| BackgroundPost-stroke aphasia is a high nerve disfunction related to the dominant hemisphere which was damaged by cerebrovascular disease. Aphasics have a communicational fundamental function barrier involved speaking, understanding, reading, writing, et al. Of all cognitive function impairment, aphasia is identified as one of the most common types and brings about the greatest harm on patients’ quality of life. However, as much as21%-38%of the acute survivors suffer from aphasia after stroke. Although most of the PSA survivors can recover part of the language spontaneously, there are still43%of the patients who have serious long-term language barrier. Previous treatment for PSA is mainly language training which has requirement for professional personnels, time and the ground, thus limits its implementation.Language, a human-specific high-ranking nervous function is also an important part of cognitive function, which has mutual relationship with memory, attention, et al. The maintance of cognitive function is the basis of relearning, and relearning ability plays an indispensable role in the process of language recovery. There are scholars who put forward hypothesis that the central cholinergic synapses are memory synapse and emphasize those synapses are structure and physiological basis of memory. Cerebral infaction and cerebral hemorrhage lead to decreasing of acetylcholine in corresponding area and result in cognitive decline such as memory, learning and language processing. Additionally, evidence indicated that cholinergic mechanism may paly a role in the regulation of regional cerebral blood flow. In short, damaged cholinergic system reduces blood flow of the hippocampus and cortex, while ischemia impairs this system in turn, thus forming a vicious circle.In recent50years, scholars have reported several medications affecting the acetylcholine transmitter, which can be used in the treatment of PSA, such as cholinesterase inhibitors (galantamine), cholinoceptor agonists (bifemelane) and cholinergic drugs (physostigmine). On the contrary, choline receptor blockers like scopolamine would damage cognitive function, including language. Donepezil as a reversible acetylcholinesterase inhibitor with s selective central action can reduce the decomposition of acetylcholine, thus increasing the concentration of acetylcholine in the synaptic cleft. For the past few years, many studies have shown that donepezil is effective in ameliorating language and cognitive deficits in vascular dementia which shares similar basic disease with PSA. In2003,Berthier carried out an open-label study of donepezil in11chronic PSA for20weeks. Three years later, the same main researcher implemented a randomized and placebo-controlled study of donepezil in26different chronic PSA patients.The two results revealed that donepezil may have beneficial effects on chronic PSA.At present, of all the foreign clinical researches, there is lack of study of early stage in PSA. Additionly, larger samples, more careful designs, and more comprehensive observation indexs are required in future studies. On the basis of above reasons, a randomized controlled study of donepezil for early PSA, and a better randomized, double-blind placebo-controlled study will be carried out in our study to evaluate the effectiveness and safety of donepezil in the treatment of PSA.ObjectThe present two studies is to evaluate the effectiveness and the safety of donepezil (Aricept, Eisai (China) pharmaceutical co., LTD) in the treatment of early stage of PSA and chronic PSA, thus providing clinical experimental evidences for the use of donepezil.The first experiment SubjectsBetween February2012and November2012, collect Stroke Aphasics in the neurology department of the Nanfang hospital and the Second People’s Hospital of Guangdong Province. Fifty PSA patients with less than1month course are being planed to recuit. The number of patients of the control group and the experimental group are all25. Antidepressant drugs are not allowed to use.All patients’admitted criterions:Fit the diagnosis criterion established by the fourth Cerebrovascular Disease Conference of Chinese Academy of Medicine, also confirmed by CT and MRI; Aphasics meet ABC diagnosis criterion; Age18-80; Cooperate and obey the test procedure. Excluding criterion:illiteracy, hearing and vision impairment; Have serious dysarthria, dementia, mental abnormality or disturbance of consciousness; Pregnancy, lactation or intended pregnancy; Have acute or servious pulmonary, cardiovascular, kidney disease or cancer; allergic history of donepezil. Notes:Written or oral informed consents from all caregivers were obtained. Other cholinesterase inhibitors, glutamate receptor antagonists, speech therapy are not allowed to use.MethodAccording to the patients’course after onset of time, visiting time and the table of random numbers, they were randomly assigned into either an experimental group or a control group. The patients in the control group received conventional treatment and those patients in the experimental group were given donepezil (5mg/night) in addition to conventional treatment. The efficacy was evaluated by the Aphasia Battery of Chinese (ABC), National Institute of Health Stroke Scale (NIHSS), Stroke Aphasic Depression Questionnaire Version (SADQ) and Treatment Emergent Symptom Scale (TESS) before and after4weeks±3days treatment. Data were analyzed with statistical package for social sciences13.0(SPSS13.0).Results1. Forty-eight eligible PSA patients with right-hand entered the statistics. The number of patients in the experimental group was24and so did the control group. Comparisons of the two groups’ age, gender, education, course, storke