THE GOOD DRUG GUIDE
"..... Rasagiline (Azilect) is a potent, selective, irreversible monoamine oxidase (MAO) type-B inhibitor. It is a useful agent in the symptomatic treatment of Parkinson's disease. Rasagiline and its analogues are under investigation for Alzheimer's disease. Both rasagiline and its aminoindan metabolite exert a neuroprotective effect by increasing brain-derived neurotrophic factor (BDNF) in the hippocampus and striatum; they may enhance memory and learning. Rasagiline may also improve mood, motivation and age-related memory decline in the ageing but nominally well adult population. Its action is typically pro-sexual, occasionally hypersexual.
Rasagiline was first synthesised and developed by the Iranian-born Israeli researcher, Professor Moussa Youdim. It is licensed for sale by Teva Pharmaceuticals under the brand name Azilect. Unfortunately, a "technical error" in the original submission delayed a US product license. In a follow-up letter to Teva received on 4th August 2005, the FDA reiterated that Azilect was "approvable", but raised additional "concerns". Teva has since agreed with the FDA to undertake a post-marketing Azilect study in order to investigate whether or not Azilect increases the risk of skin cancer. This worry seems highly unlikely; but risk of the condition may be raised in patients with Parkinson's disease. In practice, the FDA has been flexing its muscles in the wake of recent drug-industry scandals: EMSAM, transdermal selegiline, was delayed over problems centering on whether the labelling would have to display a "black box" warning for the potential tyramine interaction. The use of such labelling might simply cause needless alarm. Clinical trials of rasagiline have all been conducted without dietary restrictions. Tyramine challenge studies of healthy volunteers have been uneventful. As of mid-2016, there have been no hypertensive crises to date.
On 16 May 2006, Azilect was finally granted a US product license. The FDA panel approved Azilect both for initial single-drug therapy in early Parkinson's disease and as an adjunct therapy to standard levodopa treatment in more advanced patients.
In August 2008, Teva announced promising results from a late-stage Phase III 18-month rasagiline trial. Parkinsonians who took a 1mg Azilect pill once a day from the start of the trial showed "significant improvement" over patients who started taking Azilect nine months later. In September 2009, a study published in the New England Journal Medicine suggested rasagiline may slow the rate of progression in Parkinson's disease. It remains unclear whether rasagiline is superior to cheap and off-patent selegiline. In March 2016, Orchid Pharma received final approval from the FDA to launch its ANDA (Abbreviated New Drug Application) rasagiline tablets 0.5 mg and 1 mg in the USA.
In Europe, Azilect is co-promoted by Danish-based drug giant Lundbeck. Azilect was launched in Israel in March 2005. Rasagiline became available in the UK as Azilect from June 2005. Its roll-out in other EC countries followed. Professor Youdim believes that a few years hence we may mix a spoonful of drugs into our daily cereal bowls to protect the brain from neurodegenerative disease. Possibly in future we will take a cocktail of neuroprotective pills to retard the ageing process itself. Pitfalls doubtless lie ahead, and timescales may prove optimistic; but neither senescence nor age-related disease are inevitable.
Rasagiline can be taken orally, with or without food. Typical dosage is 1 mg per day. Absorption is rapid; peak plasma concentration is reached after around 30 minutes. Rasagiline can be used both on its own in early Parkinson's disease, and as an adjunct to levodopa (L-DOPA) treatment in later stages of the disorder, where it is beneficial against end-of-dose fluctuations in motor function. There is tentative evidence that rasagiline can slow the progression of Parkinson's disease itself as well as offer symptomatic relief. This has been shown in vitro and in non-human animals, though not yet conclusively in controlled clinical trials of human subjects.
Parkinson's disease is a degenerative disorder of the central nervous system of unknown origin. Both environmental and genetic factors play a role in its onset. Symptoms include stiffness, tremors, slowness of movement, impaired balance, decreased facial expression, fatigue, apathy and sometimes pain. Parkinsonians find it difficult to turn thought into action. A slowing down of mental processes is sometimes mistaken for dementia; but as a rule of thumb, "if you give a Parkinson's patient time to answer a question, they will answer. If you give an Alzheimer's patient time to answer a question, they will forget the question".
Parkinson's disease is often foreshadowed by diminished vitality and depression. These tend to worsen as the disease progresses. Some 50% of Parkinsonians become clinically depressed; there is accumulating evidence that the depressive symptoms of "dopamine deficiency disorder" are directly tied to the neuroanatomical degeneration.
Overt signs of Parkinson's disease are associated with an 80%-plus loss of dopamine-producing neurons in the substantia nigra of the midbrain. Sub-clinical signs and symptoms may appear earlier. Some researchers suspect that all of us would all go on to develop Parkinsonian symptoms if we lived long enough. This is because of disproportionate nigral dopamine cell loss during every decade of adult life. Increased dopamine catabolism is associated with oxidative stress and neuronal cell death. Selective MAO-B inhibitors delay this process, but the molecular mechanisms of neuroprotection appear to be independent of MAO-B inhibition itself, lying in the interference by propargylamines with apoptosis signalling pathways.
