To estimate the performance of algorithms using such profiles, manually-curated lists of known CNS-active and -inactive medications were classified using logistic regression. Algorithms with and without this similarity data were compared for prediction of CNS penetrance. RESULTS: Models incorporating adverse effect similarity data exhibited greater discrimination of brain-penetrant and non-penetrant drugs than models without this data. A visualization tool was developed to allow any medication to be evaluated for adverse effect similarity to the CNS panel or a custom panel. CONCLUSIONS: Consideration of adverse effect profiles allows in silico prioritization of compounds for follow-up investigation for CNS indications. In concert with chemical screening approaches, this may accelerate repurposing efforts for putative CNS-active medications.

[Designer drugs and caffeine - characteristics of psychoactive substances and their impact on the organism]. / Dopalacze i kofeina - charakterystyka substancji psychoaktywnych i ich wplyw na organizm.

For many teenagers the time of growing up is a period of trying prohibited substances. Nowadays apart from alcohol and tobacco new designed, psychoactive substances known as "smart drugs" or "legal highs" are available. Intensive development of their market is taking place in the last few years which is difficult to overcome by regulations only. Toxicological tests used now are not able to detect the presence of many such substances in the body. Designer drugs cause the interest of young people even from small towns and many times taking them give effects requiring medical help. Caffeine is also a psychoactive substance but depending on the dose it can have positive or detrimental effect. Recently there are more and more products with caffeine, especially drinks and dietary supplements, what can cause the increase of consumption of caffeine. Children are particularly exposed to the adverse effect of high consumption of caffeine because of their small body weight and development of the central nervous system. This article presents actual data about the market of designer drugs, frequency of using them, consumption of caffeine by children and teenagers and about the impact of these substances on the organism.

Efficacy and tolerability of risperidone, yokukansan, and fluvoxamine for the treatment of behavioral and psychological symptoms of dementia: a blinded, randomized trial.

The descriptive term behavioral and psychological symptoms of dementia (BPSD) is used to cover a range of noncognitive disturbances including anxiety, depression, irritability, aggression, agitation, eating disorders, and inappropriate social or sexual behaviors. Behavioral and psychological symptoms of dementia are seen in about 90% of patients with dementia. We aimed to compare the efficacy and tolerability of risperidone, yokukansan, and fluvoxamine used for BPSD in elderly patients with dementia. Ninety inpatients with dementia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria were investigated in Sato Hospital, Koutokukai. We conducted an 8-week, rater-blinded, randomized trial, administering flexibly dosed risperidone, yokukansan, or fluvoxamine. Primary outcome measures were Neuropsychiatric Inventory in Nursing Home Version total score and its items. Secondary outcome measures were cognitive function measured by Mini-Mental State Examination and daily life function measured by Functional Independence Measure (FIM). Neurological adverse effects were measured by the Drug-Induced Extra-Pyramidal Symptoms Scale. At the end of the study, we analyzed 76 patients (92.7%). Mean Neuropsychiatric Inventory in Nursing Home Version total score decreased in all 3 drug groups, with no significant between-group differences. Mini-Mental State Examination and Functional Independence Measure scores did not change significantly. Drug-Induced Extra-Pyramidal Symptoms Scale scores did not change in the yokukansan and fluvoxamine groups, but increased significantly in the risperidone group. Risperidone, yokukansan, and fluvoxamine were equally effective in the treatment of BPSD in elderly patients. However, yokukansan or fluvoxamine for BPSD showed a more favorable profile in tolerability compared with risperidone. This trial is registered at UMIN Clinical Trials Registry (identifier: UMIN000006146).

Exploration of 100 commonly used drugs and supplements on cognition in older adults.

