A noninterventional study evaluating the effectiveness of rotigotine and levodopa combination therapy in younger versus older patients with Parkinson’s disease

Background: PD0013 was a 6-month noninterventional study in clinical practice comparing effectiveness/tolerability of rotigotine+levodopa in younger (<70 years) vs. older (≥70 years) Parkinson’s disease (PD) patients.

Methods: Patients previously received levodopa for ≥6 months as monotherapy/in combination with another dopamine-agonist (DA). Primary variable: Unified PD Rating Scale (UPDRS) Part-II change from baseline to end-of-observation-period (EOP).

Results: 91 younger/99 older patients started rotigotine; 68 younger/62 older patients completed the study. Most switched from levodopa+another DA. Addition of rotigotine as first DA was more common in older patients (20.2% vs.15.4%). Mean ± SD rotigotine-exposure: 6.1 ± 3.4 mg/24h younger vs. 4.9 ± 2.4 mg/24h older. Eleven patients changed levodopa dose.

At EOP, improvement in mean UPDRS-II was greater in younger patients (p = 0.0289). UPDRS-II responder-rate (≥20% decrease in UPDRS-II score) was higher in younger patients (42.3% vs. 25.9%). Improvement across age groups was similar on PD Sleep Scale-2 and Clinical Global Impressions-Improvement Scale. Adverse drug reactions (ADRs), and discontinuations because of ADRs, were more common among older patients. There were no new safety signals.

Conclusions: Despite low rotigotine doses, when added to levodopa/switched from levodopa+another DA, rotigotine led to greater improvement in UPDRS-II in younger patients (<70 years). Individual patient data revealed clinically meaningful improvements in UPDRS-II in both groups.     

Emerging therapeutic targets in the short QT syndrome

Introduction: Short QT Syndrome (SQTS) is a rare but dangerous condition characterised by abbreviated repolarisation, atrial and ventricular arrhythmias and risk of sudden death. Implantable cardioverter defibrillators (ICDs) are a first line protection against sudden death, but adjunct pharmacology is beneficial and desirable.

Areas covered: The genetic basis for genotyped SQTS variants (SQT1-SQT8) and evidence for arrhythmia substrates from experimental and simulation studies are discussed. The main ion channel/transporter targets for antiarrhythmic pharmacology are considered in respect of potential genotype-specific and non-specific treatments for the syndrome.

Expert opinion: Potassium channel blockade is valuable for restoring repolarisation and QT interval, though genotype-specific limitations exist in the use of some K⁺ channel inhibitors. A combination of K⁺ current inhibition during the action potential plateau, with sodium channel inhibition that collectively result in delaying repolarisation and post-repolarisation refractoriness is likely to be valuable in prolonging effective refractory period and wavelength for re-entry. Genotype-specific K⁺ channel inhibition is limited by a lack of targeted inhibitors in clinical use, though experimentally available selective inhibitors now exist. The relatively low proportion of successfully genotyped cases justifies an exome or genome sequencing approach, to reveal new mediators and targets, as demonstrated recently for SLC4A3 in SQT8.     

The launch of opicapone for Parkinson’s disease: negatives versus positives

Introduction: Opicapone is a novel, third generation COMT inhibitor approved for the treatment of Parkinson’s disease. Safety and tolerability data is critical to determine the benefit-harm balance and anticipate therapeutic adherence.

Areas covered: This review evaluates the tolerability and safety profile of opicapone. These data were extracted from all published clinical trials, including preclinical, phase I, phase II and phase III studies as well as postmarketing data. Opicapone was safe and well tolerated, with frequencies of treatment-emergent adverse events similar to placebo.

Expert opinion: Opicapone have shown a good safety and tolerability profile. This adds to its proven efficacy and convenient once-daily administration, supporting a role of opicapone as a first-line therapy for motor complications in Parkinson’s disease patients.     

Antibody-functionalized polymer nanoparticle leading to memory recovery in Alzheimer's disease-like transgenic mouse model

Alzheimer's disease (AD) is a neurodegenerative disorder related, in part, to the accumulation of amyloid-β peptide (Aβ) and especially the Aβ peptide 1-42 (Aβ_1-42). The aim of this study was to design nanocarriers able to: (i) interact with the Aβ_1-42 in the blood and promote its elimination through the “sink effect” and (ii) correct the memory defect observed in AD-like transgenic mice. To do so, biodegradable, PEGylated nanoparticles were surface-functionalized with an antibody directed against Aβ_1-42. Treatment of AD-like transgenic mice with anti-Aβ_1-42-functionalized nanoparticles led to: (i) complete correction of the memory defect; (ii) significant reduction of the Aβ soluble peptide and its oligomer level in the brain and (iii) significant increase of the Aβ levels in plasma. This study represents the first example of Aβ_1-42 monoclonal antibody-decorated nanoparticle-based therapy against AD leading to complete correction of the memory defect in an experimental model of AD.     