By inhibiting MAO-B, rasagiline prevents the deamination of the monoamines dopamine and phenethylamine (PEA), thereby increasing their concentration in the synapse and curbing production of the reactive oxygen species, hydrogen peroxide. High concentrations of hydrogen peroxide are associated with increased oxidative stress. Rasagiline both raises levels of striatal dopamine produced from levodopa and improves the survival prospects of ailing dopaminergic neurons themselves. This salvage job helps restore a measure of normal locomotion, gait and coordination in Parkinsonian patients while delaying their physical decline.
In the brain, dopaminergic neurons in the substantia nigra project to the basal ganglia. The basal ganglia regulate bodily movement, but also play a role in thinking and emotion. To function adequately, basal ganglia cells require a proper balance between the dopamine and acetylcholine signalling systems. This balance is lost in Parkinson's disease as the dopamine neurons die off. Parkinson's patients are sometimes given anticholinergic drugs like benztropine (Cogentin), trihexyphenidyl (Artane), and ethopropazine (Parsitan) to control their tremor. At worst, these drugs are dementing; at best, they impair memory and cognition. Anticholinergics were the mainstay of treatment before the advent of levodopa. Fortunately, the benefits of rasagiline, either as monotherapy or an adjunct to levodopa treatment, extend beyond restoring motor activity. For rasagiline (modestly) improves cognitive performance on a range of tests, suggesting a role in improved central cholinergic function that is still obscure. More speculatively, a low-dosage regimen of rasagiline may prevent or retard the onset of Parkinsonian symptoms, dementia and diminished vitality in the wider, notionally healthy community as a whole. Such usage is likely to remain off-label for the foreseeable future.
The main therapeutic advantage of rasagiline over the other selective irreversible monoamine oxidase-B inhibitor selegiline (l-deprenyl, Eldepryl) is that rasagiline does not have the presumed toxic amphetamine metabolic breakdown products of the structurally similar selegiline. Subjectively, rasagiline feels "cleaner". Selegiline is metabolised to R(-)-methamphetamine and R(-)-amphetamine, whereas rasagiline is metabolised to R(+)-1-aminoindan. There is no evidence that these trace amphetamine metabolites contribute to selegiline's neuroprotective action.
Both selegiline and rasagiline are neuroprotective via multiple mechanisms that are poorly understood. However, their role in stabilising mitochondrial membrane potential is critical. The propargylamine moiety rather than MAO inhibition per se apparently holds the key to their neuroprotective action: the S isomer of rasagiline is some 1000 times less potent as an MAO inhibitor, but it's still protective against neurotoxic insults. Rasagiline inhibits activation of the apoptotic cascade triggered by dopamine neurotoxins and oxidative stress. Apoptosis is an active process of programmed cell-death induced by exposure to neurotoxins. Rasagiline and other propargylamines can rescue deteriorating dopaminergic neurons by inhibiting the "death signal" transduction-mechanism of mitochondrial permeability transition. Current evidence suggests that rasagiline may be more effective than selegiline in salvaging dopamine nerve cells from the usual neurological carnage of later life.
Chronic rasagiline use increases the activity of the antioxidative enzymes superoxide dismutase (SOD) and catalase (CAT), both in the dopaminergic systems of the brain and also in the heart and kidneys. Professor Youdim speculates that one day rasagiline will be used not just as a prophylactic against neurodegenerative disease but as a cardioprotectant.
In the brain, rasagiline increases glial cell-derived neurotrophic factor, nerve growth factor, and brain-derived neurotrophic factor. Neuroplasticity and the long-term potentiation of memory can be enhanced. More speculatively, rasagiline may at least weakly retard the onset, symptoms and progress of Alzheimer's disease. Alzheimer's disease is associated with senile plaques of beta-amyloid peptide; rasagiline facilitates the conversion of amyloid precursor protein (APP) into the neuroprotective, neurotrophic and intracellular soluble APPalpha. It should be stressed that this off-label use of rasagiline remains clinically unproven.
Rasagiline is typically well tolerated if used within the therapeutic dosage range. In one study, the efficacy of 1 mg rasagiline taken once daily was similar to 200 mg of the COMT inhibitor entacapone (Comtan) administered with each levodopa dose: the only adverse event reported to be significantly more common with rasagiline than with the placebo was postural hypotension. Professor Youdim, profiled in Haaretz, observes that rasagiline [taken at a low MAO-B selective dosage] typically has no adverse side-effects. Most recently, the well-controlled PRESTO study of the Parkinson Study Group confirmed an improvement in motor fluctuations and Parkinson's disease symptoms in levodopa-treated patients; the only adverse events significantly more common with rasagiline than with the placebo were reportedly balance difficulties in the 0.5 mg rasagiline group, and anorexia, vomiting and weight loss in the 1 mg group. Fewer patients reported depressive symptoms. In the LARGO study, the frequency of adverse side-effects in patients using rasagiline or entacapone as adjuncts to levodopa treatment was similar to those in patients taking the placebo. At dosages above around 2 mg per day, rasagiline loses its selectivity for MAO type B and also inhibits MAO type A. An MAO-B selective regimen does not cause significant tyramine potentiation, the dreaded "cheese effect" common to users of older unselective and irreversible MAOIs who eat tyramine-rich foods. Thus low-dosage rasagiline demands no special dietary restrictions. But rasagiline should not be combined with other MAO inhibitors, selective or otherwise. Concomitant use of the opioid painkiller pethidine (meperidine, Demerol) is contraindicated too. For poorly understood reasons, combining SSRIs with rasagiline is also best avoided even at a low MAO-B selective dose.