BACKGROUND: There are conflicting reports and a lack of evidence-based data regarding effects of medications on cognition in cognitively normal older adults. We explored whether use of 100 common medications taken by older adults is associated with longitudinal cognitive performance. METHODS: A longitudinal observational cohort was used with analysis of data collected from September 2005 through May 2011 and maintained in the National Alzheimer's Coordinating Center (NACC) Uniform Data Set. Participants were aged 50 years or older and cognitively normal (N = 4414). Composite scores were constructed from 10 psychometric tests. Scores for each participant reflecting change in the psychometric composite score from the baseline clinical assessment to the next assessment were calculated. General linear models were used to test whether the mean composite change score differed for participants who reported starting, stopping, continuing, or not taking each of the 100 most frequently used medications in the NACC sample. RESULTS: The average time between assessments was 1.2 years (SD = 0.42). Nine medications showed a difference (P < .05) across the four participant groups in mean psychometric change scores from the first to the second assessment. Medications associated with improved psychometric performance were naproxen, calcium-vitamin D, ferrous sulfate, potassium chloride, flax, and sertraline. Medications associated with declining psychometric performance were bupropion, oxybutynin, and furosemide. CONCLUSIONS: Reported use of common medications is associated with cognitive performance in older adults, but studies are needed to investigate the mechanisms underlying these effects.

Prescription-drug-related risk in driving: comparing conventional and lasso shrinkage logistic regressions.

BACKGROUND: Large data sets with many variables provide particular challenges when constructing analytic models. Lasso-related methods provide a useful tool, although one that remains unfamiliar to most epidemiologists. METHODS: We illustrate the application of lasso methods in an analysis of the impact of prescribed drugs on the risk of a road traffic crash, using a large French nationwide database (PLoS Med 2010;7:e1000366). In the original case-control study, the authors analyzed each exposure separately. We use the lasso method, which can simultaneously perform estimation and variable selection in a single model. We compare point estimates and confidence intervals using (1) a separate logistic regression model for each drug with a Bonferroni correction and (2) lasso shrinkage logistic regression analysis. RESULTS: Shrinkage regression had little effect on (bias corrected) point estimates, but led to less conservative results, noticeably for drugs with moderate levels of exposure. Carbamates, carboxamide derivative and fatty acid derivative antiepileptics, drugs used in opioid dependence, and mineral supplements of potassium showed stronger associations. CONCLUSION: Lasso is a relevant method in the analysis of databases with large number of exposures and can be recommended as an alternative to conventional strategies.

Botany, traditional uses, phytochemistry and pharmacology of Apocynum venetum L. (Luobuma): A review.

ETHNOPHARMACOLOGICAL RELEVANCE: Apocynum venetum L. (Apocynaceae, Luobuma ) has a long history as a Chinese traditional medicine with uses to calm the liver, soothe the nerves, dissipate heat, and promote diuresis. Recently, Luobuma tea has been commercialized as a sedative and anti-aging supplement that has become increasingly popular in North American and East Asian health food markets. AIMS OF THE REVIEW: The aim of this review is to provide an up-to-date and comprehensive overview of the botany, chemical constituents, traditional uses, pharmacological activities and safety aspects of Apocynum venetum in order to assess its ethnopharmacological use and to explore its therapeutic potentials and future opportunities for research. BACKGROUND AND METHODS: The accessible literature on Apocynum venetum written in English, Chinese and Japanese were collected and analyzed. The literatures included ancient Chinese herbal classics, pharmacopoeias and articles that included in Pubmed, Web of Science, Google Scholar and Wanfang. KEY FINDINGS: Modern pharmacological studies demonstrated that Apocynum venetum possess wide pharmacological activities that include antihypertensive, cardiotonic, hepatoprotective, antioxidant, lipid-lowering, antidepressant and anxiolytic effects, which can be explained by the presence of various flavonoid compounds in this plant. The traditional (Lop Nor region) use of Apocynum venetum with tobacco as an agent to detoxify nicotine may receive interest as a possible therapeutic option to detoxify the body from smoking. Based on animal studies and clinical trials, Apocynum venetum causes no severe side effects, even in a stable daily dosage (50mg/person/day) for more than three years. CONCLUSIONS: Apocynum venetum potentially has therapeutic potential in the prevention and treatment for the cardiovascular and neurological diseases, especially for high blood pressure, high cholesterol, neurasthenia, depression and anxiety. Further investigations are needed to explore individual bioactive compounds responsible for these in vitro and in vivo pharmacological effects and the mode of actions. Further safety assessments and clinical trials should be performed before it can be integrated into medicinal practices.

