The Experts below are selected from a list of 57 Experts worldwide ranked by ideXlab platform

D E Moss - One of the best experts on this subject based on the ideXlab platform.

  • cholinesterase inhibitor therapy in alzheimer s disease the limits and tolerability of irreversible cns selective acetylcholinesterase inhibition in primates
    Journal of Alzheimer's Disease, 2016
    Co-Authors: D E Moss, Ruth G Perez, Haruo Kobayashi
    Abstract:

    Irreversible acetylcholinesterase (AChE) inhibition accumulates to high levels in the central nervous system (CNS) because AChE turnover in the brain is much slower than in peripheral tissues. As expected from this CNS selectivity, the irreversible AChE inhibitor Methanesulfonyl Fluoride (MSF) produces significant cognitive improvement in Alzheimer's disease patients without the gastrointestinal toxicity that plagues other AChE inhibitors. However, without dose-limiting gastrointestinal toxicity, one shortcoming of the prior human studies of MSF is that the upper limits of CNS AChE inhibition that might be tolerated could not be tested. Therefore, in this study, monkeys were treated with escalating intramuscular (IM) doses of MSF that culminated with several weeks of 1.5 mg/kg dosing, more than eight times the prior human clinical dose, still without signs of toxicity. Brain biopsies showed that ∼80% AChE inhibition had been produced and that the new synthesis of cortical AChE had a half-time (t1/2) of ∼12 days. A single IM dose of 1.5 mg/kg MSF produced ∼59% inhibition in cerebrospinal fluid (CSF) AChE as measured one day later. This corresponds to a peak of ∼80% inhibition in CSF AChE at the time of the injection, recovering with a t1/2 of 2.4 days. Computational analyses suggest that MSF at clinically relevant doses could theoretically produce a steady-state AChE inhibition between 65% and 85% in the CNS. These data suggest that the full therapeutic advantage of AChE inhibition therapy can be realized without interference from dose-limiting gastrointestinal toxicity if an irreversible inhibitor is employed.

  • a randomized phase i study of Methanesulfonyl Fluoride an irreversible cholinesterase inhibitor for the treatment of alzheimer s disease
    British Journal of Clinical Pharmacology, 2013
    Co-Authors: D E Moss, Isabel C Sumaya, Ruggero G Fariello, Jorg Sahlmann, Federica Pericle, Enrico Braglia
    Abstract:

    Aims To ascertain the tolerability profile of single and repeated oral doses of Methanesulfonyl Fluoride (MSF, SNX-001) in healthy aged subjects, and to determine the degree of erythrocyte acetylcholinesterase (AChE) inhibition induced by MSF after single and repeated oral doses. Methods To calculate properly the kinetics and the duration of AChE inhibition, the effects of MSF were also studied in rodents. These experiments suggested that MSF administered three times per week should provide safe and efficacious AChE inhibition. In a randomized placebo-controlled phase I study, 3.6 mg, 7.2 mg or 10.8 mg MSF were then orally administered to 27 consenting healthy volunteers (aged 50 to 72 years). After a single dose phase and a 1 week wash-out period, the subjects received the same doses three times per week for 2 weeks. Results Twenty-two out of the 27 subjects completed the study. Four patients withdrew due to adverse events (AEs) and one for non-compliance. Erythrocyte AChE was inhibited by a total of 33%, 46%, and 62% after 2 weeks of 3.6 mg, 7.2 mg and 10.8 mg MSF, respectively. No serious AEs occurred. The most frequent AEs were headache (27%), nausea (11%) and diarrhoea (8%). Conclusions MSF proved to be well tolerated even with repeated oral dosing. It is estimated that MSF provided a degree of AChE inhibition that should effectively enhance memory. This molecule deserves to be tested for efficacy in a pilot randomized controlled study in patients with Alzheimer's disease.

