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1.
J Prev Alzheimers Dis ; 10(3): 453-463, 2023.
Article in English | MEDLINE | ID: mdl-37357285

ABSTRACT

BACKGROUND: Alzheimer's disease (AD) prevention trials require a large outreach and screening funnel to identify cognitively unimpaired adults who meet the study's inclusion criteria, such as certain clinical or demographic criteria, genetic risk factors, and/or biomarker evidence of the disease. OBJECTIVES: Describe tactics and strategies to identify and enroll cognitively unimpaired adults with one (heterozygotes [HT]) or two (homozygotes [HM]) copies of the APOE ε4 allele, a genetic risk factor for dementia due to AD, into the Alzheimer's Prevention Initiative (API) Generation Program, the largest and only prevention trials for late onset AD using this enrichment technique. DESIGN AND SETTING: The Generation Program was comprised of two global, randomized, double-blind, placebo-controlled, parallel group adaptive design with variable treatment duration clinical trials. Generation Study 1 randomized participants into one of two cohorts: Cohort 1 which evaluated CAD106 vs. placebo or Cohort 2 which evaluated umibecestat vs placebo. Generation Study 2 randomized participants into two doses of umibecestat vs. placebo. The Generation Program was terminated early in 2019, while enrollment was still occurring. PARTICIPANTS: Both Generation Study 1 and Generation Study 2 enrolled cognitively unimpaired APOE ε4 HMs aged 60-75; Generation Study 2 also enrolled APOE ε4 HTs ages 60-75 with elevated brain amyloid. METHODS AND MEASUREMENTS: Describe results of the centralized and localized outreach, recruitment, screening strategies and tactics as well as characteristics of sites successful at enrolling genetically eligible participants, with a particular focus on APOE ε4 HMs given the 2-3% prevalence of this genotype. RESULTS: At the time the trial program was terminated, 35,333 individuals had consented to the optional prescreening ICF1a/ICFA and provided a sample of DNA for APOE genotyping, 1,138 APOE ε4 HMs consented to screening for Generation Study 1 (ICF1b), and 1,626 APOE ε4 carriers were randomized into either Generation Study 1 or Generation Study 2. Genetic testing registries, partnerships with genetic testing/counseling companies, and the optional prescreening ICF1a/ICFA were the most successful strategies for identifying genetically eligible participants for screening. CONCLUSIONS: It is feasible to recruit, screen and randomize cognitively unimpaired APOE ε4 carriers, particularly APOE ε4 HMs for a global AD prevention trial. The Generation Program was on track to complete enrollment by end of 2019. Factors that were key to this success included: working with sites to develop customizable outreach, recruitment, and screening programs specific to their site needs, providing forums for sites to exchange best practices, and developing partnerships between the sponsor team and trial sites.


Subject(s)
Alzheimer Disease , Adult , Humans , Alzheimer Disease/diagnosis , Alzheimer Disease/genetics , Alzheimer Disease/prevention & control , Heterozygote , Apolipoprotein E4/genetics , Random Allocation , Genotype
2.
J Prev Alzheimers Dis ; 4(4): 242-246, 2017.
Article in English | MEDLINE | ID: mdl-29181489

ABSTRACT

Alzheimer's disease pathology begins decades before the onset of clinical symptoms. This provides an opportunity for interventional clinical trials to potentially delay or prevent the onset of cognitive impairment or dementia. CNP520 (a beta-site-amyloid precursor protein-cleaving enzyme inhibitor) is in clinical development for the treatment of preclinical Alzheimer's disease under the Alzheimer's Prevention Initiative Generation Program. The Alzheimer's Prevention Initiative is a public-private partnership intended to accelerate the evaluation of Alzheimer's disease prevention therapies. The Generation Program comprises two pivotal phase II/III studies with similar designs to assess the efficacy and safety of investigational treatments in a cognitively unimpaired population at increased risk for developing Alzheimer's disease based on age and apolipoprotein E (APOE) genotype (i.e., presence of the APOE ε4 allele). The program has been designed to maximize benefit to Alzheimer's disease research. Generation Study 1 (NCT02565511) and Generation Study 2 (NCT03131453) are currently enrolling; their key features are presented here.


