Memantine in Japanese patients with moderate to severe Alzheimer’s disease: meta-analysis of multiple-index responder analyses

Background: Responder analyses assessing clinical worsening have attempted to clarify clinically meaningful drug efficacy enhancements in patients with Alzheimer’s disease (AD).

Research design and methods: This was a meta-analysis of two multicenter, randomized, double-blind, parallel-group, 24-week studies of 633 Japanese patients with moderate to severe AD receiving memantine 20 mg/day (n = 318) or placebo (n = 315). The clinical trial registration number is UMIN000026013.

Results: Overall odds ratios (OR) for a reduced likelihood of clinical worsening (memantine versus placebo) were statistically significant on the following individual and combined rating scales: Severe Impairment Battery-Japanese version (SIB-J, OR 0.52; 95% CI: 0.37, 0.73; p = 0.0001); Behavioral Pathology in AD Rating Scale (BEHAVE-AD, OR 0.53; 95% CI: 0.37, 0.75; p = 0.0003); and SIB-J + Clinician’s Interview-Based Impression of Change-plus-Japanese version (SIB-J + CIBIC-plus-J; OR 0.53; 95% CI: 0.37, 0.77; p = 0.0009). A significantly reduced risk of triple worsening was evident in the memantine versus placebo group on the combined SIB-J + CIBIC-plus-J + BEHAVE-AD rating scales (OR 0.38; 95% CI: 0.22, 0.65; p = 0.0003).

Conclusions: Memantine is a viable treatment option for patients with AD presenting not only with cognitive impairment, but also with a broader range of symptoms, including the behavioral and psychological symptoms of dementia.     

Gender effect on the right–left discrimination task in a sample of heroin-dependent patients

Rationale Discriminating right from left is an everyday cognitive ability. Repeated exposure to certain drugs, such as heroin, can produce poor performance on many cognitive tasks. However, it is yet unclear whether drug abuse impairs the ability of right–left discrimination. Objectives The aim of the present study is to examine whether the spatial ability measured by the right–left discrimination task can be affected by heroin abuse and whether such drug effect, if it exists, is gender related. Methods A paper-and-pen test was used. The test consists of line drawings of a person with no arm, one arm, or both arms crossing the vertical body axis of the figure. The line drawings are viewed from the back, from the front, or randomly alternating between the back and front drawings. The subjects' task is to mark which is the right or left hand in the figure as fast as possible. Results A main finding in this study was that the ability to discriminate between left and right in visual space was impaired in heroin-dependent patients. Especially, heroin-dependent females performed poorer than control females in all conditions but heroin-dependent males only performed poorly in part of conditions. Conclusions Recent heroin abuse impairs the ability of right–left discrimination and such impairment is gender related: heroin-dependent females demonstrated greater performance deficits than males.     

Quantitative assessment of drug effect on QT interval： Mixed effect modeling as a practical solution to interpret drug effect in the midst of high QT variability

QT prolongation is recognized as a risk factor for cardiac arrhythmia and torsades de points. Adequate QT correction is essential for unbiased estimation of drug effect. However, evaluation of drug effect on QTc is challenging due to multiple source of variability and low precision of QT measures resulting in low signal to noise ratio, high between individual and .between occasion variabilities, the presence of circadian rhythm and inadequacy of fixed correction methods such as Bezette＇ s and Fredericia＇s. ＂Standard＂ QT analytical methods include 1 ） largest time-matched mean difference between the drug and placebo （baseline subtracted） over the collection period, 2） time-averaged QT/QTc intervals for each individual, 3） analysis for changes occurring at Cmax for each individual. However, the ＂standard＂ methods have limitations： 1 ） do not provide quantitative information on QT prolongation, potency ＆ activity, 2） unable to simulate most critical situation e.g. supra-therapeutic concentration, and 3） time averaging substantially reduces the sensitivity of the test. Quantitative PK/PD analysis could reduce the risk of false-positive or false-negative signals, and could differentiate drug effect from the multiple source of variabilities. It allows for splitting the overall variability into components and estimate them with suffcient precision in order to provide more reliable assessment of the drug induced QT prolongation. In addition, quantitative PK/PD analysis allows for determining the model-based correction factor α. With adequate data per individual per study day （10- 15）,[第一段]     

