lunes, 12 de octubre de 2009

“Treatment of dementias: present and future”

Dr. David Alejandro Yaxcal Ch.
Internist – Neurologist
The demential disease of the Alzheimer type (AD) is a progressive neurodegenerative disorder with well-known clinical and pathological features; even though there are individual differences regarding the age to start, the pattern of cognitive damage and the course of the disease, this dementia is more frequent in people older than 60 years old in the industrialized countries. We know very little about the real statistics in Latino America, but considering the characteristics of the cities in which life expectation is gradually getting better, probably the performance of this disease is not so different there.  This may be a public health problem in the occidental countries where there is a greater rate of population aging, due to the social cost that it represents.
There are evidences that the treatment should be individualized, interdisciplinary, combined with pharmacotherapy and psychological help which needs the involvement of the patient as well as the family.  The non-pharmacological intervention should be concentrated on the patient’s difficulty to adapt in the social environment and family dynamics.
The pharmacological therapy tends to reduce the damage impact of the fronto-subcortical circuits through its performance on the different neurotransmission circuits. Nowadays, different drugs are available for the treatment of the Alzheimer’s demential disease. While donepezil (approved in 1998), rivastigmine (approved in 2000), and galantamine (approved in 2001) act through the inhibition of the enzyme called acetylcholinesterase (AChE), the memantine (approved in 2009) is an antagonist of the NMDA receptors. All of them have demonstrated in several clinical assays that they decrease the cognitive damage and improve the behavioral disorders, as well as the patient’s global functioning. The AChE is indicated for the treatment of light to moderate AD, while the memantine is indicated in the treatment of moderate to severe AD.
Over the very last years, we have gone through historical stages of experimentation and treatment in which several drugs have been proved and they sometimes promised some advances.
Such is the case of the first-generation drugs:
a)      Nootrops: as piracetam, oxiracetam, pramicetam, minaprime, bifemelane, that in spite of several clinical assays, no beneficial effect in the physiopathology of AD could be demonstrated.

Among the second-generation drugs which modify neurotransmitters, we can find.
a)      Precursors of acetylcholine: choline, lecithin
b)     Inhibitors of acetylcholinesterase, such as DONEPEZIL, GALANTAMINE, RIVASTIGMINE.
c)      Anticholinesterasic as THA, fisostigmine
d)     Selective muscarinic agonists
e)      Noradrenaline as IMAO-A, (l-deprenil), IMAO B (Moclobemide)
f)       Serotonin as nalaxone, somatostanine, inhibitors of the ACE (ECA according to its abbreviation in Spanish).

Among third-generation drugs:
a)      Neurotrophic factors
b)     Modulators of neurotrophic factors
c)      Inhibitors of calcium channels
d)     Inhibitors of neurotoxins
e)      Glutamatergic regulators and NMDA
f)       Modulators of abnormal proteins
g)     Captors of free radicals

There also exist the miscellaneous, as:
a)      Estrogens
b)     Non-steroidal anti-inflammatory drugs (NSAIDs)
c)      Antioxidants

I want to emphasize that the demential disease treatment is complex.  Ideally the process should be as multidisciplinary in the evaluation as in the treatment. This multidisciplinary method may have higher impact in the treatment than any other isolated medical or pharmacological intervention.

I’ve got the impression that in some places around the world, medical doctors don’t carry out many therapeutic interventions in AD, and in a recent Argentinean article, it has been demonstrated through a survey carried out among resident and clinical doctors,  geriatricians, neurologists, and psychiatrists, that quite  a small number of doctors perform any pharmacologic intervention to cognitive disorders.  

Main Drugs available for the AD treatment

The objective of the drugs currently available in the clinical pharmacological arsenal for the treatment of AD, includes the improvement of the cognitive symptoms, and if possible, the slowing down of the memory and cognitive loss, as well as the control of comorbidity and individual functions. The acetylcholine substitution therapy (that means, the inhibition of the acetylcholine degradation) has been the main strategy applied during the last 20 years, to fight against the most important symptoms of AD.
We’ll review some of these drugs available and those which are the most used nowadays.  


It belongs to the acetylcholinesterase (AChE) inhibitors which are not chemically related to tacrine or physostigmine. It increases concentration of acetylcholine (ACh) almost exclusively in the brain synapses, which stimulate the muscarinic receptors.  After a single dose, the maximum concentration is reached in plasma in 3 to 5 hs; it has a good absorption with a 100% biodisponibility and it is not affected by the food. It is metabolized by the liver. It was approved in EEUU, in 1996.  In different clinical assays, doses of 5 and 10 mg were equally effective as much in cognitive improvement as in functional abilities in people with a light to moderate disease, with 3 to 6-month treatments and maintenance evidence in or over the baseline at 9 and 12 months.

According to Cochrane Database of Systematic Reviews (CDSR) the selected assays showed a modest progress in the global cognitive and clinical function, but a lack of improvement in surveys regarding life quality. Donepezil is indicated for the treatment of a light to moderate AD.

