Two previously conducted clinical studies assessed lost nonworkplace activity time and lost workplace productivity time due to migraine symptoms in subjects using sumatriptan for 6 months to treat their migraines after a 12- to 18-week period of using their usual therapy without sumatriptan. Although statistically significant differences in lost nonworkplace activity time and lost workplace productivity time between the usual therapy and sumatriptan treatment periods were detected using the Wilcoxon signed-rank test, this test could not determine whether differences were attributable to inherent trends in the data. This current study employed time series analysis, which detects and controls for preexisting trends in data, to further explore the possibility that the observed reductions in lost time in the two clinical studies were related to management of the subjects with sumatriptan. The intercepts and slopes of the computed linear models suggest that the initiation of sumatriptan therapy produced savings of 0.8 hours of nonworkplace activity time and 0.5 hours of workplace productivity time per patient per week. These savings were sustained throughout the sumatriptan treatment period. Preexisting trends in the data were not detected in the models. Thus the productivity gains are not associated with either time effects or the statistical phenomenon of regression to the mean, but variables that are extreme in initial measurements will tend to be closer to the center of the distribution in subsequent measurements. This strengthens the hypothesis that management of migraine with sumatriptan is associated with reductions in lost productivity time.

Activities of Daily Living↗

PubMedDate not supplied

Interactions of pluronic block copolymers with brain microvessel endothelial cells: evidence of two potential pathways for drug absorption.

Pluronic block copolymers have been previously reported to increase the delivery of agents to the brain [Kabanov et al. (1992) J. Controlled Release 22, 141-158]. In the present study, primary cultured bovine brain microvessel endothelial cells (BBMEC) were used as an in vitro model of the blood-brain barrier to examine the membrane interactions of Pluronic P85 (P85) and potential mechanisms for drug absorption. At concentrations below the critical micelle concentration (cmc), P85 enhanced the accumulation of the fluorescent probe rhodamine 123 (R123) in BBMEC through inhibition of P-glycoprotein (P-gp)-mediated drug efflux. The effects of P85 on the cellular accumulation of R123 were also observed in KBv cells (P-gp positive) but not in human umbilical vein endothelial cells (P-gp negative). In contrast to the effects with P85 below the cmc, the enhanced absorption of R123 observed with Pluronic micelles was transient and not dependent on P-gp. A transient increase in R123 accumulation was observed in both P-gp positive cells (brain microvessel endothelial cells and KBv) and P-gp negative cells (human umbilical vein endothelial cells). Therefore, it appears that P85 affects the absorption of drugs in brain microvessel endothelial cells through (1) inhibition of the P-gp-mediated drug efflux at low concentrations of the copolymer and (2) increased vesicular transport at higher concentrations of the copolymer. Furthermore, both interactions of P85 with the brain endothelial cells appear to be energy-dependent as demonstrated by the inhibitory effects of the metabolic inhibitor 2-deoxyglucose.

Absorption↗

PubMedDate not supplied

Use of 13C NMR spectrometric data to produce a predictive model of estrogen receptor binding activity.

We have developed a spectroscopic data-activity relationship (SDAR) model based on 13C NMR spectral data for 30 estrogenic chemicals whose relative binding affinities (RBA) are available for the alpha (ERalpha) and beta (ERbeta) estrogen receptors. The SDAR models segregated the 30 compounds into strong and medium binding affinities. The SDAR model gave a leave-one-out (LOO) cross-validation of 90%. Two compounds that were classified incorrectly in the SDAR model were in the transition zone between classifications. Real and predicted 13C NMR chemical shifts were used with test compounds to evaluate the predictive behavior of the SDAR model. The 13C NMR SDAR model using predicted 13C NMR data for the test compounds provides a rapid, reliable, and simple way to screen whether a compound binds to the estrogen receptors.

Carbon Isotopes↗

PubMedDate not supplied

Producing 13C NMR, infrared absorption, and electron ionization mass spectrometric data models of the monodechlorination of chlorobenzenes, chlorophenols, and chloroanilines.

We have developed four spectroscopic data-activity relationship (SDAR) models of monodechlorination of 32 chlorinated benzene compounds in anaerobic estuarine sediment. The SDAR models were based on combinations of 13C nuclear magnetic resonance (NMR), infrared absorption (IR), and electron ionization mass spectrometric (EI MS) data. The SDAR models segregated the 32 compounds into 17 readily monodechlorinated compounds and 15 not readily monodechlorinated compounds. The SDAR model based on 13C NMR, IR, and EI MS data gave a leave-one-out cross-validation of 93.8%. The SDAR model based on a composite of 13C NMR and IR data gave a leave-one-out cross-validation of 90.6%. The SDAR model based on a composite of IR and EI MS data gave a leave-one-out cross-validation of 84.4%. The SDAR model based on a composite of 13C NMR and EI MS data gave a leave-one-out cross-validation of 84.4%. These reliable SDAR models provide a rapid and simple way to predict whether a chlorinated benzene compound will readily go through monodechlorination. The FDA has filed a patent application on methods of using any combination of spectral data (NMR, MS, UV-vis, IR, and fluorescence, phosphorescence) to model a chemical, physical, or biological endpoint.

