Assessment of a Potential Synergistic Effect of Souvenaid® in Mild Alzheimer's Disease Patients on Treatment with Acetylcholinesterase Inhibitors: An Observational, Non-Interventional Study.

We evaluated the efficacy and safety of Souvenaid (a multinutrient supplement) in patients with mild Alzheimer's disease (AD) in real clinical practice and assessed a potential synergistic effect of acetylcholinesterase (AChE) inhibitors. Clinical Dementia Rating (CDR) scale was evaluated after six months follow-up. Patients were divided into 4 groups according to the treatment they received: Souvenaid + AChE inhibitors (n = 23); only Souvenaid (n = 8); only AChE inhibitors (n = 7); no treatment (n = 16). The Souvenaid + AChE inhibitors and Souvenaid alone groups were associated with significantly lower increases in CDR per month than the AChE inhibitors or no treatment ones. The efficacy of Souvenaid + AChE inhibitors tended to be higher than Souvenaid alone.

Prevalence of and factors associated with the use of methylphenidate for cognitive enhancement among university students / Prevalência e fatores associados ao uso de metilfenidato para neuroaprimoramento farmacológico entre estudantes universitários

ABSTRACT Objective To estimate the prevalence of and factors associated with the use of methylphenidate for cognitive enhancement among undergraduate students. Methods Simple random sample of students of the Universidade Federal de Minas Gerais (n=438), invited to answer an online questionnaire about the use of methylphenidate. Data collection occurred from September 2014 to January 2015. The sample was described by means of proportions, means and standard deviations. A multivariate analysis was performed using the Classification and Regression Tree algorithm to classify the cases of use of methylphenidate for cognitive enhancement in groups, based on the exposure variables. Results Out of 378 students included, 5.8% (n=22) reported using methylphenidate for cognitive enhancement; in that, 41% (9/22) in the 4 weeks prior to the survey. The housing situation was the variable most often associated with the use of methylphenidate for cognitive enhancement. Eleven students reported using methylphenidate for cognitive enhancement and other purposes 4 weeks prior to the survey, 27% of whom had no medical prescription to purchase it. Conclusion The use of methylphenidate for cognitive enhancement is frequent among Brazilian undergraduate students and should be considered a serious public health problem, especially due to risks of harm and adverse effects associated with its use.

RESUMO Objetivo Estimar a prevalência e os fatores associados ao uso de metilfenidato para neuroaprimoramento entre estudantes universitários. Métodos Amostra aleatória simples de discentes da Universidade Federal de Minas Gerais (n=438), convidados a responder um questionário online sobre o consumo de metilfenidato. A coleta ocorreu de setembro de 2014 a janeiro de 2015. A amostra foi descrita em termos de proporções, médias e desvio padrão. A análise multivariada foi realizada utilizando o algoritmo Classification and Regression Tree para classificação dos casos de uso do metilfenidato para neuroaprimoramento em grupos, com base nas variáveis de exposição. Resultados Dos 378 alunos incluídos, 5,8% (n=22) declararam ter feito uso de metilfenidato para neuroaprimoramento, sendo 41% (9/22) nas 4 semanas anteriores à pesquisa. A situação da moradia foi a variável mais associada ao uso de metilfenidato para neuroaprimoramento. Relataram o uso do metilfenidato para neuroaprimoramento e outros fins nas 4 semanas anteriores à pesquisa 11 estudantes, sendo que 27% não apresentaram prescrição médica para adquiri-lo. Conclusão O uso de metilfenidato para neuroaprimoramento ocorre no meio acadêmico brasileiro e deve ser considerado sério problema de saúde pública, principalmente diante dos riscos de danos e efeitos adversos associados ao seu uso.

Prevalence of and factors associated with the use of methylphenidate for cognitive enhancement among university students.