The starting dose is 5 mg/d before going bed. According to tolerance it can further be increased to 10 mg/d in the following 4 to 6 weeks. Muscular relaxation may be enhanced during anesthesia; it has synergic action with other anticholinergic drugs.  Drugs which inhibit the cytochrome P450 enzymes, as luoxetine, sertraline and paroxetine can increase the levels of donepezil in blood, and those which induce this enzyme, as fenitoine, fenobarbital and carbamazepine can reduce the plasmatic level.  The adverse effects associated to donepezil are usually minor: nauseas, diarrhea, vomiting, syncope, insomnia. It’s important to be cautious with sinus node disease or cardiac conduction defects, asthma, chronic obstructive pulmonary disease (COPD), and gastric ulcer histories. The purpose of the treatment is to delay the development of disease and to improve the patients’ cognitive functioning. There are not enough recommendations which clarify when to discontinue treatment, which is why the patient should continue with the treatment while he/she shows a beneficial response. If a significant damage is evident after the treatment interruption, it should be restarted.

It is a pseudoreversible AChE. Rivastigmine is selective to cerebral regions, since it preferentially inhibits the AChE and BuChE G1 isoform, which prevails in the cortex and in the limbic system, as compared with G4 isoform that is located in the striate nucleus.   In patients with AD, the inhibition of AChE is done in a dose-dependent manner up to 6 mg each 12 hs. It is quickly and completely absorbed, with maximum concentration in plasma after one hour; it is weakly joint to proteins and rapidly crosses the hematoencefalic barrier.

In 26-week assays, the treated patient showed an improvement in all the evaluations (cognitive, daily life activities (DLA), global evaluation). According to CDSR, the benefit of a high-dose treatment is reserved to cognition and DLA, while low doses show the benefit just in the global clinical impression.  This is indicated for symptomatic treatments of light to moderate AD, and it is contraindicated in hypersensibility to that drug and severe hepatic compromise.

Since DLA in general are not recuperated once they have been lost, in the best case scenario the treatment just alleviates the symptoms and prevents the decline.  These researches’ data indicate that the most favorable results regarding this can be achieved through an early intervention, since the seriousness of the disease has an influence in the treatment response. In patients who are rapidly deteriorated, the rivastigmine stabilized the decrease of the PDS total punctuation, while in a cohort of less seriously ill patients, a progress was achieved in the total punctuation. This has been confirmed through the gathered data of individual researches.  For patients in a light to moderate condition (global deterioration scale, GDS) of the disease, there exists a DLA improvement or stabilization, while the treatment of patients with a serious AD gets a less significant damage.
The rivastigmine treatment (12 mg/day) during six months is associated with an important reduction of 5-6 points in the NPI-NH total punctuation, and until 76% of the patients interrupted or reduced the additional psychotropics doses, which is why its benefit in behavior is demonstrated.  Those patients with a rapidly progressive disease usually demonstrate a greater benefit with this medication. If the starting dose of 1, 5 mg each 12 hs is well tolerated, after a minimum of 2 weeks it can be increased up to 3 mg each 12 hs, with a consecutive increment of 6mg each 12 hs maximum. Patients can continue taking it if necessary and it may be discontinued when the therapeutic effect has gone. Just like with donepezil, we should be cautious with sinus node disease or cardiac conduction defects, asthma, COPD, liver diseases, or with low-weight patients, because it has been found that 24% of those treated with high rivastigmine doses could lost until 7% of their previous weight. Rivastigmine does not have any known medicamental interaction. The most frequent adverse effects are asthenia, anorexia, dizziness, nauseas, somnolence, and vomiting.

It has most recently appeared in the AChE market. It was approved in 2001 by the Food and Drug Administration (FDA). Besides being an AChE competitive reversible inhibitor, it modulates the nicotinic ACh receptors. This last function allows it to modulate the dopamine, glutamate, and GABA release, and to improve remarkably the cholinergic transmission; it offers the regeneration of the neuronal plasticity, as well as the neuroprotection. It is rapidly absorbed in oral administration, with a 100% biodisponibility. It has hepatic metabolism.  In clinical assays, it has demonstrated an advance in global and cognitive functions in six months, keeping the basal functions after one year. It is indicated for a light to moderate disease, and it is contraindicated in patients with hepatic or renal compromise. Apparently, it can decrease the disease development. The starting dose is 16 mg/day for 4 weeks; the dose can further be increased up to 24 mg/d, administered each 12 hs, with food preferably.   It may have a pharmacological interaction with digoxin and beta-blockers.  The most frequent adverse effects are nauseas, vomiting, abdominal pains, and diarrhea. Just like with the other AChEs, we should be cautious with sinus node disease or cardiac conduction defects, asthma, COPD, and gastric ulcer. With low-weight patients, it should be taken into account that this drug can cause weight loss. 


