Search PubMed⌕ Search

Biomedical subjects

D M Stone

Publications and source records attributed to D M Stone.

At least 73 records · Page 4Linked to original sources
PubMed1989

In vitro reactivation of rat cortical tryptophan hydroxylase following in vivo inactivation by methylenedioxymethamphetamine.

The activity of tryptophan hydroxylase (EC 1.14.16.4) from rat brain was significantly decreased 1 h following a single systemic injection of 3,4-methylenedioxymethamphetamine (MDMA) when assessed ex vivo by radioenzymatic assay or in vivo by the quantitation of 5-hydroxytryptophan accumulation following central L-aromatic amino acid decarboxylase inhibition. Recovery of enzymatic activity in vivo, which occurred within 24 h of low-dose MDMA treatment, appeared not to involve synthesis of new enzyme protein, because the return of enzymatic activity was not prevented by prior cycloheximide. Acutely MDMA-depressed cortical tryptophan hydroxylase activity could be completely restored in vitro by a prolonged (20-24 h) anaerobic incubation in the presence of dithiothreitol and Fe2+ at 25 degrees C; partial reconstitution occurred when 2-mercapto-ethanol was substituted for dithiothreitol. Cortical tryptophan hydroxylase acutely inactivated by methamphetamine or p-chloroamphetamine could be similarly reactivated. MDMA-inactivated cortical tryptophan hydroxylase derived from rats killed later than 3 days after drug treatment could not be significantly reactivated under the conditions described above, indicating the development of irreversible enzymatic damage. Kinetic analysis of enzyme reactivation revealed an approximate doubling of enzyme Vmax with no change in enzyme affinity for either substrate, tryptophan, or pterin cofactor. These studies suggest that MDMA and its congeners inactivate central tryptophan hydroxylase by inducing oxidation of key enzyme sulfhydryl groups. The reactivation capacity of drug-inactivated enzyme at various times after MDMA treatment may provide a means of assessing the development of MDMA-induced neurotoxicity.

3,4-Methylenedioxyamphetamine↗
PubMed1988

Role of endogenous dopamine in the central serotonergic deficits induced by 3,4-methylenedioxymethamphetamine.

Similar to other amphetamine analogs 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"), a currently popular illicit drug, has been characterized recently as a serotonergic neurotoxin due to its ability to cause long-lasting deficits in markers of central serotonergic function in animals. Because the serotonergic toxicity associated with the MDMA analog methamphetamine has been linked previously to endogenous dopamine and because MDMA, like methamphetamine, elicits pronounced dopamine release in vitro, we have examined the role of endogenous dopamine in both the immediate (3 hr) and longer-term (3 days) central serotonergic deficits induced by systemic MDMA administration to rats. Depletion of central dopamine content with alpha-methyl-p-tyrosine or reserpine, or selective destruction of nigrostriatal dopamine projections with bilateral 6-hydroxydopamine-induced substantia nigral lesions, partially blocked the immediate MDMA-induced reduction in rat striatal tryptophan hydroxylase (TPH) activity. In addition, the longer-term TPH deficits caused by a high single dose of MDMA were completely prevented by prior alpha-methyl-p-tyrosine or reserpine, and attenuated significantly by inhibition of dopamine uptake with the selective dopamine-uptake blocker GBR 12909. These results implicate endogenous drug-released dopamine as a partial mediator of the initial decrease in TPH activity caused by MDMA and as an important prerequisite to the development of long-term MDMA-induced neurotoxicity. Potential mechanisms of dopamine-mediated toxicity are discussed.

3,4-Methylenedioxyamphetamine↗
PubMed1987

Effects of amphetamine analogs on neurotensin concentrations in rat brain.

The present study investigates the effects of amphetamine-like analogs on neurotensin systems and compares the same to those of methamphetamine. Like methamphetamine, multiple high doses of each of the analogs examined significantly increased the concentrations of neurotensin-like immunoreactivity in the striatum, substantia nigra and nucleus accumbens; these effects were reversible and specific. The changes in the neurotensin systems developed rapidly and were evident within 6 h following a single administration of two of the analogs studied.

