Is Drug Treatment for Dementia Followed Up in Primary Care? A Swedish Study of Dementia Clinics and Referring Primary Care Centres

Purpose

It is largely unknown how the medical treatment of patients diagnosed with dementia is followed up in primary care. Therefore, we studied patient medical records from two dementia clinics and from the referring primary care centres.

Methods

A retrospective study of 241 patients was conducted from April to October 2011 in north west Stockholm, Sweden. Over half (51.5%) of the patients had Alzheimer’s disease (AD), the remainder had mixed AD/vascular dementia (VaD). Eighty-four medical reports from primary care (35% of the study group) were analysed at follow-up 18 months after diagnosis.

Results

All four dementia drugs available on the Swedish market (three cholinesterase inhibitors [donepezil, rivastigmine and galantamine] and memantine) were prescribed at the two dementia clinics. The most commonly used dementia drug was galantamine. There were differences between the two dementia clinics in preference and combination of drugs and of treatment given to male and female patients. At follow-up, 84% were still on dementia medication. Drug use was followed up by the general practitioners (GPs) in two-thirds of the cases. Eighteen per cent of the GPs’ medical records made no reference to the patient’s dementia or treatment even though dementia drugs were included in the list of medications prescribed.

Conclusions

The results indicate that the Swedish guidelines for treatment of cognitive symptoms in AD are being followed in primary care. However, documentation of follow-up of drug treatment was sometimes insufficient, which calls for development of guidelines for complete medical records and medication lists.     

Familial Alzheimer’s disease modelling using induced pluripotent stem cell technology

Alzheimer’s disease(AD)is a progressive neurodegenerative disease in which patients exhibit gradual loss of memory that impairs their ability to learn or carry out daily tasks.Diagnosis of AD is difficult,particularly in early stages of the disease,and largely consists of cognitive assessments,with only one in four patients being correctly diagnosed.Development of novel therapeutics for the treatment of AD has proved to be a lengthy,costly and relatively unproductive process with attrition rates of90%.As a result,there are no cures for AD and few treatment options available for patients.Therefore,there is a pressing need for drug discovery platforms that can accurately and reproducibly mimic the AD phenotype and be amenable to high content screening applications.Here,we discuss the use of induced pluripotent stem cells(iPSCs),which can be derived from adult cells,as a method of recapitulation of AD phenotype in vitro.We assess their potential use in high content screening assays and the barriers that exist to realising their full potential in predictive efficacy,toxicology and disease modelling.At present,a number of limitations need to be addressed before the use of iPSC technology can be fully realised in AD therapeutic applications.However,whilst the use of AD-derived iPSCs in drug discovery remains a fledgling field,it is one with immense potential that is likely to reach fruition within the next few years.     

Current Therapeutic Options for Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common neurodegenerative disease in the developed world. The increasing life expectancy in the last years has led to an increase in the prevalence of this age-related condition and has posed an important medical and social challenge for developed societies. The mainstays of current therapy for AD rely on the cholinergic hypothesis developed more than 20 years ago. These compounds, known as acetylcholinesterase inhibitors (AChEIs), inhibit the cholinesterases and aim at improving the brain synaptic availability of acetylcholine. These drugs have been approved for the treatment of AD based on pivotal clinical trials showing modest symptomatic benefit on cognitive, behavioral, and global measures. Memantine, an NMDA antagonist, has been recently included as a therapeutic option for AD. Memantine can be combined safely with AChEIs for an additional symptomatic benefit. During the last years our understanding of the mechanisms underlying the pathogenesis of AD has markedly expanded. Several putative neuroprotective drugs are thoroughly investigated and many of them have reached the clinical arena. It can be anticipated that some of these drugs will be able to slow/prevent the progression of this condition in the near future.     

Prescribing at the hospital-general practice interface. II: Impact of hospital outpatient dispensing policies in England on general practitioners and hospital consultants.