Carbon Isotopes↗

PubMedDate not supplied

Results of a new classification algorithm combining K nearest neighbors and recursive partitioning.

We present results of a new computational learning algorithm combining favorable elements of two well-known techniques: K nearest neighbors and recursive partitioning. Like K nearest neighbors, the method provides an independent prediction for each test sample under consideration, while like recursive partitioning, it incorporates an automatic selection of important input variables for model construction. The new method is applied to the problem of correctly classifying a set of chemical data samples designated as being either active or inactive in a biological screen. Training is performed at varying levels of intrinsic model complexity, and classification performance is compared to that of both K nearest neighbor and recursive partitioning models trained using the identical protocol. We find that the cross-validated performance of the new method outperforms both of these standard techniques over a considerable range of user parameters. We discuss advantages and drawbacks of the new method, with particular emphasis on its parameter robustness, required training time, and performance with respect to chemical structural class.

Journal Article↗

PubMedDate not supplied

Microbial hydroxylation of quadrone to 8a-hydroxyquadrone.

Microbial transformation of quadrone and its 4-ethylene ketal with Cunninghamella echinulata afforded the 8a-hydroxyquadrone and its 4-ethylene ketal, respectively.

Antibiotics, Antineoplastic↗

PubMedDate not supplied

Microsomal metabolism of 4-(N,N-diacetylamino)benzo[a]pyrene: a potent mutagenic arylamide derived from a carcinogenic polycyclic aromatic hydrocarbon.

4-(N,N-Diacetylamino)benzo[a]pyrene, a potent mutagen, is derived from a carcinogenic polycyclic aromatic hydrocarbon, benzo[a]pyrene. Metabolism of this compound by rat liver microsomes was studied. Metabolites were separated by reversed-phase high-performance liquid chromatography and were identified by analysis of their UV-vis absorption, mass, and proton nuclear magnetic resonance spectral data. Seven metabolites were identified, namely, the 9-phenol, 1,9-hydroquinone, and trans-9,10-dihydrodiol of 4-(N,N-diacetylamino)benzo[a]pyrene, 4-(N-acetylamino)benzo[a]pyrene, and the 5-phenol, 5,9-hydroquinone, and trans-9,10-dihydrodiol of 4-(N-acetylamino)benzo[a]pyrene. Comparison of these results with those of metabolism of benzo[a]pyrene indicates that the N,N-diacetylamino substitutent at the 4-carbon of benzo[a]pyrene inhibits metabolism at the peri position (3-carbon) and positions (6-, 7-, and 8-carbons) remote from the substituent. The results also indicate that while 4-(N,N-diacetylamino)-benzo[a]pyrene is a substrate of the rat liver microsomal deacetylase, the formed 4-(N-acetylamino)benzo[a]pyrene apparently is not a substrate.

Animals↗

PubMedDate not supplied

Identification of N-(Deoxyguanosin-8-yl)-2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine as the major adduct formed by the food-borne carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, with DNA.

The covalent binding of the N-acetoxy-, N-hydroxy-, and nitro derivatives of the food-borne carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) to 2'-deoxyribonucleosides or DNA was investigated in vitro and in vivo. N-Acetoxy-PhIP reacted with deoxyguanosine (dG), but not with the other deoxyribonucleosides, to form N-(deoxyguanosin-8-yl)-PhIP (dG-C8-PhIP), whose structure was determined by NMR and mass spectral analyses and by ultraviolet absorption and pH-solvent partitioning characteristics. While reaction of N-acetoxy-PhIP with calf thymus DNA at pH 5.0 yielded 5.38 +/- 1.16 nmol of bound PhIP residues/mg of DNA, N-hydroxy-PhIP gave only 0.13-0.23 nmol binding/mg of DNA under identical reaction conditions. Nitro-PhIP produced no detectable binding under these conditions. HPLC analysis of 1-butanol extracts of enzymatically hydrolyzed DNA that had been modified by N-acetoxy-PhIP in vitro showed a major adduct which coeluted with and had an ultraviolet absorption and a mass spectrum that were identical to that of authentic dG-C8-PhIP. 32P-Postlabeling analysis of DNA isolated from colon, pancreas, lung, heart, and liver of rats treated orally with PhIP revealed the presence of a major PhIP-DNA adduct. This adduct had chromatographic properties identical to that of the 32P-labeled bis(phosphate) derivative of dG-C8-PhIP and represented 35-45% of the total adducts.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Metabolism of doxylamine succinate in Fischer 344 rats. Part II: Nonconjugated urinary and fecal metabolites.