Subject(s)
Alzheimer Disease/prevention & control , Enzyme Inhibitors/therapeutic use , Oxazines/therapeutic use , Age Factors , Alzheimer Disease/genetics , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Apolipoprotein E4/genetics , Disease Susceptibility , Humans , Patient Selection , Public-Private Sector Partnerships
3.
Epilepsy Res ; 43(2): 115-24, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11164700

ABSTRACT

OBJECTIVE: This was the first proof of principle clinical trial assessing the efficacy and safety of rufinamide as adjunctive therapy in epileptic patients. The pharmacokinetic (PK) profile of rufinamide was also determined. METHODS: Fifty patients with diagnoses of partial or primary generalized tonic-clonic seizures were enrolled in this 28-day double-blind, placebo-controlled, weekly rising dose (400-1600 mg/day) trial. PK profiles were obtained after administration of single-dose rufinamide prior to and after the Double-blind phase. RESULTS: In the evaluable patient population, seizure frequency decreased by 41% in the rufinamide group and increased by 52% in the placebo group (P=0.040). Thirty-nine percent (39%) of rufinamide-treated and 16% of placebo-treated patients experienced reduction in seizure frequency of at least 50% relative to baseline (P=0.096). SAFETY: Treatment-emergent adverse events (AEs) consisted mainly of neurologic signs and symptoms commonly associated with antiepileptic drugs (AEDs). PHARMACOKINETICS: At steady state, rufinamide reached a peak plasma concentration with a mean time (Tmax) of 3.4 h and a mean half-life (t1/2) of 7.3 h. No autoinduction of rufinamide metabolism occurred. Rufinamide did not influence the plasma concentration of carbamazepine, phenytoin or valproate when added to these single AED regimens. CONCLUSION: Rufinamide has been shown, in this proof of principle trial, to be safe and effective in reducing seizure frequency in epileptic patients with no relevant influence on the metabolism of other AEDs.


Subject(s)
Anticonvulsants/therapeutic use , Epilepsy/drug therapy , Triazoles/therapeutic use , Adult , Anticonvulsants/adverse effects , Anticonvulsants/blood , Double-Blind Method , Drug Therapy, Combination , Female , Half-Life , Humans , Incidence , Male , Middle Aged , Nervous System Diseases/chemically induced , Seizures/epidemiology , Triazoles/adverse effects , Triazoles/blood
4.
Am J Psychiatry ; 156(3): 419-25, 1999 Mar.
Article in English | MEDLINE | ID: mdl-10080558

ABSTRACT

OBJECTIVE: The authors' objective was to assess the potential efficacy of fananserin (RP62203), a potent antagonist at the D4 and serotonin2A (5-HT2A) receptors, on symptoms of schizophrenia. METHOD: A double-blind, placebo-controlled study was conducted in 97 patients. Doses of fananserin reached 250 mg b.i.d. over 28 days, starting with an 8-day escalation. Most of the patients were men with paranoid schizophrenia; they were approximately 38 years old. The primary outcome measure was the total Positive and Negative Syndrome Scale score. The patients' mean score on the Positive and Negative Syndrome Scale at entry was 91.8 (SD=16.5). A low dropout rate was observed in both groups of patients (19 [30%] of those given fananserin and nine [27%] of those given placebo). RESULTS: The total Positive and Negative Syndrome Scale score of the patients given fananserin decreased at endpoint by a mean of 4.2 points (SD=15.4); the score of the patients given placebo decreased by 6.7 points (SD=19.6). No differences between treatments were found on secondary measures such as the Clinical Global Impression, Positive and Negative Syndrome Scale subscores or individual items, and Brief Psychiatric Rating Scale total score. The patients' extrapyramidal symptoms did not worsen during the trial, but the patients given fananserin had an increase in akathisia. The safety profile was good in both groups of patients. CONCLUSIONS: The results of this study do not support the prediction that a selective D4 antagonist associated with strong 5-HT2A antagonism will exhibit an antipsychotic effect.


Subject(s)
Cyclic S-Oxides/therapeutic use , Naphthalenes/therapeutic use , Schizophrenia/drug therapy , Serotonin Antagonists/therapeutic use , Adolescent , Adult , Double-Blind Method , Drug Administration Schedule , Female , Hospitalization , Humans , Male , Patient Dropouts , Placebo Effect , Placebos , Psychiatric Status Rating Scales/statistics & numerical data , Schizophrenia/diagnosis , Schizophrenic Psychology , Treatment Outcome
5.
Cell Mol Biol (Noisy-le-grand) ; 41(2): 289-96, 1995 Mar.
Article in English | MEDLINE | ID: mdl-7787739