Management of neuropsychiatric symptoms in people with dementia.

Neuropsychiatric symptoms are frequent and troublesome in people with dementia and present a major treatment challenge for clinicians. Most good practice guidelines suggest non-pharmacological treatments as the first-line therapy and there is emerging evidence, including randomized controlled trials, that a variety of psychological and training interventions, including social interaction and person-centred care training, are effective. There is evidence from meta-analyses that some atypical antipsychotic drugs, specifically risperidone and aripiprazole, confer benefit in the treatment of aggression in people with Alzheimer's disease over a period of up to 12 weeks. However, these benefits have to be considered in the context of significant adverse events, including extrapyramidal symptoms, accelerated cognitive decline, stroke and death. In addition, the limited evidence available does not indicate ongoing treatment benefits over longer periods of therapy. The evidence is limited for other pharmacological treatment approaches, but the best evidence is probably for carbamazepine, memantine and citalopram. There is very limited evidence for any therapies in non-Alzheimer dementias. In conclusion, it is important in most situations to limit the use of antipsychotic medication to short-term treatment (up to 12 weeks) of severe neuropsychiatric symptoms to limit harm. Non-pharmacological therapies offer a viable and effective alternative in many situations. Adequately powered randomized controlled trials for the treatment of clinically significant agitation are urgently needed to explore alternative pharmacological therapies.

Ayurvedic processed seeds of nux-vomica: neuropharmacological and chemical evaluation.

The effect of detoxification on Strychnos nux-vomica seeds by traditional processing with aloe and ginger juices (B), by frying in cow ghee (C), and by boiling in cow milk (D) was investigated. The ethanolic extracts of these samples were subjected to spontaneous motor activity (SMA), pentobarbitone-induced hypnosis, PTZ induced convulsions, diazepam-assisted protection, and morphine-induced catalepsy. All samples reduced SMA and inhibited catalepsy. The seeds processed in milk (D) showed the lowest strychnine content in the cotyledons, exhibited marked inhibition of PTZ induced convulsions and maximal potentiation of hypnosis, and were the safest (LD(50)).

Efficacy of Ginkgolide B in the prophylaxis of migraine with aura.

In a multicentric, open, preliminary trial, we evaluated the use of ginkgolide B, a herbal constituent extract from Ginkgo biloba tree leaves, in the prophylactic treatment of migraine with aura (MA). Fifty women suffering from migraine with typical aura, or migraine aura without headache, diagnosed according to International Headache Society criteria, entered a six-month study. They underwent a two month run-in period free of prophylactic drugs, followed by a four month treatment period (subdivided into two bimesters, TI and TII) with a combination of 60 mg ginkgo biloba terpenes phytosome, 11 mg coenzyme Q 10, and 8.7 mg vitamin B2 (Migrasoll), administered twice daily. A detailed diary reporting neurological symptoms, duration, and frequency of MA was compiled by patients throughout the trial. The number of MA significantly decreased during treatment (from 3.7 +/- 2.2 in the run-in period, to 2.0 +/- 1.9 during TI and to 1.2 +/- 1.6 during TII; Anova for repeated measures: P < 0.0001). There was also a statistically significant decrease in the average MA duration, which was 40.4 +/- 19.4 min during run-in, 28.2 +/- 19.9 during TI, and 17.6 +/- 20.6 during TII. Total disappearance of MA was observed in 11.1% patients during TI and in 42.2% of patients during T2. No serious adverse event was provoked by Migrasoll administration. Ginkgolide B is effective in reducing MA frequency and duration. The effect is clearly evident in the first bimester of treatment and is further enhanced during the second.