A multinational, randomised, 12-week study comparing the effects of donepezil and galantamine in patients with mild to moderate Alzheimer's disease

To compare directly, in the same patient cohort, the ease of use and tolerability of donepezil and galantamine in the treatment of Alzheimer's disease (AD), and investigate the effects of both treatments on cognition and activities of daily living (ADL).

A Phase I and Pharmacokinetic Study of OSI-7904L, a Liposomal Thymidylate Synthase Inhibitor in Combination with Oxaliplatin in Patients with Advanced Colorectal Cancer.

OSI-7904L is a liposomal formulation of a potent thymidylate synthase (TS) inhibitor. This phase I study evaluated the safety, tolerability and pharmacokinetics (PK) of OSI-7904L administered in combination with oxaliplatin every 21 days in patients with advanced colorectal carcinoma. METHOD: A 3+3 study design was utilized at predefined dose levels. Polymorphisms in the TS enhancer region and XPD enzyme were investigated as potential predictors of efficacy and toxicity. RESULTS: Fourteen patients received 76 cycles of treatment. At the highest dose level (OSI-7904L 9 mg/m(2), oxaliplatin 130 mg/m(2)) investigated, one of nine patients experienced dose-limiting toxicity of grade 3 oral mucositis with cycle 1 and five further patients required dose reductions. The toxicity profile of stomatitis, diarrhea, nausea, fatigue, sensory neuropathy and skin rash was consistent with that expected for a TS inhibitor/oxaliplatin combination regimen. PK analysis showed high interpatient variability with no detectable interaction between OSI-7904L and oxaliplatin. Partial radiological responses were documented in two patients. CONCLUSIONS: The recommended regimen for further investigation is OSI-7904L 9 mg/m(2) and oxaliplatin 130 mg/m(2).

High-dose adenosine overcomes the attenuation of myocardial perfusion reserve caused by caffeine.

Objectives:
We studied whether an increase in adenosine dose overcomes caffeine antagonism on adenosine-mediated coronary vasodilation.

Background:
Caffeine is a competitive antagonist at the adenosine receptors, but it is unclear whether caffeine in coffee alters the actions of exogenous adenosine, and whether the antagonism can be surmounted by increasing the adenosine dose.

Methods:
Myocardial perfusion scintigraphy (MPS) was used to assess adenosine-induced hyperemia in 30 patients before (baseline) and after coffee ingestion (caffeine). At baseline, patients received 140 µg/kg/min of adenosine combined with low-level exercise. For the caffeine study, 12 patients received 140 µg/kg/min of adenosine (standard) and 18 patients received 210 µg/kg/min (high dose) after caffeine intake (200 mg). Myocardial perfusion was assessed semiquantitatively and quantitatively, and perfusion defect was characterized according to the presence of reversibility.

Results:
Caffeine reduced the magnitude of perfusion abnormality induced by standard adenosine as measured by the summed difference score (SDS) (12.0 ± 4.4 at baseline vs. 4.1 ± 2.1 after caffeine, p < 0.001) as well as defect size (18% [3% to 38%] vs. 8% [0% to 22%], p < 0.01), whereas it had no effect on the abnormalities caused by high-dose adenosine (SDS, 7.7 ± 4.0 at baseline vs. 7.8 ± 4.2 after caffeine, p = 0.7). There was good agreement between baseline and caffeine studies for segmental defect category (kappa = 0.72, 95% confidence interval: 0.65 to 0.79) in the high-dose group. An increase in adenosine after caffeine intake was well tolerated.

Conclusions:
Caffeine in coffee attenuates adenosine-induced coronary hyperemia and, consequently, the detection of perfusion abnormality by adenosine MPS. This can be overcome by increasing the adenosine dose without compromising test tolerability.

Vandetanib with FOLFIRI in patients with advanced colorectal adenocarcinoma: results from an open-label, multicentre phase I study.