OBJECTIVE--To assess the impact on general practitioners and hospital consultants of hospital outpatient dispensing policies in England. DESIGN--Postal questionnaire and telephone interview survey of general practitioners and hospital consultants in January 1991. SETTING--94 selected major acute hospitals in England. PARTICIPANTS--20 general practitioners in the vicinity of each of 94 selected hospitals and eight consultants from each, selected by chief pharmacists. MAIN OUTCOME MEASURES--Proportions of general practitioners unable to assume responsibility for specialist drugs and of consultants wishing to retain responsibility; association between dispensing restrictions and the frequency of general practitioners being asked to prescribe hospital initiated treatments. RESULTS--Completed questionnaires were obtained from 1207 (64%) of 1887 general practitioners and 457 (63%) of 729 consultants. 570 (46%) general practitioners felt unable to take responsibility for certain treatments, principally because of difficulty in detecting side effects (367, 30%), uncertainty about explaining treatment to patients (332, 28%), and difficulty monitoring dosage (294, 24%). Among consultants 328 (72%) wished to retain responsibility, principally because of specialist need for monitoring (93, 20%), urgent need to commence treatment (64, 14%), and specialist need to initiate or stabilise treatment (63, 14%). The more restricted the drug supply to outpatients, the more frequently consultants asked general practitioners to prescribe (p less than 0.01) and complete a short course of treatment initiated by the hospital (p less than 0.001). CONCLUSIONS--Restrictive hospital outpatient dispensing shifts clinical responsibility on to general practitioners. Hospital doctors should be able to retain responsibility for prescribing when the general practitioner is unfamiliar with the drug or there is a specialist need to initiate, stabilise, or monitor treatment.     

Bronchodilator treatment in moderate asthma or chronic bronchitis: continuous or on demand? A randomised controlled study.

OBJECTIVE--To examine the effect of bronchodilator treatment given continuously versus on demand on the progression of asthma and chronic bronchitis and to compare the long term effects of a beta 2 adrenergic drug (salbutamol) and an anticholinergic drug (ipratropium bromide). DESIGN--Two year randomised controlled prospective ''crossover'' study in which patients were assigned to one of two parallel treatment groups receiving continuous treatment or treatment on demand. SETTING--29 general practices in the catchment area of the University of Nijmegen. PATIENTS--223 patients aged greater than or equal to 30 with moderate airway obstruction due to asthma or chronic bronchitis, selected by their general practitioners. INTERVENTIONS--1600 micrograms salbutamol or 160 micrograms ipratropium bromide daily (113 patients) or salbutamol or ipratropium bromide only during exacerbations or periods of dyspnoea (110). No other pulmonary treatment was permitted. MAIN OUTCOME MEASURES--Decline in ventilatory function and change in bronchial responsiveness, respiratory symptoms, number of exacerbations, and quality of life. RESULTS--Among 144 patients completing the study, after correction for possible confounding factors the decline in forced expiratory volume in one second was -0.072 l/year in continuously treated patients and -0.020 l/year in those treated on demand (p less than 0.05), irrespective of the drug. The difference in the decline in patients with asthma was comparable with that in patients with chronic bronchitis (asthma: 0.092 v -0.025 l/year; chronic bronchitis: -0.082 v -0.031 l/year). Bronchial responsiveness increased slightly (0.4 doubling dose) with continuous treatment in chronic bronchitis, but exacerbations, symptoms, and quality of life were unchanged. Salbutamol and ipratropium bromide had comparable effects on all variables investigated. CONCLUSIONS--Continuous bronchodilator treatment without anti-inflammatory treatment accelerates decline in ventilatory function. Bronchodilators should be used only on demand, with additional corticosteroid treatment, if necessary.     

Synthesis and biological activity of derivatives of tetrahydroacridine as acetylcholinesterase inhibitors

Current state of medical sciences does not allow to treatment neurodegenerative diseases such as Alzheimer’s disease (AD). At present treatment of AD is severely restricted. The main class of medicines which are applied in AD is acetylcholinesterase inhibitors (AChEIs) like tacrine, donepezil, galantamine and rivastigmine that do not contribute to significant and long-term improvement in cognitive and behavioural functions.In this work, we report synthesis and biological evaluation of new hybrids of tacrine-6-hydrazinonicotinamide. The synthesis was based on the condensation reaction between tacrine derivatives and the hydrazine nicotinate moiety (HYNIC). All obtained compounds present affinity for both cholinesterases and are characterized by high selectivity in relation to butyrylcholinesterase (BChE).     

Findings of a national survey of the role of general practitioners in the treatment of opiate misuse: dealing with the opiate misuser.