No harmful effects from rasagiline have been detected either in pregnancy or post-natal development, at least in "[non-human] animal models".
The optimal dosage of rasagiline has yet to be exactly established, whether for Parkinsonians, or for depressives who may benefit from higher rasagiline dosages that inhibit both types of MAO enzyme, or for use of rasagiline prophylactically as a neuroprotectant by the "worried well", i.e. sufferers from the fatal hereditary disorder we know as the ageing process. Over the clinical dosage range, rasagiline displays a more-or-less linear pharmacokinetics. An excessively high dosage of rasagiline apparently shrinks the cell sizes of nigral tyrosine hydroxylase-positive neurons. This is currently of unknown significance, but suggests a dose-effect graph with an inverted U shape, possible toxicity, and consequently the need for caution.
The effects of a long-term regimen of rasagiline on human life-expectancy and maximum lifespan are unknown. Yet since low-dosage selegiline can increase both life-expectancy and maximum lifespan in a number of non-human animal species, it is possible, though again unproven, that rasagiline's superior metabolic profile may offer advantages for life-extension. The only other current routes to enhanced longevity are either caloric restriction (CR) - which takes brutal self-discipline and can compromise mood, virility and vitality - or, hypothetically, the use of compounds like resveratrol which mimic the effects of caloric restriction without provoking its troublesome side-effects. But they remain clinically unproven too.
Rasagiline doesn't displace catecholamines from their intracellular stores. It lacks any significant "abuse potential", though this is seldom a problem with selegiline either. Neither acute nor chronic rasagiline taken at MAO-B selective dosages increase tissue levels of the monoamine neurotransmitters noradrenaline, serotonin and dopamine. In common with selegiline, rasagiline may be protective against the serotonergic damage caused by the widely used drug MDMA (Ecstasy). Unfortunately, the risks of taking any MAOI with MDMA probably statistically outweigh any neuroprotective benefit. A post-E fluoxetine (Prozac) or other SSRI may offer a less hazardous form of neuroprotection; but this carries theoretical risks too. Until safe and sustainable insight-and-empathy drugs are developed, it may be prudent either to use them only very sparingly or avoid them altogether. An enriched conception of mental health is of limited use until we have the means to sustain it.
If rasagiline is good news, then other pharmaceutical products on the commercial horizon are better. Perhaps most notable is the neuroprotectant ladostigil (TV3326), again designed by the redoubtable Professor Youdim. Ladostigil inhibits both cholinesterase and MAO activity, enhancing cognitive function and mood alike. Ladostigil is cunningly designed with a propargyl group for MAO inhibition and a carbamate moiety to inhibit cholinesterase. Both the MAO type A and MAO type B inhibition of ladostigil are relatively selective to the brain: liver and small intestine enzymes are less affected.
This advance is important for several reasons. One reason is obviously the plight of a rapidly growing population of elderly Parkinsonian and Alzheimer's patients in need of more effective drug therapies with fewer risks and adverse side-effects. But the potential range of therapeutic application is broader. Most people would like to feel happier, smarter, younger and sexier. Sadly, contemporary antidepressants and nootropics are badly flawed. It's not just that they are often ineffective. They either have anticholinergic "dumb drug" effects like the older tricyclics, or they flatten emotions and kill libido, like the SSRIs. Older unselective, irreversible MAOIs like tranylcypromine (Parnate) and phenelzine (Nardil) can elevate mood, but their risks and accompanying dietary restrictions make them unattractive even for the clinically depressed and their wary physicians. Meanwhile classic nootropic agents such as cholinergic boosters are liable to subdue mood and cause behavioural inhibition. The attraction of dual action agents like ladostigil, on the other hand, is that they promise to lift mood and intellectual performance alike, while offering a measure of protection against the ravages of ageing.
Even so, tomorrow's neuroprotective smart mood-brighteners are just stopgaps. They offer only palliative relief on the route to germ-line gene therapy in decades to come, and perhaps the wholesale genomic rewrites of the posthuman era beyond. The global pandemic of human ageing can ultimately be cured; but eradicating the lethal disorder we call old age may still take several centuries. In the meantime, rasagiline and its derivatives are potentially valuable drugs that can improve the quality of life of sick and ageing Darwinians in the years ahead ...."
Merck Manual Search Medline
and further reading
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