The safety and tolerability of vandetanib (ZACTIMA; ZD6474) plus FOLFIRI was investigated in patients with advanced colorectal cancer (CRC). METHODS: Patients eligible for first- or second-line chemotherapy received once-daily oral doses of vandetanib (100 or 300 mg) plus 14-day treatment cycles of FOLFIRI. RESULTS: A total of 21 patients received vandetanib 100 mg (n = 11) or 300 mg (n = 10) + FOLFIRI. Combination therapy was well tolerated at both vandetanib dose levels. There were no DLTs in the vandetanib 100 mg cohort and one DLT of hypertension (CTCAE grade 3) in the 300 mg cohort. The most common adverse events were diarrhoea (n = 20), nausea (n = 12) and fatigue (n = 10). Two patients (one in each cohort) discontinued vandetanib due to adverse events (rash, 100 mg cohort; hypertension, 300 mg cohort). There was no apparent pharmacokinetic interaction between vandetanib and FOLFIRI. Preliminary efficacy results included two confirmed partial responses in the 100 mg cohort and 9 patients with stable disease > or =8 weeks (100 mg, n = 7; 300 mg, n = 2). CONCLUSIONS: Once-daily vandetanib (100 or 300 mg) in combination with a standard FOLFIRI regimen was generally well tolerated in patients with advanced CRC.

A multinational, randomised, 12-week, comparative study of donepezil and rivastigmine in patients with mild to moderate Alzheimer's disease

This 12-week, multinational study compared the tolerability and cognitive effects of donepezil (up to 10 mg once daily) and rivastigmine (up to 6 mg twice daily) in 111 patients with mild to moderate Alzheimer's disease. Both medications were administered open label according to recommended dosing regimens from the respective product labelling available during the conduct of the study. More patients in the donepezil group (89.3%) completed the study compared with the rivastigmine group (69.1%; p=0.009), and 10.7% of the donepezil group and 21.8% of the rivastigmine group discontinued due to adverse events (AEs); 87.5% of donepezil-treated patients and 47.3% of rivastigmine-treated patients remained on the maximum approved dose of each drug at the last study visit. Both groups showed comparable improvements on the ADAS-cog administered by raters blind to study medication at weeks 4 and 12. Thus, using the recommended dosing schedules, donepezil was better tolerated with fewer discontinuations due to AEs, and both agents improved cognition to a similar extent.

Cochrane review on 'Statins for the treatment of dementia'

OBJECTIVES: This review aimed to assess the clinical efficacy and tolerability of statins in the treatment of dementia. METHODS: We searched the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group, The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS, as well as many trials registries and grey literature sources (27 October 2008). Double-blind, randomized controlled trials of statins given for at least 6?months in people with a diagnosis of dementia were included. Two independent authors extracted and assessed data independently against the inclusion criteria. Data were pooled where appropriate and entered into a meta-analysis. RESULTS: Three studies were identified (748 participants, age range 50-90?years). All patients had a diagnosis of probable or possible Alzheimer's disease according to standard criteria, and most patients were established on a cholinesterase inhibitor. Change in Alzheimer's Disease Assessment Scale cognitive subscale from baseline was a primary outcome in three studies; when data were pooled, statins did not provide any beneficial effect in this cognitive measure (mean difference -1.12; 95% confidence interval -3.99, 1.75; p?=?0.44). All studies provided a change in Mini-Mental State Examination from baseline; there was no significant benefit from statins in this cognitive measure when the data were pooled (mean difference -1.53; 95% confidence interval -3.28; 0.21, p?=?0.08). There were no studies identified assessing the role of statins in treatment of vascular dementia. There was no evidence that statins were detrimental to cognition. CONCLUSIONS: There is insufficient evidence to recommend statins for the treatment of dementia. Copyright © 2012 John Wiley & Sons, Ltd.

Effect of sublingual application of cannabinoids on intraocular pressure:A pilot study

