Multi-target drugs for the treatment of cognitive impairment and fatigue in post-COVID syndrome: focus on Ginkgo biloba and Rhodiola rosea.

Cognitive impairment, depression and (mental) fatigue represent the most frequent neuropsychiatric symptoms of the post-COVID syndrome. Neuroinflammation, oxidative stress and mitochondrial dysfunction have been identified as common pathophysiological mechanisms underlying these symptoms. Attempts to treat post-COVID-associated cognitive impairment and fatigue with different drugs available for other diseases have not yet been successful. One probable explanation could be that these drugs work by one specific mechanism of action only and not in a broad multi-target way. Therefore, they will not address the broad pathophysiological spectrum possibly responsible for cognitive impairment, depression and fatigue in post-COVID syndrome. Notably, nearly all drugs currently under investigation for fatigue in post-COVID syndrome are rather addressing one single target instead of the several pathomechanisms underlying this condition. Contrary to this approach, herbal drugs often consist of many different ingredients with different pharmacological properties and pharmacological targets. Therefore, these drugs might be a promising approach for the treatment of the broad symptomatic presentation and the pathophysiological mechanisms of cognitive impairment and fatigue following a SARS-CoV-2 infection. Of these herbal drugs, extracts of Ginkgo biloba and Rhodiola rosea probably are the best investigated candidates. Their broad pharmacological spectrum in vitro and in vivo includes anti-oxidative, anti-inflammatory, antidepressant as well as properties reducing cognitive impairment and fatigue. In several studies, both drugs showed positive effects on physical and mental fatigue and impaired cognition. Moreover, depressive symptoms were also reduced in some studies. However, even if these results are promising, the data are still preliminary and require additional proof by further studies.

Neuropsychiatric Drugs Against COVID-19: What is the Clinical Evidence?

Since the beginning of the coronavirus disease (COVID)-19 pandemic, the need for effective treatments for COVID-19 led to the idea of "repurposing" drugs for antiviral treatment. Several antipsychotics and antidepressants have been tested for in vitro activity against the severe acute respiratory syndrome coronavirus 2. Chlorpromazine, other phenothiazine antipsychotics, and the antidepressant fluoxetine were found to be rather potent in these studies. However, whether effective plasma concentrations can be obtained with clinically accepted doses of these drugs is not clear. Data of COVID-19 patients are not yet available but several clinical studies are currently underway.The specific serotonin reuptake inhibitor fluvoxamine is a potent Sigma-1 receptor agonist and reduces inflammation in animal models of cytokine-stress. Accordingly, fluvoxamine treatment was superior to placebo in reducing impaired respiratory function and other symptoms of inflammation in COVID-19 patients in a placebo-controlled clinical study and another open clinical trial. The beneficial effects of fluvoxamine on the course of COVID-19 were recently confirmed in a large placebo-controlled double-blind trial with several hundred patients.Inflammation represents a major risk factor for many psychiatric disorders which explains the high susceptibilitiy of COVID-19 patients for psychiatric diseases. Many antidepressants and antipsychotics possess anti-inflammatory properties independent of sigma-1 activity which might be important to reduce psychiatric symptoms of COVID-19 patients and to improve respiratory dysfunction and other consequences of inflammation. This might explain the rather unspecific benefit which has been reported for several cohorts of COVID-19 patients treated with different psychotropic drugs.

No Abuse Potential of Silexan in Healthy Recreational Drug Users: A Randomized Controlled Trial.

BACKGROUND: Silexan is a lavender essential oil with established anxiolytic and calming efficacy. Here we asked whether there is a potential for abuse in human patients. METHODS: We carried out a phase I abuse liability single-center, double-blind, 5-way crossover study in healthy users of recreational central nervous system depressants. They received single oral doses of 80 mg (therapeutic dose) and 640 mg Silexan, 2 mg and 4 mg lorazepam (active control) and placebo in randomized order, with 4- to 14-day washout periods between treatments. Pharmacodynamic measures included validated visual analogue scales assessing positive, negative, and sedative drug effects and balance of effects; a short form of the Addiction Research Center Inventory; and a drug similarity assessment. The primary outcome measure was the individual maximum value on the drug liking visual analogue scale during 24 hours post-dose. RESULTS: Forty participants were randomized and 34 were evaluable for pharmacodynamic outcomes. In intraindividual head-to-head comparisons of the drug liking visual analogue scale maximum value, both doses of Silexan were rated similar to placebo whereas differences were observed between Silexan and lorazepam and between placebo and lorazepam (P < .001). These data were supported by all secondary measures of positive drug effects and of balance of effects. Differences between placebo and both doses of Silexan were always negligible in magnitude. Moreover, Silexan showed no sedative effects and was not perceived to be similar to commonly used drugs that participants had used in the past. CONCLUSIONS: Silexan did not exhibit any abuse potential in a standard abuse potential detection screen study and is unlikely to be recreationally abused.

