Dr Krishna Prasad Pathak
Current AD therapy is based on the administration of the drugs donepezil, galantamine, rivastigmine and memantine. Still current drugs are not ease to the treatment and administration strategies (Stefano, Iannitelli, Laserran & Sozio, 2011). In advanced stages of AD, for the physicians, a higher tolerability rate provides to continue for the treatment with higher doses and also, ease of use, easy-to-follow schedule, less administration time spent by the caregiver result in greater adherent to the treatment. So it may anticipate options for treatment for future AD (Amanatkar & Grossberg, 2014). The currently used inhibitors (physostigmine, tacrine, donepezil, rivastigmine etc) are traditional clinical application and having limitation than novel inhibitors like various physostigmine-derivatives. This was followed by a short stare on inhibitors derived from nature (Shaikh et al. 2014).
From now on, there are two pharmacological and nonpharmacological treatment are used for AD treatment. Pharmacological treatments approach administered medication and stop the illness while the nonpharmacological therapies provide beyond the medicine like; behavioural training/interventions, cognitive improvements training and help to maintain the brain impairments (Alzheimer association report, 2013, P.214). Many of therapeutic options including three new anti-dementia drugs (Galantamine, Rivastigmine and Memantine (NMDA antagonist) are available. Unless those were not lunched in 2011, for the treatment of Donepezil, was the one of the available cholinesterase inhibitors till 2010. The use of Galantamine has significant effect for mild to moderate-severe AD and can be referred with one cholineinhibitor, and Rivastigmine, which is available only in the patch formulation, also has the indication for mild to moderate AD. But, co-medication of cholinesterase inhibitors is not allowed (Nakamura, 2012). Acetylcholinesterase inhibitors (AChEIs) are globally referred in the treatment of AD with the elderly people. However, data of clinical studies revealed that a slightly cardiac risk for all user of AChEIs (galantamine, donepezil and rivastigmine) not observed in previous clinical trials (Tournoy, Van derLinden, 2014). Donepezil, rivastigmine, and galantamine are part of the same therapeutic group, they can differ in their pharmacology and pharmacokinetics. Even though no clear clinical proof of this pharmacological heterogeneity, there is the effect in the liver for AD patients (Scarpini, Scheltens, & Feldman, 2003).
Current investigators of a Nordic multicenter found that Alzheimer’s patients had been treated with citalopram that showed greater improvements in irritability and restlessness (Nyth, & Gottfries 1990; Drye et al., 2012). An Australian study showed that cardiovascular is very uncommon adverse effects of acetylcholinesterase inhibitors (ACHIs) to AD patients. Evidence show that ACHIs therapies are associated less but significantly increase the risk of syncope and bradycardia, but they remain important considerations in susceptible individuals. Some clinical studies and animal studies suggest that ACHIs may reduce heart failure, myocardial infarction, and cardiovascular mortality as well as favorable effects on hemodynamics (Howes, 2014).
To date, Citalopram is used as antidepressant medicine, less expensive and clinically safe, tolerability and efficacy and does not cause cardiovascular or anticholinergic adverse effects (Parker & Brown, 2002, Keller, 2000). It is a selective serotonin-reuptake inhibitor antidepressant, commonly used in the treatment of a major depressive disorder. Citalopram are implicated in cell survival. Likewise, citalopram does not inter-fare molecular controls of the cell (Palota, et al, 2004). In some studies the use of Citalopram have shown its effective for the cognitive functioning impairment with AD and in difficulties with activities of daily living through improvement in mood and non-mood symptoms. Furthermore, because increased agitation adds to the burden of the caregivers of those with AD, treatment with antidepressants has the potential to benefit those who care for patients with AD. CitAD will serve as an efficient setting for addressing these secondary hypotheses and for exploring the interrelationships between these outcomes (Drye, 2012). The results demonstrate that rivastigmine and citalopram are able to improve symptoms of depression, memory and cognitive loss in AD patients. The study of Leblhuber, 1994 shows that (after 3 weeks of treatment of citalopram with 20 patients with dementia) the improvement of the behavioural disturbance symptoms, confusion and restlessness, Gottfries-Brane-Steen Geriatric Scale was found (p< 0.05) and underlined the effect of citalopram as emotional "stabilizer" in demented patients (Leblhuber, 1994).
The population treated with Excelon and rivastigmine showed an improvement in depression and global functions as measured by the MMSE, the Hamilton and the NPI. Significant improvements in MMSE was maintained until 48 months subsequently, a gradual and progressive decline of performances was observed, indicating continued disease progression symptoms. A Netherland data base study observed within 8.9 years duration in 3358 patients noted that use of Rivastigmine or Glantamine serious cardiac events increased before ChEI initiation. Further they suggested that probably the increased risk of cardiac exposure may be pathways of their pharmacology mechanism (Kroger, et al, 2012).
Santoro A et al., 2010, An Italian clinical study, over a 36-week follow-up, was shown no significant difference in the effects of galantamine, donepezil, and rivastigmine on a variety of functional and cognitive parameters was observed in a large number of ApoE-genotyped patients with mild to moderate AD (Wolfson, 2002). Moreover, patients receiving galantamine worsened significantly compared with the donepezil-treated group on the IADL scale. As the effect of drug therapy, ApoE ε4 allele did not influence. But in one review study summarized that both donepezil and rivastigmine can delay cognitive impairment and deterioration in global health for at least 6 months in patients with mild to moderate AD (Wolfson, et al., 2002).