PURPOSE: The purpose of this study was to assess the effect on intraocular pressure (IOP) and the safety and tolerability of oromucosal administration of a low dose of delta-9-tetrahydrocannabinol (?-9-THC) and cannabidiol (CBD). PATIENTS AND METHODS: A randomized, double-masked, placebo-controlled, 4 way crossover study was conducted at a single center, using cannabis-based medicinal extract of ?-9-THC and CBD. Six patients with ocular hypertension or early primary open angle glaucoma received a single sublingual dose at 8 AM of 5 mg ?-9-THC, 20 mg CBD, 40 mg CBD, or placebo. Main outcome measure was IOP. Secondary outcomes included visual acuity, vital signs, and psychotropic effects. RESULTS: Two hours after sublingual administration of 5 mg ?-9-THC, the IOP was significantly lower than after placebo (23.5 mm Hg vs. 27.3 mm Hg, P=0.026). The IOP returned to baseline level after the 4-hour IOP measurement. CBD administration did not reduce the IOP at any time. However, the higher dose of CBD (40 mg) produced a transient elevation of IOP at 4 hours after administration, from 23.2 to 25.9 mm Hg (P=0.028). Vital signs and visual acuity were not significantly changed. One patient experienced a transient and mild paniclike reaction after ?-9-THC administration. CONCLUSIONS: A single 5 mg sublingual dose of ?-9-THC reduced the IOP temporarily and was well tolerated by most patients. Sublingual administration of 20 mg CBD did not reduce IOP, whereas 40 mg CBD produced a transient increase IOP rise. Copyright © 2006 by Lippincott Williams & Wilkins.

Freeze-dried strawberry powder improves lipid profile and lipid peroxidation in women with metabolic syndrome:baseline and post intervention effects

Strawberry flavonoids are potent antioxidants and anti-inflammatory agents that have been shown to reduce cardiovascular disease risk factors in prospective cohort studies. Effects of strawberry supplementation on metabolic risk factors have not been studied in obese populations. We tested the hypothesis that freeze-dried strawberry powder (FSP) will lower fasting lipids and biomarkers of oxidative stress and inflammation at four weeks compared to baseline. We also tested the tolerability and safety of FSP in subjects with metabolic syndrome. FSP is a concentrated source of polyphenolic flavonoids, fiber and phytosterols.

Multicentre trial of weekly risedronate on bone density in adults with cystic fibrosis

Background: The aim of this study was to assess the efficacy, tolerability and safety of risedronate in adults with CF. Methods: Patients with a lumbar spine (LS), total hip (TH) or femoral neck (FN) bone mineral density (BMD) Z-score of -1 or less were randomised to receive risedronate 35mg weekly or placebo, and calcium (1g)+vitamin D (800IU). Results: At baseline, BMD Z-scores in the risedronate (n = 17) and placebo (n = 19) groups were similar. By 24. months, 7/17 risedronate patients vs 0/19 placebo patients stopped the study medication due to bone pain. After 24. months treatment, the mean difference (95% CI) in change in LS, TH and FN BMD between the risedronate vs placebo groups was 4.3% (0.4, 8.2) p = 0.03; 4.0% (-0.5, 8.6) p = 0.08; and 2.4% (-3.5, 8.2) p =0.41. Conclusions: After two years treatment there was a significant increase in LS BMD with weekly risedronate compared to placebo. © 2011 European Cystic Fibrosis Society.

Will VEGF Trap-Eye reduce the treatment burden in neovascular age-related macular degeneration?

Evaluation of: Brown DM, Heier JS, Ciulla T et al. Primary end point results of a Phase II study of vascular endothelial growth factor trap-eye in wet age-related macular degeneration. Ophthalmology 118(6), 1089-1097 (2011); Heier JS, Boyer D, Nguyen QD et al. The 1-year results of CLEAR-IT 2, a Phase 2 study of vascular endothelial growth factor trap-eye dosed as-needed after 12-week fixed dosing. Ophthalmology 118(6), 1098-1106 (2011). Age-related macular degeneration is the most common cause of blindness in older adults in western countries, and is likely to become the largest cause of irreversible sight loss in the developing world. Treatments such as ranibizumab and bevacizumab that inhibit VEGF have improved visual outcomes markedly. Controlled trials and clinical experience have shown that the best outcomes are achieved when monthly treatment has been administered over 2 years. This poses a significant burden on health providers and patients. A novel inhibitor of VEGF, VEGF Trap-Eye, which allows less frequent dosing without loss of efficacy, has emerged as a potential treatment. CLEAR-IT 2 was a prospective randomized Phase II trial designed to assess the safety, tolerability and the anatomic and visual effects of repeated treatments with a range of doses of VEGF Trap-Eye. Impressive anatomic and visual improvements were noted with no safety concerns. © 2011 Expert Reviews Ltd.