Neurotrophic Properties of Silexan, an Essential Oil from the Flowers of Lavender-Preclinical Evidence for Antidepressant-Like Properties.

BACKGROUND: Silexan, a special essential oil from flowering tops of lavandula angustifolia, is used to treat subsyndromal anxiety disorders. In a recent clinical trial, Silexan also showed antidepressant effects in patients suffering from mixed anxiety-depression (ICD-10 F41.2). Since preclinical data explaining antidepressant properties of Silexan are missing, we decided to investigate if Silexan also shows antidepressant-like effects in vitro as well as in vivo models. METHODS: We used the forced swimming test (FST) in rats as a simple behavioral test indicative of antidepressant activity in vivo. As environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology-resulting in dysfunction of the circuitry that is essential for mood regulation and cognitive function-we investigated the neurotrophic properties of Silexan in neuronal cell lines and primary hippocampal neurons. RESULTS: The antidepressant activity of Silexan (30 mg/kg BW) in the FST was comparable to the tricyclic antidepressant imipramine (20 mg/kg BW) after 9-day treatment. Silexan triggered neurite outgrowth and synaptogenesis in 2 different neuronal cell models and led to a significant increase in synaptogenesis in primary hippocampal neurons. Silexan led to a significant phosphorylation of protein kinase A and subsequent CREB phosphorylation. CONCLUSION: Taken together, Silexan demonstrates antidepressant-like effects in cellular as well as animal models for antidepressant activity. Therefore, our data provides preclinical evidence for the clinical antidepressant effects of Silexan in patients with mixed depression and anxiety.

Changes in prescribed medicines in older patients with multimorbidity and polypharmacy in general practice.

BACKGROUND: Treatment complexity rises in line with the number of drugs, single doses, and administration methods, thereby threatening patient adherence. Patients with multimorbidity often need flexible, individualised treatment regimens, but alterations during the course of treatment may further increase complexity. The objective of our study was to explore medication changes in older patients with multimorbidity and polypharmacy in general practice. METHODS: We retrospectively analysed data from the cluster-randomised PRIMUM trial (PRIoritisation of MUltimedication in Multimorbidity) conducted in 72 general practices. We developed an algorithm for active pharmaceutical ingredients (API), strength, dosage, and administration method to assess changes in physician-reported medication data during two intervals (baseline to six-months: ∆1; six- to nine-months: ∆2), analysed them descriptively at prescription and patient levels, and checked for intervention effects. RESULTS: Of 502 patients (median age 72 years, 52% female), 464 completed the study. Changes occurred in 98.6% of patients (changes were 19% more likely in the intervention group): API changes during ∆1 and ∆2 occurred in 414 (82.5%) and 338 (67.3%) of patients, dosage alterations in 372 (74.1%) and 296 (59.2%), and changes in API strength in 158 (31.5%) and 138 (27.5%) respectively. Administration method changed in 79 (16%) of patients in both ∆1 and ∆2. Simvastatin, metformin and aspirin were most frequently subject to alterations. CONCLUSION: Medication regimens in older patients with multimorbidity and polypharmacy changed frequently. These are mostly due to discontinuations and dosage alterations, followed by additions and restarts. These findings cast doubt on the effectiveness of cross-sectional assessments of medication and support longitudinal assessments where possible. TRIAL REGISTRATION: 1. Prospective registration: Trial registration number: NCT01171339 ; Name of registry: ClinicalTrials.gov; Date of registration: July 27, 2010; Date of enrolment of the first participant to the trial: August 12, 2010. 2. Peer reviewed trial registration: Trial registration number: ISRCTN99526053 ; Name of registry: Controlled Trials; Date of registration: August 31, 2010; Date of enrolment of the first participant to the trial: August 12, 2010.