OBJECTIVE: To estimate the prevalence of and factors associated with the use of methylphenidate for cognitive enhancement among undergraduate students. METHODS: Simple random sample of students of the Universidade Federal de Minas Gerais (n=438), invited to answer an online questionnaire about the use of methylphenidate. Data collection occurred from September 2014 to January 2015. The sample was described by means of proportions, means and standard deviations. A multivariate analysis was performed using the Classification and Regression Tree algorithm to classify the cases of use of methylphenidate for cognitive enhancement in groups, based on the exposure variables. RESULTS: Out of 378 students included, 5.8% (n=22) reported using methylphenidate for cognitive enhancement; in that, 41% (9/22) in the 4 weeks prior to the survey. The housing situation was the variable most often associated with the use of methylphenidate for cognitive enhancement. Eleven students reported using methylphenidate for cognitive enhancement and other purposes 4 weeks prior to the survey, 27% of whom had no medical prescription to purchase it. CONCLUSION: The use of methylphenidate for cognitive enhancement is frequent among Brazilian undergraduate students and should be considered a serious public health problem, especially due to risks of harm and adverse effects associated with its use.

A fixed-dose combination of memantine extended-release and donepezil in the treatment of moderate-to-severe Alzheimer's disease.

Currently available therapies for the treatment of Alzheimer's disease (AD) consist of cholinesterase inhibitors (ChEIs), such as donepezil, and the N-methyl-D-aspartate receptor antagonist memantine. In December 2014, the US Food and Drug Administration approved Namzaric™, a once-daily, fixed-dose combination (FDC) of memantine extended-release (ER) and donepezil for patients with moderate-to-severe AD. The FDC capsule is bioequivalent to the coadministered individual drugs, and its bioavailability is similar when taken fasting, with food, or sprinkled onto applesauce. The combination of memantine and ChEIs in moderate-to-severe AD provides additional benefits to ChEI monotherapy across multiple domains and may delay the time to nursing home admission. A dedicated study of memantine ER compared to placebo in patients on a stable dose of a ChEI found statistically significant benefits on cognition and global status but not functioning. Treatment with memantine ER and donepezil is generally well tolerated, although higher doses of ChEIs are associated with more serious adverse events such as vomiting, syncope, and weight loss. Potential advantages of the FDC include a simpler treatment regimen, reduction in pill burden, and the ability to sprinkle the capsule onto soft foods. Patients who may benefit from the FDC include those with significant dysphagia, a history of poor compliance, or limited caregiver interaction. However, available evidence that these advantages would increase treatment adherence and persistence is conflicting, meaning that the added cost of switching patients from generic options to an FDC may not always be justified.

Taste-masked and affordable donepezil hydrochloride orally disintegrating tablet as promising solution for non-compliance in Alzheimer's disease patients.

CONTEXT: Manufacturing process and superdisintegrants used in orally disintegrating tablet (ODT) formulation are often time discussed. However, the effect of suitable filler for ODT formulation is not explored thoroughly. OBJECTIVE: The aim of this study was to develop a novel taste masked and affordable donepezil hydrochloride ODT with fast disintegration time and stable to improve medication compliance of Alzheimer's disease patient. METHODS AND MATERIALS: The ODT was manufactured using simple wet-granulation method. Crospovidone XL-10 was used as superdisintegrant and optimization was done by comparing the effect of three grades of lactose monohydrate compound as filler: Starlac®, Flowlac® and Tablettose®. RESULTS AND DISCUSSION: Formulations containing higher amount of colloidal silicon dioxide showed increase in hardness, weight, disintegration time and wetting time after stability study. Formulation E which containing 50% of Starlac® was found with shortest in vitro disintegration time (21.7 ± 1.67 s), in vivo disintegration time (24.0 ± 1.05 s) and in vitro disintegration time in artificial salvia (22.5 ± 1.67 s). Physical stability studies at 40 °C/75% RH for 6 months, Fourier transform infrared spectroscopy analysis and X-ray diffraction results showed that the formulation was stable. The drug-released profile showed that 80% of donepezil hydrochloride was released within 1 min. A single-dose, fasting, four-period, seven-treatment, double-blinded study involving 16 healthy human volunteers was performed to evaluate the palatability of ODT. Formulation VII containing 10 mg of ammonium glycyrrhizinate was able to mask the bitter taste of the drug. CONCLUSION: The product has the potential to be commercialized and it might serve as solution for non-compliance among the Alzheimer's disease patients.

The implications of methylphenidate use by healthy medical students and doctors in South Africa.