type, total scores of NIHSS and SADQ, hypertension, diabetes, hyperlipidemia, heart disease, history of stroke or transient ischemic attack, smoking, drinking showed no statistical significances (P=0.415-P=0.983).2. Comparisons in the groups:The experimental group and the control group all showed significant differences in the performances of ABC test before and after the treatment (P<0.01).3. Comparisons between the two groups:Auditory comprehension [(47.8±24.7)versus (22.0±15.4); t=4.342, P=0.000] and reading comprehension [(20.5±14.0)versus (8.1±10.5); t=3.483, P<0.01] of the ABC improved more in the experimental group compared with those of the control group at end-point and the two results had statistically significant differences. Comparisons of the subsets of speech information, fluency, language sequence, repetition, naming and reading aloud didn’t reveal significant differences between the two groups (P=0.597～P=0.918).4. The mean score of SADQ in the experimental group were significantly lower than that of the control group at end-point and also had statistically difference [(6.2±6.0) versus (2.5±3.0); t=2.717, P<0.01].The second experiment SubjectsBetween August2009and September2012, collect Stroke Aphasics with more than3month course who have ever been in the neurology department of the Nanfang hospital. Sixty eligible PSA patients are being planed to recuit. The number of patients of the control group and the experimental group are all30. All patients were identified as non-fluent aphasics by the Aphasia Battery of Chinese (ABC). The patients’admitted criterions are the same as the first experiment.MethodThe protocol was approved by the Local Community Ethics Committee for Clinical Trials and then registed in the Chinese Clinical Trial Register (Registration ID:ChiCTR-TRC-10000942). After baseline evaluation, the patients were randomized in a1:1fashion, using a layered segment randomizied procedure, into donepezil (5mg/day) or placebo during a4-week titration phase, followed by a12-week maintenance phase (10mg/day of donepezil or placebo) and a4-week washout phase. The Western Aphasia Battery, ABC, SADQ, TESS, NIHSS and the Activity of Daily Living Scale were adopted to perform at weeks0,16(endpoint), and20(washout). Data were analyzed with statistical package for social sciences9.2R (SAS9.2R).Results1.48eligible cases were selected into the study, of which25cases were from the placebo group and23were from the experimental group.27cases could be selected to enter the statistical analysis, including13cases of the placebo and14cases of the experimental group.20cases were PPP (per-protocol population) who completed all return visits, of which11cases of the placebo group and9cases of the experimental group.2. Comparisons of the two groups’ age, gender, height, weight, education, course, types of stroke and aphasia showed no differences statistically. Total scores of SADQ, NIHSS, ADL, aphasia quotient and subsets of WAB and ABC were balanced at the first time assessment between the two groups.3. Comparisons in the groups:The placebo group’s aphasia quotient, spontaneous speech of WAB and spontaneous speech, repetition of ABC revealed statistical differences. While, the experimental group’s aphasia quotient, spontaneous speech of WAB and spontaneous speech, reading of ABC, total scores of NIHSS and ADL showed statistical differences. The auditory comprehension of ABC at the first visit and related cognitive function (including visual-space, execution, calculation function) at the second visit also showed differences statistically (P=0.002-P=0.047). After1month post-washout, the donepezil group showed a decline in the scores of auditory comprehension (9.22â†'7.14), but still far above the baseline. Other differences in the groups had no statistical significance (P=0.054-P=0.834).4. Comparisons between the groups:At the second visit, spontaneous speech of WAB showed statistically significant difference between the groups (P=0.011, P=0.011). As to the PPP, spontaneous speech of WAB at the first visit also had stastical difference (P=0.010). Other differences between the groups had no statistical significance (P=0.054～P=0.874).5. There were no statistical differences in the aspect of safety between the two groups (P=0.125～P=0.353). But three moderate-severe adverse events were appeared in the experimental group, including insomnia, dry mouth, sweating, diarrhea, constipation, urinary incontinence and irritability.Total Conclusions1. Early PSA, all aspects of the language has strong natural recovery. As for chronic non-fluent aphasics (course of disease≥3months), the severity of language can still be observed natural reducing, mainly reflected in the spontaneous speech and repetition.2. Use of donepezil in the early stage of stroke may facilitate the recovery on the auditory comprehension and reading comprehension in PSA patients. As for chronic non-fluent aphasics, donepezil is effective in the spontaneous speech.3. Donepezil may lessen the severity of chronic non-fluent aphasics’ impaired language and may have a role in the auditory comprehension, naming, reading and other related cognitive function, including visual-space and executive ability, and calculation.4. Donepezil may take effect in improving chronic non-fluent aphasics’ability of daily life and clinical neurological function deficit.5. After1month post-washout, the donepezil group show a decline in the performance of auditory comprehension, but still far above the baseline.6. Side effects of Donepezil for PSA mainly manifest in insomnia, dry mouth, sweating, diarrhea and irritability. |
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