Enhanced Neuroplasticity by the Metabolic Enhancer Piracetam Associated with Improved Mitochondrial Dynamics and Altered Permeability Transition Pore Function.

The mitochondrial cascade hypothesis of dementia assumes mitochondrial dysfunction leading to reduced energy supply, impaired neuroplasticity, and finally cell death as one major pathomechanism underlying the continuum from brain aging over mild cognitive impairment to initial and advanced late onset Alzheimer's disease. Accordingly, improving mitochondrial function has become an important strategy to treat the early stages of this continuum. The metabolic enhancer piracetam has been proposed as possible prototype for those compounds by increasing impaired mitochondrial function and related aspects like mechanisms of neuroplasticity. We here report that piracetam at therapeutically relevant concentrations improves neuritogenesis in the human cell line SH-SY5Y over conditions mirroring the whole spectrum of age-associated cognitive decline. These effects go parallel with improvement of impaired mitochondrial dynamics shifting back fission and fusion balance to the energetically more favorable fusion site. Impaired fission and fusion balance can also be induced by a reduction of the mitochondrial permeability transition pore (mPTP) function as atractyloside which indicates the mPTP has similar effects on mitochondrial dynamics. These changes are also reduced by piracetam. These findings suggest the mPTP as an important target for the beneficial effects of piracetam on mitochondrial function.

Basic data for bipolar disorders: genetics, neurobiology and pharmacology. / Bipolare Störungen: Basiswissen Aktueller Forschungsstand zu Genetik, Neurobiologie und Pharmakologie .

Bipolar disorders are quite common (lifetime prevalence 1­2 %) and have a substantial genetic risk (total heritability about 80 %). However, the contribution of individual genes to the total genetic risk is very small. Accordingly, no specific genes are known which show a larger contribution. Nevertheless, many of the known genes involved encode for proteins important for neural plasticity, mitochondrial function, dopaminergic neurotransmission and calcium channels. Similarly, the few data about neurobiological alterations in the brains of bipolar patients also point into the same direction. However, these observations are not very specific. A possible exception might be mitochondrial dysfunction seen in bipolar patients, which could integrate several of the other findings into one concept. The pharmacology of the drugs used to treat bipolar disorders is also not pointing to one common mechanism of action. While the mechanisms of action of antidepressants and antipsychotics probably are not different from the mechanisms relevant to treat depression and schizophrenia, the mechanisms of the anticonvulsants used in bipolar disorders (valproic acid, carbamazepine, lamotrigine) are probably different from their mechanism of action as anticonvulsant drugs. More likely, these drugs improve neuronal plasticity similarly to lithium and antidepressants.

Editorial: Siegfried Hoyer's concept of Alzheimer pathophysiology.

The concept of central insulin resistance and dysfunctional insulin signaling in Alzheimer's Disease (AD) has been developed by Siegfried Hoyer in 1985-2000. It is widely recognized that the mechanisms underlying neuronal energy deficiency and in particular to elucidate insulin/insulin receptor cascade deficiencies are some of the most relevant proximate characteristics of sporadic AD. The imbalance between cerebral oxygen utilization and cerebral glucose utilization may cause rise in reactive oxygen species production and this might be causal for synapse degeneration. This concept has been substantiated by work on postmortem Alzheimer brains and has been translated back into the streptozotozin animal model, which has stimulated much further research by other researchers. Finally, the insulin hypothesis of Alzheimer's disease has currently advanced into a potential therapeutic avenue.

Expression and functional activity of the bitter taste receptors TAS2R1 and TAS2R38 in human keratinocytes.

