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The New England Journal of Medicine May 2021A hallmark of Alzheimer's disease is the accumulation of amyloid-β (Aβ) peptide. Donanemab, an antibody that targets a modified form of deposited Aβ, is being... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
A hallmark of Alzheimer's disease is the accumulation of amyloid-β (Aβ) peptide. Donanemab, an antibody that targets a modified form of deposited Aβ, is being investigated for the treatment of early Alzheimer's disease.
METHODS
We conducted a phase 2 trial of donanemab in patients with early symptomatic Alzheimer's disease who had tau and amyloid deposition on positron-emission tomography (PET). Patients were randomly assigned in a 1:1 ratio to receive donanemab (700 mg for the first three doses and 1400 mg thereafter) or placebo intravenously every 4 weeks for up to 72 weeks. The primary outcome was the change from baseline in the score on the Integrated Alzheimer's Disease Rating Scale (iADRS; range, 0 to 144, with lower scores indicating greater cognitive and functional impairment) at 76 weeks. Secondary outcomes included the change in scores on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), the 13-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Inventory (ADCS-iADL), and the Mini-Mental State Examination (MMSE), as well as the change in the amyloid and tau burden on PET.
RESULTS
A total of 257 patients were enrolled; 131 were assigned to receive donanemab and 126 to receive placebo. The baseline iADRS score was 106 in both groups. The change from baseline in the iADRS score at 76 weeks was -6.86 with donanemab and -10.06 with placebo (difference, 3.20; 95% confidence interval, 0.12 to 6.27; P = 0.04). The results for most secondary outcomes showed no substantial difference. At 76 weeks, the reductions in the amyloid plaque level and the global tau load were 85.06 centiloids and 0.01 greater, respectively, with donanemab than with placebo. Amyloid-related cerebral edema or effusions (mostly asymptomatic) occurred with donanemab.
CONCLUSIONS
In patients with early Alzheimer's disease, donanemab resulted in a better composite score for cognition and for the ability to perform activities of daily living than placebo at 76 weeks, although results for secondary outcomes were mixed. Longer and larger trials are necessary to study the efficacy and safety of donanemab in Alzheimer's disease. (Funded by Eli Lilly; TRAILBLAZER-ALZ ClinicalTrials.gov number, NCT03367403.).
Topics: Activities of Daily Living; Administration, Intravenous; Aged; Alzheimer Disease; Brain Edema; Cognition; Disease Progression; Double-Blind Method; Epitopes; Female; Humans; Male; Mental Status and Dementia Tests; Plaque, Amyloid; Pyrrolidonecarboxylic Acid; Severity of Illness Index
PubMed: 33720637
DOI: 10.1056/NEJMoa2100708 -
Expert Review of Neurotherapeutics 2016Adult Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent psychiatric condition associated with high disability and frequent comorbidity. Current standard... (Review)
Review
Adult Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent psychiatric condition associated with high disability and frequent comorbidity. Current standard pharmacotherapy (methylphenidate and atomoxetine) improves ADHD symptoms in the short-term, but poor data were published about long-term treatment. In addition a number of patients present partial or no response to methylphenidate and atomoxetine. Research into the main database sources has been conducted to obtain an overview of alternative pharmacological approaches in adult ADHD patients. Among alternative compounds, amphetamines (mixed amphetamine salts and lisdexamfetamine) have the most robust evidence of efficacy, but they may be associated with serious side effects (e.g. psychotic symptoms or hypertension). Antidepressants, particularly those acting as noradrenaline or dopamine enhancers, have evidence of efficacy, but they should be avoided in patients with comorbid bipolar disorder. Finally metadoxine and lithium may be particularly suitable in case of comorbid alcohol misuse or bipolar disorder.
