ABSTRACT
INTRODUCTION: We report the effects of plasma exchange (PE) with albumin replacement on neuropsychological, neuropsychiatric, and quality-of-life (QoL) outcomes in mild-to-moderate Alzheimer's disease (AD) patients in a phase 2b/3 trial (Alzheimer's Management by Albumin Replacement [AMBAR] study). METHODS: Three hundred forty-seven patients were randomized into placebo (sham-PE) and three PE-treatment arms with low/high doses of albumin, with/without intravenous immunoglobulin (IVIG). Specific test measurements were performed at baseline; month 2 (weekly conventional PE); months 6, 9, and 12 (monthly low-volume PE [LVPE]); and month 14. RESULTS: The PE-treated mild-AD cohort improved their language fluency and processing speed versus placebo at month 14 (effect sizes: >100%; P-values: .03 to .001). The moderate-AD cohort significantly improved short-term verbal memory (effect sizes: 94% to >100%; P-values: .02 to .003). The progression of the neuropsychiatric symptoms of PE-treated was similar to placebo. Mild-AD patients showed improved QoL (P-values: .04 to .008). DISCUSSION: PE-treated AD patients showed improvement in memory, language abilities, processing speed, and QoL-AD. No worsening of their psychoaffective status was observed.
Subject(s)
Alzheimer Disease , Plasma Exchange , Humans , Albumins , Alzheimer Disease/diagnosis , Alzheimer Disease/therapy , Methacrylates , Neuropsychological Tests , Quality of Life/psychologyABSTRACT
INTRODUCTION: This phase 2b/3 trial examined the effects of plasma exchange (PE) in patients with mild-to-moderate Alzheimer's disease (AD). METHODS: Three hundred forty-seven patients (496 screened) were randomized (1:1:1:1) into three PE treatment arms with different doses of albumin and intravenous immunoglobulin replacement (6-week period of weekly conventional PE followed by a 12-month period of monthly low-volume PE), and placebo (sham). RESULTS: PE-treated patients performed significantly better than placebo for the co-primary endpoints: change from baseline of Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL; P = .03; 52% less decline) with a trend for Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog; P = .06; 66% less decline) scores at month 14. Moderate-AD patients (baseline Mini-Mental State Examination [MMSE] 18-21) scored better on ADCS-ADL (P = .002) and ADAS-Cog (P = .05), 61% less decline both. There were no changes in mild-AD patients (MMSE 22-26). PE-treated patients scored better on the Clinical Dementia Rating Sum of Boxes (CDR-sb) (P = .002; 71% less decline) and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) (P < .0001; 100% less decline) scales. DISCUSSION: This trial suggests that PE with albumin replacement could slow cognitive and functional decline in AD, although further studies are warranted.
Subject(s)
Alzheimer Disease/therapy , Plasma Exchange/methods , Aged , Aged, 80 and over , Albumins/administration & dosage , Cognitive Dysfunction , Female , Humans , Immunoglobulins, Intravenous/administration & dosage , Male , Middle AgedABSTRACT
This month's Spotlight on... reviews autoimmune lymphoproliferative syndrome (ALPS) and its treatment. ALPS is an inherited disease caused by defects in lymphocyte apoptosis that cause nonmalignant proliferation of lymphocytes with autoimmune manifestations. Although there is yet no specific treatment for ALPS, therapies selectively targeting lymphocyte apoptosis may open a new avenue in the treatment of this rare disorder.
Subject(s)
Apoptosis/physiology , Autoimmune Diseases/pathology , Lymphocytes/physiology , Lymphoproliferative Disorders/pathology , Animals , Caspase 8/physiology , Humans , Mitochondria/physiologyABSTRACT
Chronicles in Drug Discovery features special interest reports on advances in drug discovery. This month we highlight agents that target and deplete immunosuppressive regulatory T cells, which are produced by tumor cells to hinder innate immunity against, or chemotherapies targeting, tumor-associated antigens. Antiviral treatments for respiratory syncytial virus, a severe and prevalent infection in children, are limited due to their side effect profiles and cost. New strategies currently under clinical development include monoclonal antibodies, siRNAs, vaccines and oral small molecule inhibitors. Recent therapeutic lines for Huntington's disease include gene therapies that target the mutated human huntingtin gene or deliver neuroprotective growth factors and cellular transplantation in apoptotic regions of the brain. Finally, we highlight the antiinflammatory and antinociceptive properties of new compounds targeting the somatostatin receptor subtype sst4, which warrant further study for their potential application as clinical analgesics.