Recent studies have shown that human bitter taste receptors (TAS2Rs) are not only expressed in mucous epithelial cells of the tongue, but also in epithelial cells of the colon, stomach and upper respiratory tract. These cell types come in close contact with external bitter compounds by ingestion or breathing. In the present work we addressed the question whether bitter taste receptors might also be expressed in cornified epithelial cells of the skin. Here, we show for the first time the expression of TAS2R1 and TAS2R38 in human skin. Double staining of HaCaT cells and primary keratinocytes demonstrated the colocalization of TAS2R1 and TAS2R38 with the adaptor protein α-gustducin that is essential for signal transduction upon ligand binding. To test if TAS2Rs in keratinocytes are functional, we stimulated HaCaT cells with diphenidol, a clinically used bitter-tasting antiemetic, or amarogentin, the bitterest plant substance, that binds TAS2Rs, including TAS2R1 and TAS2R38. Diphenidol and amarogentin induced calcium influx. Furthermore, in keratinocytes diphenidol and amarogentin stimulated the expression of the differentiation markers keratin 10, involucrin and transglutaminase. Therefore, apart from the known role in mucous membranes of the gastrointestinal tract, TAS2Rs are expressed in the epidermis and might play a role in keratinocyte differentiation.

Cholesterol as a causative factor in Alzheimer's disease: a debatable hypothesis.

High serum/plasma cholesterol levels have been suggested as a risk factor for Alzheimer's disease (AD). Some reports, mostly retrospective epidemiological studies, have observed a decreased prevalence of AD in patients taking the cholesterol lowering drugs, statins. The strongest evidence causally linking cholesterol to AD is provided by experimental studies showing that adding/reducing cholesterol alters amyloid precursor protein (APP) and amyloid beta-protein (Ab) levels. However, there are problems with the cholesterol-AD hypothesis. Cholesterol levels in serum/plasma and brain of AD patients do not support cholesterol as a causative factor in AD.Prospective studies on statins and AD have largely failed to show efficacy. Even the experimental data are open to interpretation given that it is well-established that modification of cholesterol levels has effects on multiple proteins, not only amyloid precursor protein and Ab. The purpose of this review, therefore, was to examine the above-mentioned issues, discuss the pros and cons of the cholesterol-AD hypothesis, involvement of other lipids in the mevalonate pathway, and consider that AD may impact cholesterol homeostasis.

Impaired geranylgeranyltransferase-I regulation reduces membrane-associated Rho protein levels in aged mouse brain.

Synaptic impairment rather than neuronal loss may be the leading cause of cognitive dysfunction in brain aging. Certain small Rho-GTPases are involved in synaptic plasticity, and their dysfunction is associated with brain aging and neurodegeneration. Rho-GTPases undergo prenylation by attachment of geranylgeranylpyrophosphate (GGPP) catalyzed by GGTase-I. We examined age-related changes in the abundance of Rho and Rab proteins in membrane and cytosolic fractions as well as of GGTase-I in brain tissue of 3- and 23-month-old C57BL/6 mice. We report a shift in the cellular localization of Rho-GTPases toward reduced levels of membrane-associated and enhanced cytosolic levels of those proteins in aged mouse brain as compared with younger mice. The age-related reduction in membrane-associated Rho proteins was associated with a reduction in GGTase-Iß levels that regulates binding of GGPP to Rho-GTPases. Proteins prenylated by GGTase-II were not reduced in aged brain indicating a specific targeting of GGTase-I in the aged brain. Inhibition of GGTase-I in vitro modeled the effects of aging we observed in vivo. We demonstrate for the first time a decrease in membrane-associated Rho proteins in aged brain in association with down-regulation of GGTase-Iß. This down-regulation could be one of the mechanisms causing age-related weakening of synaptic plasticity.

Lavender oil preparation Silexan is effective in generalized anxiety disorder--a randomized, double-blind comparison to placebo and paroxetine.