Association of baseline C-reactive protein and prior anti-tumor necrosis factor therapy with need for weekly dosing during maintenance therapy with adalimumab in patients with moderate to severe Crohn’s disease

Abstract

Objective:

A post hoc analysis of data from the adalimumab Crohn’s disease (CD) maintenance trial (CHARM, NCT00077779), examining the relationship between adalimumab dosing and maintenance of remission and response in subgroups stratified by previous anti-TNF use and baseline CRP.     

Comparison of the hypoglycemic effect of sitagliptin versus the combination of mitiglinide and voglibose in drug-naïve Japanese patients with type 2 diabetes

Objective: The postprandial glucose (PPG) level is reduced by α-GIs, glinides and DPP4Is through different pharmacological actions. The aim of this study was to compare the effect of sitagliptin (S) versus that of the combination of mitiglinide and voglibose (M+V) on markers of glycemic control.

Research design and methods: A randomized cross-over trial was performed in 20 patients with drug-naïve type 2 diabetes. The patients were randomized to receive S (50 mg/day) or M+V (1 tablet 3 times daily). Treatment was continued for 8 weeks, after which they were switched to the other regimen and treated for another 8 weeks. At baseline, after the first regimen, and after the second regimen, a meal test was performed.

Main outcome measures: The markers of glycemic control were examined.

Results: Reduction of glucose excursion was significantly greater with M+V than with S. HbA_1c did not change with either regimen. However, 1,5-anhydroglucitol showed a significant increase from baseline with both regimens (7.9 ± 4.3 μg/ml at baseline vs. 10.6 ± 5.5 with S, p < 0.05 and 15.1 ± 6.2 with M+V, p < 0.01). Compared with baseline, glycoalbumin was significantly reduced by M+V, but not S (19.6 ± 2.9% at baseline vs. 17.3 ± 3.8% with M+V, p < 0.05).

Conclusion: M+V achieved better control of PPG excursion than S.     

Monitoring of the antiplatelet drugs effect in patients with coronary artery disease: what is the real clinical impact?

Antiplatelet therapy is used to reduce the risk of ischemic events in patients with cardiovascular disease. The balance of benefits and risks of antiplatelet drugs in coronary artery disease has been evaluated in large-scale randomised trials, however the absolute benefit for an individual patient and a specific platelet-active drug need further evaluation. Several well-conducted studies have demonstrated a substantial inter-individual variability in the platelet responsiveness to drugs. The historical "gold standard" test of platelet function (optical aggregation) has well established limitations for measuring the effect of antiplatelet drugs. Other new tests developed (i.e. PFA-100, VerifyNow) may overcome some of these limitations but they do not correlate well with each other. Despite these unresolved methodological questions, several recent clinical studies, but not all, suggest a significant correlation between antiplatelet resistance status and serious vascular events. In these conditions, laboratory monitoring for antiplatelet therapies raises several questions: (i) the necessity for a consensus on the definition of resistance and on the best test for evaluation of the condition, (ii) the demonstration that biological resistance has clinical significance, and (iii) the clinical impact of adapting the antiplatelet therapy. Therefore, it is not currently appropriate to test patients or to change therapy on the basis of such tests, other than in prospective and adequately powered clinical trials.     