  • in utero Methanesulfonyl Fluoride differentially affects learning and maze performance in the absence of long lasting cholinergic changes in the adult rat
    Pharmacology Biochemistry and Behavior, 2008
    Co-Authors: Luis M Carcoba, D E Moss, Miguel Santiago, Rafael Cabeza
    Abstract:

    There is increasing evidence that acetylcholinesterase (AChE) may have various specific developmental roles in brain development. Nevertheless, specific effects of AChE inhibition during early brain development have not been adequately described. Therefore, Methanesulfonyl Fluoride (MSF), an irreversible AChE inhibitor that shows high selectivity for the CNS was used to produce AChE inhibition in utero to study subsequent adult behaviors, sleep, and cholinergic markers. Rats exposed to MSF in utero showed a deficit in spatial learning tasks using appetitive motivation but, surprisingly, they performed equally well or better than controls when aversive motivation was used. One hypothesis was that MSF treatment in utero affected the response to stress. Tests of anxiety however showed no differences in basal levels of anxiety. Studies of sleep behavior, however, indicated a higher level of REM sleep which is only seen during the light phase of male rats exposed to MSF in utero as compared to controls. No differences in cholinergic markers in the brains of adults were found except that females exposed to MSF in utero had a higher level of ChAT activity in the synaptosomal fraction of the hippocampus. Even so, whether cholinergic alterations accompany the in utero MSF exposure remains to be determined. The failure to find widespread changes in cholinergic markers in the adult brains suggests changes in behaviors should be further investigated by testing the participation of postsynaptic mechanisms, measuring of cholinergic markers during earlier development periods and the possible participation of other neurotransmitter systems to clearly reveal the role of the cholinergic system following in utero MSF exposure.

  • prenatal exposure to the acetylcholinesterase inhibitor Methanesulfonyl Fluoride alters forebrain morphology and gene expression
    Developmental Brain Research, 2005
    Co-Authors: Donna M Byers, D E Moss, Louis N Irwin, Isabel C Sumaya, Christine F Hohmann
    Abstract:

    Methanesulfonyl Fluoride (MSF) is a CNS-selective acetylcholinesterase (AChE) inhibitor, currently being developed and tested for the treatment of symptoms of Alzheimer's disease. We have previously confirmed that a single in utero exposure to MSF at clinically appropriate doses inhibits AChE activity in fetal rat brain by 20%, and when administered throughout gestation, MSF achieves a 40% level of inhibition. Here, we show that rats chronically exposed in utero to MSF display marked sex-specific differences in morphological development of the cerebral cortical layers compared with controls at 7 days of age. Forebrain size and cortical thickness were increased in females and decreased in males. An analysis of gene expression in neonate brain on the day of birth revealed sex-specific differential expression of over 25 genes, including choline acetyltransferase (ChAT), which were affected by prenatal MSF exposure. Many of these genes are associated with sexual differentiation and brain development, while others are involved in more generalized cellular and metabolic processes. The changes observed in cortical morphology and gene expression suggest a critical developmental role for AChE in the fetal nervous system, most likely through its effect on cholinergic neurotransmission.

  • Methanesulfonyl Fluoride an acetylcholinesterase inhibitor attenuates simple learning and memory deficits in ischemic rats
    Brain Research, 2005
    Co-Authors: Cesario V Borlongan, Isabel C Sumaya, D E Moss
    Abstract:

    Abstract Methanesulfonyl Fluoride (MSF), a highly selective CNS inhibitor of acetylcholinesterase, has been recently demonstrated to promote improvement in cognitive performance in patients with senile dementia of Alzheimer type. Because a similar cognitive impairment may accompany stroke, we investigated in the present study whether treatment with MSF could produce beneficial effects in adult rats subjected to an experimental stroke model. Sprague–Dawley rats received transient 60 min intraluminal occlusion of the right middle cerebral artery (MCAo) and were given i.p. injections of either MSF (1 mg/kg at 24 and 48 h post-MCAo and 0.3 mg/kg thereafter every other day) or the vehicle, peanut oil, for 4 weeks. Behavioral tests and biochemical assays were performed at 28 days post-surgery. MSF treatment produced about 90% inhibition of acetylcholinesterase in the brain. Ischemic animals that received the vehicle displayed significant elevated body swing biased activity (84.8 ± 10%) and significantly prolonged acquisition (398 ± 62 s) and shortened retention (79 ± 26 s) of the passive avoidance task. Interestingly, while the ischemic animals that received the MSF exhibited elevated body swing biased activity (87.7 ± 8%), they performed significantly better in the passive avoidance task (255 ± 36 s and 145 ± 18 s in acquisition and retention) than the vehicle-treated animals. Moreover, whereas brains from both groups of animals revealed similar extent and degree of cerebral infarction, the MSF-treated ischemic animals showed more intense immunoreactivity, as well as a significantly higher number (10–15% increase) of septal choline acetyltransferase-positive cells than the vehicle-treated ischemic animals. These results show that MSF, possibly by preserving a functional cholinergic system, attenuated stroke-induced deficits in a simple learning and memory task.