The anxiolytic efficacy of the orally administered lavender oil preparation Silexan was investigated in generalized anxiety disorder (GAD) in comparison to placebo and paroxetine. In this randomized, double-blind, double-dummy trial 539 adults with GAD according to DSM-5 criteria and a Hamilton Anxiety Scale (HAMA) total score ⩾ 18 points participated and received 160 or 80 mg Silexan, 20 mg paroxetine, or placebo once daily for 10 wk. The primary efficacy endpoint was the HAMA total score reduction between baseline and treatment end. The HAMA total score decreased by 14.1 ± 9.3 points for Silexan 160 mg/d, 12.8 ± 8.7 points for Silexan 80 mg/d, 11.3 ± 8.0 points for paroxetine, and 9.5 ± 9.0 points for placebo (mean ± s.d.). Silexan 160 and 80 mg/d were superior to placebo in reducing the HAMA total score (p < 0.01) whereas paroxetine showed a trend towards significance (p = 0.10) in the full analysis set. The difference between paroxetine and placebo was more pronounced in the analysis of observed cases (HAMA total score reduction: p < 0.01). In the Silexan 160 mg/d group 73/121 patients (60.3%) showed a HAMA total score reduction ⩾ 50% of the baseline value and 56 (46.3%) had a total score <10 points at treatment end, compared to 70/135 (51.9%) and 45 (33.3%) for Silexan 80 mg/d, 57/132 (43.2%) and 45 (34.1%) for paroxetine, and 51/135 (37.8%) and 40 (29.6%) for placebo. In addition, Silexan showed a pronounced antidepressant effect and improved general mental health and health-related quality of life. Incidence densities of adverse events (AEs) were 0.006 AEs/d for Silexan 160 mg/d, 0.008 AEs/d for 80 mg/d, 0.011 AEs/d for paroxetine, and 0.008 AEs/d for placebo. In GAD Silexan is more efficacious than placebo. AE rates for Silexan were comparable to placebo and lower than for the active control paroxetine.

TRPC6 channel-mediated neurite outgrowth in PC12 cells and hippocampal neurons involves activation of RAS/MEK/ERK, PI3K, and CAMKIV signaling.

The non-selective cationic transient receptor canonical 6 (TRPC6) channels are involved in synaptic plasticity changes ranging from dendritic growth, spine morphology changes and increase in excitatory synapses. We previously showed that the TRPC6 activator hyperforin, the active antidepressant component of St. John's wort, induces neuritic outgrowth and spine morphology changes in PC12 cells and hippocampal CA1 neurons. However, the signaling cascade that transmits the hyperforin-induced transient rise in intracellular calcium into neuritic outgrowth is not yet fully understood. Several signaling pathways are involved in calcium transient-mediated changes in synaptic plasticity, ranging from calmodulin-mediated Ras-induced signaling cascades comprising the mitogen-activated protein kinase, PI3K signal transduction pathways as well as Ca(2+) /calmodulin-dependent protein kinase II (CAMKII) and CAMKIV. We show that several mechanisms are involved in TRPC6-mediated synaptic plasticity changes in PC12 cells and primary hippocampal neurons. Influx of calcium via TRPC6 channels activates different pathways including Ras/mitogen-activated protein kinase/extracellular signal-regulated kinases, phosphatidylinositide 3-kinase/protein kinase B, and CAMKIV in both cell types, leading to cAMP-response element binding protein phosphorylation. These findings are interesting not only in terms of the downstream targets of TRPC6 channels but also because of their potential to facilitate further understanding of St. John's wort extract-mediated antidepressant activity. Alterations in synaptic plasticity are considered to play an important role in the pathogenesis of depression. Beside several other proteins, TRPC6 channels regulate synaptic plasticity. This study demonstrates that different pathways including Ras/MEK/ERK, PI3K/Akt, and CAMKIV are involved in the improvement of synaptic plasticity by the TRPC6 activator hyperforin, the antidepressant active constituent of St. John's wort extract.

Improvement of mitochondrial function and dynamics by the metabolic enhancer piracetam.

The metabolic enhancer piracetam is used in many countries to treat cognitive impairment in aging, brain injuries, as well as dementia such as AD (Alzheimer's disease). As a specific feature of piracetam, beneficial effects are usually associated with mitochondrial dysfunction. In previous studies we were able to show that piracetam enhanced ATP production, mitochondrial membrane potential as well as neurite outgrowth in cell and animal models for aging and AD. To investigate further the effects of piracetam on mitochondrial function, especially mitochondrial fission and fusion events, we decided to assess mitochondrial morphology. Human neuroblastoma cells were treated with the drug under normal conditions and under conditions imitating aging and the occurrence of ROS (reactive oxygen species) as well as in stably transfected cells with the human wild-type APP (amyloid precursor protein) gene. This AD model is characterized by expressing only 2-fold more human Aß (amyloid ß-peptide) compared with control cells and therefore representing very early stages of AD when Aß levels gradually increase over decades. Interestingly, these cells exhibit an impaired mitochondrial function and morphology under baseline conditions. Piracetam is able to restore this impairment and shifts mitochondrial morphology back to elongated forms, whereas there is no effect in control cells. After addition of a complex I inhibitor, mitochondrial morphology is distinctly shifted to punctate forms in both cell lines. Under these conditions piracetam is able to ameliorate morphology in cells suffering from the mild Aß load, as well as mitochondrial dynamics in control cells.

