Efficacy and safety of donepezil in patients with Alzheimer's disease: results of a global, multinational, clinical experience study

BACKGROUND: Donepezil has consistently been shown to be effective and well tolerated in the symptomatic treatment of Alzheimer's disease in placebo-controlled clinical trials. It has been shown to provide significant benefits in cognition, global function and activities of daily living in patients with mild-to-moderate Alzheimer's disease. However, in order to control for confounding factors, some clinical trials of donepezil have excluded patients with comorbid illness and concomitant medication use. OBJECTIVE: The objective of this study was to evaluate the efficacy, tolerability and safety of donepezil in a wider and more diverse sample of patients and centres than previous trials, reflecting routine clinical practice. METHODS: In this 12-week, open-label, multicentre trial, patients with probable mild-to-moderate Alzheimer's disease received donepezil 5 mg/day for 28 days, after which the dosage was increased to 10 mg/day according to the investigating clinician's judgement. Patients were enrolled at 246 study centres in 18 countries worldwide. Cognition was assessed by a trained clinician using the Mini-Mental State Examination (MMSE) at baseline, week 4 and week 12 (or last visit). Changes in patient activity and social interaction were evaluated using a caregiver diary. Each week, caregivers recorded their impression of change compared with baseline on three aspects of patient behaviour using a 5-point scale. Efficacy analyses were performed on the intent-to-treat population. Significance was determined using the paired t-test (0.05 significance level). Tolerability and safety were assessed by monitoring adverse events, physical examinations, vital signs, clinical laboratory test abnormalities and ECG findings throughout the study. RESULTS: A total of 1113 patients received donepezil (mean baseline MMSE score [+/-SD] 18.74 +/- 5.21). 989 (88.9%) patients completed the study; 59 (5%) patients discontinued because of adverse events. Most patients were taking at least one concomitant medication (n = 802; 72%) and had at least one comorbid medical condition (n = 745; 67%) on study entry. Donepezil significantly improved cognition compared with baseline at weeks 4 and 12, and at week 12 using a last observation carried forward (LOCF) analysis (all p < 0.0001). Mean change from baseline MMSE score (+/-SE) at week 12-LOCF was +1.73 +/- 0.10. Donepezil was also associated with significant improvements in patient social interaction, engagement and interest, and initiation of pleasurable activities at all weekly assessments and week 12-LOCF (all p < 0.0001). Donepezil was generally well tolerated; adverse events were consistent with the known safety profile of donepezil. CONCLUSION: Donepezil treatment resulted in statistically significant improvements in cognition and patient activity and social behaviour, and was generally well tolerated despite high levels of comorbid illness and concomitant medication use. The results of this open-label study in a large patient population are consistent with those from controlled trials and support that donepezil is effective in the treatment of mild-to-moderate Alzheimer's disease in everyday practice.     

An alarming sign for serious diseases in children: bilateral facial paralysis

Facial paralysis in children is most often idiopathic, and isolated facial nerve palsy resulting from leukemic infiltration is a rare occurrence. We report a 13-year-old male with acute lymphoblastic leukemia presenting with bilateral facial palsy, who was previously diagnosed with idiopathic facial palsy and treated with steroids. This rare presentation of acute lymphoblastic leukemia should be kept in mind as a diagnostic possibility in a patient with bilateral facial nerve paralysis.     

Cognitive impairment in amyotrophic lateral sclerosis: evidence from neuropsychological investigation and event-related potentials

The presence of subclinical cognitive impairment in patients with amyotrophic lateral sclerosis (ALS) is investigated using neuropsychological assessment and event-related potential recordings (ERP). An extensive battery of neuropsychological tests assessing the domains of attention, memory, language, visuo-spatial and executive functions were administered to 20 non-demented patients with sporadic ALS and 13 age- and education-matched healthy control subjects. Mismatch negativity (MMN), P3b, P3a (novelty P300) and contingent negative variation (CNV) were recorded. ALS patients were significantly impaired in tests of working memory, sustained attention, response inhibition, naming, verbal fluency and complex visuo-spatial processing. The memory impairment seemed to be secondary to deficits in forming learning strategies and retrieval. In ERP recordings, P3a and P3b amplitudes of ALS patients were lower compared with the controls, P3a latencies were significantly longer and mean CNV amplitudes were higher. These results indicate subclinical impairment of cognitive functions in patients with ALS. The pattern of cognitive impairment suggests the dysfunction of the frontal network.     