Topics: Adrenergic alpha-Agonists; Adult; Amphetamines; Antidepressive Agents; Attention Deficit Disorder with Hyperactivity; Benzhydryl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Bupropion; Central Nervous System Stimulants; Desipramine; Dopamine Agents; Droxidopa; Drug Combinations; Duloxetine Hydrochloride; Guanfacine; Histamine Agents; Humans; Lisdexamfetamine Dimesylate; Lithium Compounds; Lobeline; Mecamylamine; Memantine; Modafinil; Morpholines; Nicotinic Agonists; Nicotinic Antagonists; Nomifensine; Paroxetine; Pyridines; Pyridoxine; Pyrrolidonecarboxylic Acid; Quinazolinones; Reboxetine; Venlafaxine Hydrochloride; Wakefulness-Promoting Agents
PubMed: 26693882
DOI: 10.1586/14737175.2016.1135735 -
Italian Journal of Pediatrics Oct 2021Recurrent respiratory infections (RRIs) are a common clinical condition in children, in fact about 25% of children under 1 year and 6% of children during the first...
Recurrent respiratory infections (RRIs) are a common clinical condition in children, in fact about 25% of children under 1 year and 6% of children during the first 6 years of life have RRIs. In most cases, infections occur with mild clinical manifestations and the frequency of episodes tends to decrease over time with a complete resolution by 12 years of age. However, RRIs significantly reduce child and family quality of life and lead to significant medical and social costs.Despite the importance of this condition, there is currently no agreed definition of the term RRIs in the literature, especially concerning the frequency and type of infectious episodes to be considered. The aim of this consensus document is to propose an updated definition and provide recommendations with the intent of guiding the physician in the complex process of diagnosis, management and prevention of RRIs.
Topics: Adenoidectomy; Adjuvants, Immunologic; Administration, Intranasal; Algorithms; Antibiotic Prophylaxis; Antioxidants; Child; Complementary Therapies; Humans; Hyaluronic Acid; Influenza Vaccines; Pneumococcal Vaccines; Prebiotics; Probiotics; Pyrrolidonecarboxylic Acid; Recurrence; Respiratory Tract Infections; Resveratrol; Thiazolidines; Tonsillectomy; Vitamins
PubMed: 34696778
DOI: 10.1186/s13052-021-01150-0 -
Nutrients Aug 2020Magnesium deficiency may occur for several reasons, such as inadequate intake or increased gastrointestinal or renal loss. A large body of literature suggests a... (Review)
Review
Magnesium deficiency may occur for several reasons, such as inadequate intake or increased gastrointestinal or renal loss. A large body of literature suggests a relationship between magnesium deficiency and mild and moderate tension-type headaches and migraines. A number of double-blind randomized placebo-controlled trials have shown that magnesium is efficacious in relieving headaches and have led to the recommendation of oral magnesium for headache relief in several national and international guidelines. Among several magnesium salts available to treat magnesium deficiency, magnesium pidolate may have high bioavailability and good penetration at the intracellular level. Here, we discuss the cellular and molecular effects of magnesium deficiency in the brain and the clinical evidence supporting the use of magnesium for the treatment of headaches and migraines.
Topics: Administration, Oral; Biological Availability; Dietary Supplements; Headache; Humans; Magnesium; Magnesium Deficiency; Migraine Disorders; Pyrrolidonecarboxylic Acid; Randomized Controlled Trials as Topic
PubMed: 32878232
DOI: 10.3390/nu12092660 -
JAMA Neurology Oct 2022β-amyloid plaques and neurofibrillary tau deposits biologically define Alzheimer disease. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
β-amyloid plaques and neurofibrillary tau deposits biologically define Alzheimer disease.
OBJECTIVE
To perform post hoc analyses of amyloid reduction after donanemab treatment and assess its association with tau pathology and clinical measures.
DESIGN, SETTING, AND PARTICIPANTS
The Study of LY3002813 in Participants With Early Symptomatic Alzheimer's Disease (TRAILBLAZER-ALZ) was a phase 2, placebo-controlled, randomized clinical trial conducted from December 18, 2017, to December 4, 2020, with a double-blind period of up to 76 weeks and a 48-week follow-up period. The study was conducted at 56 centers in the US and Canada. Enrolled were participants from 60 to 85 years of age with gradual and progressive change in memory function for 6 months or more, early symptomatic Alzheimer disease, elevated amyloid, and intermediate tau levels.