Rice bran extract protects from mitochondrial dysfunction in guinea pig brains.

Mitochondrial dysfunction plays a major role in the development of age-related neurodegenerative diseases and recent evidence suggests that food ingredients can improve mitochondrial function. In the current study we investigated the effects of feeding a stabilized rice bran extract (RBE) on mitochondrial function in the brain of guinea pigs. Key components of the rice bran are oryzanols, tocopherols and tocotrienols, which are supposed to have beneficial effects on mitochondrial function. Concentrations of α-tocotrienol and γ-carboxyethyl hydroxychroman (CEHC) but not γ-tocotrienol were significantly elevated in brains of RBE fed animals and thus may have provided protective properties. Overall respiration and mitochondrial coupling were significantly enhanced in isolated mitochondria, which suggests improved mitochondrial function in brains of RBE fed animals. Cells isolated from brains of RBE fed animals showed significantly higher mitochondrial membrane potential and ATP levels after sodium nitroprusside (SNP) challenge indicating resistance against mitochondrial dysfunction. Experimental evidence indicated increased mitochondrial mass in guinea pig brains, e.g. enhanced citrate synthase activity, increased cardiolipin as well as respiratory chain complex I and II and TIMM levels. In addition levels of Drp1 and fis1 were also increased in brains of guinea pigs fed RBE, indicating enhanced fission events. Thus, RBE represents a potential nutraceutical for the prevention of mitochondrial dysfunction and oxidative stress in brain aging and neurodegenerative diseases.

Liposome-incorporated DHA increases neuronal survival by enhancing non-amyloidogenic APP processing.

The fluidity of neuronal membranes plays a pivotal role in brain aging and neurodegeneration. In this study, we investigated the role of the omega-3 fatty acid docosahexaenoic acid (DHA) in modulation of membrane fluidity, APP processing, and protection from cytotoxic stress. To this end, we applied unilamellar transfer liposomes, which provided protection from oxidation and effective incorporation of DHA into cell membranes. Liposomes transferring docosanoic acid (DA), the completely saturated form of DHA, to the cell cultures served as controls. In HEK-APP cells, DHA significantly increased membrane fluidity and non-amyloidogenic processing of APP, leading to enhanced secretion of sAPPα. This enhanced secretion of sAPPα was associated with substantial protection against apoptosis induced by ER Ca(2+) store depletion. sAPPα-containing supernatants obtained from HEK-APP cells exerted similar protective effects as DHA in neuronal PC12 cells and HEK293 control cells. Correlating to further increased sAPPα levels, supernatants obtained from DHA-treated HEK-APP cells enhanced protection, whereas supernatants obtained from DHA-treated HEK293 control cells did not inhibit apoptosis, likely due to the low expression of endogenous APP and negligible sAPPα secretion in these cells. Further experiments with the small molecule inhibitors LY294002 and SP600125 indicated that sAPPα-induced cytoprotection relied on activation of the anti-apoptotic PI3K/Akt pathway and inhibition of the stress-triggered JNK signaling pathway in PC12 cells. Our data suggest that liposomal DHA is able to restore or maintain physiological membrane properties, which are required for neuroprotective sAPPα secretion and autocrine modulation of neuronal survival.

Effects of the standardized Ginkgo biloba extract EGb 761® on neuroplasticity.

Neuroplasticity, the ability of synapses to undergo structural adaptations in response to functional demand or dysfunctions is increasingly impaired in aging and Alzheimer's disease. EGb761® has been shown in several preclinical reports to increase nearly all aspects of impaired neuroplasticity (long-term potentiation, spine density, neuritogenesis, neurogenesis). While all three fractions of constituents (ginkgolides, flavonoids, bilobalide) seem to be active, the flavonoids and specifically the aglycone isorhamnetin seem to be most relevant.