The memantine hydrochloride is a noncompetitive antagonist of the NMDA receptors; it has moderate affinity with phencyclidine which protects neurons from excitotoxicity induced by glutamate during moderate to severe AD, which presumably starts a series of events that finally cause neuronal death. Memantine presents elevated voltage dependence and a receptor kinetic on/off, without avoiding the physiologic activation of the NMDA receptor. Memantine blocks in a selective way, the excitotoxicity effects associated with the abnormal glutamate transmission, while permitting the physiological transmission associated with the normal functioning of cells.
Memantine has a 100% biodisponibility. Its plasmatic concentration is reached 3-8 hors after the oral administration. A stable equilibrium is accomplished 21 days after starting the treatment.   It crosses the hematoencefalic barrier, but up to 50% less than the seric concentration. In several random clinical researches, as well as in scales used to measure, a global improvement of cognitive function, using up to 20 mg a day, was demonstrated. The assay results showed that memantine improved the functional and behavioral symptoms in severe dementia patients, while reducing their dependence to other people’s care.

Which is the best therapy?

There are several clinical assays that prove the effectiveness of the aforementioned most used drugs in AD. Assays have proved that said drugs are effective for the cognitive symptoms treatment. However, not many assays compare these drugs. In a recent issue, an analysis of 299 patients with AD is described, finding out that the most used drugs are donepezil 33.8%, rivastigmine 35.1%, galantamine just 17.1%, and memantine 14%. However, it was observed that the patients with AD treated with donepezil presented a bigger persistence to treatment than those who received rivastigmine, galantamine or memantine.
Besides the pharmacological treatment, the following proposal should be considered, which is based on an important bibliographic revision by the Doctors Scharovsky and Barboza.


The acetylcholinesterase, donepezil, rivastigmine, and galantine inhibitors are indicated as a part of the light to moderate Alzheimer disease handling, under the following conditions:
1)      The dementia diagnosis should be made according to the standard diagnoses criteria of the specialists in that area.
2)      The probability of the accomplishment of commands given by a relative or caregiver in charge, should be evaluated.
3)      The patient or family’s economical resources to acquire the medication should be evaluated, without generating conflictive situation.
4)      Only specialists, including internists, psychogeriatricians, neurologists, or geriatrics which know about the subject should start the treatment.
5)      These patients should be evaluated each 6 months with an MMSE; if the punctuation is higher than 12, the treatment can continue. In our environment, it is advisable to have meetings with caregivers or relatives to determine if the patient presents functional or behavioral changes.
6)      It is advisable to interrupt the pharmacological treatment if:
a.      the MMSE gets less than 12 points in one of the controls.
b.      the patient shows damage in the daily life activities, until reaching the total dependence.
c.       the patient presents predominant behavioral damage.
d.     there are not beneficial effects with medication, according to the caregiver or attending physician.
e.      adverse effects appear which make the continued treatment difficult.
f.        once the medication is suspended, it may be taken back if the patient globally aggravates.

What is there in the near future?

Fortunately there is a worldwide significant concern about developing therapies capable to solve the AD problem. Currently, there are at least 25 clinical new molecules assays which seem encouraging, however, we should wait for results.  
New therapeutic strategies for the AD treatment include those which are closely concentrated on the overcoming of pathogenesis of disease, like the noncompetitive antagonist of the NMDA receptors, as well as other strategies like Anti-amyloid therapy: secretase inhibitors, Aβ peptid vaccination, antiagregant therapy, reduction of the levels of serum amyloid P-component (SAP), drugs to lower cholesterol, metal quelants, antioxidants, and anti-inflammatory drugs.


There are other drugs, some of them older ones, which may be considered a therapeutic option in AD.
Vitamin E (1.000 IU twice a day) and seleginine (5 mg twice a day) have demonstrated to be effective to detect the dementia progress in patients with light AD, even though the cognitive function does not improve.
Observational researches assure that postmenopausal women treated with estrogens have less cognitive damage risk [50]. However, there are not researches that prove the estrogens benefits, and because of their adverse effects, they should not be indicated to older patients with the purpose of improving their cognitive function.
Raloxifene, a selective modulator of the estrogens receptor, didn’t prove any benefit on the postmenopausal women’s cognitive function.
Lithium is a well known drug with unsuspected qualities: it is able to inhibit the fosforilation of tau protein, probably through its very specific action in glycogen synthase kinase-3 (GSK-3), and protects the growing hormones from toxicity of β-amyloid protein.
Furthermore, it has been demonstrated that lithium interferes in the production of β-amyloid in AD animal models.
Some authors suggest that GSK-3 is required for the γ-secretase. We still don’t have assays with lithium in AD, but there are some curious clinical observations.  Because of the experience with this drug and its low price, it is a good option to test in AD.
Valproate seems to be another possibility in AD, too. It has been suggested that this drug is another tau fosforilation inhibitor.
For some time now, it is known that non-steroideal analgesics decrease the risk of developing AD.
The prolonged use of these drugs was associated to an outstanding reduction, which was only applied to AD, not to vascular dementia. The action mechanism is not yet clear. Several and interesting drugs are waiting in the starting line to be used in the next five years, including new ampakines.
It is very probable that in the future we will use a combination of the active principles in AD.