3,4-Methylenedioxyamphetamine↗
PubMed1987

Role of the dopaminergic nigrostriatal pathway in methamphetamine-induced depression of the neostriatal serotonergic system.

The prevention of the decrease in neostriatal tryptophan hydroxylase (TPH) activity with a single dose of methamphetamine (MA) was attempted by lesioning the nigrostriatal dopaminergic projections with bilateral nigral injections of 6-hydroxydopamine (6-OHDA). The rats were injected with MA (10 mg/kg) 11 days later, and killed 3 h after the injection. The 6-OHDA lesions prevented the decrease of TPH activity in the neostriatum, while the decrease of enzyme activity was slightly attenuated in the hippocampus and unaffected in the frontal cortex. This study demonstrates: that the attenuation of TPH activity can be prevented in a selected brain area by destroying its dopaminergic afferents, and implicates central dopamine (DA), or its metabolite, in the decrease in central TPH activity observed after a single injection of MA.

Animals↗
PubMed1987

A comparison of the neurotoxic potential of methylenedioxyamphetamine (MDA) and its N-methylated and N-ethylated derivatives.

Three psychoactive amphetamine congeners were evaluated for their ability to cause long-term changes in several neurochemical parameters indicative of central serotonergic function. Two weeks after multiple doses (10 mg/kg) of 3,4-methylenedioxyamphetamine (MDA) or its N-methylated derivative, 3,4-methylenedioxymethamphetamine (MDMA), selective and dramatic decreases were observed in regional brain tryptophan hydroxylase (TPH) activities, and in corresponding concentrations of 5-hydroxytryptamine (5-HT) and its primary metabolite, 5-hydroxyindoleacetic acid (5-HIAA). However, the N-ethylated derivative of MDA, N-ethyl-3,4-methylenedioxyamphetamine (MDE), was much less potent in its ability to lower brain hydroxyindoles, and in most regions examined did not significantly affect TPH activity. The neurotoxic implications of these results are discussed.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1987

Limitations of indirect methods of estimating small bowel transit in man.

Experiments were carried out in healthy volunteers to explore the utility of a new [14C]lactulose breath test for measuring small intestinal transit time in man and to use this procedure to test whether two antidiarrheal agents, codeine and clonidine, alter small intestinal transit time during digestion of a liquid meal. In an initial validation study performed in 12 subjects (three studies in each subject), a liquid test meal containing 10 g [14C]lactulose was administered and the colonic entry time estimated from the time course of 14CO2 excretion in breath compared with that of H2 excretion. There was a fair correlation (r = 0.77; P less than 0.001) between results obtained by the two methods; both methods gave similar results, but 14CO2 output was delayed when compared to H2 output and was incomplete. The meal also contained xylose and [13C]glycine, permitting the duodenal entry time of the meal to be estimated by the appearance of xylose in blood and 13CO2 in breath, respectively. The same liquid meal was then used to examine the effect on small intestinal transit time (colonic entry time minus duodenal entry time) of codeine or clonidine. 99Tc-sulphur colloid was also added to the meal to permit a comparison of small intestinal transit estimated by imaging with that estimated by the 14CO2-lactulose breath test. 99Tc radioactivity appeared in the cecum (as assessed using gamma scintigraphy) about 2 hr before 14CO2 radioactivity appeared in breath; the correlation between transit time estimated by the two methods was moderate (r = 0.61; P less than 0.05). Based on the [14C]lactulose data, small intestinal transit time ranged from less than 1 to 3 hr for a liquid meal containing 10 g lactulose; within-subject variation (coefficient of variation 17%) was considerably less than between-subject variation (coefficient of variation 56%). Codeine increased the small intestinal transit time significantly (from 2.7 +/- 0.3 hr to 5.0 +/- 0.9 hr; mean +/- SE), whereas clonidine did not alter small intestinal transit time, as estimated by the colonic entry time minus duodenal entry time. Neither drug influenced duodenal entry time. These results suggest that the [14C]lactulose breath test, which has only moderate accuracy, may have occasional utility as a convenient, noninvasive method for estimating small intestinal transit time in man. However, this study also suggests that indirect methods of estimating small bowel transit in man have limitations, variability, and possibly may lack the desired sensitivity.