Ginkgo biloba extract EGb 761® in the context of current developments in the diagnosis and treatment of age-related cognitive decline and Alzheimer's disease: a research perspective.

In June 2011 a two-day expert meeting "The Ageing Brain" took place in Amsterdam, The Netherlands. The main aim was to discuss the available preclinical and clinical data on Ginkgo biloba special extract EGb 761® in the context of current developments in the diagnosis and treatment of age-related cognitive decline and Alzheimer's disease. 19 dementia experts covering the disciplines bio- and neurochemistry, gerontology, neurology, pharmacology, and psychiatry from Australia, Asia, Europe and North America reviewed available preclinical and clinical data for EGb 761® and identified core topics for future research. Based on a wide range of preclinical effects demonstrated for Ginkgo biloba, EGb 761® can be conceptualized as a multi-target compound with activity on distinct pathophysiological pathways in Alzheimer's disease (AD) and age-related cognitive decline. While symptomatic efficacy in dementia and mild cognitive impairment (MCI) has been demonstrated, interpretation of data from dementia prevention trials is complicated by important methodological issues. Bridging pre-clinical research and clinical research as well as deciding on suitable study designs for future trials with EGb 761® remain important questions. The participants of the "Ageing Brain" meeting on Ginkgo biloba special extract EGb 761® concluded that there is plenty of promising data, both pre-clinical and clinical, to consider future research with the compound targeting cognitive impairment in old age as a worthwhile activity.

Treatment duration (persistence) of basal insulin supported oral therapy (BOT) in Type-2 diabetic patients: comparison of insulin glargine with NPH insulin.

OBJECTIVE: To compare the persistence (treatment duration) of basal insulin supported oral therapy (BOT) using insulin glargine (GLA) or NPH insulin (NPH) in Type-2 diabetic patients. METHODS: This retrospective cohort study reports results from an analysis of claims data from prescriptions for ambulatory patients within the German Statutory Health Insurance scheme. The study is based on claims data from more than 80% of German community pharmacies. Treatment duration until switching to a basal bolus treatment regimen (intensified conventional insulin therapy: ICT) was determined in insulin-naïve patients who began treatment with BOT using GLA or NPH between 01/2003 and 12/2006. RESULTS: A total of 97,998 patients (61,070 GLA and 36,928 NPH) were included. Within the observation period, 23.5% of GLA patients and 28.0% of NPH patients switched from BOT to ICT. The upper quartile of probability of continuation of therapy (the 75th percentile) was reached after 769 days in GLA patients and after 517 days in NPH patients. Therefore, the risk of switching to ICT was significantly higher with NPH compared to GLA: hazard ratios were 1.34 (99% CI: 1.29-1.38; unadjusted) and 1.22 (99% CI: 1.18-1.27) after adjustment for predefined covariates. Various sensitivity analyses using modified inclusion criteria and endpoint definitions were applied and these confirmed the initial results. CONCLUSION: Type-2 diabetic patients under BOT with GLA stayed significantly longer on the initial therapy before switching to ICT than patients on BOT using NPH.

Effect of anxiolytic drug silexan on sleep - a narrative review.

OBJECTIVES: Silexan is an orally administered, proprietary essential oil from Lavandula angustifolia with significant anxiolytic and sleep improving properties. Here we present a narrative review that provides an overview of the available evidence of the effects of silexan on sleep. METHODS: We start with a summary of the pharmacological background and continue with presenting sleep-related results from controlled clinical trials with silexan. Then we report on a meta-analysis of item 'insomnia' from the Hamilton Anxiety Scale, which includes data from all randomised, placebo-controlled clinical trials with silexan in which the scale was administered. Finally, we summarise the results of a mediation analysis that was performed to elucidate the pathway of the effect of silexan on sleep. RESULTS: In randomised, placebo-controlled trials in patients suffering from anxiety disorders silexan had a significant anxiolytic effect and improved sleep along with recovery from anxiety. Mediation analysis demonstrates that more than 98% of the effect of silexan on sleep was mediated by its anxiolytic effect while the direct effect on sleep was marginal. CONCLUSIONS: Silexan improves sleep as a result of its anxiolytic effect.