Assessing the selective therapeutic efficacy of superparamagnetic erlotinib nanoparticles in lung cancer by using quantitative magnetic resonance imaging and a nuclear factor kappa-B reporter gene system

Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are commonly used as the first-line treatment for advanced NSCLC; however, the efficacy of drug delivery remains unknown. Hence, we successfully developed erlotinib-conjugated iron oxide nanoparticles (FeDC-E NPs) as theranostic probe that can potentially provide a new avenue for monitoring drug delivering through noninvasive magnetic resonance imaging. MRI ΔR2* relaxivity measurements offer an opportunity to quantitatively evaluate the uptake of FeDC-E NPs at cellular and tumoral levels. Additionally, NF-κB reporter gene system provides NF-κB activation status monitoring to validate the therapeutic efficiency of FeDC-E NPs. FeDC-E NPs not only inhibit the tumor growth and NF-κB-modulated antiapoptotic mechanism but also trigger extrinsic and intrinsic apoptotic pathways. Taken together, dual functional FeDC-E NPs offer diagnostic and therapeutic benefits against lung cancers, indicating that our presented probe could be applied in clinical.     

Neuroprotective effect of gold nanoparticles composites in Parkinson's disease model

Parkinson’s disease (PD) is second most common neurodegenerative disorder worldwide. Although drugs and surgery can relieve the symptoms of PD, these therapies are incapable of fundamentally treating the disease. For PD patients, over-expression of α-synuclein (SNCA) leads to the death of dopaminergic neurons. This process can be prevented by suppressing SNCA over-expression through RNA interference. Here, we successfully synthesized gold nanoparticles (GNP) composites (CTS@GNP-pDNA-NGF) via the combination of electrostatic adsorption and photochemical immobilization, which could load plasmid DNA (pDNA) and target specific cell types. GNP was transfected into cells via endocytosis to inhibiting the apoptosis of PC12 cells and dopaminergic neurons. Simultaneously, GNP composites are also used in PD models in vivo, and it can successfully cross the blood-brain barrier by contents of GNP in the mice brain. In general, all the works demonstrated that GNP composites have good therapeutic effects for PD models in vitro and in vivo.     

维持性血液透析患者死亡原因及相关因素探讨

目的进一步认识维持性血液透析(MHD)患者的死亡原因,从而采取一体化综合防治措施。方法回顾性分析我院血液透析中心68例患者的临床资料,探讨MHD的死亡原因及相关因素。结果在MHD患者的死因中,尿毒症并发心血管病变死亡占首位(42.85%),其次为并发脑血管病(17.14%)及感染(14.28%)死亡。死亡原因与透析间期体重增长过多、心衰、贫血、高血压、营养不良有关。结论早期充分透析、积极纠正贫血、营养不良、严格控制血压及防治并发症可降低血液透析患者的病死率。     

Microbe-metabolite-host axis,two-way action in the pathogenesis and treatment of human autoimmunity

The role of microorganism in human diseases cannot be ignored. These microorganisms have evolved together with humans and worked together with body's mechanism to maintain immune and metabolic function. Emerging evidence shows that gut microbe and their metabolites open up new doors for the study of human response mechanism. The complexity and interdependence of these microbe-metabolite-host interactions are rapidly being elucidated. There are various changes of microbial levels in models or in patients of various autoimmune diseases (AIDs). In addition, the relevant metabolites involved in mechanism mainly include short-chain fatty acids (SCFAs), bile acids (BAs), and polysaccharide A (PSA). Meanwhile, the interaction between microbes and host genes is also a factor that must be considered. It has been demonstrated that human microbes are involved in the development of a variety of AIDs, including organ-specific AIDs and systemic AIDs. At the same time, microbes or related products can be used to remodel body's response to alleviate or cure diseases. This review summarizes the latest research of microbes and their related metabolites in AIDs. More importantly, it highlights novel and potential therapeutics, including fecal microbial transplantation, probiotics, prebiotics, and synbiotics. Nonetheless, exact mechanisms still remain elusive, and future research will focus on finding a specific strain that can act as a biomarker of an autoimmune disease.     

Amino acid metabolism as drug target in autoimmune diseases

In mammals, amino acid metabolism has evolved to control immune responses. Autoimmune diseases are heterogeneous conditions that involve the breakdown of tolerogenic circuitries and consequent activation of autoreactive immune cells. Therefore, critical enzymes along amino acid degradative pathways may be hijacked to keep in check autoimmunity. We examined here current knowledge of indoleamine 2,3-dioxygenase 1 (IDO1) and arginase 1 (ARG1), the main enzymes catabolizing tryptophan and arginine, respectively, in organ-specific and systemic autoimmune diseases as well as in the development of autoantibodies to therapeutic proteins. At variance with neoplastic contexts, in which it is known to act as a pure immunosuppressive molecule, ARG1 exhibited a protective or pathogenetic profile, depending on the disease. In contrast, in several autoimmune conditions, the bulk of data indicated that drugs capable of potentiating IDO1 expression and activity may represent valuable therapeutic tools and that IDO1-based immunotherapeutic protocols could be more effective if tailored to the genetic profile of individual patients.     

Diabetes drugs in the fight against Alzheimer's disease

Alzheimer’s disease (AD) is the most prevalent form of dementia, particularly in old age subjects. Hyperinsulinemia and insulin resistance, which are known as pathophysiological features of Type 2 Diabetes Mellitus (T2DM), have also been demonstrated to have a significant impact on cognitive impairment. Studies have shown that an altered insulin pathway may interact with amyloid-β protein deposition and tau protein phosphorylation, both leading factors for AD development. Drugs used for T2DM treatment from insulin and metformin through dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists may represent a promising approach to fight AD. With this review from animal to human studies, we aim at responding to the reasons why drugs for diabetes may represent potential treatments for AD.