Phosphonate analogues of 1α, 25 dihydroxyvitamin D3 are promising candidates for antitumoural therapies.

The active metabolite of vitamin D, 1α, 25 dihydroxyvitamin D3 (calcitriol) is classically known to regulate calcium and phosphate homeostasis and bone mineralization. In addition, calcitriol has also been documented to act as a potent anticancer agent in multiple cell culture and animal models of cancer. However, major side effects, such as hypercalcemia, hinder broad-spectrum therapeutic uses of calcitriol in cancer chemotherapy. Synthesis of calcitriol analogues with the same or increased antiproliferative and pro-differentiating activities, and with reduced undesired effects on calcium and bone metabolism, is getting significant attention towards rational therapeutics to treat cancer. In this regard, phosphonate analogues have been shown to display a certain degree of dissociation between the vitamin D activity in vitro and undesired hypercalcemia in vivo. However, few phosphonates have been described in the literature and fewer of them tested for antitumoral effects. Our group has synthesized a novel vitamin D analogue (EM1) bearing an alkynylphosphonate moiety that combines the low calcemic properties of phosphonates with the decreased metabolic inactivation due to the presence of a triple bond between C-23 and C-24. Biological assays demonstrated that this analogue has potent antiproliferative effects in a wide panel of tumour cell lines, even in those resistant to calcitriol treatment. Importantly, EM1 does not show toxic effects in animals, even administered at high doses and for extended periods of time. In the current review we discuss the effects and the potential application in cancer of vitamin D and its derivatives, with an emphasis on phosphonate analogues.

Clinical studies with oxiracetam in patients with dementia of Alzheimer type and multi-infarct dementia of mild to moderate degree.

The cognitive and behavioral effects and the safety of oxiracetam therapy during a placebo-controlled trial and the relevant follow-up up to 1 year in patients with senile dementia of Alzheimer type (SDAT) and multi-infarct dementia (MID) of mild to moderate degree were studied. Sixty male and female outpatients participated in the double-blind, placebo-controlled, parallel-group, randomized trial, comparing the effects of oxiracetam 800 mg b.i.d. and placebo during 90 days of treatment. At the end of therapy, statistical analysis evidenced significant improvements in the group receiving oxiracetam in respect to the placebo group on Mini Mental State Examination, Auditory Continuous Performance Test, Rey's 15 Words Test, Block Tapping Test, Mattis Word Fluency, Luria Alternating Series and Instrumental Activities of Daily Living. Afterwards, 29 of the 30 patients who received oxiracetam, participated in the open follow-up study, receiving 800 mg b.i.d. oxiracetam for a total standard period of 1 year. Statistical improvements in comparison to baseline were again found on the same tests of the first 90 days (except for Rey's 15 Words Test) and on the Memory item of the Inventory of Psychic and Somatic Complaints Elderly. During the late phase of the follow-up, statistically significant worsenings in comparison to baseline were observed on Digit Span Backward, Gibson's Spiral and some non-memory items of IPSC-E. Neither severe adverse events were observed during the whole study, nor changes in routine laboratory examinations. In conclusion, in the present population of patients with mild to moderate degree dementia, the safety of 1,600 mg/day of oxiracetam also up to 1 year of treatment was confirmed.(ABSTRACT TRUNCATED AT 250 WORDS)

Pyroglutamic acid improves the age associated memory impairment.

Pyroglutamic acid (PCA) was compared with placebo in a randomized, double blind trial for assessing its efficacy in treating memory deficits in 40 aged subjects. Twenty subjects were treated with PCA and 20 with placebo over a period of 60 d. Memory functions were evaluated at baseline and after 60 d of treatment by means of a battery made up of 6 memory tasks. The results suggest that PCA is effective in improving some verbal memory functions in subjects affected by age-related memory decline.

Concreteness/abstractness of stimulus-words and semantic clustering in right brain-damaged patients.

Fifteen right brain-damaged patients and 15 normal controls were tested for learning, delayed recall and semantic clustering abilities using two lists of two/three-syllable words. The first list consisted of 12 familiar, concrete, high-imageability nouns belonging to three semantic categories and the second of 12 abstract, low-imageability, familiar nouns also belonging to three semantic categories. The right brain-damaged patients proved to have a learning and semantic clustering deficit for concrete but not for abstract words. This was interpreted as evidence for a selective right hemisphere capability for processing concrete, high-imageability words.

Clinical and neuropsychological study with oxiracetam versus placebo in patients with mild to moderate dementia.

40 out-patients with a mild to moderate degree of dementia (11 less than or equal to MMSE less than 24) participated in a between-subjects (n = 20 + 20) double-blind placebo-controlled randomized trial comparing the effects of oxiracetam 800 mg bid and placebo during 90 days of treatment. At the end of therapy, statistical analysis (ANOVA) detected significant differences between groups: after oxiracetam treatment, improvements were observed on Mini Mental State Examination, Auditory Continuous Performance Test, Block Tapping Test, Word Fluency and Instrumental Activities of Daily Living. No side effects were observed. In conclusion, in the present population of patients with mild to moderate degree dementia, 1600 mg/day of oxiracetam was effective in enhancing both attentional activities and other, more complex, neuropsychological functions.