The limitations of current therapeutic interventions for Parkinson disease - Essay Example

Discuss the limitations of current therapeutic interventions for Parkinson disease, and discuss the potential therapeutic use of embryonic stem cellsfor this disease. Introduction Parkinson’s disease is a chronic progressive motor disorder, which gains its presence because of damage to the cells located in the basal ganglia of the brain. Thus, Parkinson’s disease can be considered to be a neurological disability. Parkinson’s disease can affect both male and females above the age of 50 years. The major types of Parkinson’s disease are as under: 1. Idiopathic Parkinson’s disease 2. Arteriosclerosis 3. Post-encephalitic 4. Drug-induced parkinsonism The three main features that characterize Parkinson’s disease: tremor, rigidity, and bradykinesia. The tremor as existent is Parkinson’s disease is fine (3-6/seconds) and is repetitive (pill-rolling). The rigidity is mild and plastic and gives unwanted birth to series of jerks. The Parkinson’s disease also results in the production of few spontaneous movements i.e. a condition known as bradykinsia or akinesia. Parkinson’s disease is progressive and results finally in total disability ad intellectual deterioration. In the neurochemical basis of Parkinson’s disease we learn that the pathological lesion in Parkinsonism lies in the corpus striatum and basal ganglia. In addition, the never cell bodies located in the substantia nigra shows signs of degeneration. The histochemical techniques have brought to notice that corpus striatum and basal ganglia are electively depleted of the monoamine, dopamine. The present time holds two major therapeutic interventions to fight back Parkinson’s disease. The first one involves the development of specific therapies for each of the existent problems in the patient that cannot be answerable otherwise by means of L-dopa and the second is by virtue of embryonic stem cells. It is essential to mention here that L-Dopa is more efficacious and less expensive as compared to other dopamine agonists (Rascol, et al., 1998; “Parkinson Study Group”, 2000) The drug therapies for Parkinson’s disease hold their presence of importance by their efficient functioning at two major lines: 1. Administration of anticholinergic drugs to decrease the cholinergic excitatory activity 2. Administration of dopaminergic drugs for enhancing dopaminergic inhibitory activity Some important therapeutic agents for the treatment of Parkinson’s disease I Drugs Affecting Brain Dopamine Drugs increasing brain dopamine level - L-dopa ( Larodopa, Levodopa) Dopamine releasing drug - Amantadine (Amantrel, Symmetrel) Dopaminergic Agonist - Bromocriptine (Parlodel), apomorphine, cabergoline, dihydroergocriptine, lisuride, pergolide, piribedil, pramipexole, ropinirole Inhibition of Monoamine Oxidase Type B – selegiline, Deprenyl II Centrally – active anticholinergic agents Anticholinergic agents -Benztropine (Cogentin), Cycrimine (Pagitane), Procyclidine (Kemadrin), Trihexyphenidyl (Artane, Benzhexol) Antihistamines -Diphenhydramine (Benadryl), Orphenadrine (Disipal), Chorphenoxamine (Phenoxene) Phenothiazine -Ethopropazine (Parsidol) Throwing specific light - Anticholinergic therapy For several years, the drug therapy for Parkinson’s disease had its base of development on the belladonna alkaloids. However, in the newer synthetic alkaloids attempts to increase the central anticholnergic effects and reduce the undesirable peripheral effects have been made. The synthetic anticholinergic agents of interest include benztropine mesylate, trihexyphenidyl, procyclidine, and biperiden. The side effects of these agents are severe and included within its margins of potential adverse effects are delusions, hallucinations, ataxia, somnolence, and dysarthria. The peripheral side effects of these agents include blurred vision, dry mouth, urinary retention, constipation, and tachycardia. The improvement as resulting from anticholnergic agents is rarely more than 20%. However, despite the continued usage of anticholinergic agents the symptoms of Parkinson’s disease continue to progress. Thus, we can state that anticholinergic agents do not exhibit the desired potential to inhibit the progression of Parkinson’s disease. The most essentially important usage of anticholnergic agents is in conjugation with L-dopa. This feature enables to diminish the cholinergic straital effect and inhibit the reuptake and storage of dopamine in striatum. It is also crucial to point out here that antihistamines, are generally better tolerated in the elderly people and thereby present themselves with comparatively less side effects. The antihistamine agents of probable attention here are diphenhydramine hydrochloride, orphenadrine hydrochloride and the phenothiazines antihistamines (ethopropazine hydrochloride). Throwing specific light - Levo-dopa It was not before the 1967 that the dramatic symptomatic improvement in Parkinson’s disease was realized by the administration of high doses of racemic dopa. The research was further followed with several other studies