Responders and non-responders to bifemelane hydrochloride in Alzheimer-type and multi-infarct dementia

Shigeta, Masahiro; Nishikawa, Y.; Shimizu, Makoto; Usui, M; Hyoki, Kazushi; Kawamuro, Yu

doi:10.1097/00004850-199300820-00005

Cited by 7 publications

(6 citation statements)

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“…2b). As had been observed in rat astrocytes (6), lower concentration of bifemelane induced a slow onset increase in the [Ca 2+ ] i of human origin astrocytes, but at a concentration of 1000 µM, the drug induced a ] i during the administration, and a second increase during washing of the drug (Fig. 2: a and b).…”

Section: +supporting

confidence: 73%

“…Interestingly, the drug induced rapid onset and highly reversible blocking effects on the SOCC activated in the cells treated with thapsigargin and bathed in normal medium (5). Although the dose required to cause the effect seemed to be much higher than its therapeutic dose, the effects of bifemelane on the [Ca 2+ ] i of astrocytes found in our previous study might have some relationship to the pharmacological and therapeutic efficiency of the drug (6,7).…”

Section: Introductionmentioning

confidence: 67%

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Effects of Bifemelane on the Calcium Level and ATP Release of the Human Origin Astrocyte Clonal Cell

et al. 2006

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Abstract. The effect of bifemelane hydrochloride (bifemelane) was examined on human origin astrocyte clonal cells (Kings-1). Bifemelane (125 -1000 µM) induced a dose-dependent increase in the intracellular calcium concentration ([Ca 2+ ] i ). In the highest concentration (1000 µM), the drug caused the second large increase in [Ca 2+ ] i during the washing. The increase that occurred during the administration partially remained in the Ca 2+-free medium and was blocked by 2-aminoethoxydiphenyl borate (2-APB), an IP 3 -receptor blocker, indicating that the source of Ca ] i induced by bifemelane is not due to its direct effect on the cells, but is dependent upon the ATP released from the cells.

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Section: +supporting

confidence: 73%

Section: Introductionmentioning

confidence: 67%

Effects of Bifemelane on the Calcium Level and ATP Release of the Human Origin Astrocyte Clonal Cell

et al. 2006

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“…Differential responses of patient subpopulations to different treatments were described in the past for various diseases including ALS (Abe et al, 2017;Agnoli et al, 1981;Date et al, 2018;Factor et al, 1989;Fujimori et al, 2018;Morello et al, 2019;Okamoto et al, 2008;Roberts et al, 2014;Shigeta et al, 1993;Venneri et al, 2009). The difficulty is to predict such responses ahead of enrollment into a clinical trial and to determine the best treatment options for patients.…”

Section: Discussionmentioning

confidence: 99%

CuATSM effectively ameliorates ALS patient astrocyte‐mediated motor neuron toxicity in human in vitro models of amyotrophic lateral sclerosis

Dennys

Roussel

Rodrigo

et al. 2022

Glia

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Patient diversity and unknown disease cause are major challenges for drug development and clinical trial design for amyotrophic lateral sclerosis (ALS). Transgenic animal models do not adequately reflect the heterogeneity of ALS. Direct reprogramming of patient fibroblasts to neuronal progenitor cells and subsequent differentiation into patient astrocytes allows rapid generation of disease relevant cell types. Thus, this methodology can facilitate compound testing in a diverse genetic background resulting in a more representative population for therapeutic evaluation. Here, we used established co‐culture assays with motor neurons and reprogrammed patient skin‐derived astrocytes (iAs) to evaluate the effects of (SP‐4‐2)‐[[2,2’‐(1,2‐dimethyl‐1,2‐ethanediylidene)bis[N‐methylhydrazinecarbothioamidato‐κN2,κS]](2‐)]‐copper (CuATSM), currently in clinical trial for ALS in Australia. Pretreatment of iAs with CuATSM had a differential effect on neuronal survival following co‐culture with healthy motor neurons. Using this assay, we identified responding and non‐responding cell lines for both sporadic and familial ALS (mutant SOD1 and C9ORF72). Importantly, elevated mitochondrial respiration was the common denominator in all CuATSM‐responders, a metabolic phenotype not observed in non‐responders. Pre‐treatment of iAs with CuATSM restored mitochondrial activity to levels comparable to healthy controls. Hence, this metabolic parameter might allow selection of patient subpopulations best suited for CuATSM treatment. Moreover, CuATSM might have additional therapeutic value for mitochondrial disorders. Enhanced understanding of patient‐specific cellular and molecular profiles could help improve clinical trial design in the future.