Because there has been a substantial increase in the scale of drug misuse general practitioners have become increasingly concerned in responding to this problem. Little is known, however, about how general practitioners manage drug misusers. The findings from a national survey carried out in mid-1985 of a 5% random sample of general practitioners in England and Wales show the extent to which various actions were undertaken by general practitioners who reported on the consultation with the opiate misuser whom they last attended. In more than half of the cases the opiate misuser had been under the care of the general practitioners for this problem for at least six months. The findings indicate that most general practitioners refer these patients to specialist drug dependence clinics or to general psychiatric services but rarely to other agencies. Opiate drugs had been prescribed in nearly a third of cases. The rate of notification to the Home Office conforms with that in other studies and indicates a high degree of undernotification. More detailed study of general practitioners'' activities in managing drug misusers is needed.     

Design,synthesis and biological evaluation of coumarin alkylamines as potent and selective dual binding site inhibitors of acetylcholinesterase

Acetylcholinesterase inhibitors (AChEIs) are currently the drugs of choice, although only symptomatic and palliative, for the treatment of Alzheimer’s disease (AD). Donepezil is one of most used AChEIs in AD therapy, acting as a dual binding site, reversible inhibitor of AChE with high selectivity over butyrylcholinesterase (BChE). Through a combined target- and ligand-based approach, a series of coumarin alkylamines matching the structural determinants of donepezil were designed and prepared. 6,7-Dimethoxycoumarin derivatives carrying a protonatable benzylamino group, linked to position 3 by suitable linkers, exhibited fairly good AChE inhibitory activity and a high selectivity over BChE. The inhibitory potency was strongly influenced by the length and shape of the spacer and by the methoxy substituents on the coumarin scaffold. The inhibition mechanism, assessed for the most active compound 13 (IC₅₀ 7.6 nM) resulted in a mixed-type, thus confirming its binding at both the catalytic and peripheral binding sites of AChE.     

Conflict of evidence: carotenoids and other micronutrients in the prevention and treatment of cognitive impairment

Cognitive impairment is a common age-related disorder which affects in the stadium and type Alzheimer's Disease (AD) a steadily growing number of patients. AD is not curable and is not being easily diagnosed in its preclinical phase. This work aims at highlighting the complex though promising rationale for the use of selected micronutrients against age-related cognitive impairment and its progression. The advances made in the last decades in both defining the etiopathogenesis of cognitive impairment and in revealing mechanisms of action underlying possible preventive effects of several vitamins and micronutrients--likely related to antioxidant activity and modulation of cellular signaling--is being accompanied by conflicting results of most clinical trials. Therefore, available data do not currently support the use of substances such as carotenoids, polyphenols, vitamin D, curcumin, vitamin E, vitamin C, or lipoic acid in AD prevention and/or treatment. This might be partly due to the fact that cognitive impairment and especially AD are extremely complex disorders. The main obstacle to the inclusion of micronutrients among anticognitive impairment drug strategies, however, is that studies conducted so far are poorly comparable and probably underestimate of the role of vascular damage in age-related cognitive impairment. A possible clinical benefit of these substances in AD is not disproved to date, thus further better designed studies are needed.     

A Synergetic Screening Approach with Companion Effector for Combination Therapy: Application to Retinoblastoma

For many cancers, the lack of potency and the toxicity of current drugs limits the dose achievable in patients and the efficacy of treatment. Among them, retinoblastoma is a rare cancer of the eye for which better chemotherapeutic options are needed. Combination therapy is a compelling approach to enhance the efficacy of current treatment, however clinical trials to test rationally designed combinations of approved drugs are slow and expensive, and limited by our lack of in-depth knowledge of drug specificity. Since many patients already turn to nutraceuticals in hopes of improving their condition, we hypothesized that certain approved drugs could potentially synergize with widely consumed supplements. Following this hypothesis, we devised an alternative screening strategy aimed at taking advantage of a bait compound such as a nutraceutical with potential therapeutic benefits but low potency, by screening chemical libraries for approved drugs that synergize with this companion effector. As a proof of concept, we sought to identify approved drugs with synergetic therapeutic effects toward retinoblastoma cells in combination with the antioxidant resveratrol, popular as a supplement. We systematically tested FDA-approved drugs and known bioactives seeking to identify such pairs, which led to uncovering only a few additive combinations; but to our surprise, we identified a class of anticancer drugs widely used in the clinic whose therapeutic effect is antagonized with resveratrol. Our observations could explain in part why some patients do not respond well to treatment. Our results validate this alternative approach, and we expect that our companion effector strategy could significantly impact both drug discovery and the nutraceutical industry.     