INTERVENTIONS
Donanemab (an antibody specific for the N-terminal pyroglutamate β-amyloid epitope) dosing was every 4 weeks: 700 mg for the first 3 doses, then 1400 mg for up to 72 weeks. Blinded dose-reduction evaluations occurred at 24 and 52 weeks based on amyloid clearance.
MAIN OUTCOMES AND MEASURES
Change in amyloid, tau, and clinical decline after donanemab treatment.
RESULTS
The primary study randomized 272 participants (mean [SD] age, 75.2 [5.5] years; 145 female participants [53.3%]). The trial excluded 1683 of 1955 individuals screened. The rate of donanemab-induced amyloid reduction at 24 weeks was moderately correlated with the amount of baseline amyloid (Spearman correlation coefficient r, -0.54; 95% CI, -0.66 to -0.39; P < .001). Modeling provides a hypothesis that amyloid would not reaccumulate to the 24.1-centiloid threshold for 3.9 years (95% prediction interval, 1.9-8.3 years) after discontinuing donanemab treatment. Donanemab slowed tau accumulation in a region-dependent manner as measured using neocortical and regional standardized uptake value ratios with cerebellar gray reference region. A disease-progression model found a significant association between percentage amyloid reduction and change on the integrated Alzheimer Disease Rating Scale only in apolipoprotein E (APOE) ε4 carriers (95% CI, 24%-59%; P < .001).
CONCLUSIONS AND RELEVANCE
Results of post hoc analyses for donanemab-treated participants suggest that baseline amyloid levels were directly associated with the magnitude of amyloid reduction and inversely associated with the probability of achieving complete amyloid clearance. The donanemab-induced slowing of tau was more pronounced in those with complete amyloid clearance and in brain regions identified later in the pathologic sequence. Data from other trials will be important to confirm aforementioned observations, particularly treatment response by APOE ε4 status.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03367403.
Topics: Aged; Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Amyloidosis; Apolipoprotein E4; Epitopes; Female; Humans; Infant; Plaque, Amyloid; Positron-Emission Tomography; Pyrrolidonecarboxylic Acid; tau Proteins
PubMed: 36094645
DOI: 10.1001/jamaneurol.2022.2793 -
Nature Medicine Apr 2019Cancer cells can evade immune surveillance through the expression of inhibitory ligands that bind their cognate receptors on immune effector cells. Expression of...
Cancer cells can evade immune surveillance through the expression of inhibitory ligands that bind their cognate receptors on immune effector cells. Expression of programmed death ligand 1 in tumor microenvironments is a major immune checkpoint for tumor-specific T cell responses as it binds to programmed cell death protein-1 on activated and dysfunctional T cells. The activity of myeloid cells such as macrophages and neutrophils is likewise regulated by a balance between stimulatory and inhibitory signals. In particular, cell surface expression of the CD47 protein creates a 'don't eat me' signal on tumor cells by binding to SIRPα expressed on myeloid cells. Using a haploid genetic screen, we here identify glutaminyl-peptide cyclotransferase-like protein (QPCTL) as a major component of the CD47-SIRPα checkpoint. Biochemical analysis demonstrates that QPCTL is critical for pyroglutamate formation on CD47 at the SIRPα binding site shortly after biosynthesis. Genetic and pharmacological interference with QPCTL activity enhances antibody-dependent cellular phagocytosis and cellular cytotoxicity of tumor cells. Furthermore, interference with QPCTL expression leads to a major increase in neutrophil-mediated killing of tumor cells in vivo. These data identify QPCTL as a novel target to interfere with the CD47 pathway and thereby augment antibody therapy of cancer.