Predominantβ-adrenoceptor blocking effect of xamoterol averaged over the day in patients with mild to moderate heart failure: insight into the mechanism of its long-term clinical efficacy

Summary Xamoterol acts as a ₁-adrenoceptor agonist at low sympathetic activity and as an antagonist at high activity. Although its long-term efficacy has been proven in patients with mild to moderate heart failure, it remains unclear which effect, agonism or antagonism, accounts for its long-term activity.To clarify the effect of xamoterol on cardiac sympathetic activity in daily life, 24-h R-R interval histograms were obtained during administration of xamoterol 100 mg b. d. for 1 week to 10 patients with mild to moderate heart failure. Eight normal subjects were also studied as controls. To examine the relation between the effect of xamoterol and sympathetic activity, plasma noradrenaline (NA) levels were measured under 5 graded conditions simulating daily living.Xamoterol administration significantly decreased the standard deviation of the R-R interval, both in patients with heart failure and in normal subjects. The mean R-R interval, however, was increased in patients with heart failure, relative to normal subjects.In both groups, the R-R interval histograms had two peaks, i. e. a short daytime peak and a long night-time peak. Xamoterol decreased the median of the night-time peak without changing the daytime peak in normal subjects. In contrast, it increased the median of the daytime peak without producing a significant change in the nighttime peak in patients with heart failure. Levels of plasma NA were significantly higher in patients than in normal subjects under all conditions.Thus, in normal subjects xamoterol predominantly increased the slower heart rate at night with only a minor effect on the higher heart rate in the daytime, whereas it predominantly attenuated the daytime tachycardia induced by sympathetic stimulation in patients with heart failure.It is concluded that xamoterol tends overall to act as a-adrenoceptor antagonist during the day, especially in the daytime in patients with mild to moderate heart failure. Its antagonist rather than its agonist effect may account for the long-term efficacy of xamoterol in patients with mild to moderate heart failure.     

Effect of captopril on myocardial β-adrenoceptor density and Giα-proteins in patients with mild to moderate heart failure due to dilated cardiomyopathy

In end-stage heart failure due to idiopathic dilated cardiomyopathy ₁-adrenoceptors are downregulated and G₁-proteins are upregulated. The aim of the present study was to investigate the influence of the angiotensin-converting enzyme inhibitor captopril on -adrenoceptor density and G_i-proteins in sequential endomyocardial biopsies. Nineteen patients with mild to moderate congestive heart failure due to idiopathic dilated cardiomyopathy (NYHA Class II–III) were studied before and after 8–11 weeks of therapy. Patients were randomised into a captopril and a control group; 9 patients received captopril 12.5–50 mg per day, (divided in 2–3 doses) p.o. in addition to conventional therapy with digoxin and diuretics, and 10 controls received conventional therapy only. Echocardiography, spiroergometry, right heart catheterisation and endomyocardial biopsies were performed before (baseline) and after treatment. Compared to baseline, captopril increased total -adrenoceptor density by selectively increasing ₁-adrenoceptors (31.6 vs 41.2 fmol·mg^–1; p<0.05) but had no significant effect on G_i-proteins. The results indicate that treatment with angiotensin-converting enzyme inhibitors partly restores myocardial ₁-adrenoceptor density, and this action effect may contribute to the clinical improvement of patients with idiopathic dilated cardiomyopathy treated in this way.     

Pharmacotherapy for the treatment of depression in patients with alzheimer’s disease: a treatment-resistant depressive disorder

Introduction: Pharmacotherapy for the treatment of depressive disorders in Alzheimer’s Disease (AD) represents a clinical challenge. pharmacological options are often attempted after a period of watchful waiting (8–12 weeks). monoaminergic antidepressant drugs have shown only modest or null clinical benefits, maybe because the etiology of depressive symptoms in ad patients is fundamentally different from that of nondemented subjects.

Areas covered: The following article looks at the selective serotonin reuptake inhibitor sertraline, which is one of the most frequently studied antidepressant medications in randomized controlled trials (RCTs). It also discusses many other pharmacological approaches that have proven to be inadequate (antipsychotics, acetylcholinesterase inhibitors, anticonvulsants, hormone replacement therapy) and new drug classes (mainly affecting glutamate transmission) that are being studied for treating depression in AD. It also gives discussion to the phase II RCT on the alternative drug S47445 and the potential effect on cognition of the multimodal antidepressant vortioxetine in older depressed patients. Finally, it discusses the N-methyl-D-aspartate antagonist ketamine.