Switching cholinesterase inhibitors in patients with Alzheimer's disease

Despite recognition that cholinesterase inhibitors can provide clinical benefits for patients with Alzheimer's disease (AD), the average durations of treatment and beneficial effects are not optimal in all cases. This may be due to disappointing efficacy or poor tolerability of the initial treatment, as well as secondary efficacy failure or adverse effects emerging during the maintenance phase. In such cases, pharmacological differences between available cholinesterase inhibitors provide a good rationale to switch to another drug in the same class. The pharmacological properties of rivastigmine, a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase, and donepezil and galantamine, two AChE-selective inhibitors, are reviewed. Rivastigmine is reported to show brain- and brain region-selectivity. Donepezil appeared to be more selective for central than peripheral enzymes in rats. Galantamine and donepezil have also been shown to exert nicotinic receptor allosteric modulation in vitro, while rivastigmine has been shown to increase binding of acetylcholine to nicotinic receptors in the AD brain. Donepezil and galantamine are metabolised by the hepatic CYP450 system, whereas rivastigmine is metabolised by its target enzymes. Several switching studies indicated that a substantial proportion of patients who fail to benefit from treatment with donepezil could draw benefits after being switched to rivastigmine. An immediate switch from donepezil to rivastigmine was reported to be well tolerated and was not associated with cholinergic side effects. A post hoc analysis of a 5-month trial with galantamine showed that patients had similar efficacy outcomes, whether or not they had received prior anticholinesterase therapy, suggesting that a previous failure to respond to another cholinesterase inhibitor did not predict response to galantamine. On the basis of available data it is suggested that patients not tolerating or not responding to one particular cholinesterase inhibitor may still draw benefits upon switching to another.     

Syngeneic living-donor liver transplantation without the use of immunosuppression

Transplantation between monozygotic twins has been successfully performed using the kidney, small intestine, and pancreas. Identical HLA matching has enabled these individuals to be transplanted without the need for immunosuppressive medication. Liver transplantation without immunosuppression would lessen the risk of recurrent viral hepatitis and eliminate much of the morbidity associated with long-term use of immunosuppressive medication. Living-donor liver transplantation (LDLT) has been performed with increasing success in recent years without an opportunity arising to use a monozygotic twin as a donor. We report 2 cases of LDLT between identical twins wherein perfect haploidentity has allowed these recipients to be transplanted without the need for immunosuppression. Although HLA matched genotypically, there may be differences in anatomy between donor and recipient. Mild liver chemistry test abnormalities may occur after transplant despite the absence of immunosuppression.     

Endometriosis: interaction of immune and endocrine systems

Endometriosis is a common gynecologic disorder characterized by the presence of endometrial tissue outside the uterine cavity. Although no single theory can explain all cases of endometriosis, the most commonly accepted theory is Sampson's theory of retrograde menstruation. Retrograde menstruation occurs in 76 to 90% of women. The much lower prevalence of endometriosis suggests that additional factors determine susceptibility to endometriosis. Endometriosis is associated with changes in both cell-mediated and humoral immunity. Impaired natural killer cell activity resulting in inadequate removal of refluxed menstrual debris may play a role in the development of endometriotic implants. Moreover, although the peritoneal fluid of women with endometriosis contains increased numbers of immune cells, these seem to facilitate rather than inhibit the development of endometriosis. Macrophages that would be expected to clear endometrial cells from the peritoneal cavity appear to enhance their proliferation by secreting growth factors and cytokines. Although it is unclear whether these immunologic alterations induce endometriosis or are a consequence of its presence, they appear to play an important role in allowing endometriosis implants to persist and progress and contribute to the development of associated infertility and pelvic pain. Danazol and gonadotropin-releasing hormone (GnRH) agonists are commonly used for the medical treatment of endometriosis. These medications seem to down-regulate cellular and humoral immune responses concomitant with their effect on endometriotic implants. Immunomodulatory effects of danazol and GnRH agonists are likely to contribute to the observed clinical improvement associated with their use.     