Diagnostic and therapeutic efficacy of barium meal examination: a prospective evaluation in general practice.

OBJECTIVE--To assess the efficacy of barium meal examinations in managing patients with dyspepsia in general practice. DESIGN--Prospective study by questionnaires completed by general practitioners before and within three to six months after the barium meal examination. Information was requested about the patients'' symptoms, current treatment, reason for requesting the examination, and the working diagnosis, including degree of certainty and, after the examination, about any change in diagnosis, diagnostic confidence, or management and to determine whether the examination was judged to be helpful or not. SETTING--Inner city health district. PATIENTS--133 Patients with dyspepsia referred by general practitioners for outpatient barium meal examination, 31 of whom failed to attend for the examination, or refused it on arrival, or did not have fully completed questionnaires. Two patients were not available for follow up. MAIN OUTCOME MEASURES--Prevalence of radiological abnormalities and the influence of the examination result on management, particularly changes in drug treatment. RESULTS--Fully completed pairs of questionnaires were available for 100 patients, 58 of whom were aged below 50. Most of the barium meal reports (64) were to confirm the clinical diagnosis; only 22 were to exclude serious disease. Ninety nine patients were already receiving treatment, with 39 taking an H2 receptor antagonist. Fifty eight barium meal examinations showed abnormalities (31 major abnormalities); there were no cancers and in only 18 patients was the working diagnosis changed as a result of the findings. Although the barium meal result increased management confidence (63 patients) and allayed patients'' anxiety (46), changes in management attributed directly to the examination occurred in only 22 patients. Management changes were minor, usually comprising interchange of antacids and H2 receptor antagonists. CONCLUSIONS--Young patients (aged below 50) with dyspepsia are still being overinvestigated. Although barium meal examination improves diagnostic confidence and allays patients'' anxiety, fully utilising communication skills at the initial consultation might allay anxiety more economically.     

Limited list: limited effects?

During the first month after the limited National Health Service drug list came into effect 17 cooperative general practitioners recorded the actions taken when a now prohibited drug would formerly have been prescribed. An average of 6% of direct surgery contacts with patients and 8% of indirect contacts with patients were affected by the new regulations, but in 2% and 4% of cases respectively the patient received the same pharmacological substance under a different (generic or approved) name. Where a real change in pharmacological constitution or formulation had been required four fifths of these substitutes were considered by the doctors to result in less effective treatment. In 1% of contacts no drug was issued or recommended where one would formerly have been given.     

Detecting hypertension: screening versus case finding in Norway.

OBJECTIVE--Evaluation of detection of hypertension in adults in the county of Nord-Trøndelag, Norway. DESIGN--Cross sectional survey with clinical follow up examinations. SETTING--Health survey by screening teams from the national health screening service, and examinations by all 106 general practitioners in the county. SUBJECTS--During 1984-6, 74,977 persons (88.1% of those aged 20 years and over) participated in the health survey. MAIN OUTCOME MEASURES--Hypertension (when assessed by standardised recording and by questionnaires on drug treatment for hypertension) according to the blood pressure thresholds used in the Norwegian treatment programme. Subjects positive on screening were grouped after clinical examination into treatment groups. RESULTS--In all, 2399 subjects were positive for hypertension. Before screening 6210 (8.3%) patients reported taking antihypertensive drugs and another 3849 (5.1%) had their blood pressure monitored regularly. All who screened positive were referred to their general practitioner and evaluated according to a standard programme. As a result, drug treatment was started in 406 (0.5%) participants screened and blood pressure monitoring in another 1007 (1.3%). Of all patients taking antihypertensive drugs after the screening, 6399 (94.0%) had been diagnosed before screening, and of those whose blood pressure was monitored after the screening, 79.3% had been diagnosed before screening. CONCLUSIONS--At the blood pressure screening thresholds used, and when hypertension is defined by an overall clinical diagnosis, the results indicate that general practitioners can find and diagnose hypertensive patients with the case finding strategy.     