Subject(s)
Drug Discovery , Molecular Targeted Therapy , Analgesics/therapeutic use , Animals , Antiviral Agents/therapeutic use , Genetic Therapy/methods , Humans , Huntington Disease/genetics , Huntington Disease/therapy , Immunotherapy/methods , Neoplasms/drug therapy , Neoplasms/immunology , Receptors, Somatostatin/agonists , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Viruses/drug effects , Respiratory Syncytial Viruses/pathogenicity , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunologyABSTRACT
INTRODUCTION: Pooled human immunoglobulins (IGs) are prepared from plasma obtained from healthy donors as a concentrated antibody-containing solution. In addition, high-titer IGs (hyperimmune) against a specific pathogen can be obtained from vaccinated or convalescing donors. Currently, IGs can be used for the treatment of a variety of infections for which no specific therapy exists or that remain difficult to treat. Moreover, the recent pathogen outbreaks for which there is no approved treatment have renewed attention to the role of convalescent plasma and IGs. Areas covered: In this review, a historical perspective of the use of sera and IGs in humans as anti-infective agents (any viral, bacterial, parasitic infection), excluding immunodeficient patients, is presented from early development to the latest clinical studies. A Medline search was conducted to examine the peer-reviewed literature, with no date limits. Expert commentary: Human pooled plasma-derived IG products benefit from the polyclonal response of every individual donor and from the interindividual variability in such response. The trend to increased availability of vaccines for infectious diseases also opens new potential applications of hyperimmune IGs for emerging or re-emerging infectious diseases (e.g.: Ebola, Zika, Dengue), for the prevention and treatment in the general population, healthcare personnel and caregivers.
Subject(s)
Communicable Diseases, Emerging/drug therapy , Hemorrhagic Fever, Ebola/drug therapy , Immune Sera/administration & dosage , Immunization, Passive/methods , Immunoglobulins/therapeutic use , Severe Dengue/drug therapy , Zika Virus Infection/drug therapy , Clinical Trials as Topic , Communicable Diseases, Emerging/immunology , Communicable Diseases, Emerging/prevention & control , Communicable Diseases, Emerging/virology , Convalescence , Dengue Virus/drug effects , Dengue Virus/immunology , Dengue Virus/pathogenicity , Ebolavirus/drug effects , Ebolavirus/immunology , Ebolavirus/pathogenicity , Hemorrhagic Fever, Ebola/immunology , Hemorrhagic Fever, Ebola/prevention & control , Hemorrhagic Fever, Ebola/virology , Humans , Severe Dengue/immunology , Severe Dengue/prevention & control , Severe Dengue/virology , Vaccination , Viral Vaccines/administration & dosage , Viral Vaccines/biosynthesis , Zika Virus/drug effects , Zika Virus/immunology , Zika Virus/pathogenicity , Zika Virus Infection/immunology , Zika Virus Infection/prevention & control , Zika Virus Infection/virologyABSTRACT
Tumor-associated NOX (tNOX) is a novel cell surface ECTO-NOX protein that represents a promising target for selective antitumor therapy. Studies have confirmed the unique presence of tNOX on the cell surface of invasive human cancers and in the sera of cancer patients. Furthermore, as there is a resolute difference between tNOX and the drug-resistant constitutive NOX isoform constitutive NOX, it represents an attractive target for drug, vaccine and diagnostic strategies for cancer. Interestingly, several products currently utilized or under development for cancer display tNOX inhibition as one of their underlying mechanisms, these include non- steroidal antiinflammatory drugs, (-)-epigallocatechin gallate, phenoxodiol and doxorubicin hydrochloride (Adria- mycin). This spotlight article will also highlight tNOX inhibitors under preclinical development and new lines of research to target tNOX for cancer therapeutics.
Subject(s)
Antineoplastic Agents/therapeutic use , NADH, NADPH Oxidoreductases/drug effects , Neoplasms/drug therapy , Neoplasms/genetics , Drug Delivery Systems , Humans , NADH, NADPH Oxidoreductases/geneticsABSTRACT
Chronicles in Drug Discovery features special interest reports on advances in drug discovery and development. This month we focus on the progress of the ongoing search for safe and effective chemopreventive agents. Chemoprevention is a strategy to decrease the risk of developing cancer by using agents that prevent or abrogate carcinogenic processes. Bowman- Birk inhibitor concentrate, budesonide, NCX-4016 and statins are all undergoing investigation in the clinical setting as potential chemopreventive agents for head and neck, lung, colon and breast cancers, respectively.