BACKGROUND: The use of medical stimulants to sustain attention, augment memory and enhance intellectual capacity is increasing in society. The use of Methylphenidate for cognitive enhancement is a subject that has received much attention in the literature and academic circles in recent times globally. Medical doctors and medical students appear to be equally involved in the off-label use of Methylphenidate. This presents a potential harm to society and the individual as the long-term side effect profile of this medication is unknown. DISCUSSION: The implication of the use of Methylphenidate by medical students and doctors has not been fully explored. This article considers the impact of this use on the traditional role of medicine, society, the patient and suggests a way forward. We discuss the salient philosophy surrounding the use of cognitive enhancement. We query whether there are cognitive benefits to the use of Methylphenidate in healthy students and doctors and whether these benefits would outweigh the risks in taking the medication. Could these benefits lead to tangible outcomes for society and could the off label-use of Methylphenidate potentially undermine the medical profession and the treatment of patients? If cognitive benefits are proven then doctors may be coerced explicitly or implicitly to use the drug which may undermine their autonomy. The increased appeal of cognitive enhancement challenges the traditional role of medicine in society, and calls into question the role of a virtuous life as a contributing factor for achievement. In countries with vast economic disparity such as South Africa an enhancement of personal utility that can be bought may lead to greater inequities. SUMMARY: Under the status quo the distribution of methylphenidate is unjust. Regulatory governmental policy must seek to remedy this while minimising the potential for competitive advantage for the enhanced. Public debate on the use of cognitive enhancement is long overdue and must be stimulated. The use of Methylphenidate for cognitive enhancement is philosophically defendable if long-term research can prove that the risks are negligible and the outcomes tangible.

Neuroenhancing public health.

One of the most fascinating issues in the emerging field of neuroethics is pharmaceutical cognitive enhancement (CE). The three main ethical concerns around CE were identified in a Nature commentary in 2008 as safety, coercion and fairness; debate has largely focused on the potential to help those who are cognitively disabled, and on the issue of 'cosmetic neurology', where people enhance not because of a medical need, but because they want to (as many as 25% of US students already use nootropic cognitive enhancers such as ritalin). However, the potential for CE to improve public health has been neglected. This paper examines the prospect of improving health outcomes through CE among sections of the population where health inequalities are particularly pronounced. I term this enhancement of the public's health through CE 'neuroenhancing health'. It holds great promise, but raises several ethical issues. This paper provides an outline of these issues and related philosophical problems. These include the potential effectiveness of CE in reducing health inequalities; issues concerning autonomy and free will; whether moral enhancement might be more effective than CE in reducing health inequalities; and the problem of how to provide such CE, including the issue of whether to provide targeted or universal coverage.

The impact of memantine in combination with acetylcholinesterase inhibitors on admission of patients with Alzheimer's disease to nursing homes: cost-effectiveness analysis in France.

The costs associated with the care of Alzheimer's disease patients are very high, particularly those associated with nursing home placement. The combination of a cholinesterase inhibitor (ChEI) and memantine has been shown to significantly delay admission to nursing homes as compared to treatment with a ChEI alone. The objective of this cost-effectiveness analysis was to evaluate the economic impact of the concomitant use of memantine and ChEI compared to ChEI alone. Markov modelling was used in order to simulate transitions over time among three discrete health states (non-institutionalised, institutionalised and deceased). Transition probabilities were obtained from observational studies and French national statistics, utilities from a previous US survey and costs from French national statistics. The analysis was conducted from societal and healthcare system perspectives. Mean time to nursing home admission was 4.57 years for ChEIs alone and 5.54 years for combination therapy, corresponding to 0.98 additional years, corresponding to a gain in quality adjusted life years (QALYs) of 0.25. From a healthcare system perspective, overall costs were €98,609 for ChEIs alone and €90,268 for combination therapy, representing cost savings of €8,341. From a societal perspective, overall costs were €122,039 and €118,721, respectively, representing cost savings of €3,318. Deterministic and probabilistic (Monte Carlo simulations) sensitivity analyses indicated that combination therapy would be the dominant strategy in most scenarios. In conclusion, combination therapy with memantine and a ChEI is a cost-saving alternative compared to ChEI alone as it is associated with lower cost and increased QALYs from both a societal and a healthcare perspective.

Distributive justice and cognitive enhancement in lower, normal intelligence.