David H Malin - One of the best experts on this subject based on the ideXlab platform.

  • chronic Methanesulfonyl Fluoride enhances one trial per day reward learning in aged rats
    Neurobiology of Aging, 1993
    Co-Authors: David H Malin, Robert E Plotner, Sarah J Radulescu, Robert N Ferebee, Ronald J Lake, Pilar G Negrete, Peggy J Schaefer, Marie K Crothers, D E Moss
    Abstract:

    Abstract Aged (24-months-old) rats were treated chronically with Methanesulfonyl Fluoride (MSF), an acetylcholinesterase (AChE) inhibitor with selectivity for central nervous system AChE, or with injection vehicle alone. Twelve 0.22 mg/kg IP injections were given over 4 weeks. MSF rats showed significantly greater speed and accuracy on a 1 trial/day discriminative reward learning task. The chronic MSF treatment resulted in a 56% decrease in brain AChE activity but no discemable locomotor side effects and no liver damage as indicated by aspartate transferase activity.

  • Methanesulfonyl Fluoride enhances one trial reward learning in mid aged rats
    Neurobiology of Aging, 1991
    Co-Authors: David H Malin, Patricia J Toups, Linda D Osgood, David Fowler, Christopher L Hunter, Kanne R Arcangeli, D E Moss
    Abstract:

    In previous studies, 18-month-old rats have shown no significant retention 24 hours after the single acquisition trial in a one-trial discriminative reward learning task. In the present study, ten 18-month-old rats pretreated with 0.5 mg/kg MSF IP showed significantly better retention in terms of speed and errors than eleven 18-month-old rats pretreated with injection vehicle alone. However, twelve two-three-month-old rats pretreated with the same dose of MSF failed to show better retention than eleven two-three-month-old rats pretreated with vehicle alone.

Hisao Kato - One of the best experts on this subject based on the ideXlab platform.

  • a kinetic analysis of the interaction of human recombinant tissue factor pathway inhibitor with factor xa utilizing an immunoassay and the effect of antithrombin iii heparin on the complex formation
    Thrombosis Research, 1998
    Co-Authors: Yuichi Kamikubo, Tsutomu Hamuro, Sumiyo Takemoto, Yo Nakahara, Shintaro Kamei, Tomohiro Nakagaki, Seiji Miyamoto, Akinobu Funatsu, Hisao Kato
    Abstract:

    We have recently shown that a complex formation of tissue factor pathway inhibitor (TFPI) and factor Xa (Xa) promotes a clearance of proteoglycans-associated TFPI. In the current studies, the interaction between human recombinant TFPI (h-rTFPI) and Xa were kinetically analyzed by utilizing both a protease inhibitor, p-(amidophenyl) Methanesulfonyl Fluoride hydrochloride, and a specific enzyme-linked immunosorbent assay for the complex of h-rTFPI with Xa. We further investigated the effect of antithrombin III on the complex formation between h-rTFPI and Xa. We found that the h-rTFPI/Xa complex formed in a time-dependent manner: the second-order rate constant (K1) for the complex formation was calculated to be 0.86×106 M−1s−1. The addition of antithrombin III to the h-rTFPI solution modestly reduced the rate of the complex formation between h-rTFPI and Xa. Heparin strikingly enhanced antithrombin III’s inhibition of Xa and resulted in complete abrogation of the complex formation between h-rTFPI and Xa in the absence or presence of acidic phospholipids. Furthermore, antithrombin III induced dissociation of the preformed h-rTFPI/Xa complex in the presence of heparin. These results suggest that in the presence of heparin, antithrombin III interferes with the catabolism of TFPI mediated via Xa.