Elimination and metabolic profiles of doxylamine and its nonconjugated metabolites were determined after the oral administration of [14C]-doxylamine succinate (13.3 mg/kg and 133 mg/kg doses) to male and female Fischer 344 rats. Total urine and fecal recovery of the administered dose was greater than 90% regardless of sex or dose. The cumulative urinary and fecal elimination of these nonconjugated doxylamine metabolites at the 13.3 mg dose was 44.4 +/- 4.4% and 36.0 +/- 5.8% of the total recovered dose for male and female rats, respectively. The cumulative urinary and fecal elimination of the doxylamine nonconjugated metabolites at the 133 mg/kg dose was 38.7 +/- 2.7% and 41.4 +/- 1.0% of the total recovered dose for male and female rats, respectively. In order to determine the contribution of mammalian and bacterial enzymes in the overall metabolism and excretion patterns for doxylamine, two in vitro techniques were investigated. Incubation of [14C]-doxylamine succinate with human and rat intestinal microflora indicated that anaerobic bacteria were not capable of effecting the degradation of [14C]-doxylamine succinate. However, the incubation of [14C]-doxylamine succinate with isolated rat hepatocytes generated several metabolites similar to those observed in vivo. The nonconjugated doxylamine metabolites isolated and identified include: doxylamine N-oxide, desmethyldoxylamine, didesmethyldoxylamine and ring-hydroxylated products of doxylamine and desmethyldoxylamine. The studies demonstrate the role of hepatic metabolism in the elimination of doxylamine succinate in the rat.

Animals↗

PubMedDate not supplied

Cytological and cytoarchitectural changes in the feline cerebral cortex during experimental infantile hydrocephalus.

While many reports have documented the effects of hydrocephalus on the ependyma and periventricular white matter, primarily in adult animal models, little is known about alterations specific to neurons. The present study has evaluated qualitatively the effects of hydrocephalus on the neurons and vasculature of the cerebral cortex in a neonatal animal model. The cisterna magna of 4 to 11-day-old kittens was injected with a solution of 25% kaolin to induce hydrocephalus. Ultrasonographic evidence of hydrocephalus was noted within 3-5 days of injection. Hydrocephalus progressed until day 18-25 postinjection when the animals were sacrificed. The cytologic and cytoarchitectural changes within the cortical mantle of affected animals were compared with control age-matched counterparts who had undergone intracisternal saline injections. Areas 4 (primary motor), 22 (association) and 17 (primary visual sensory) were examined light microscopically. Neurons from hydrocephalic brains exhibited 3 types of pathological response. Pyknotic somata were shrunken, disoriented and so hyperchromatic that neither nuclei or nucleoli could be delineated. Reactive somata were also shrunken and hyperchromatic, but nuclei and nucleoli could still be observed. Many neurons contained an abundance of vacuoles, giving their somata a flocculent appearance; these cells were termed 'spongy' neurons. Both normal and pathological neurons were smaller and disoriented, with a considerable decrease in neurons noted in areas 22 and 17 from severely hydrocephalic animals. The deeper cortical layers were more affected than the more superficial laminae in that more reactive and pyknotic neurons were present in layers V and VI. As the ventriculomegaly became more severe, changes could be observed in neurons within layers II and III. Furthermore, the cerebral vasculature exhibited a decrease in the number of vessels and a preponderance of profiles oriented parallel to the meningeal surface. The severity of these effects followed a rostral to caudal gradient, such that the occipital cortex demonstrated the most damage. These results suggest that both the motor deficits and the subtle cognitive deficiencies seen with hydrocephalus may be attributed to perturbation of neuronal and vascular elements in the cerebral cortex.

Animals↗

PubMedDate not supplied

Celiac artery aneurysm: rationale for celiac axis ligation with excisional treatment.

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Aged↗

PubMedDate not supplied

Stereotactically guided thrombolysis of deep cerebral hemorrhage: preliminary results.

BACKGROUND: The neurologic outcome from conventional medical or surgical therapy of intracerebral hemorrhage (ICH) is poor; however, stereotactically guided instillation of thrombolytic agents to dissolve parenchymal clots due to hypertensive hemorrhage has recently produced results equal to or better than those obtained with conventional therapies. OBJECTIVE: To determine whether stereotactic thrombolysis of deep ICH is safe and effective. METHODS: We administered urokinase to clots in four patients with hypertensive ICH. After the hemorrhage was localized using angiography and computed tomography-assisted stereotactic technique, a ventricular catheter was used to administer urokinase to the clot. RESULTS: Preliminary results showed dramatic reduction in clot volume within 48 hours of initiating treatment and modest clinical improvement in all four patients. No further hemorrhages were seen after treatment. Three patients ultimately died of non-neurologic causes. CONCLUSIONS: With careful patient selection, stereotaxy-assisted thrombolytic therapy may be an advance in the treatment of certain cases of ICH.

Aged↗