There exists a significant disparity within society between individuals in terms of intelligence. While intelligence varies naturally throughout society, the extent to which this impacts on the life opportunities it affords to each individual is greatly undervalued. Intelligence appears to have a prominent effect over a broad range of social and economic life outcomes. Many key determinants of well-being correlate highly with the results of IQ tests, and other measures of intelligence, and an IQ of 75 is generally accepted as the most important threshold in modern life. The ability to enhance our cognitive capacities offers an exciting opportunity to correct disabling natural variation and inequality in intelligence. Pharmaceutical cognitive enhancers, such as modafinil and methylphenidate, have been shown to have the capacity to enhance cognition in normal, healthy individuals. Perhaps of most relevance is the presence of an 'inverted U effect' for most pharmaceutical cognitive enhancers, whereby the degree of enhancement increases as intelligence levels deviate further below the mean. Although enhancement, including cognitive enhancement, has been much debated recently, we argue that there are egalitarian reasons to enhance individuals with low but normal intelligence. Under egalitarianism, cognitive enhancement has the potential to reduce opportunity inequality and contribute to relative income and welfare equality in the lower, normal intelligence subgroup. Cognitive enhancement use is justifiable under prioritarianism through various means of distribution; selective access to the lower, normal intelligence subgroup, universal access, or paradoxically through access primarily to the average and above average intelligence subgroups. Similarly, an aggregate increase in social well-being is achieved through similar means of distribution under utilitarianism. In addition, the use of cognitive enhancement within the lower, normal intelligence subgroup negates, or at the very least minimises, several common objections to cognitive enhancement. Subsequently, this paper demonstrates that there is a compelling case for cognitive enhancement use in individuals with lower, normal intelligence.

Prohibition or coffee shops: regulation of amphetamine and methylphenidate for enhancement use by healthy adults.

This article analyzes appropriate public policies for enhancement use of two most important stimulant drugs: Ritalin (methylphenidate) and Adderall (mixed amphetamine salts). The author argues that appropriate regulation of cognition enhancement drugs cannot be a result of a general discussion on cognitive enhancements as such, but has to be made on a case-by-case basis. Starting from the recently proposed taxation approach to cognition enhancement drugs, the author analyzes available, moderately permissive models of regulation. After a thorough analysis of relevant characteristics of methylphenidate and amphetamine, the author concludes that a moderately liberal permissive regulation of enhancement use by healthy adults might be appropriate for extended release forms of methylphenidate. However, due to their danger profile, amphetamine and instant release forms of methylphenidate should not be made readily available to healthy adults and would need to be prohibited.

A population-based study of dosing and persistence with anti-dementia medications.

PURPOSE: Cholinesterase inhibitors and memantine are the mainstay of pharmacological intervention for the cognitive symptoms of Alzheimer's disease (AD). This study assessed the adequacy of dosing and persistence with AD medications and the predictors of these variables in the 'real world' (outside the clinical trial setting). METHODS: The Health Service Executive-Primary Care Reimbursement Services prescription claims database in the Republic of Ireland contains prescription information for 1.6 million people. Patients aged >70 years who received at least two prescriptions for donepezil, rivastigmine, galantamine and memantine between January 2006 and December 2010 were included in the study. Rates of dose-maximisation were recorded by examining the initiation dose of each AD drug commenced during the study period and any subsequent dose titrations. Non-persistence was defined by a gap in prescribing of more than 63 consecutive days. Predictors of dose-maximisation and non-persistence were also analysed. RESULTS: Between January 2006 and December 2010, 20,729 patients aged >70 years received a prescription for an AD medication. Despite most patients on donepezil and memantine receiving a prescription for the maximum drug dose, this dose was maintained for 2 consecutive months in only two-thirds of patients. Patients were significantly more likely to have their doses of donepezil and memantine maximised if prescribed in more recent years (2010 vs. 2007). Rates of non-persistence were 30.1 % at 6 months and 43.8 % at 12 months. Older age [75+ vs. <75 years; hazards ratio (HR) 1.16, 95 % confidence interval (CI) 1.06-1.27] and drug type (rivastigmine vs. donepezil; HR 1.15, 95 % CI 1.03-1.27) increased the risk of non-persistence. Non-persistence was lower for those commencing therapy in more recent years (2010 vs. 2007; HR 0.81, 95 % CI 0.73-0.89, p < 0.001) and for those on multiple anti-dementia medications (HR 0.59, 95 % CI 0.54-0.65, p < 0.001). Persistence was significantly higher when memantine was co-prescribed with donepezil (p < 0.0001). CONCLUSION: Future studies should explore the reasons underlying non-persistence and failure to maintain dose-maximisation in patients on AD medications. There may be scope to improve the dosing and persistence with these medications in the community.