Plasma homocysteine concentrations in adolescents with subclinical hypothyroidism

OBJECTIVE: Hyperhomocysteinemia is a risk factor for premature atherosclerotic vascular disease and venous thrombosis. The aim of the present study was to assess plasma total homocysteine (tHCys) concentrations in adolescent patients with subclinical hypothyroidism. PATIENTS AND METHODS: Nineteen patients with subclinical hypothyroidism and 19 healthy children were studied. Fasting plasma concentrations of tHCys and its putative determinants (plasma concentrations of free thyroxine [FT4], folate, vitamin B12 and renal function) were measured. RESULTS: tHCys concentrations showed no statistical difference between patients and controls (p > 0.05). Moreover, the difference in tHCys and total cholesterol concentrations was not significant between patients with mild TSH elevations (< or = 10 mIU/l) and patients with prominent TSH elevations (> 10 mIU/l). No correlation was found between tHCys concentrations and its putative determinants. CONCLUSIONS: We concluded that plasma tHCys concentrations were not increased in adolescent patients with subclinical hypothyroidism.     

Neutrophilic pleocytosis in cerebrospinal fluid: adult-onset Still's disease

We describe a unique patient whose clinical and laboratory findings fulfill diagnostic criteria of adult onset Still's disease and at the same time, this case was complicated by aseptic meningitis with neutrophilic pleocytosis in cerebrospinal fluid, as well as sensorineural hearing loss. The symptoms of the patient improved greatly with prednisolone therapy. Some studies in the literature suggest that this disease may lead to aseptic meningitis with neutrophilic pleocytosis.     

Plasma homocysteine and its relationships with atherothrombotic markers in psoriatic patients

BACKGROUND: Hyperhomocysteinemia may constitute an independent risk factor for cardiovascular disease and may promote atherothrombosis. Psoriasis is one of the diseases associated with increased atherothrombosis. The aim of the present study was to examine serum total homocysteine (tHcy) level and its relationships with atherothrombotic markers. METHODS: The study group included 30 patients with psoriasis (17 females and 13 males) with a mean age of 34.2 (age range: 27-40) and 30 sex and age matched healthy volunteers (15 females and 15 males) with a mean age of 36.7 (age range: 26-48). The concentrations of lipids, lipoproteins, acute phase reactants, tHcy and atherothrombotic markers [fibronectin, soluble vascular adhesion molecules-1 (sVCAM-1), soluble intercellular adhesion molecules-1 (sICAM-1), tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), autoantibodies against oxidized LDL (AuAb-oxLDL)] were determined. RESULTS: The mean levels of serum tHcy, fibrinogen, fibronectin, sICAM, PAI-1 and AuAb-oxLDL were increased in patients whereas tPA, vitamin B(12) and folate levels were decreased significantly. Increased levels of sVCAM were not statistically significant. tHcy levels were negatively correlated with vitamin B(12) (r=-0.40, P=0.027) and positively correlated with PAI-1 and AuAb-oxLDL levels (r=0.46, P=0.011; r=0.39, P=0.035, respectively). CONCLUSIONS: It was concluded that the increased homocysteine concentration and altered endothelial cell-mediated proteins associated with increased lipids and LDL oxidation may play an important role for the development of atherothrombotic complications with psoriasis.     

Prevalence of Behçet's disease in Istanbul, Turkey

Background The prevalence of Behçet's disease (BD) is much higher in countries along the ancient Silk Route, extending from Japan to Mediterranean countries including Turkey, than in northern Europe and the USA. Three previous epidemiologic surveys have been carried out in different regions of Turkey. Patients and methods This study investigated the cross‐sectional prevalence of BD in individuals aged > 12 years in Istanbul, Turkey, in two stages. The first stage aimed to identify individuals with recurrent oral ulcers (ROUs) by visiting them in their homes, and the second stage aimed to further examine those with ROUs for the presence of other BD‐related manifestations under hospital conditions. The sample size was determined to be 24,000 with an expected BD prevalence rate of 1/1000 and a sampling error of 4/10,000, with a 95% confidence interval (CI) of 6–14/10,000. The number of individuals to be screened in each district was determined in proportion to the population of all districts in Istanbul. Results The standard questionnaire was applied to a total of 23,986 individuals at their homes. A history of ROU was recorded in 2289 individuals (9.5%), and a previous diagnosis of BD was recorded in 47. The diagnosis of ROU was confirmed in 700, and the diagnosis of BD was established in 101 according to the International Study Group criteria. The prevalence rate of BD was estimated as 42/10,000 (95% CI, 34–51/10,000) in Istanbul, Turkey. Conclusions This survey conducted in Istanbul, the largest cosmopolitan city in Turkey with immigrants from all over the country, has a larger sample size than other previous studies, and therefore the reported prevalence rate of BD has a more acceptable confidence interval. This study aids in the estimation of the prevalence of BD in Turkey, and supports previous findings that Turkey has the highest prevalence rate of the disease in the world.