Expert opinion: The present RCT methodologies are too disparate to draw firm conclusions. Future studies are required to identify effective and multimodal pharmacological treatments that efficiently treat depression in AD. Genotyping may boost antidepressant treatment success.     

Comparison of the antidiabetic effects of linagliptin among groups with a normal renal function and a mild or severe renal impairment – retrospective observation study of Japanese patients with type 2 diabetes mellitus

Objective: The clinical course > 6 months after the initiation of linagliptin in patients with type 2 diabetes was compared among the groups divided by their renal function.

Methods: Two hundred and sixteen Japanese patients with type 2 diabetes treated with 5 mg once daily linagliptin were studied as the treated set. One hundred and forty-five subjects whose medications were not changed during the observation period were investigated as the full analysis set to assess the effectiveness. The subjects were divided into three groups based on an eGFR: eGFR ≥ 60, 59 – 45 and < 45 ml/min/1.73 m². The parameters were analyzed separately in the patients receiving monotherapy and additional therapy of linagliptin.

Results: The HbA1c (NGSP) levels significantly improved in both the patients receiving monotherapy and additional therapy. The changes in the HbA1c levels at 6 months were not significantly different between the groups with an eGFR ≥ 60, 59 – 45 and < 45 ml/min/1.73 m² receiving monotherapy (?1.0, ?0.8 and ?0.8%, respectively). Similarly, those were not significantly different between the different groups receiving additional therapy (?0.6, ?0.5 and ?0.7%, respectively).

Conclusions: Linagliptin is considered to be effective for patients with type 2 diabetes and renal impairment in the present analysis performed at our institution.     

Pharmacokinetic–pharmacodynamic model of fimasartan applied to predict the influence of a high fat diet on its blood pressure-lowering effect in healthy subjects

Purpose

Fimasartan is a non-peptide angiotensin II receptor antagonist which selectively blocks the AT₁ receptor. The aim of our study was to perform a population pharmacokinetic–pharmacodynamic (PK–PD) analysis of fimasartan to evaluate the effect of food on the mechanistic PK–PD relationship.

Methods

This was a food–drug interaction single-center study involving 24 healthy subjects that was designed as a randomized, open-label, single-dosing, two-way crossover trial. Extensive PK data was obtained on blood samples collected at 0, 0.5, 1, 2, 2.5, 3, 4, 6, 8, 12, and 24 h post-dosing and five systolic/diastolic blood pressure (BP) measurements made at 0, 4, 8, 12 and 24 h post-dosing and used to construct a mixed effect model (NONMEM, ver. 6.2).

Results

A two-compartment linear PK model with zero-order (fasted) or Weibull (fed with high-fat diet) absorption best described the PK of fimasartan. Relative bioavailability decreased by 37 % when the subjects were given a high-fat diet.

Conclusions

The turnover PK–PD model combined with pre-defined cosine function for circadian rhythm described the BP changes measured within 24 h after dosing better than the effect compartment or transduction models. To predict the influence of a high-fat diet on the blood pressure-lowering effect of fimasartan in healthy subjects, we simulated changes in BP when fimasartan was given daily for 30 days. The overlapping pattern of simulated BP curves in the fasted versus fed group demonstrated that a high-fat diet would not cause a clinically significant reduction in the BP-lowering effect of fimasartan, despite a significant reduction in bioavailability.     

Association of the DRD2 and DRD3 polymorphisms with response to pramipexole in Parkinson’s disease patients