"Doctor, would you prescribe a pill to help me ?" a national survey of physicians on using medicine for human enhancement.

Using medical advances to enhance human athletic, aesthetic, and cognitive performance, rather than to treat disease, has been controversial. Little is known about physicians' experiences, views, and attitudes in this regard. We surveyed a national sample of physicians to determine how often they prescribe enhancements, their views on using medicine for enhancement, and whether they would be willing to prescribe a series of potential interventions that might be considered enhancements. We find that many physicians occasionally prescribe enhancements, but doctors hold nuanced and ambiguous views of these issues. Most express concerns about the potential effects of enhancements on social equity, yet many also believe specific enhancements that are safe and effective should be available but not covered by insurance. These apparently contradictory views might reflect inherent tensions between the values of equity and liberty, which could make crafting coherent social policies on medical enhancements challenging.

Non-medical use of prescription stimulants and illicit use of stimulants for cognitive enhancement in pupils and students in Germany.

INTRODUCTION: The aim of this study was to assess for the first time the prevalence and factors associated with stimulant use exclusively for cognitive enhancement among pupils and university students in Germany. METHODS: A sample of 1 035 pupils (vocational and grammar schools) in small and big cities and 512 university students of 3 Departments (Medicine, Pharmacy, Economics) completed a questionnaire regarding knowledge and use of stimulants for cognitive enhancement and factors associated with their use. RESULTS: Lifetime prevalence for use of prescription stimulants (methylphenidate, amphetamines) for cognitive enhancement in pupils was 1.55% and in students 0.78%. Last-year and last-month prevalence rates were significantly lower. 2.42% of pupils and 2.93% of students reported lifetime illicit use of stimulants (amphetamines, cocaine, ecstasy) for cognitive enhancement with lower last-year and last-month rates. Prevalence was higher in male pupils, pupils from vocational schools and pupils with bad marks. DISCUSSION: The illicit use of stimulants for cognitive enhancement is significantly higher than non-medical use of prescription stimulants among pupils and students. Stimulant use is determined by gender, school type, and school marks. The potential risks associated with stimulant use require early awareness and intervention strategies.

Compliance assessment of ambulatory Alzheimer patients to aid therapeutic decisions by healthcare professionals.

BACKGROUND: Compliance represents a major determinant for the effectiveness of pharmacotherapy. Compliance reports summarising electronically compiled compliance data qualify healthcare needs and can be utilised as part of a compliance enhancing intervention. Nevertheless, evidence-based information on a sufficient level of compliance is scarce complicating the interpretation of compliance reports. The purpose of our pilot study was to determine the compliance of ambulatory Alzheimer patients to antidementia drugs under routine therapeutic use using electronic monitoring. In addition, the forgiveness of donepezil (i.e. its ability to sustain adequate pharmacological response despite suboptimal compliance) was characterised and evidence-based guidance for the interpretation of compliance reports was intended to be developed. METHODS: We determined the compliance of four different antidementia drugs by electronic monitoring in 31 patients over six months. All patients were recruited from the gerontopsychiatric clinic of a university hospital as part of a pilot study. The so called medication event monitoring system (MEMS) was employed, consisting of a vial with a microprocessor in the lid which records the time (date, hour, minute) of every opening. Daily compliance served as primary outcome measure, defined as percentage of days with correctly administered doses of medication. In addition, pharmacokinetics and pharmacodynamics of donepezil were simulated to systematically assess therapeutic undersupply also incorporating study compliance patterns. Statistical analyses were performed with SPSS and Microsoft Excel. RESULTS: Median daily compliance was 94% (range 48%-99%). Ten patients (32%) were non-compliant at least for one month. One-sixth of patients taking donepezil displayed periods of therapeutic undersupply. For 10 mg and 5 mg donepezil once-daily dosing, the estimated forgiveness of donepezil was 80% and 90% daily compliance or two and one dosage omissions at steady state, respectively. Based on the simulation findings we developed rules for the evidence-based interpretation of donepezil compliance reports. CONCLUSIONS: Compliance in ambulatory Alzheimer patients was for the first time assessed under routine conditions using electronic monitoring: On average compliance was relatively high but variable between patients. The approach of pharmacokinetic/pharmacodynamic in silico simulations was suitable to characterise the forgiveness of donepezil suggesting evidence-based recommendations for the interpretation of compliance reports.