ABSTRACT

A comparative study of Nocardia water soluble mitogen (NWSM) action on membrane potential and proliferation rate of murine peritoneal lymphocytes was performed at various incubation times. The membrane surface charge was evaluated by laser doppler velocimetry (LDV) through the measurement of the cell electrophoretic mobility at different pH values (from pH 5 to 9). We demonstrated that NWSM treatment decreases the lymphocyte membrane potential. This variation reached a maximal level after 24 hrs. at pH 7 and remained unchanged during the 72 hrs. observation. A significant stimulation of lymphocyte proliferation was noted after a 24 hrs. incubation. However, the highest rate of [3H]-thymidine incorporation was observed at 48 hrs. with a subsequent decrease at 72 hrs. On the basis of these data, it is suggested, that membrane potential changes may represent an early important step in the mechanism of lymphocyte activation by NWSM, as it has been shown for some mitogenic compounds.


Subject(s)
Cell Division/drug effects , Lymphocyte Activation , Lymphocytes/cytology , Lymphocytes/physiology , Membrane Potentials/drug effects , Mitogens/pharmacology , Animals , Cells, Cultured , DNA/biosynthesis , Hydrogen-Ion Concentration , Kinetics , Lymphocytes/immunology , Male , Mice , Mice, Inbred C3H , Nocardia , Peritoneal Cavity , Thymidine/metabolism
6.
Arch Biochem Biophys ; 306(1): 254-60, 1993 Oct.
Article in English | MEDLINE | ID: mdl-8215412

ABSTRACT

Biochemical properties of the ATPase from the plasma membrane of the cyanobacteria Synechococcus PCC 6311 and PCC 7942 were examined. ATPase activity associated with purified plasma membrane vesicles was strongly inhibited by 100 microM vanadate (87%), 100 microM diethylstilbestrol (70%) and 100 mM fluoride ions (83%). No inhibition was observed in the presence of dicyclohexylcarbodiimide, nitrate, azide, or molybdate. A 50% activation was observed in the presence of 50 mM KCl but none was observed in the presence of NaCl or NH4Cl. This ATPase was able to form a pH gradient, the amplitude of which was decreased by the presence of 100 microM vanadate. On Western blot of the plasmalemma proteins, no labeling was observed with a monoclonal antibody against the beta subunit of the F0-F1 ATPase, although staining was observed with the 55-kDa subunit of the thylakoid membrane ATPase. After phosphorylation of plasmalemma vesicles, by [gamma-32P]ATP, the autoradiograms of the electrophoreses, performed under acid conditions, exhibited labeling of a 110-kDa protein. The results indicated that the Synechococcus plasma membrane ATPase can be classified as a H+ translocating P-type ATPase and compared to the plant plasmalemma ATPase.


Subject(s)
Adenosine Triphosphatases/metabolism , Cyanobacteria/enzymology , Adenosine Triphosphatases/isolation & purification , Blotting, Western , Cell Membrane/enzymology , Chromatography, High Pressure Liquid , Kinetics , Membrane Proteins/isolation & purification , Membrane Proteins/metabolism , Molecular Weight , Phosphoproteins/isolation & purification , Phosphoproteins/metabolism , Phosphorylation , Proton-Translocating ATPases/isolation & purification , Proton-Translocating ATPases/metabolism , Ribonucleotides/metabolism , Substrate Specificity , Vanadates/pharmacology
7.
Arch Biochem Biophys ; 284(1): 1-8, 1991 Jan.
Article in English | MEDLINE | ID: mdl-1989488

ABSTRACT

The role of the divalent cations in the purple membrane is generally understood as the release mechanism of the blue form appearance. The reconstitution by cation addition leads to the recovery of the initial spectral properties. Numerous data are available in the literature on this matter but they are scattered, so that synthetic understanding is not easy. The role of divalent cations was studied through spectrophotometric titrations and electrophoretic mobility measurements, i.e., zeta potential valuations. Thus, correlations between the bacteriorhodopsin (bR) state and the whole membrane in equilibrium with a definite medium could be made. Deionization was not a fully reversible process. The absence of cations affect neither the rate of the M412 formation nor its lifetime but the yield of M412/bR was 50% lower. The number of protons involved in the blue to purple transition of both membranes was different and the reconstitution did not erase this difference. It was observed that the number of protons dissociated upon cation addition corresponded approximately to the number of positive charges removed by deionization. Electrophoretic mobility titrations showed large differences between the membranes, illustrating the influence of the surface charge density on the pK of the transition. Taking advantage of the reversible light adaptation process, the reciprocal influence of the charge density of the membrane surface and the retinal state in bR was shown. Specificity of the divalent cations was questioned by a direct substitution of them by imidazol, which left the membrane intact. The partial reversibility of the deionization, the decrease of the M412 yield, the differences in the titratable protons, and the nonstrict specificity toward divalent cations suggested that another unknown factor could be removed from the membrane.


