„Repositioning“ of Approved Drugs for the Treatment of Alzheimer’s Dementia

The drug treatment of patients with Alzheimer’s disease is currently only possible with three acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) and the NMDA antagonist memantine. These substances lead to a symptomatic improvement of up to 12 months (according to the latest results even 24 months, see my post dated 13/12/2012). So-called disease-modifying therapies are unfortunately still not available. In fact, the pharmaceutical industry recently had suffered numerous partly bitter setbacks in clinical trials of such new therapies. Despite the enormous economic potential, which a new drug that slows the disease process would have, currently only a few substances are in clinical trials in phases II and III (compared to more than 1000 drugs against cancer) due to the high economic risk, which such research poses.In a review article in the November 2012 issue of Nature Reviews Drug Discovery, Anne Corbett from King’s College in London and co-authors therefore propose to consider the use of drugs that are already approved for other indications for the treatment of dementia of Alzheimer’s type (Corbett et al, Nat Rev Drug Discov 2012, 11:. 833-846). This strategy is called “repositioning”. This idea is not new in psychiatry. An example is the clinical testing and approval of second-generation, so-called “atypical” antipsychotics in affective disorders. Corbett and co-authors systematically studied the available literature for evidence of the effectiveness of approved drugs and natural products in Alzheimer’s dementia. In a consensus process, various substances for which there is at least some evidence of a neuroprotective effect, were excluded because the currently available evidence is insufficient to justify their further development for the treatment of Alzheimer’s disease. These include selective serotonin reuptake inhibitors (SSRIs), lithium, NSAIDs, B vitamins, cannabinoids or metformin.

For the following substances or classes of substances the data are according to the authors, however, so convincing, that the examination of a repositioning in the dementia of Alzheimer’s type seems to be promising:

Antihypertensives

A high blood pressure is mainly in middle age a risk factor for the development of Alzheimer’s dementia. In old age, the relationship is weaker. The exact role that hypertension plays in the pathogenesis of Alzheimer’s disease is unclear, however, because high blood pressure often occurs along with other vascular risk factors and various cerebrovascular disease processes. However, there is increasing evidence that different antihypertensive drugs irrespective of their blood pressure-lowering properties exert neuroprotective effects. These mainly include angiotensin receptor antagonists (ARBs for angiotensin receptor blockers) and calcium antagonists (CCBs for calcium channel blockers).

The centrally acting angiotensin II plays a central role in the release of inflammatory mediators, vasoconstriction, mitochondrial dysfunction and inhibition of acetylcholine release, all processes which are regarded as potential targets for anti-dementia drugs. It is believed that ARBs develop their potential antidementive effects in two ways: first, through the blockade of angiotensin receptors type 1 (AT1) and secondly by the increased formation of angiotensin III and IV from angiotensin II, resulting in an increased stimulation of angiotensin IV receptors. All available ARBs (losartan, irbesartan, telmisartan, candesartan) reduce the central effects of angiotensin II. Candesartan is the most potent of these substances. There is now considerable preclinical data and large clinical studies that suggest that ARBs might delay the development of dementia. According to the authors losartan or valsartan will require further examination. 

Dihydropyridines from the class of calcium channel blockers are used as antihypertensives for their relaxing effects on smooth muscle. Since they usually cross the blood-brain barrier, they also lead to an dilation of the cerebral vessels and an increase in cerebral blood flow. In vitro studies and results from animal models suggest that these compounds have neuroprotective properties. For nimodipine there is a Cochrane review, which concludes that the substance improved short term cognitive, but not everyday functions, in patients with dementia. Currently, it is also examined whether CCBs may have a dementia-protective effect. The authors come to the overall conclusion that the effects of nitrendipine, nimodipine and nilvaldipine should be further explored. 

Antidiabetics

Type 2 diabetes is an established risk factor for Alzheimer’s disease. Insulin resistance is not only apparent in type 2 diabetes, but also in Alzheimer’s dementia. Insulin not only regulates the blood glucose concentration, the hormone is also an important growth factor. Insulin has neuroprotective and pro-cognitive properties in humans. Intranasal administration improves cognitive function in patients with Alzheimer’s dementia, but is accompanied by significant hypoglycemia. Therefore, the administration of substances that promote insulin release are believed to be more promising approaches. The analogues of glucagon-like peptide 1 (GLP1), exenatide and liraglutide, stimulate insulin secretion, they are approved for the treatment of diabetes mellitus. In animal models, these substances reduce the histological changes typically associated with Alzheimer’s disease and they improve cognitive deficits. Various GLP1 analogs pass the blood-brain barrier. In normoglycaemic people they do not lead to hypoglycemia. Human studies in patients with Alzheimer’s disease are not yet available, but they are currently being carried out. The first results are expected in 2013/2014 .

Minocycline

Minocycline is a tetracycline antibiotic, which because of its lipophilicity particularly easily crosses the blood-brain barrier. In some, but not all, animal models, minocycline reduces the Aß accumulation, the levels of pro-inflammatory mediators and the activation of microglia. Human studies in patients with Alzheimer’s disease are not yet available, but studies in other neurodegenerative diseases have been performed. Studies in amyotrophic lateral sclerosis and Huntington’s disease were negative, but pilot studies in Parkinson’s disease suggest a possible efficacy that warrants further examination in Alzheimer’s disease. 

Retinoids

Retinoids are derivatives of retinoic acid (vitamin A acid) that exert their effects via specific receptors (retinoic acid receptors, RARs). Retinoic acids have a significant impact on growth and cell differentiation. Retinoids are used to treat various skin disorders such as acne and psoriasis. In animal models several synthetic retinoids (tamibarotene, bexarotene, acitretin)  lead to a reduction of Aß concentrations and to an improvement of cognitive and behavioral dysfunctions. In addition to influencing the processing of Aß amyloid, retinoids affect a number of other biological processes, which are attributed a role in Alzheimer’s disease. Although a strong theoretical evidence for potential therapeutic effects of retinoids in Alzheimer’s disease exists, human experimental data are not yet available. Retinoids are sometimes poorly tolerated, which may limit their clinical application.

In summary, Corbett et al. come to the conclusion that the best evidence for efficacy in Alzheimer’s disease exists for calcium channel blockers. For the other drug classes mentioned above there is at least good data from in vivo studies. The overall relatively poor toleratibility of retinoids may preclude their broad application. Furthermore, it has to be determiend whether these substances may be effective in preclinical stages of the disease or even prophylactically. 

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