It works for 24 hours -both capsule and patch forms of rivastigmine, is prescribed for the treatment of mild- moderate- severe memory problem of AD. Transdermal patches provide non-invasive, continuous drug delivery and offer significant potential advantages over oral treatments. With all transdermal treatments, a proportion of patients will experience some form of skin reaction. The rivastigmine patch has been approved for the treatment of mild-to-moderate AD since July 2007 in the US.
Dhillon (2011) suggests that rivastigmine transdermal patch is an effective treatment option for patients with AD with the potential for improving compliance and providing sustained clinical benefit because of its ease of use and generally favorable tolerability profile. A double-blind phase of the another study, no one patients in any patch treatment reported as adverse experience with signs and symptoms for their most severe application-site reaction, over a 24-week experiment (Cummings, Farlow, Meng, Tekin, & Olin, 2010). Therefore, rivastigmine is commonly prescribed for the treatment of AD however it has side effects of cardiac, including all cholinesterase inhibitors. With AD patient, rivastigmine formulation was not associated to increasing arrhythmogenic or hypotensive effects and was not superior to each other. As well as result showed that with eighty-five AD patients, who were treated with rivastigmine and were retrospectively evaluated by 12 mg oral rivastigmine or 10 cm2 transdermal rivastigmine, except heart rate (P ¼ .035) was not change in any of the ECG parameters (Shah & Reichman, 2006).
In some practice of UK, CHEIs have an important role in the treatment of patients with dementia with Lewy bodies and Parkinsons disease, but at this point there would seem to be only a limited case for recommending ChEIs in mild cognitive impairment, Down syndrome, progressive supranuclear palsy, pure vascular dementia, frontotemporal lobar degeneration, Huntington’s disease, multiple sclerosis, epilepsy, delirium, traumatic brain injury, sleep-related disorders or certain psychiatric disorders (schizophrenia and bipolar disorder). Clinical practice with respect to non-Alzheimers disease indications for ChEIs may vary according to jurisdiction, specifically with regards to whether national guidelines effectively limit off-licence drug use (Larner, 2010).
Latest news from an experts- a lead authors Cummings (2014), announced that 99.6 percent AD drugs trials fail. It was discovered from 2002-2012 and tested with 244 drugs. They added that AD drugs are in a disastrous condition so we have to change it in the coming days. However to see the result of AD drugs it takes around 10 years and also, yet, no changeable of the treatment protocols. That means it leads to be delay than assumption. Hopefully since last 10 years, newly adapted drugs were able to relief the symptomatic symptoms but poorly affect the progression of the disease. In the current time the new diagnostic criteria has been developing so these new criteria may impact on drug development that future trials on disease modifying drugs will include populations susceptible to AD, before clinical onset (Slomone, Caraci, Leggio, Fedotova, Grago, 2012.). Accordingly, it is urgent to develop novel and effective medications for AD that goes beyond AChEIs and NMDA (N-methyl-D-aspartate) antagonists. Modern research has focused on discovering effective disease-modifying therapies, which specifically target the pathophysiologic cascade, hoping to delay the onset of the disease and slow its progression (Tayeb, Yang, Price & Tarazi, 2012). This research also concentrated to find the effectiveness of AD drugs with depression.
At last, Gene therapy is under investigation and assessment for future investigation and hope is that it helps to make slow and prevent AD as well as the production of beta-amyloid aggregation. Both drugs Donepezil and Rivastigmine are more effective and safe than Tacrine, it is less used due to its hepatotoxicity. Antioxidant therapy, Vitamin E and Selegeline can prevent or halt pathological process; they disrupt or prevent the free radical beta- amyloid recirculating cascade. Oestrogen replacement therapy in post-menopausal woman and nonsteroidal anti-inflammatory drugs may play a role in slowing or preventing AD (Yaqub, 1999). As new horizons in the treatment of Alzheiemr’s Disease have been emerging in the clinical praxis continuously. These findings in this area examines some of the exciting pharmacological innovations that may improve cognition in the future. The proper use of peri-spinal etanercept (Tobinick, 2008) and Immunotherapeutic (Morley, 2015) can be another considerable out comes to the patients. On the other hand, the use of Chemotherapy (Bexarotene) is able to reduce cognitive impairment on AD patients (Pathak, Tsolaki & Gaire, 2015). However there is very hard to find studies aimed at therapeutic links between Alzheimer’s disease and Anti-cancer drugs in human model. The sufficient studies are conducted with animal model (mice) and indicating the positive benefits to the AD patients. Bexarotene is useful for the reduction of cholesterol, loss of function associated with APOE ε4, peripheral thyroid hormone metabolism and athyreotic and amyloid beta that is a key cofactor of Alzheimer’s disease. Also, Bexarotene has been shown to restore cognitive functions. Bexarotene is a compound chemically related to vitamin A that activates Retinoic X Receptors (RXR) found everywhere in the body and rapidly cleared amyloid plaques from the brains of Alzheimer’s model mice. On the other hand, benefits of cholinesterase inhibitors for the treatment of mild-to-moderate Alzheimer’s disease have shown in the Clinical trials (Robert Howard et al., 2012) So cholinesterase inhibitors are another mainstay in the treatment of mild to moderate AD (Seibert, Tracik, Articus & Spittlers, 2012).