Microphysiological modeling of the reproductive tract: A fertile endeavor

Preclinical toxicity testing in animal models is a cornerstone of the drug development process, yet it is often unable to predict adverse effects and tolerability issues in human subjects. Species-specific responses to investigational drugs have led researchers to utilize human tissues and cells to better estimate human toxicity. Unfortunately, human cell-derived models are imperfect because toxicity is assessed in isolation, removed from the normal physiologic microenvironment. Microphysiological modeling often referred to as 'organ-on-a-chip' or 'human-on-a-chip' places human tissue into a microfluidic system that mimics the complexity of human in vivo physiology, thereby allowing for toxicity testing on several cell types, tissues, and organs within a more biologically relevant environment. Here we describe important concepts when developing a repro-on-a-chip model. The development of female and male reproductive microfluidic systems is critical to sex-based in vitro toxicity and drug testing. This review addresses the biological and physiological aspects of the male and female reproductive systems in vivo and what should be considered when designing a microphysiological human-on-a-chip model. Additionally, interactions between the reproductive tract and other systems are explored, focusing on the impact of factors and hormones produced by the reproductive tract and disease pathophysiology.

Achieving optimal dose intensity with adjuvant chemotherapy in elderly breast cancer patients:A 10-year retrospective study in a UK institution

The study was to determine if breast cancer patients aged 65 and above could be given adjuvant chemotherapy safely while achieving an acceptable relative dose intensity of at least 85%. We identified all patients aged 65 and over who received adjuvant chemotherapy over the 10 year period, November 1999 to October 2009, and determined the proportion that achieved a relative dose intensity of at least 85% as well as the tolerability of their treatment. A total of 101 patients were identified, with a median age of 69 years (range 65-78).Of these, 25.7% of patients had at least one major comorbidity, 84.2% had a tumor size of 5 cm or less, 73.3% were node positive and 58.4% were hormone receptor positive. The chemotherapy regimens used were AC (Doxorubicin and Cyclophosphamide), FEC (Fluorouracil, Epirubicin, and Cyclophosphamide), CMF (Cyclophosphamide, Methotrexate, and Fluorouracil) and ECMF (Epirubicin followed by CMF). Seventy-nine patients (78.2%) achieved the relative dose intensity of at least 85%. With respect to toxicity, 11.9% of patients developed febrile neutropenia and 23.8% of patients required hospital admission during the treatment period, but there were no treatment-related deaths in the group. A significant proportion of patients aged 65 and above achieved the intended dose intensity of at least 85% over this 10-year period, with manageable toxicity levels. This supports the use of these regimens as adjuvant chemotherapy for breast cancer in this age group. © 2011 Wiley Periodicals, Inc.

SWORD: an intelligent vibratory wearable device to improve rehabilitation in stroke patients

Anualmente ocorrem cerca de 16 milhões AVCs em todo o mundo. Cerca de metade dos sobreviventes irá apresentar défice motor que necessitará de reabilitação na janela dos 3 aos 6 meses depois do AVC. Nos países desenvolvidos, é estimado que os custos com AVCs representem cerca de 0.27% do Produto Interno Bruto de cada País. Esta situação implica um enorme peso social e financeiro. Paradoxalmente a esta situação, é aceite na comunidade médica a necessidade de serviços de reabilitação motora mais intensivos e centrados no doente. Na revisão do estado da arte, demonstra-se o arquétipo que relaciona metodologias terapêuticas mais intensivas com uma mais proficiente reabilitação motora do doente. Revelam-se também as falhas nas soluções tecnológicas existentes que apresentam uma elevada complexidade e custo associado de aquisição e manutenção. Desta forma, a pergunta que suporta o trabalho de doutoramento seguido inquire a possibilidade de criar um novo dispositivo de simples utilização e de baixo custo, capaz de apoiar uma recuperação motora mais eficiente de um doente após AVC, aliando intensidade com determinação da correcção dos movimentos realizados relativamente aos prescritos. Propondo o uso do estímulo vibratório como uma ferramenta proprioceptiva de intervenção terapêutica a usar no novo dispositivo, demonstra-se a tolerabilidade a este tipo de estímulos através do teste duma primeira versão do sistema apenas com a componente de estimulação num primeiro grupo de 5 doentes. Esta fase validará o subsequente desenvolvimento do sistema SWORD. Projectando o sistema SWORD como uma ferramenta complementar que integra as componentes de avaliação motora e intervenção proprioceptiva por estimulação, é descrito o desenvolvimento da componente de quantificação de movimento que o integra. São apresentadas as diversas soluções estudadas e o algoritmo que representa a implementação final baseada na fusão sensorial das medidas provenientes de três sensores: acelerómetro, giroscópio e magnetómetro. O teste ao sistema SWORD, quando comparado com o método de reabilitação tradicional, mostrou um ganho considerável de intensidade e qualidade na execução motora para 4 dos 5 doentes testados num segundo grupo experimental. É mostrada a versatilidade do sistema SWORD através do desenvolvimento do módulo de Tele-Reabilitação que complementa a componente de quantificação de movimento com uma interface gráfica de feedback e uma ferramenta de análise remota da evolução motora do doente. Finalmente, a partir da componente de quantificação de movimento, foi ainda desenvolvida uma versão para avaliação motora automatizada, implementada a partir da escala WMFT, que visa retirar o factor subjectivo da avaliação humana presente nas escalas de avaliação motora usadas em Neurologia. Esta versão do sistema foi testada num terceiro grupo experimental de cinco doentes.