Subject(s)
Anticarcinogenic Agents/therapeutic use , Aspirin/analogs & derivatives , Budesonide/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Trypsin Inhibitor, Bowman-Birk Soybean/therapeutic use , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Anticarcinogenic Agents/pharmacology , Aspirin/pharmacology , Aspirin/therapeutic use , Budesonide/pharmacology , Cell Transformation, Neoplastic/drug effects , Chemoprevention , Clinical Trials as Topic , Drug Evaluation, Preclinical , Glucocorticoids/therapeutic use , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Neoplasms/prevention & control , Precancerous Conditions/drug therapy , Trypsin Inhibitor, Bowman-Birk Soybean/pharmacology , Trypsin Inhibitors/therapeutic useABSTRACT
Erectile dysfunction is a common disorder that involves impairment of the vascular endothelium and has been associated with cardiovascular disease. Despite the general effectiveness of phosphodiesterase type 5 (PDE5) inhibitors, some erectile dysfunction patients are resistant to or do not tolerate treatment with them, thus requiring further treatment alternatives. Statins have emerged as a promising therapeutic option due to their multiple modes of action. The use of statins as adjuvant or alternative therapy in erectile dysfunction has opened new avenues for the treatment of this disorder.
Subject(s)
Erectile Dysfunction/drug therapy , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Penile Erection/physiology , Phosphodiesterase Inhibitors/therapeutic use , Cardiovascular Diseases/complications , Drug Synergism , Drug Therapy, Combination , Humans , MaleABSTRACT
Pharmacological strategies aimed at the prevention of thrombotic complications are in continuous development. Argatroban is a synthetic small molecule derived from l-arginine with specific antithrombotic activity. Argatroban is a direct thrombin inhibitor that binds avidly and reversibly to the catalytic site of thrombin and that does not require other cofactors to exert its antithrombotic action. Due to its selective inhibitory mechanism, argatroban blocks both circulating and clot-bound thrombin. A rapid onset of its anticoagulant action is achieved after intravenous administration. The short elimination half-life of argatroban (52+/-16 minutes) ensures a rapid restoration of hemostasis upon cessation of treatment. Argatroban produces a predictable dose response, and its anticoagulant actions can be monitored easily through the routine coagulation tests activated partial thromboplastin time (aPTT) and activated clotting time (ACT). The specific mechanism of action and favorable pharmacokinetic profile of argatroban suggest that it could be beneficial in all indications where other intravenous anticoagulants are used. Results from clinical studies performed to date show that, when administered to patients with heparin-induced thrombocytopenia (HIT) or HIT with thrombosis (HITTS) in two large-scale, nonrandomized, prospective trials, argatroban reduced a combined endpoint of morbidity and mortality when compared with historical controls. Argatroban was well tolerated in clinical trials of patients with HIT and caused no increase in bleeding risk compared with historical controls. Argatroban does not induce the formation of antibodies that can neutralize its anticoagulant effect, prolong its half-life or enhance its activity. The U.S. Food and Drug Administration has approved the use of this drug as an alternative antithrombotic treatment for patients with HIT as well as for patients with or at risk for HIT undergoing percutaneous coronary interventions. In 2004 (Sweden), 2005 (Germany, the Netherlands, Austria and Iceland) and 2006 (Denmark) argatroban was approved for anticoagulation in adult patients with heparin-induced thrombocytopenia type II who require parenteral antithrombotic therapy.
Subject(s)
Anticoagulants/therapeutic use , Intracranial Thrombosis/drug therapy , Pipecolic Acids/therapeutic use , Stroke/drug therapy , Thrombocytopenia/drug therapy , Animals , Anticoagulants/adverse effects , Arginine/analogs & derivatives , Blood Coagulation/drug effects , Drug Monitoring , Humans , Intracranial Thrombosis/blood , Pipecolic Acids/adverse effects , Randomized Controlled Trials as Topic , Stroke/blood , Sulfonamides , Thrombin/antagonists & inhibitors , Thrombocytopenia/blood , Thrombocytopenia/chemically inducedABSTRACT
Cardiovascular disease and major depression are highly prevalent disorders in our society. Evidence has been found that confirms a reciprocal relationship between mechanisms of depression and those of cardiovascular pathology. This possible feedback between both pathologies is a subject of great concern. In recent years some studies suggest that platelets and serotonergic mechanisms could be involved in both conditions. The present review seeks a better understanding of the mechanisms that could link depression with an enhanced cardiovascular risk.
ABSTRACT
Cardiovascular disease and major depression are highly prevalent disorders in our society. Evidence has been found that confirms a reciprocal relationship between mechanisms of depression and those of cardiovascular pathology. This possible feedback between both pathologies is a subject of great concern. In recent years some studies suggest that platelets and serotonergic mechanisms could be involved in both conditions. The present review seeks a better understanding of the mechanisms that could link depression with an enhanced cardiovascular risk.
