Effect of six months of treatment with V0191 in patients with suspected prodromal Alzheimer's disease.

New criteria related to prodromal Alzheimer's disease (AD) have been proposed to overcome the issue of heterogeneity of patients with mild cognitive impairment (MCI) and to better define patients in early stage AD. Only few therapeutic trials, if any, have been reported using this newly defined population. The objective of this study was to assess the clinical efficacy and safety of a novel pro-cholinergic drug (V0191) in patients with prodromal AD. Two hundred forty two (242) patients with a diagnosis of prodromal AD were randomized in an approximately 1 : 1 ratio to receive either 1500 mg V0191 or matching placebo once daily for 24 weeks. Changes in global cognitive functioning were assessed using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog; responder rate as primary efficacy measure). Standardized measures of memory, executive function, attention, functional capacity, and apathy were also obtained. Despite some interesting trends at week 12 and conversion rates favoring V0191, no statistically significant differences in cognitive function between V0191 and placebo were noted. In addition to the absence of drug efficacy on this population, several design features may have hindered this study, including insufficient powering to assess changes in cognition over time, a relatively short duration of treatment, and the lack of validated clinical trial measures designed to assess the prodromal AD population. Lessons learned in AD study design optimization, including those presented in this paper, could be valuable for further investigation with pro-cholinergic drugs such as V0191.

Evaluation of retro-inverso modifications of HTLV-1 protease inhibitors containing a hydroxyethylamine isoster.

Effects of retro-inverso (RI) modifications of HTLV-1 protease inhibitors containing a hydroxyethylamine isoster backbone were clarified. Construction of the isoster backbone was achieved by a stereoselective aldol reaction. Four diastereomers with different configurations at the isoster hydroxyl site and the scissile site substituent were synthesized. Inhibitory activities of the new inhibitors suggest that partially modified RI inhibitors would interact with HTLV-1 protease in the same manner as the parent hydroxyethylamine inhibitor.

Effects of dimethylaminoethanol pyroglutamate (DMAE p-Glu) against memory deficits induced by scopolamine: evidence from preclinical and clinical studies.

RATIONALE: Dimethylaminoethanol pyroglutamate (DMAE p-Glu) is a compound resulting from the reaction between dimethylaminoethanol (an indirect precursor of acetylcholine) and pyroglutamic acid (a cyclic derivative of glutamic acid having procholinergic properties and promnesic effects in both animals and man). OBJECTIVES: The present study undertook preclinical and clinical evaluations to test a potential therapeutic utility for DMAE p-Glu in cognitive impairments related to central cholinergic deficit. MATERIALS AND METHODS: In preclinical study, DMAE p-Glu was studied in rats by intracerebral microdialysis in conscious freely moving animals, on performance of rats in the Morris water maze test of spatial memory, and on the deficit in passive avoidance behavior induced by scopolamine. The clinical study examined the effect of DMAE p-Glu on cognitive deficits induced by an intravenous injection of scopolamine in healthy young male subjects. RESULTS: In rat experiments, DMAE p-Glu increased the extracellular levels of choline and acetylcholine in the medial prefrontal cortex, as assessed by intracerebral microdialysis, improved performance in a test of spatial memory, and reduced scopolamine-induced memory deficit in passive avoidance behavior. Clinical study results show that scopolamine induced a memory deficit and that DMAE p-Glu produced a significant positive effect on scores in the Buschke test, as well as a slight but significant difference on choice reaction time. CONCLUSION: These results indicate that DMAE p-Glu reduces the deleterious effect of scopolamine on long-term memory in healthy volunteers and suggest that DMAE p-Glu might be effective in reducing memory deficits in patients with cognitive impairment.

Isolation and characterization of heterotrophic bacteria able to grow aerobically with quaternary ammonium alcohols as sole source of carbon and nitrogen.

The quaternary ammonium alcohols (QAAs) 2,3-dihydroxypropyl-trimethyl-ammonium (TM), dimethyl-diethanol-ammonium (DM) and methyl-triethanol-ammonium (MM) are hydrolysis products of their parent esterquat surfactants, which are widely used as softeners in fabric care. We isolated several bacteria growing with QAAs as the sole source of carbon and nitrogen. The strains were compared with a previously isolated TM-degrading bacterium, which was identified as a representative of the species Pseudomonas putida (Syst. Appl. Microbiol. 24 (2001) 252). Two bacteria were isolated with DM, referred to as strains DM 1 and DM 2, respectively. Based on 16S-rDNA analysis, they provided 97% (DM 1) and 98% (DM 2) identities to the closest related strain Zoogloea ramigera Itzigsohn 1868AL. Both strains were long, slim, motile rods but only DM 1 showed the floc forming activity, which is typical for representatives of the genus Zoogloea. Using MM we isolated a Gram-negative, non-motile rod referred to as strain MM 1. The 16S-rDNA sequence of the isolated bacterium revealed 94% identities (best match) to Rhodobacter sphaeroides only. The strains MM 1 and DM 1 exclusively grew with the QAA which was used for their isolation. DM 2 was also utilizing TM as sole source of carbon and nitrogen. However, all of the isolated bacteria were growing with the natural and structurally related compound choline.

