The rise and fall of tobacco as a botanical medicine.

A forgotten and valuable chapter in the history of tobacco concerns its role as a botanical medicine. For three hundred years following its importation into Europe, tobacco came to be considered a universal remedy highly prescribed by physicians. In the early history of tobacco, the literature on its medicinal benefits was voluminous. Nonetheless, bitter opposition to its use for non-medicinal purposes began to arise. There was little doubt of its medicinal efficacy at first, but with time, as the concepts and practice of medicine changed, the tide of medical opinion turned against it. Medical support for the therapeutic use of tobacco reached its nadir during the mid-nineteenth century, when it was dropped from most medical pharmacoepiae. Medical opinion on the health hazards of recreational smoking required another 100 years to arrive at the contemporary opinion that cigarette smoking is the single most important preventable environmental factor contributing to illness, disability and death in the U. S.

Improving solubility and pharmacokinetics of meloxicam via multiple-component crystal formation.

Meloxicam is a nonsteroidal anti-inflammatory drug prescribed for rheumatoid arthritis, osteoarthritis, postoperative pain and fever. Meloxicam exhibits low solubility in acidic aqueous media and a slow onset of action in biological subjects. An oral dosage form of meloxicam with enhanced aqueous solubility is desired to enable a faster onset of action and its use for mild-to-medium-level acute pain relief. With this in mind, we examine the solubility and pharmacokinetics of 12 meloxicam cocrystals with carboxylic acids. Dissolution studies of meloxicam and its cocrystals were performed in pH 6.5 phosphate buffer solutions at 37 °C. In addition, pharmacokinetic profiles over four hours were acquired after oral administration of a 10 mg/kg (meloxicam equivalent) solid suspension in rats. The majority of meloxicam cocrystals were found to achieve higher meloxicam concentrations in dissolution media and enhanced oral absorption compared to that of pure meloxicam. All meloxicam cocrystals were converted to meloxicam form I when the slurry reached equilibrium. To better understand how cocrystallization impacts the absorption of meloxicam after oral administration, correlations between the in vitro and in vivo data were explored. The results suggest that the meloxicam cocrystals with a faster dissolution rate would exhibit increased oral absorption and an earlier onset of action.

Effects of melanin and manganese on DNA damage and repair in PC12-derived neurons.

The mechanism of neurotoxicity produced by the interaction of melanin with manganese was investigated in PC12-derived neuronal cell cultures. The cells were incubated with melanin (25-500 microg/ml), MnCl2 (10 ng/ml-100 microg/ml) and a combination of both substances for 24 and 72 h. Incubation with either toxicant alone resulted in a minimal decrease in cell viability. The combination of melanin and manganese caused significant (up to 60%) decreases in viability of PC12 cells in a dose-dependent manner. Increases in oxidative DNA damage, indicated by levels of 8-hydroxy-2'deoxyguanosine (8-oxodG), was associated with decreased cell viability. Melanin alone, but not manganese alone, resulted in increased oxidative DNA damage. The maximal increase in 8-oxodG caused by melanin was about seven times higher than control after 24 h of exposure. The activity of the DNA repair enzyme, 8-oxoguanine DNA glycosylase (OGG1), was increased in cells incubated with single toxicants and their combinations for 24 h. On the third day of incubation with the toxicants, activity of OGG1 declined below control levels and cell viability significantly decreased. Melanin was observed to have an inhibitory effect on OGG1 activity. Study of the regulation of OGG1 activity in response to melanin and manganese may provide insights into the vulnerability of nigral neurons to oxidative stress in Parkinson's disease.

Neural cells derived from adult bone marrow and umbilical cord blood.

Under experimental conditions, tissue-specific stem cells have been shown to give rise to cell lineages not normally found in the organ or tissue of residence. Neural stem cells from fetal brain have been shown to give rise to blood cell lines and conversely, bone marrow stromal cells have been reported to generate skeletal and cardiac muscle, oval hepatocytes, as well as glia and neuron-like cells. This article reviews studies in which cells from postnatal bone marrow or umbilical cord blood were induced to proliferate and differentiate into glia and neurons, cellular lineages that are not their normal destiny. The review encompasses in vitro and in vivo studies with focus on experimental variables, such as the source and characterization of cells, cell-tracking methods, and markers of neural differentiation. The existence of stem/progenitor cells with previously unappreciated proliferation and differentiation potential in postnatal bone marrow and in umbilical cord blood opens up the possibility of using stem cells found in these tissues to treat degenerative, post-traumatic and hereditary diseases of the central nervous system.

Effects of diethylmaleate on DNA damage and repair in the mouse brain.

The enzyme 8-oxoguanine DNA glycosylase 1 participates in the repair of damaged DNA by excising the oxidized base 8-hydroxy-2'-deoxyguanosine. We have previously demonstrated that enzymatic activity of this enzyme is inversely related to the levels of the damaged base in specific brain regions. We now report that the activity of 8-oxoguanine DNA glycosylase 1 is increased in a region-specific manner following treatment with diethylmaleate, a compound that reduces glutathione levels in the cell. A single treatment with diethylmaleate elicited a significant increase ( approximately 2-fold) in the activity of 8-oxoguanine DNA glycosylase 1 in three brain regions with low basal levels of activity (cerebellum, cortex, and pons/medulla). There was no change in the activity of 8-oxoguanine DNA glycosylase 1 in those regions with high basal levels of activity (hippocampus, caudate/putamen, and midbrain). This is the first report to demonstrate that DNA repair capacity can be upregulated in the CNS, and the increased repair activity correlates with a reduction in the levels of DNA damage. The brain region-specific capacity to deal with increased oxidative damage to DNA may be responsible, in part, for the vulnerability of specific neuronal populations with aging, sources of oxidative stress, and neurodegenerative diseases.