that confirmed the efficacy and safety of levo isomer of dopa for the treatment of Parkinson’s disease. The effectiveness of levodopa held an essential requirement of penetration of the drug into the central nervous system and its subsequent enzymatic decarboxylation to dopamine. Thus, we would like to point out here that dopamine does not hold the efficiency to cross the blood brain barrier and this can be ascribed to its basic nature. The effect of levo-dopa accompanies several side effects as well. The actions of dopamine are complex to understand and it is chiefly so because of the presence of amine that acts on several different receptors located both centrally and peripherally. In the periphery, levodopa administration results in the stimulation of adrenoreceptors and thus causation of an increase in the heart rate and side effect of vasoconstriction. The stimulation of dopaminergic receptors results in renal and mesenteric vasodilation. One of the significant side effects of levodopa therapy is gastric upset accompanied with nausea and vomiting. The effect of levodopa on the GIT can be attributed to the stimulation of the chemoreceptor trigger zone in the medulla. In order to beat the heat of these side effects, a combination therapy is often administered to the patients of Parkinson’s disease. The administration of levodopa along with decarboxylase inhibitor such as carbidopa results in a significant decrease in the incidence of and severity of nausea and vomiting in addition to decreased side effects on the cardiovascular system. The combination therapy of levodopa along with other suitable medications helps relieve the side effect threat by a significant level of 75% to 80%. Pyridoxine, a coenzyme of dopa decarboxylase if administered with levodopa results in reversing the therapeutic effect of levodopa by increasing the decarboxylase activity, which results in more levodopa being converted to dopamine in the periphery. This action of pyridoxine results in the penetration of less amount of levodopa in the central nervous system. Carbidopa blocks the peripheral decarboxylation and thus prevents the metabolism of levodopa in the peripheral region. This certainly helps relieve side effects especially the peripheral side effects that are induced by the administration of levodopa. Throwing specific light - Embryonic Stem Cell We would like to throw some light on what exactly an embryonic stem cell is. Human embryonic stem cells are cultured cell lines that hold their place of birth from the inner cell mass of the blastocyst that can be grown indefinitely in their undifferentiated state, still being efficient enough to differentiate into all cells of the adult body. It is essential to note here that the most versatile stem cell is the embryonic stem cell. This cell is distinct from the stem cells that find their presence in the adult body. The embryonic stem cell can only be derived from cells found in the embryo. During the period of development, the human fertilized egg grows into a ball of cells that is being called as blastocyst in the scientific terminology. The blastocyst then develops through a number of embryonic stages before becoming a fetus. Embryonic stem cell research holds its essential area of focus on cells derived from the inner cell mass of blastocyst. The embryonic stem cell is of great value in the research for the treatment of Parkinson’s disease because of its significant ability to retain the developmental capacity to generate all functional adult cell types (Freed, et al., 2001). The culture methods have been therefore developed to turn embryonic stem cells into brain, heart, blood cells, blood vessels, skin, islet cells, muscle cells, and bone cells. It is therefore understandable that research and development projection on embryonic stem cells can help discover the factors that are crucial for regeneration and repair of tissues. It is with this reason that experts are attempting to coax embryonic stem cells into producing cells and tissues for replacement therapies for treating disorders such as Parkinson’s disease. Some experts even believe that stem cells can help grow entire hearts, livers, and kidneys. Though the primary treatment of Parkinson’s disease is replacement of dopamine with medications, they fail to stop the degeneration caused by the disease and the symptoms suppressed for a period of time can reappear. Therefore grafting of dopaminergic neurons from the fetal tissue has been considered as a potential solution to the problems that fail to be addressed by therapeutic agents. The studies that relate their base for the evaluation of grafting of embryonic stem cells has been conducted in about 400 patients and has presented some success in reducing the symptoms of Parkinson’s disease. However, the responses as observed by the grafting have been very much different in different patients of Parkinson’s disease. In addition, usage of fetal tissue holds within its area of applicability potential ethical issues to be addressed. It is with this reason that the experts in the field address the problem of