Assessing and Reporting the Adverse Effects of Antipsychotic Medication: A Systematic Review of Clinical Studies, and Prospective, Retrospective, and Cross-Sectional Research

Objective: Adverse effects (AEs) of antipsychotic medication have important implications for patients and prescribers in terms of wellbeing, treatment adherence and quality of life. This review summarises strategies for collecting and reporting AE data across a representative literature sample to ascertain their rigour and comprehensiveness. Methods: A PsycINFO search, following PRISMA Statement guidelines, was conducted in English-language journals (1980–July 2014) using the following search string: (antipsychotic* OR neuroleptic*) AND (subjective effect OR subjective experience OR subjective response OR subjective mental alterations OR subjective tolerability OR subjective wellbeing OR patient perspective OR self-rated effects OR adverse effects OR side-effects). Of 7,825 articles, 384 were retained that reported quantified results for AEs of typical or atypical antipsychotics amongst transdiagnostic adult, adolescent, and child populations. Information extracted included: types of AEs reported; how AEs were assessed; assessment duration; assessment of the global impact of antipsychotic consumption on wellbeing; and conflict of interest due to industry sponsorship. Results: Neurological, metabolic, and sedation-related cognitive effects were reported most systematically relative to affective, anticholinergic, autonomic, cutaneous, hormonal, miscellaneous, and non-sedative cognitive effects. The impact of AEs on patient wellbeing was poorly assessed. Cross-sectional and prospective research designs yielded more comprehensive data about AE severity and prevalence than clinical or observational retrospective studies. 3 Conclusions: AE detection and classification can be improved through the use of standardised assessment instruments and consideration of subjective patient impact. Observational research can supplement information from clinical trials to improve the ecological validity of AE data.

Relationships between imatinib plasma levels and efficacy

Purpose: While imatinib has revolutionized the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumors (GIST), its pharmacokinetic-pharmacodynamic relationships have been poorly studied. This study aimed to explore the issue in oncologic patients, and to evaluate the specific influence of the target genotype in a GIST subpopulation. Patients and methods: Data from 59 patients (321 plasma samples) were collected during a previous pharmacokinetic study. Based on a population model purposely developed, individual post-hoc Bayesian estimates of pharmacokinetic parameters were derived, and used to estimate drug exposure (AUC; area under curve). Free fraction parameters were deduced from a model incorporating plasma alpha1-acid glycoprotein levels. Associations between AUC (or clearance) and therapeutic response (coded on a 3-point scale), or tolerability (4-point scale), were explored by ordered logistic regression. Influence of KIT genotype on response was also assessed in GIST patients. Results: Total and free drug exposure correlated with the number of side effects (p < 0.005). A relationship with response was not evident in the whole patient set (with good-responders tending to receive lower doses and bad-responders higher doses). In GIST patients however, higher free drug exposure predicted better responses. A strong association was notably observed in patients harboring an exon 9 mutation or a wild type KIT, known to decrease tumor sensitivity towards imatinib (p < 0.005). Conclusions: Our results are arguments to further evaluate the potential benefit of a therapeutic monitoring program for imatinib. Our data also suggest that stratification by genotype will be important in future trials.