Vitamin D status in the elderly: seasonal substrate deficiency causes 1,25-dihydroxycholecalciferol deficiency

The seasonal variation of 25-hydroxycholecalciferol and 1,25-dihydroxycholecalciferol was analyzed in 240 elderly subjects (mean age: 78 yr) in Belgium. Serum 25-hydroxycholecalciferol was lowest from February until May (mean levels less than 25 nmol/L). Summer peak levels were, however, not higher than nadir levels in younger control subjects. A seasonal variation in total and free 1,25-dihydroxycholecalciferol concentrations was also observed in the geriatric population with a nadir in February and March (50 +/- 24 pmol/L). The peak values in summer (110 +/- 33 pmol/L) were not different from those of the younger controls. Serum calcium and phosphate were decreased whereas alkaline phosphatase and parathyroid hormone were increased throughout the year in the geriatric patients. Oral 25-hydroxycholecalciferol treatment rapidly normalized serum 1,25-dihydroxycholecalciferol concentrations in vitamin D-deficient subjects. Deficiency of both the vitamin D substrate and hormone is frequent in the elderly population in Belgium

Pancreatic secretion in man with subclinical vitamin D deficiency

The effects of subclinical vitamin D deficiency and vitamin D supplementation on oral glucose tolerance and secretion of pancreatic hormones were studied in 10 diphenylhydantoin-treated epileptic patients and 15 geriatric patients. Their mean serum concentrations of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 decreased markedly, but returned to normal within 2 weeks of oral supplementation with 25-hydroxyvitamin D3. The serum concentration of ionized calcium was within the normal range before treatment, and remained unchanged. Serum parathyroid hormone was increased during vitamin D deficiency, but decreased significantly (p less than 0.05) afterwards. In vitamin D-deficient epileptic and geriatric patients, the 2- and 3-h insulin levels after glucose ingestion were increased when compared with control values, and glucagon secretion was not suppressed by glucose. Oral glucose tolerance of both groups of patients did not change after 25-hydroxyvitamin D3 supplementation. Insulin secretion remained unchanged in geriatric patients, but was reduced to normal values in epileptic patients. Glucagon suppressibility by glucose was partly restored after vitamin D supplementation in epileptic patients but not in geriatric patients. In contrast to that observed in severely vitamin D-deficient rats or rabbits, correction of subclinical vitamin D deficiency failed to enhance insulin secretion or to improve glucose tolerance in man

Discovery and Structure-Based Optimization of 2-Ureidothiophene-3-carboxylic Acids as Dual Bacterial RNA Polymerase and Viral Reverse Transcriptase Inhibitors

We are concerned with the development of novel anti-infectives with dual antibacterial and antiretroviral activities for MRSA/HIV-1 co-infection. To achieve this goal, we exploited for the first time the mechanistic function similarity between the bacterial RNA polymerase (RNAP) "switch region" and the viral non-nucleoside reverse transcriptase inhibitor (NNRTI) binding site. Starting from our previously discovered RNAP inhibitors, we managed to develop potent RT inhibitors effective against several resistant HIV-1 strains with maintained or enhanced RNAP inhibitory properties following a structure-based design approach. A quantitative structure-activity relationship (QSAR) analysis revealed distinct molecular features necessary for RT inhibition. Furthermore, mode of action (MoA) studies revealed that these compounds inhibit RT noncompetitively, through a new mechanism via closing of the RT clamp. In addition, the novel RNAP/RT inhibitors are characterized by a potent antibacterial activity against S. aureus and in cellulo antiretroviral activity against NNRTI-resistant strains. In HeLa and HEK 293 cells, the compounds showed only marginal cytotoxicity