Objective  To evaluate the impact of the DRD2 TaqIA and DRD3 Ser9Gly polymorphisms on the efficacy of pramipexole in treating patients with Parkinson’s disease (PD). Methods  Thirty patients with PD prospectively received pramipexole 0.25 mg three times daily for 2 months. Unified Parkinson Disease Rating Scale (UPDRS) assessments were conducted at baseline and 2 months after treatment initiation. Improvement by 20% or more in the total score on the UPDRS was considered to indicate responsiveness. The PCR–restriction fragment length polymorphism analysis was used to analyze the DRD2 Taq1A and DRD3 Ser9Gly genotype. Results  The DRD2 Taq1A allele frequencies were A141.7 (A1) and 58.3% (A2), and the DRD3 Ser9Gly allele frequencies were 68.3 (Ser) and 31.7% (Gly). When the subjects were grouped by the DRD3 Ser9Gly polymorphism, the response rates for pramipexole treatment were significantly higher in the Ser/Ser group (60%) than in the group containing the Gly allele (13%). There was a significant association between the DRD3 Ser9Gly polymorphism and response rate to pramipexole in PD patients (P = 0.024). When the subjects were grouped by the DRD2 Taq1A polymorphism, there were no significant differences among the three Taq1A genotypes. Conclusions  DRD3 Ser9Gly polymorphisms are significantly associated with the therapeutic efficacy of pramipexole in Chinese patients with PD. A large-scale and multi-dose group study in patients with PD is necessary for evaluating the impact of the genetic polymorphisms of the dopamine receptor on the therapeutic effects of pramipexole.     

Effects of atorvastatin on systemic and renal NO dependency in patients with non-diabetic stage II–III chronic kidney disease

Aims

Clinical trials suggest that statins have beneficial effects on the cardiovascular system independent from their cholesterol lowering properties. In patients with chronic kidney disease stage II–III, we tested the hypothesis that atorvastatin increased systemic and renal nitric oxide (NO) availability using L-N^G-monomethyl arginine (L-NMMA) as an inhibitor of NO production.

Methods

In a randomized, placebo-controlled, crossover study patients were treated with atorvastatin for 5 days with standardized diet and fluid intake. Glomerular filtration reate (GFR), fractional excretions of sodium (FE_Na), urinary excretion of aquaporin-2 (u-AQP2) and epithelial sodium channels (u-ENaC_γ), vasoactive hormones (renin, angiotensin II, aldosterone, arginine vasopressin, endothelin-1 and brain natriuretic peptide) and central blood pressure (BP) estimated by applanation tonometry were measured before and after systemic administration of the NO inhibitor L-NMMA.

Results

Atorvastatin caused a significant reduction in U-ENaC_γ, but sodium excretion, , FE_Na and u-AQP2 were not changed by atorvastatin. L-NMMA reduced renal effect variables, including GFR, FE_Na and u-ENaC_γ and increased brachial BP and central BP to a similar extent during both treatments. Vasoactive hormones were changed in the same way by L-NMMA during atorvastatin and placebo treatment.

Conclusion

During, atorvastatin and placebo treatment, inhibition of nitric oxide synthesis induced the same response in brachial and central blood pressure, GFR, renal tubular function and vasoactive hormones. Thus, the data do not support that atorvastatin changes nitric oxide availability in patients with mild nephropathy. The reduced u-ENaC may reflect changes in sodium absorption in the nephron induced by atorvastatin.     

A multicenter,epidemiological study of the treatment patterns,comorbidities and hypoglycemia events of patients with type 2 diabetes and moderate or severe chronic kidney disease – the ‘LEARN’ study

Objective Management of patients with type 2 diabetes (T2DM) and stage 3 to 5 chronic kidney disease (CKD) is challenging. The aim of the ‘LEARN’ study was to describe treatment patterns employed in this population and to record comorbidities, glycemic control and hypoglycemia episodes in routine clinical practice in Greece.

Research design and methods ‘LEARN’ was a non-interventional, multicenter, cross-sectional study conducted in Greece between 15 February 2013 and 4 July 2013. A total of 120 adult patients were enrolled from four hospital sites in different geographic regions of Greece.