Predictors of adherence among Alzheimer's disease patients receiving oral therapy.

OBJECTIVES: Treatment effectiveness depends upon administering medications as prescribed, and adherence is critical for Alzheimer's disease (AD) patients to receive optimal benefit from therapy. The objective of this study was to investigate factors associated with adherence to AD oral medications. METHODS: This retrospective claims analysis identified AD patients who initiated oral AD therapy (rivastigmine, donepezil, galantamine, or memantine) between January 1, 2006 and December 31, 2007 from a large US health plan. Patient baseline characteristics were assessed during the 6-month pre-index period; outcomes were assessed during the 1-year post-index period. Pill burden was measured as a count of unique units of medication/day. Adherence was measured by medication possession ratio (MPR), with MPR >or=80% defined as adherent. Multivariate logistic regression was used to assess how potential covariates affect adherence probability. RESULTS: A total of 3091 AD patients (36% male; mean age 80 [8.25 SD]) were identified. Only 58% of patients were adherent to oral AD medications. Compared to patients <75 years, patients >or=86 years were likely to be more adherent (OR = 1.401, p < 0.001). Other factors found to be positively associated with the probability of adherence to AD medications were male gender (OR = 1.175, p < 0.05), overall pill burden (OR = 1.192, p < 0.001), and a lower formulary tier status of the AD medication (OR = 1.332, p < 0.001). CONCLUSION: Among the several variables assessed, being male, >or=86 years of age, having a greater overall daily pill burden, or using a lower formulary tier AD medication was associated with better adherence to oral AD medication in patients diagnosed with AD. The database had no information on caregiver support, medication management interventions, or use of adherence aids that may have affected adherence in this cohort, yet, a substantial proportion of patients (42%) remained non-adherent. A better understanding of the causes of non-adherence is necessary, and methods to improve adherence, such as transdermal medications and educational programs, should be considered.

Prescribing of drugs for Alzheimer's disease: a South African database analysis.

BACKGROUND: Relatively few studies of mental illness in Africa have focused on dementia. The primary aim of this study was to determine the prescribing patterns and cost of drugs for Alzheimer's disease in a private health care sector patient population. METHODS: A retrospective, exposure-cohort pharmacoepidemiological study was conducted. Data were obtained from a South African private pharmacy group for 2008. The database consisted of 1,578,346 medicine records. RESULTS: A total of 588 patients (326 females and 262 males) received 2623 medicine items for Alzheimer's disease at a cost of R1,563,701.18 (average cost per item R596.15). The average age of the patients was 75.54 (SD = 10.48) years. Donepezil was the most frequently prescribed active ingredient (37.09%), followed by galantamine (36.94%). Donepezil accounted for 39.50% of the cost of Alzheimer medication. The average cost per prescription was R634.76 for donepezil and R551.35 for memantine. Only 5.27% of patients were prescribed more than one active ingredient for Alzheimer's disease during the year (mostly donepezil or galantamine, and memantine). Average prescribed daily doses (PDDs) of all active ingredients were generally lower than their respective defined daily doses (DDDs). The average PDD for donepezil was 7.45 mg (DDD = 7.5 mg), for galantamine 13.56 mg (DDD = 16 mg), for memantine 17.46 mg (DDD = 20 mg) and for rivastigmine 6.89 mg (DDD = 9 mg). CONCLUSIONS: A small number of patients were prescribed medicine for Alzheimer's disease. It is recommended that qualitative studies be undertaken to determine the cost-effectiveness of the different treatment options according to family members and carers.