grafting stem cells by taking the same from fetus and adults alternatively. Current therapeutic interventions – A general discussion In recent times, several scientifically important studies as pertinent to the treatment of Parkinson’s disease by means of drug therapy have been conducted and evaluated (Goetz, et al., 2002; Rascol, et al., 2002). Many well-designed, randomized, placebo –controlled studies have revealed the efficacy of dopamine agonists in the treatment of Parkinson’s disease (Adler, et al., 1997; Barone, et al., 1999; “Parkinson Study Group”, 1997). The studies as pertinent to the advantage and effective level of dopamine agonists have been published (Colzi A, et al., 1998; Guttman, 1997; Lieberman, et al., 1998; Olanow, 1998; “Parkinson Study Group”, 2002; Rascol, et al., 2000; Rinne, et al., 1998; Stocchi, et al., 2002; Whone, et al., 2002) has been greatly cited. Dopamine agonists hold the potential in treating and preventing motor complications. It has also been pointed that additions of an agonist to L-dopa in patients who are experiencing motor fluctuations reduced the total amount of time that is being otherwise spend in the off concision. The acceptance of dopamine agonists in the therapeutic interventions may also project the advantage of improving on the grounds of motor fluctuations and dyskinesias. However, the therapeutic benefit of dopamine agonists is mostly restricted in the circumference that holds the patients who have not been exposed to L-dopa. This certainly sets a noticeable limit of the application of dopamine agonists as pertinent to its advantages as seen in Parkinson’s patients. However, it is also essential to note that long-term, randomized, double blind studies have reported a significant advantage of dopamine agonists above L-dopa in patients who have been addressed for follow-up to the time frame of five years. Thus, we might state that in some well-designed studies, the risk of motor complications is reduced to a greater extent by dopamine agonists than possible with L-dopa. This certainly presents the added benefit of dopamine agonists over all other therapeutic means available. In the category of non-dopaminergic anti-Parkinson’s medications, the drug molecules that enjoy the most precious stand are anticholinergics and amantadine (Uitti, et al., 1996). Anticholinergics exhibit mild symptomatic effect on the motor triad, especially tremor (Martin, et al., 1974) and are amongst the cheapest antiparkinsonian medications. The anticholinergic side effects as induced by this commodity of drug molecule include hallucinations and confusion. Amantadine has regained its stand of a therapeutic commodity of benefit in the treatment of Parkinson’s disease because of its antidyskinetic effect (Verhagen Metman, et al., 1998; Metman, et al., 1999; Del Dotto, et al., 2001). The mechanism of action of amantadine as related to its antidyskinetic effect is its weak glutamate antagonist property that holds the potential to block N-methyl-D-aspartate (NMDA) receptors. Thus, it has been stated that the effect of amantadine results in neuroprotection and also slows the rate of Parkinson’s progression. The surgical procedures of Parkinson’s disease includes thalamotomy, subthalamotomy, pallidotomy, and deep brain stimulation involving thalamus, pallidum, subthalamus nucleus and is adopted only if therapeutic effect achieved from medications is not to the point of requirement (Olanow, et al., 2001). This is because surgical interventions hold the disadvantage of inducing even potential side effects in around 2 to 5 % people (“The Deep-Brain Stimulation for Parkinson’s Disease Study Group”, 2001). The efficacy of surgical procedures is still in the need of randomized controlled trail to prove their applicability and effectiveness in the treatment of Parkinson’s disease. For example, fetal nigral transplantation showed therapeutic benefit in an open-label study, but failed to reveal the same benefit in two consecutive placebo-controlled double-blind studies. The side effects that resulted by its acceptance as a surgical means resulted in off-medication dyskinesia. We would also like to bring to the platform of facts that certain other surgical interventions including the stem cell and gene therapies though have presented a promising stand in other diseases are not addressed with complete attention in the case of Parkinson’s disease. In addition, no evidence is available on the lines that surgical interventions shall improve the resistant symptoms of L-dopa, disease progression or life expectancy. Medications for L-dopa resistant features presents the fact that Parkinson’s disease patients suffer from symptoms that do not respond to the level of satisfaction by administration of dopaminergic drug molecules. For example no therapeutic interventions has been proved to be of benefit in the treatment of Parkinson’s disease. Atypical neuroleptics have been stated of being lower in potential in causing extra pyramidal adverse reactions as compared to the older atypical dugs. 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