Antidiarrheals↗
PubMed1987

Differences in the central serotonergic effects of methylenedioxymethamphetamine (MDMA) in mice and rats.

The effects of subcutaneous injection of 3,4-methylenedioxymethamphetamine (MDMA), a psychoactive amphetamine congener, on mouse central monoaminergic systems were assessed and compared to effects in rats. Whereas neostriatal concentrations of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in mouse were transiently decreased after a single moderately high dose of MDMA (15 mg/kg), mouse neostriatal or hippocampal tryptophan hydroxylase activity was not significantly affected, even after a dose of 60 mg/kg. These results are in contrast to effects in rats, in which a single 10 mg/kg dose of MDMA induced immediate and prolonged decreases in both central tryptophan hydroxylase activity and 5-hydroxyindole concentrations. Decreases in mouse central tryptophan hydroxylase activity, and prolonged decreases in mouse 5-hydroxyindole concentrations, were observed only after multiple doses of MDMA, suggesting that the duration of exposure may be an important determinant of toxic effects. These results show mice to be less susceptible than rats to MDMA-induced neurotoxicity, and are discussed in terms of possible interspecies differences in MDMA pharmacokinetics.

3,4-Methylenedioxyamphetamine↗
PubMed1987

Immediate and long-term effects of 3,4-methylenedioxymethamphetamine on serotonin pathways in brain of rat.

In the rat, administration of the psychoactive analog of amphetamine 3,4-methylenedioxymethamphetamine (MDMA), causes selective, pronounced decreases in markers of central serotonergic function. The time course of these neurochemical changes was examined in several serotonergic nerve terminal regions of the brain. Fifteen min after subcutaneous injection of MDMA (10 mg/kg), the enzymatic activity of tryptophan hydroxylase (the rate-limiting enzyme for the biosynthesis of serotonin) was significantly decreased in the frontal cortex; by 1 hr after the injection, the activity of tryptophan hydroxylase had significantly declined in the neostriatum, hippocampus and hypothalamus as well. Although extensive recovery had occurred by 2 weeks, the activity of the enzyme remained significantly depressed in most regions. Decline of the regional content of 5-hydroxytryptamine (5-HT) closely paralleled, but was usually preceded by, that of the enzyme. Concentrations of the primary metabolite of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), were less responsive: in most regions levels of 5-HIAA had significantly decreased by 3 hr, but not by 1 hr, following treatment. Markers of dopamine function were altered transiently but had returned to control values by 24 hr. Administration of multiple doses of MDMA (5 doses over a 24-hr period) resulted in significant decreases in serotonergic parameters for up to 110 days after treatment. The rate and extent of recovery varied according to both the dose administered and the region examined. The persistence of these serotonergic deficits suggests that MDMA induced the destruction of serotonin-containing axon terminals.

3,4-Methylenedioxyamphetamine↗
PubMed1987

The effects of amphetamine-like designer drugs on monoaminergic systems in rat brain.

The response of brain dopaminergic and serotonergic systems to the amphetamine-like designer drugs, 3,4-methylenedioxyamp amphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA), was investigated and compared to methamphetamine (METH). Like METH, single or multiple doses of either drug caused marked reductions in both tryptophan hydroxylase (TPH) activity and concentrations of 5-hydroxytryptamine (5HT) and 5-hydroxyindoleacetic acid (5HIAA) in several brain regions. The reduction in 5HT content corresponded to the depression of TPH activity in all regions examined. In contrast to METH, which induced pronounced deficits in dopaminergic neuronal markers, repeated doses of MDA or MDMA did not alter striatal tyrosine hydroxylase (TH) activities or reduce striatal dopamine concentrations. A single dose of MDA or MDMA significantly elevated striatal dopamine content; however, after repeated drug administrations dopamine concentrations were comparable to control values. The effects of MDA or MDMA administration in the rat brain are reminiscent of those elicited by p-chloroamphetamine, a presumed serotonergic neurotoxin.