Subject(s)
Bacteriorhodopsins/physiology , Halobacterium/physiology , Membrane Potentials , Buffers , Calcium/physiology , Cell Membrane/physiology , Hydrogen-Ion Concentration , Imidazoles/chemistry , In Vitro Techniques , Light , Spectrum Analysis , Temperature
8.
Arch Biochem Biophys ; 280(1): 159-66, 1990 Jul.
Article in English | MEDLINE | ID: mdl-2112897

ABSTRACT

Photoautotrophically growing cultures of the freshwater cyanobacterium Anacystis nidulans (Synechococcus sp.) became adapted to the presence of 0.4-0.5 M NaCl in the growth medium (about seawater level) with a lag phase of 2 days after which time the growth rate resumed at 80-90% of the control. Major changes in structure and function of the plasma membranes (and, to a much lesser extent, of the thylakoid membranes) were found to accompany the adaptation process. Plasma and thylakoid membranes were separated from crude cell-free extracts of French pressure cell-treated Anacystis by discontinuous sucrose density gradient centrifugation and purified by repeated recentrifugation on fresh gradients. Concentrations of copper, iron, calcium, and magnesium ions were determined by inductively coupled plasma atomic emission spectrometry with EDTA-washed and dialyzed membrane preparations; salt adaptation was found to increase (decrease) the concentration of membrane-bound calcium in plasma (thylakoid) membranes, qualitatively reciprocal results being obtained for magnesium. Levels of plasma membrane-bound copper and iron roughly tripled during the adaptation process; by contrast, corresponding effects on thylakoid membranes were negligible. The size of the membrane vesicles was measured by quasi-elastic laser light-scattering and the electric surface charge of the membranes was measured by laser Doppler velocimetry. Salt adaptation decreased the mean diameter of plasma membrane vesicles to a much higher extent than that of thylakoid membrane vesicles. Overall surface charge densities of resting vesicles were only slightly affected by the salt treatment as was also seen from titration of the electrophoretic mobility of the vesicles with electrolytes. Yet, induction of (photosynthetic or respiratory) electron transport provoked a charge separation across the membrane which was easily measurable in terms of electrophoretic mobility. The results will be discussed with particular emphasis on the stimulated cytochrome c oxidase activity of plasma (but not thylakoid) membranes from salt-adapted cells compared to control cells and also with respect to the decreased ion permeability of the plasma membrane of salt grown cells.


Subject(s)
Cyanobacteria/physiology , Acclimatization , Cell Fractionation , Cell Membrane/physiology , Cell Membrane/ultrastructure , Cyanobacteria/growth & development , Cyanobacteria/ultrastructure , Intracellular Membranes/physiology , Intracellular Membranes/ultrastructure , Light , Osmolar Concentration , Sodium Chloride/pharmacology
9.
Arch Biochem Biophys ; 277(1): 130-6, 1990 Feb 15.
Article in English | MEDLINE | ID: mdl-2306114

ABSTRACT

Photoionization of hydrophobic probes has been developed in micelles or synthetic vesicles. Studies of the yields, compartmentation, and lifetimes of the photo-produced charged species have gathered reliable information on the interfacial and structural properties of these assemblies. Such an approach has never been applied to biological membranes. The present system is tetramethylbenzidine as the probe in native or modified (deionized and/or bleached) purple membrane from halobacteria. The data on photocation formation yields (phi ion) and lifetimes (tau 1/2) allow two main conclusions to be made: (1) tetramethylbenzidine, as the cation, is buried in the membrane core, and (2) its incorporation does not alter the biological activity of the protein. In this biological membrane the photocation lifetime and yield present the same trend of variation with the surface potential but to less of an extent than in model membranes. Bleaching of purple membrane completely modifies the photoionization process and the photocation decay. In addition, these experiments reveal a tight correlation between membrane structure and probe photoionization. Further evidence for structural modification of purple membrane, either by deionization or by bleaching is pointed out.


Subject(s)
Bacteriorhodopsins/metabolism , Benzidines/metabolism , Membranes/metabolism , Bacteriorhodopsins/radiation effects , Chromogenic Compounds , Halobacterium/metabolism , Kinetics , Models, Biological , Photochemistry , Protein Binding , Spectrometry, Fluorescence , Spectrophotometry, Ultraviolet , Ultraviolet Rays
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