Subject(s)
Cardiovascular Diseases/etiology , Mood Disorders/complications , Serotonin/physiology , Antidepressive Agents/therapeutic use , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/pathology , Clinical Trials as Topic , Depressive Disorder/complications , Depressive Disorder/drug therapy , Depressive Disorder/metabolism , Humans , Mood Disorders/drug therapy , Mood Disorders/metabolism , Receptors, Serotonin/physiology , Serotonin/metabolism , Serotonin Antagonists/therapeutic use , Serotonin Plasma Membrane Transport Proteins/physiology , Selective Serotonin Reuptake Inhibitors/therapeutic useABSTRACT
BACKGROUND/AIMS: The contact of blood with artificial surfaces may activate blood leukocytes and platelets and initiate the leukocyte inflammatory response. We have investigated the effect of a hemodialysis (HD) with a cellulosic- and a synthetic-based membrane on circulating leukocyte activation. METHODS: Samples were obtained from patients with ESRD at baseline, and at 15 and 120 min of a hemodialysis session from both the arterial and venous lines. Leukocyte respiratory burst was analyzed by luminol chemiluminescence. Actin polymerization, expression of CD11b, and heterotypic aggregation were studied by flow cytometry, leukocyte labeling with NBD phallacidin and monoclonal antibodies, respectively. RESULTS: HD with a cellulosic membrane induced a transient fall in neutrophil (1.2 +/- 0.5 x 10(9) vs. 3.6 +/- 0.6 x 10(9) cells/l; p < 0.05) and monocyte counts (0.2 +/- 0.1 x 10(9) vs. 0.7 +/- 0.1 x 10(9) cells/l; p < 0.05). There was also an increase in respiratory burst in the venous line during a HD with a cellulosic membrane, at 15 and 120 min (100 +/- 41 and 143.2 +/- 45.3 vs. 23.8 +/- 15.7; p < 0.05). Polymerized actin, expressed as fluorescence arbitrary units, was increased in baseline samples from uremic patients versus control subjects (327.8 +/- 60.8 for a cellulosic membrane, p < 0.005, and 205 +/- 26.5 for a synthetic one, p < 0.05 vs. 97.8 +/- 27.6 in controls). The percentage of CD11b+ cells increased in samples during a HD with a cellulosic membrane at the venous line at 15 and 120 min (9.6 +/- 4.5 and 18.4 +/- 7.1% vs. 3.3 +/- 1.9%; p < 0.05%). Changes in heterotypic aggregation during HD did not reach statistical significance, but levels were higher in patients treated with a cellulosic membrane at all points than in patients dialyzed with a synthetic one. CONCLUSION: There is evidence of a priming state of leukocytes from uremic patients, which is more evident in patients dialyzed with a cellulosic membrane. Cellulosic membranes also induce greater leukocyte activation than synthetic membranes during hemodialysis.
Subject(s)
Biocompatible Materials , Leukocytes/physiology , Membranes, Artificial , Adult , Aged , Cellulose , Female , Humans , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/therapy , Male , Middle Aged , Renal Dialysis , Surface PropertiesABSTRACT
BACKGROUND AND OBJECTIVES: The possibility of developing synthetic platelet substitutes is a subject of current interest. We explored the possible hemostatic effect of synthetic phospholipid incorporated in multilamellar vesicles (MLVs) or intermediate unilamellar vesicles (IUVs) using a well-characterized experimental system with circulating human thrombocytopenic blood (10 min, 250 s(-1)). DESIGN AND METHODS: The ability of the liposomes containing different combinations of dipalmitoylphosphatidylcholine (DPPC), phosphatidylethanolamine (PE) and dipalmitoylphosphatidylserine (DPPS) to promote fibrin formation (%F) on the damaged subendothelium was morphometrically evaluated. Generation of thrombin in the system was monitored through prothrombin fragment F1+2 determination. RESULTS: IUV liposomes containing DPPC, 1DPPS:9DPPC, 1DPPS:3DPPC, 1PE:1DPPC increased fibrin deposition on the subendothelium (53.87 +/- 11.0%; 39.76 +/- 6.75%; 40.69 +/- 10.54% and 32.22 +/- 7.35%, respectively vs. thrombocytopenic blood 11.5 +/- 1.2%; p<0.05), while 9PE:1DPPS IUV liposome failed to promote a procoagulant effect. MLV liposomes containing DPPC alone, 1DPPS:3DPPC and 1PE:1DPPC showed a positive effect on fibrin deposition (85.50 +/- 5.95%, 59.86 +/- 11.55% and 43.73 +/- 7.84% respectively; p<0.05). However, no effect was observed in those experiments performed with liposomes containing 3DPPS:1DPPC. After perfusion experiments, the coagulation system became activated, but differences were not statistically significant vs. control experiments, except for MLV liposomes containing DPPC alone (p<0.05). INTERPRETATION AND CONCLUSIONS: These results confirm that, at an experimental level, liposomes containing phospholipids could potentially be used to improve hemostasis in patients with quantitative or qualitative platelet disorders.