The worldwide market for therapies for CNS disorders is worth more than $50 billion and is set to grow substantially in the years ahead. This is because: 1) the incidence of many CNS disorders (e.g., Alzheimer’s disease, stroke, and Parkinson’s disease) increase exponentially after age 65 and 2) the number of people in the world over 65 is about to increase sharply because of a marked rise in fertility after World War II. However, CNS research and development are associated with significant challenges: it takes longer to get a CNS drug to market (12–16 years) compared with a non-CNS drug (10–12 years) and there is a higher attrition rate for CNS drug candidates than for non-CNS drug candidates. This is attributable to a variety of factors, including the complexity of the brain, the liability of CNS drugs to cause CNS side effects, and the requirement of CNS drugs to cross the blood-brain barrier (BBB). This review focuses on BBB penetration, along with pharmacokinetics and drug metabolism, in the process of the discovery and development of safe and effective medicines for CNS disorders.

https://link.springer.com/content/pdf/10.1602/neurorx.2.4.554.pdf

Drug Metabolism and Pharmacokinetics, the Blood-Brain Barrier, and Central Nervous System Drug Discovery

https://link.springer.com/content/pdf/10.1007%2Fs13311-011-0047-z.pdf

Vascular cognitive impairment: disease mechanisms and therapeutic implications.

Available symptomatic therapies for the treatment of Alzheimer's disease (AD) have been based on known neurotransmitter dysfunctions associated with the illness. The second-generation cholinesterase inhibitors and the N-methyl D-aspartate receptor antagonist memantine have been widely prescribed and studied. Meta-analyses of these therapies were reviewed, focusing on effectiveness and tolerability. Although many of the meta-analyses demonstrate statistically significant improvements, some question if these benefits are sufficient to justify their current widespread and protracted use. This has spurred the development of new disease-modifying therapies that aim to have a greater impact on this debilitating illness.

/pdf/therapy-for-alzheimer-s-disease-how-effective-are-current-2jolqjfy98.pdf

Therapy for Alzheimer's Disease: How Effective are Current Treatments?

Vascular dementia is a common condition for which there are no effective approved pharmacological treatments available. Absence of effective treatments creates a difficult situation for those suffering from the disease, their caregivers, and healthcare providers. This review will address our current understanding of the mechanisms of nerve cell damage due to ischemia and summarize available clinical trial data on several commonly used compounds including memantine, donepezil, galantamine, rivastigmine, nimodipine, hydergine, nicergoline, CDP-choline, folic acid, as well as such nonpharmacological approaches as validation therapy.

/pdf/vascular-dementia-pharmacological-treatment-approaches-and-3mb9eepw05.pdf

Vascular dementia: pharmacological treatment approaches and perspectives.

The prevention and treatment of cognitive impairment in the elderly has assumed increasing importance in an aging population. This article presents a qualitative review of recent research on experimental interventions for the prevention and treatment of mild cognitive impairment and Alzheimer's disease in elderly subjects. Interventions addressed range from lifestyle measures to pharmacological treatments. Epidemiological studies suggest that dietary measures, physical exercise, and mental activity may reduce the risk of cognitive impairment and Alzheimer's disease in elderly subjects. Statins may protect against incident dementia, and lithium may convey similar benefits to bipolar patients. Ginkgo appears ineffective as a primary preventive measure. Donepezil but not Vitamin E may benefit persons with mild cognitive impairment. Experimental treatments potentially useful for Alzheimer's disease include dimebon, PBT2 and etanercept; the safety and efficacy of the Alzheimer's vaccine remains to be proven, and growth hormone secretagogue and tarenflurbil are likely ineffective. Herbal treatments merit study in elderly subjects with cognitive syndromes.

The prevention and treatment of cognitive decline and dementia: An overview of recent research on experimental treatments.

Background
Currently hydergine is used almost exclusively for treating patients with either dementia, or 'age-related' cognitive symptoms. Since the early 1980s there have been over a dozen more clinical trials, yet hydergine's efficacy remains uncertain. Although previous reviews offer generally favourable support for hydergine's efficacy, they were, however, limited by a bias with respect to the particular clinical studies chosen (e.g., the inclusion of case reports, and uncontrolled trials), and by authors' impressionistic assessments of results. Not surprisingly, there has been a lack of consensus among reviewers with regard to the efficacy of hydergine.

In 1994, a meta-analysis was published by the present reviewers who reported that overall, hydergine was more effective than placebo. However they also observed that the statistical evidence for efficacy in 'possible or probable Alzheimer's disease' patients was so modest that one additional statistically non-significant trial would have reduced the results to non-significance.

Objectives
Because of uncertainty surrounding the efficacy of hydergine, the goals of this overview were to assess its overall effect in patients with possible dementia, and to investigate potential moderators of an effect.

Search methods
The trials were identified from a searches of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group, The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS, clinical trials registries and grey literature sources on 2 March 2009 using the terms hydergin*, ergoloid* and dihydroergo*. Two proprietary databases were also searched. Published reviews were inspected for further sources.

Selection criteria
Trials to be included must be randomized, double-blind, parallel-group, and unconfounded comparisons of hydergine with placebo for a treatment duration of greater than one week in subjects with dementia or symptoms consistent with dementia.

Data collection and analysis
Data were extracted independently by the reviewers, pooled where appropriate and possible, and the pooled odds ratios (95% CI) or the average differences (95% CI) were estimated. Where possible, intention-to-treat data were used.

Outcomes of interest included clinical global impressions of change and comprehensive rating scales. Potential moderating variables of a treatment effect included: inpatient/outpatient status, trial duration, age, sex, medication dose, publication year, and diagnostic grouping.

Main results
There were a total of 19 trials that met inclusion criteria and that had data sufficient for analysis.

Thirteen trials reported sufficient information to use a global rating of improvement and nine trials provided information on a comprehensive rating scale. Three trials provided both outcome measures.

It was not possible to use many of the published results in a combined analysis owing to the lack of sufficient data to perform statistical analyses.

For the 12 trials that used global ratings, there was a significant effect favouring hydergine (OR 3.78, 95% CI, 2.72 to 5.27). For the nine trials that used comprehensive ratings, there was a significant mean difference favouring hydergine (WMD 0.96, 95%CI, 0.54 to 1.37).

Hydergine was well tolerated in these trials, with 78% of randomized subjects available for data analyses.

Greater effect sizes on global ratings were associated with younger age, and possibly higher dose, although most of the subgroup analyses were statistically insignificant.

Authors' conclusions
As in an earlier systematic review, we found hydergine to show significant treatment effects when assessed by either global ratings or comprehensive rating scales (based here on a smaller set of trials than in the earlier published systematic review because trials were required to have data that could conform with MetaView, the Cochrane Collaboration statistics software). The small number of trials available for analysis, however, limited the ability of subgroup analyses to identify statistically significant moderating effects.

Unfortunately, most of the randomized, double-blind, and placebo-controlled trials of hydergine were conducted and published before the advent of consensus-based diagnostic standards of dementia in 1984; therefore diagnostic criteria were less specific. As a result, uncertainty remains regarding hydergine's efficacy in dementia.

Hydergine for dementia.

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Hydergine for dementia.