Results Participants had a mean age of 69.1?±?10.3 years and a male:female ratio of 2:1. Nearly all patients (99.2%) suffered from at least one comorbidity, with hypertension (95.8%) and hyperlipidemia/dyslipidemia (78.3%) being the most prevalent. Of the overall study population, 57.5% was managed with insulin therapy only, 30.8% with oral antidiabetics only and 11.7% with a combination of insulin and oral antidiabetics. The overall rate of glycemic control, defined as glycated hemoglobin (HbA_1c)?≤?7.0% during the most recent assessment, was 55.0%. This rate was significantly higher among those receiving oral antidiabetics only (73.0%) compared to insulin only (47.8%) or a combination of both types of treatment (42.9%) (p?=?0.03). Moreover, patients receiving oral antidiabetics only had experienced fewer hypoglycemia episodes over the last 7 days prior to the study visit (0.1?±?0.4) compared to patients receiving insulin only (0.9?±?1.7) (p?=?0.03).

Conclusions Although this is an observational study, it seems that oral antidiabetic therapy might be advantageous for heavily burdened T2DM patients with moderate or severe CKD in terms of glycemic control and hypoglycemia episodes. More data preferably from randomized trials is needed in order to validate this hypothesis.     

Use of lamotrigine to augment clozapine in patients with resistant schizophrenia and comorbid alcohol dependence: a potent anti-craving effect?

Comorbid alcohol dependence is common in patients with schizophrenia and is associated with a variety of serious adverse consequences. Although case reports exist concerning the positive impact of lamotrigine addition on clozapine treatment in resistant schizophrenia, a review of the literature fails to document any evidence regarding a combination of the two in the treatment of patients with schizophrenia and comorbid alcohol dependence. In the present study, we present three cases in which patients with resistant schizophrenia and comorbid alcohol use disorder were given lamotrigine to augment clozapine. Our findings suggest that clozapine plus lamotrigine may be helpful in reducing alcohol consumption and craving among patients with schizophrenia and comorbid alcohol dependence.     

Multivariate Mann–Whitney Estimators for the Comparison of Two Treatments in a Three-Period Crossover Study with Randomly Missing Data

This paper discusses the application of multivariate Mann–Whitney estimators to the comparison of two treatments for a strictly ordinal response variable in a crossover study with four sequence groups and three periods. Ways of managing randomly missing data and nonparametric covariance adjustment for no differences among groups for a baseline period have consideration as well. Estimators pertaining to treatment comparisons in linear logistic models for the Mann–Whitney estimators have determination through a Bradley–Terry model for dimension reduction and weighted least squares. These estimators can be the basis for both statistical tests and confidence intervals. The methods in this paper have their results presented for an example. Simulation studies for the methods show that they have reasonable control of type 1 error and power.     

Impact of treatment algorithms on the prescribing of antithrombotic therapy in patients with suspected acute coronary syndrome – a prospective audit

Aims

Chest pain presentations are common although most patients do not have an acute coronary syndrome (ACS). We hypothesized that our local therapeutic guideline was leading to many low risk patients being inappropriately treated with potent anti-thrombotic therapy for ACS.

Methods

We conducted a prospective analysis of patients presenting with suspected ACS to the Western Infirmary Glasgow over a 2 month period between 6/10/13–3/11/13 and 5/4/14–2/5/14. We collated data on demographics, investigation, initial management and final diagnosis. Patients taking warfarin were excluded. We calculated sensitivity, specificity and receiver operating characteristic (ROC) curves for our local guideline, the SIGN guideline and a new guideline proposal.

Results

We studied 202 patients of whom 112 (55%) were male with mean (SD) age 60 (15) years. Full anti-thrombotic therapy for ACS was recommended in 91 patients (45%) according to the NHS GG&C guideline, 37 (18%) by the SIGN guideline and 30 (15%) by our new guideline proposal. The final diagnosis was ACS in 39 patients (19%). The current NHS GG&C guideline had a sensitivity of 80%, specificity 63% and AUROC 0.71 (95% CI 0.63, 0.80). The respective values were 62%, 92% and 0.77 (95% CI 0.67, 0.86) for the SIGN guideline and 54%, 94% and 0.74 (95% CI 0.64, 0.84) for our new proposed guideline.

Conclusions

Only one-fifth of patients who present with chest pain or suspected ACS have ACS as their final diagnosis. Our new guideline proposal is highly specific and would minimize unnecessary administration of potent anti-thrombotic therapy to low risk patients.