3,4-Methylenedioxyamphetamine↗
PubMed1986

The effects of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) on monoaminergic systems in the rat brain.

The effects of two amphetamine-like designer drugs, 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA), on dopaminergic and serotonergic systems in the rat brain were investigated and compared to those of methamphetamine (METH). Like METH, single or multiple 10 mg/kg doses of either drug caused marked reductions in both tryptophan hydroxylase (TPH) activity and concentrations of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid, in several serotonergic nerve terminal regions. In all regions examined, the reduction in 5-HT content corresponded to the depression of TPH activity. Unlike multiple METH administrations, which induced pronounced deficits in dopaminergic neuronal markers, repeated doses of MDA or MDMA did not alter striatal tyrosine hydroxylase (TH) activities or reduce striatal dopamine concentrations. A single dose of MDA or MDMA significantly elevated striatal dopamine content; however, after repeated drug administrations dopamine concentrations were comparable to control values. At this time, striatal levels of homovanillic acid were significantly elevated suggesting that both drugs influence dopamine turnover. The effects of MDA or MDMA administration in the rat brain are reminiscent of those elicited by p-chloroamphetamine, a presumed serotonergic neurotoxin.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1986

Monoclonal antibodies binding to the human neutrophil C3bi receptor have disparate functional effects.

Three monoclonal antibodies (MAb)--OKMI, 7C3, and 60.3--immunoprecipitated a common 170-kd neutrophil membrane antigen closely associated with, or identical to, the C3bi receptor (CR3). Despite binding to a common receptor, these antibodies displayed marked differences in their effects on C3bi-mediated neutrophil function as assessed by the binding and ingestion of opsonized zymosan and the subsequent triggering of the respiratory burst. Antibody 7C3 caused a time-dependent, irreversible inhibition of the neutrophil oxidative response to opsonized zymosan that correlated with capping of the bound antibody. In contrast, antibody 60.3 caused an immediate inhibition of the neutrophil oxidative response to opsonized zymosan that required the continuous presence of exogenous antibody to achieve the maximal inhibitory effect. Antibody OKMI demonstrated minimal inhibition of O2- release. Despite their functional differences, binding of either 7C3 or 60.3 led to up-regulation of new antigen, presumably from intracellular sites as previously described using OKMI. Crossed immunoprecipitations of radiolabeled neutrophil lysates indicated that each MAb bound to different antigens near or within the CR3 complex. Thus three MAb binding to the neutrophil CR3 receptor each caused receptor up-regulation but had markedly different functional effects on the cell.

Antibodies, Monoclonal↗
PubMed1985

Hypoparathyroidism following total laryngopharyngectomy and gastric pull-up.

We have used the gastric pull-up technique for closure of large pharyngoesophageal defects after radical oncological surgery since 1979. The management of severe hypocalcemia and hypovitaminosis D seemed more difficult in patients undergoing pull-up reconstruction than in patients undergoing the same extirpative surgery, but reconstructed with more traditional methods. To determine if hypocalcemia and hypovitaminosis D were more common in gastric pull-up patients, and if postoperative management of these conditions is more problematic in this group, we retrospectively compared three groups of head and neck surgery patients. Group 1 consisted of 17 patients undergoing total laryngectomy with thyroid complex preservation. Group 2 consisted of 7 patients undergoing mediastinal dissection with total laryngectomy-thyroidectomy previously or concurrently. Group 3 consisted of 30 patients undergoing total laryngopharyngoesophagectomy-thyroidectomy and gastric pull-up reconstruction. The incidences of hypocalcemia requiring therapy were 12%, 50%, and 73%, respectively, with an overall incidence of 51%. The average amounts of supplemental calcium and vitamin D in the three groups were compared. A significant between the three groups was noted. Finally, the dietary calcium and vitamin D requirements for one problematic patient were prospectively recorded and summarized graphically. We conclude that any patient should be carefully monitored for the signs and symptoms of hypocalcemia after major head and neck surgery. In the special instance of the gastric pull-up patient, calcium requirements and the range of serum calcium fluctuation are greatly increased compared to patients undergoing more traditional methods of reconstruction.

Esophagus↗