Protection of murine L1210 leukemia and bone marrow progenitor cells against mechlorethamine and inhibition of choline uptake as a structure-activity relationship of 2-dimethylaminoethanol and its analogues.

The structure-activity relationships of 2-dimethylaminoethanol and its analogues as protectors against mechlorethamine cytotoxicity and as inhibitors of choline uptake were evaluated. Of a series of inhibitors and protectors, 2-dimethylaminoethanol was the most potent inhibitor of choline uptake and the most potent protector of both hematopoietic progenitor cells and murine L1210 leukemia cells. Two analogues that exhibited both potent protection and inhibition were 1-dimethylamino-2-propanol and 2-ethylmethylaminoethanol. 2-Di-n-butylaminoethanol, while protecting against mechlorethamine cytotoxicity, was not an inhibitor of choline uptake. 2-n-Butylmethylaminoethanol, while an inhibitor of choline uptake, was not a protector against mechlorethamine cytotoxicity. Addition of 2-dimethylaminoethanol to mechlorethamine in a mole ratio of 1000:1 did not improve survival of tumor-bearing mice beyond that of mice treated with mechlorethamine alone.

o-Toluoylcholine as substrate for measurement of serum pseudo-cholinesterase activity.

New synthetic substrates for serum pseudo-cholinesterase activity were compared with the common substrates for the routine assays, with regard to reactivity, specificity and stability; o- and m-toluoylcholine as well as o- and m-toluoyldimethylaminoethanol esters had selective specificities for pseudo-cholinesterase. The last three substrates, however, were unstable in solution at 4 degrees C. On the other hand, o-toluoylcholine could be stored in solution for several days with no appreciable degradation, and it was extremely stable with regard to pH and temperature. No or little hydrolysis of o-toluoylcholine was observed by various enzymes other than pseudo-cholinesterase. The enzymatic method using o-toluoylcholine as substrate was reproducible, and the results correlated well with those obtained using butylthiocholine as substrate and 5,5'-dithiobis-(2-nitrobenzoic acid) as color reagent. In conclusion, o-toluoylcholine is a favorable substrate for the determination of serum pseudo-cholinesterase activity.

Cytolysis of neuroblastoma cells in vitro and treatment of neuronal tumors in vivo with bromoacetylcholine.

The effect of bromoacetylcholine on mouse neuroblastoma C-1300 was investigated in cell culture as well as in A/J mice. In vitro, bromoacetylcholine (1 X 10(-5) M) was a potent cytolytic agent and produced an additive effect in combination with vincristine (3 X 10(-9) M). Since the choline acetyltransferase inhibitor, dimethylaminoethyl chloroacetate, does not inhibit neuroblastoma efficiently in vitro, the potent cytolytic action of bromoacetylcholine is probably not due to its choline acetyltransferase inhibitory action. Furthermore, the neuroblastoma inhibitory effect of bromoacetylcholine was not affected by atropine. Therefore, the inhibitory action is not related to the interaction of bromoacetylcholine with muscarinic receptors either. In in vivo experiments, 1, 10, or 30 mg/kg of bromoacetylcholine was injected directly into the tumors three times daily for 6 weeks. Bromoacetylcholine at 10 and 30 mg/kg gave significant protection of A/J mice from the death induced by neuroblastoma inoculation, and the lifespan was prolonged significantly with these bromoacetylcholine treatments.

Kinins and central effects of the acetylcholine.

The interaction between kinins formed in central nervous system and acetylcholine was studied. Endogenous ACh in excess acted psychodepressively on the animal's behavior as evaluated with Lat's test. This effect was more intense in those rats in which the activity of kinin-forming enzymes in the nervous tissue had been increased with either kallikrein or bradykinin. Both kallikrein and bradykinin intensified the psychodepressive action of exogenous ACh given into the brain ventricle. Results show that kinins can enhance the inhibitory central action of ACh.