Enrico Braglia - One of the best experts on this subject based on the ideXlab platform.

  • a randomized phase i study of Methanesulfonyl Fluoride an irreversible cholinesterase inhibitor for the treatment of alzheimer s disease
    British Journal of Clinical Pharmacology, 2013
    Co-Authors: D E Moss, Isabel C Sumaya, Ruggero G Fariello, Jorg Sahlmann, Federica Pericle, Enrico Braglia
    Abstract:

    Aims To ascertain the tolerability profile of single and repeated oral doses of Methanesulfonyl Fluoride (MSF, SNX-001) in healthy aged subjects, and to determine the degree of erythrocyte acetylcholinesterase (AChE) inhibition induced by MSF after single and repeated oral doses. Methods To calculate properly the kinetics and the duration of AChE inhibition, the effects of MSF were also studied in rodents. These experiments suggested that MSF administered three times per week should provide safe and efficacious AChE inhibition. In a randomized placebo-controlled phase I study, 3.6 mg, 7.2 mg or 10.8 mg MSF were then orally administered to 27 consenting healthy volunteers (aged 50 to 72 years). After a single dose phase and a 1 week wash-out period, the subjects received the same doses three times per week for 2 weeks. Results Twenty-two out of the 27 subjects completed the study. Four patients withdrew due to adverse events (AEs) and one for non-compliance. Erythrocyte AChE was inhibited by a total of 33%, 46%, and 62% after 2 weeks of 3.6 mg, 7.2 mg and 10.8 mg MSF, respectively. No serious AEs occurred. The most frequent AEs were headache (27%), nausea (11%) and diarrhoea (8%). Conclusions MSF proved to be well tolerated even with repeated oral dosing. It is estimated that MSF provided a degree of AChE inhibition that should effectively enhance memory. This molecule deserves to be tested for efficacy in a pilot randomized controlled study in patients with Alzheimer's disease.

Medicherla V Jagannadham - One of the best experts on this subject based on the ideXlab platform.

  • carnein a serine protease from noxious plant weed ipomoea carnea morning glory
    Journal of Agricultural and Food Chemistry, 2007
    Co-Authors: Ashok Kumar Patel, Vijay K Singh, Medicherla V Jagannadham
    Abstract:

    A new serine protease from the latex of Ipomoea carnea spp. fistulosa (Morning glory), belonging to the Convolvulaceae family, was purified to homogeneity by ammonium sulfate fractionation followed by cation exchange chromatography. The enzyme, named carnein, has a molecular mass of 80.24 kDa (matrix-assisted laser desorption/ionization time-of-flight) and an isoelectric point of pH 5.6. The pH and temperature optima for proteolytic activity were 6.5 and 65 °C, respectively. The extinction coefficient (280 1% ) of the enzyme was estimated as 37.12, and the protein molecule consists of 35 tryptophan, 76 tyrosine, and seven cysteine residues. The effect of several inhibitors such as iodoacetic acid, diisopropylfluorophosphate, phenyl-Methanesulfonyl Fluoride, chymostatin, soybean trypsin inhibitor, HgCl2 ,3 S-3-(N-{(S)-1-[N-(4-guanidinobutyl)carbamoyl]3-ethylbutyl}carbamoyl)oxirane-2carboxylic acid, N-ethyl maleimide, ethylene glycol-bis(R-amino ethyl ether)tetraacetic acid, ethylenediamminetetraacetic acid, and o-phenonthroline indicates that carnein belongs to the family of serine proteases. The enzyme is not prone to autolysis even at very low concentrations. The N-terminal sequence of carnein (T-T-H-S-P-E-F-L-G-L-A-E-S-S-G-L-X-P-N-S) exhibited considerable similarity to those of other plant serine proteases; the highest similarity was with alnus AG12, one of the subtilase family endopepetidases.