Topics: Aminoacyltransferases; Animals; Antigens, Differentiation; CD47 Antigen; Cell Line, Tumor; Cell Membrane; Humans; Immunotherapy; Mice, Transgenic; Neoplasms; Opsonin Proteins; Pyrrolidonecarboxylic Acid; Receptors, Immunologic
PubMed: 30833751
DOI: 10.1038/s41591-019-0356-z -
QJM : Monthly Journal of the... Aug 2019
Topics: Acetaminophen; Acidosis; Aged; Analgesics, Non-Narcotic; Humans; Male; Pain Management; Pyrrolidonecarboxylic Acid
PubMed: 31086977
DOI: 10.1093/qjmed/hcz107 -
Minerva Pediatrica Oct 2020The rising incidence of allergic disease requires more specific, effective and safe therapeutic strategies. In this regard, several kinds of biologically active... (Review)
Review
The rising incidence of allergic disease requires more specific, effective and safe therapeutic strategies. In this regard, several kinds of biologically active substances, commonly known as immunostimulants, have been introduced for the prevention and treatment of allergic diseases in pediatric population. Among the heterogeneous group of biologically active molecules to date available, pidotimod (Axil, Valeas S.p.A, Milan) is proved to be able to ameliorate both innate and adaptive immunity and enhances the immune system properties often impaired in patients with allergic disorders.
Topics: Adaptive Immunity; Adjuvants, Immunologic; Adolescent; Asthma; Child; Child, Preschool; Chronic Urticaria; Dermatitis, Atopic; Desensitization, Immunologic; Food Hypersensitivity; Humans; Hypersensitivity; Immunity, Innate; Immunologic Factors; Pyrrolidonecarboxylic Acid; Rhinitis, Allergic; Thiazolidines
PubMed: 32731733
DOI: 10.23736/S0026-4946.20.05967-8 -
International Journal of Molecular... Jul 2014The single-mutation of genes associated with Alzheimer's disease (AD) increases the production of Aβ peptides. An elevated concentration of Aβ peptides is prone to... (Review)
Review
The single-mutation of genes associated with Alzheimer's disease (AD) increases the production of Aβ peptides. An elevated concentration of Aβ peptides is prone to aggregation into oligomers and further deposition as plaque. Aβ plaques and neurofibrillary tangles are two hallmarks of AD. In this review, we provide a broad overview of the diverses sources that could lead to AD, which include genetic origins, Aβ peptides and tau protein. We shall discuss on tau protein and tau accumulation, which result in neurofibrillary tangles. We detail the mechanisms of Aβ aggregation, fibril formation and its polymorphism. We then show the possible links between Aβ and tau pathology. Furthermore, we summarize the structural data of Aβ and its precursor protein obtained via Nuclear Magnetic Resonance (NMR) or X-ray crystallography. At the end, we go through the C-terminal and N-terminal truncated Aβ variants. We wish to draw reader's attention to two predominant and toxic Aβ species, namely Aβ4-42 and pyroglutamate amyloid-beta peptides, which have been neglected for more than a decade and may be crucial in Aβ pathogenesis due to their dominant presence in the AD brain.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Cholinesterase Inhibitors; Humans; Nootropic Agents; Protein Isoforms; Pyrrolidonecarboxylic Acid; tau Proteins
PubMed: 25032844
DOI: 10.3390/ijms150712631 -
Analytical Biochemistry Oct 2020α-Ketoglutaramic acid (KGM, α-ketoglutaramate), also known as 2-oxoglutaramic acid (OGM, 2-oxoglutaramate), is a substrate of ω-amidase, also known as Nitrilase 2...
α-Ketoglutaramic acid (KGM, α-ketoglutaramate), also known as 2-oxoglutaramic acid (OGM, 2-oxoglutaramate), is a substrate of ω-amidase, also known as Nitrilase 2 (NIT2), and is essential for studying the canonical role of ω-amidase, as well as its role in multiple diseases. Until now, KGM used for biological studies has been prepared most often by the enzymatic oxidation of l-glutamine using snake venom l-amino acid oxidase, which provides KGM as an aqueous solution, containing by-products including 5-oxoproline and α-ketoglutarate. The enzymatic method for KGM preparation, therefore, cannot provide pure product or an accurate percent yield evaluation. Here, we report a synthetic method for the preparation of this important substrate, KGM, in 3 steps, from l-2-hydroxyglutaramic acid, in pure form, in 53% overall yield.
Topics: Amidohydrolases; Aminohydrolases; Animals; Catalysis; Glutamates; Glutamine; Ketoglutaric Acids; L-Amino Acid Oxidase; Pyrrolidonecarboxylic Acid; Snake Venoms
PubMed: 32771374
DOI: 10.1016/j.ab.2020.113862