New approaches for the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is the most prevalent chronic neurodegenerative disease. Current approved therapies are symptomatic treatments having some effect on cognitive function. Therapies that target β-amyloid (Aβ) have been the focus of efforts to develop a disease modification treatment for AD but these approaches have failed to show any clinical benefit so far. Beyond the ‘Aβ hypothesis’, there are a number of newer approaches to treat AD with neuroinflammation emerging as a very active area of research based on risk gene analysis. This short review will summarize approved drug therapies, recent clinical trials and new approaches for the treatment of AD.     

Acetylcholinesterase inhibitors increase ADAM10 activity by promoting its trafficking in neuroblastoma cell lines

Acetylcholinesterase inhibitors (AChEIs) are the only currently available drugs for treating Alzheimer's Disease (AD). Some authors have suggested a function of AChEIs not only in the induction of AChE overproduction and alternative splicing shifts but also a possible role of these drugs in amyloid metabolism beyond their well-known symptomatic effect. Here, we investigate the mechanisms of action of the AChEI donepezil on APP (amyloid precursor protein) metabolism and on the activity/trafficking of the alpha-secretase candidate ADAM 10, in differentiated human neuroblastoma cells (SH-SY5Y). In these cells, the activity of AChE is significantly decreased after 2 h of donepezil treatment. Further, SH-SY5Y cells released significantly more sAPPalpha into the medium, whereas total APP levels in cell lysates were unchanged. Interestingly, treated cells showed increased ADAM 10 levels in membrane compartments. This effect was prevented by pretreatment with tunicamycin or brefeldin, suggesting that donepezil affects trafficking and/or maturation of ADAM 10; additionally, this pretreatment significantly decreased sAPPalpha levels. Pre-incubation with atropine decreased release of sAPPalpha significantly but did not revert ADAM 10 activity to control levels further suggesting that donepezil acts not solely through a purely receptor mediated pathway. These findings indicate that donepezil exerts multiple mechanisms involving processing and trafficking of key proteins involved in AD pathogenesis.     

The immunotherapy of Alzheimer's disease

Only a small percentage of patients with Alzheimer's disease benefit from current drug therapy and for only a relatively short time. This is not surprising as the goal of these drugs is to enhance existing cerebral function in Alzheimer patients and not to block the progression of cognitive decline. In contrast, immunotherapy is directed at clearing the neurotoxic amyloid beta peptide from the brain that directly or indirectly leads to cognitive decline in patients with Alzheimer's disease. The single trial of active immunization with the amyloid beta peptide provided suggestive evidence of a reduction in cerebral amyloid plaques and of stabilization in cognitive function of half the patients who developed good antibody responses to the amyloid beta peptide. However, 6% of actively immunized Alzheimer patients developed sterile meningoencephalitis that forced the cessation of the clinical trial. Passive immunotherapy in animal models of Alzheimer's disease has provided similar benefits comparable to those seen with active immunotherapy and has the potential of being effective in the half of Alzheimer's disease patients who do not make a significant anti-amyloid beta peptide antibody response and without inducing T-cell-mediated encephalitis. Published studies of 5 patients with sporadic Alzheimer disease treated with intravenous immunoglobulin containing anti-amyloid beta peptide antibodies showed that amyloid beta peptide was mobilized from the brain and cognitive decline was interrupted. Further studies of passive immunotherapy are urgently required to confirm these observations.     

AIDS and the general practitioner: views of patients with HIV infection and AIDS.

An unselected series of outpatients infected with the human immunodeficiency virus (HIV) who attended two London hospitals were interviewed to assess their relationship with their general practitioner. Although most of the 192 patients were registered with a general practitioner, the doctors of only one half knew of the diagnosis. Patients feared a negative reaction from their general practitioner or were concerned about confidentiality. Although those who had told their doctor had received favourable reactions, few general practitioners attempted to counsel or educate their patients. The patients who previously had been open about their homosexuality were not more likely to have told their general practitioner of their HIV infection. Although most did not think that general practitioners were well informed about AIDS, half of the patients wished that general practitioners could take a bigger part in their care.     

Consultants' workload in outpatient clinics.

The impact on hospital resources of variability in referral rates among general practitioners was of concern throughout the 1980s. The overall number of patients referred to outpatient clinics, however, has increased only slowly since the NHS began; in contrast, the number of new outpatients seen by each hospital consultant has declined appreciably. Ironically, despite this decline, further increasing the number of consultants in now being presented as a solution to the demand for outreach clinics in general practice.