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“…Large-scale drug studies in AD are usually restricted to rather short periods of this slowly progressive disorder lim iting the treatment and observation periods to 6-12 weeks, e.g., tacrine for 6 weeks [5], tacrine and lecithin for 6 weeks [50] , tacrine for 12 weeks [6], physostigmine for 6 weeks [51] , oxiracetam for 4-12 weeks [52], Trials designed for longer observation periods are mostly restricted to smaller patients populations (levocamitine 3 plus 3 months [7], piracetam 1 year [11]) and the effects of treatment were evident only in subtests (levocamitine [7]), indicated as a trend to slow the progression of the disease (piracetam [11], indomethacin [53]) or demonstrable only in a rather small number of responders (bifemelane [54], tacrine [50]). The influence of memory training or cognitive rehabilita tion programs were usually followed for longer periods, but gains have been generally small or nonexistent [ 13] and the effects seen in only a few studies were restricted to persis tence of performance in everyday cognitive and memory tasks and daily life activities compared to a decline in these tasks in the untreated control groups [55][56][57], Since previous investigations of our group have indi cated an effect of several drugs on brain glucose metabo lism and cognitive performance when given for 2-6 weeks [58][59][60], a parallel 4-group trial was designed to evaluate the efficacy of several therapeutic strategies over 6 months, which is to be considered a meaningful period for a chronic progressive disorder like AD.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Effects of Phosphatidylserine, Pyritinol, and Cognitive Training in Alzheimer's Disease

Heiss¹,

Kessler²,

Mielke³

et al. 1994

Dement Geriatr Cogn Disord

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70 patients with probable Alzheimer''s disease were randomly allocated to four groups: 17 patients received only social support, 18 cognitive training twice a week, in 17 cognitive training was combined with pyritinol 2 x 600 mg/day and in 18 cognitive training was combined with phosphatidylserine 2 x 200 mg/day. Treatment duration was 6 months. Before and after treatment, the patients underwent neuropsychological testing as well as measurement of the regional cerebral metabolic rate for glucose using positron emission tomography and ¹⁸F-2-fluoro-2-deoxy-D-glucose. Before treatment the groups were comparable in respect to resting and activated glucose pattern achieved by a visual recognition task. Electrophysiological changes were assessed as EEG power, globally and in 4 frequency bands. This 6-month study in four groups of patients with Alzheimer''s disease indicated that phosphatidylserine treatment has an effect on different measures of brain function. Since neuropsychological improvements were best documented after 8 and 16 weeks and faded towards the end of the treatment period, it must be concluded that this symptomatic therapy is mainly of short-term benefit and was overcome by the progressive pathological changes at the end of the treatment period.

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Responders and non-responders to bifemelane hydrochloride in Alzheimer-type and multi-infarct dementia

Cited by 7 publications

References 0 publications

Effects of Bifemelane on the Calcium Level and ATP Release of the Human Origin Astrocyte Clonal Cell

Effects of Bifemelane on the Calcium Level and ATP Release of the Human Origin Astrocyte Clonal Cell

CuATSM effectively ameliorates ALS patient astrocyte‐mediated motor neuron toxicity in human in vitro models of amyotrophic lateral sclerosis

Long-Term Effects of Phosphatidylserine, Pyritinol, and Cognitive Training in Alzheimer's Disease

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