QSAR and k-nearest neighbor classification analysis of selective cyclooxygenase-2 inhibitors using topologically-based numerical descriptors.

Experimental IC(50) data for 314 selective cyclooxygenase-2 (COX-2) inhibitors are used to develop quantitation and classification models as a potential screening mechanism for larger libraries of target compounds. Experimental log(IC(50)) values ranged from 0.23 to > or = 5.00. Numerical descriptors encoding solely topological information are calculated for all structures and are used as inputs for linear regression, computational neural network, and classification analysis routines. Evolutionary optimization algorithms are then used to search the descriptor space for information-rich subsets which minimize the rms error of a diverse training set of compounds. An eight-descriptor model was identified as a robust predictor of experimental log(IC(50)) values, producing a root-mean-square error of 0.625 log units for an external prediction set of inhibitors which took no part in model development. A k-nearest neighbor classification study of the data set discriminating between active and inactive members produced a nine-descriptor model able to accurately classify 83.3% of the prediction set compounds correctly.

NMR spectroscopic investigations of mixed aggregates underlying highly enantioselective 1,2-additions of lithium cyclopropylacetylide to quinazolinones.

The solution structures of mixed aggregates derived from lithium alkoxides and lithium acetylides were investigated as part of a program to develop practical syntheses of quinazolinone-based nonnucleoside reverse transcriptase inhibitors. Low-temperature (6)Li, (13)C, and (15)N NMR spectroscopies reveal that mixtures of lithium cyclopropylacetylide (RCCLi), a (+)-carene-derived amino alkoxide (ROLi), and lithium hexamethyldisilazide (LiHMDS) in THF/pentane afford a (RCCLi)(3)(ROLi) mixed tetramer, a C(2)-symmetric and asymmetric (RCCLi)(2)(ROLi)(2) mixed tetramer, and a C(3)-symmetric (RCCLi)(ROLi)(3) mixed tetramer. Analogous mixtures of RCCLi/ROLi in Et(2)O and Me(2)NEt also provide 3:1, 2:2, and 1:3 mixed tetramers. The stereochemistry of aggregation is highly sensitive to the medium. The C(2)-symmetric (RCCLi)(2)(ROLi)(2) mixed tetramer is formed in Et(2)O, whereas the asymmetric isomer is formed in Me(2)NEt. LiHMDS in THF is shown to be an efficient proton scavenger without forming LiHMDS-RCCLi or LiHMDS-ROLi mixed aggregates. LiHMDS-RCCLi mixtures form mixed aggregates in Me(2)NEt.

Prediction of surface tension, viscosity, and thermal conductivity for common organic solvents using quantitative structure-property relationships.

Predictive models for the surface tension, viscosity, and thermal conductivity of 213 common organic solvents are reported. The models are derived from numerical descriptors which encode information about the topology, geometry, and electronics of each compound in the data set. Multiple linear regression and computational neural networks are used to train and evaluate models based on statistical indices and overall root-mean-square error. Eight-descriptor models were developed for both surface tension and viscosity, while a nine-descriptor model was developed for thermal conductivity. In addition, a single nine-descriptor model was developed for prediction of all three properties. The results of this study compare favorably to previously reported prediction methods for these three properties.

Duodenal ulcer disease: treatment by surgery, antibiotics, or both.

Peptic ulcer disease is a function of derangements in intraluminal aggressive factors and defects in endogenous defense mechanisms. Some of these previously described abnormalities may be caused by the presence of H pylori colonization of the antral mucosa and antral mucosal metaplasia of the proximal duodenum. In vivo and in vitro data are being accrued that support this concept, particularly with reference to the mechanisms of H pylori-induced aberrations in gastric and duodenal mucosal function. Standard medical therapy for PUD includes antisecretory medications as well as antibiotics designed to eradicate H pylori colonization. It is rare for patients with an asymptomatic but nonhealed DU to come to surgical attention. Those who do, along with those with a symptomatic DU refractory to all forms of medical therapy, should be offered a proximal gastric vagotomy. Life-threatening bleeding from a DU requires secure suture ligation of the base of the ulcer combined with truncal vagotomy and pyloroplasty. Those patients with non-life-threatening hemorrhage most likely will have been treated with intensive medical therapy, including antibiotics, and should be treated with truncal vagotomy and antrectomy. If H pylori is still present histologically in the antral specimen, sensitivity testing of the bacteria should lead to the use of appropriate antibiotic therapy. Both of these populations of patients with bleeding DU will likely have a lower rebleeding rate if H pylori is eradicated than if they are treated with surgery alone. Perforated DU should be treated with omental patch closure and antisecretory medications and antibiotics to eradicate H pylori, particularly when there are comorbid conditions such as shock, perforation for more than 24 hours, or if the patient has not had significant symptoms for 3 months preperforation. Those patients with perforated DU who are appropriate candidates for proximal gastric vagotomy in addition to omental patch closure and antibiotic therapy do well; however, the true benefit of proximal gastric vagotomy over omental patch closure with antibiotic therapy, in this population, has yet to be clearly demonstrated.

An efficient chiral moderator prepared from inexpensive (+)-3-carene: synthesis of the HIV-1 non-nucleoside reverse transcriptase inhibitor DPC 963.

The beta-amino alcohol 4 beta-morpholinocaran-3 alpha-ol is prepared by addition of morpholine to alpha-3,4-epoxycarane utilizing anhydrous magnesium bromide as Lewis acid promoter. The enantiopure amino alcohol is uniquely effective as a chiral moderator for the addition of lithium cyclopropylacetylide to an unprotected N-acylketimine. This reaction provides an efficient route to the second generation NNRTI drug candidate DPC 963.

Giant fundic polyp complicating attenuated familial adenomatous polyposis.

This case details the development of a rapidly growing polypoid mass in the proximal stomach in a patient with known attenuated familial adenomatous polyposis. Surgical resection was required and histology showed hyperplasia with extensive areas of dysplastic adenomatous change. This case illustrates that patients with the attenuated form of familial adenomatous polyposis are at risk for multiple neoplasia distinct from those patients with the classic form of familial adenomatous polyposis.

Prediction of inhibition of the sodium ion-proton antiporter by benzoylguanidine derivatives from molecular structure.

The use of quantitative structure-activity relationships to predict IC50 values of 113 potential Na+/H+ antiporter inhibitors is reported. Multiple linear regression and computational neural networks (CNNs) are used to develop models using a set of information-rich descriptors. The descriptors encode information about topology, geometry, electronics, and combination hybrids. A five-descriptor CNN model with root-mean-square (rms) errors of 0.278 log units for the training set and 0.377 log units for the prediction set was developed. Examination of data set subclasses showed that systematic structural variations were also well-encoded resulting in 100% accuracy of prediction trends. An experiment involving a committee of five CNNs was also performed to examine the effect of network output averaging. This showed improved results decreasing the training and cross-validation set rms error to 0.228 log units and the prediction set rms error to 0.296 log units.

The origins of heterogeneous catalysis by platinum: Johann Wolfgang Döbereiner's contributions.

A number of examples of what Jöns Jacob Berzelius was later (1835) to call catalysis, have been known from antiquity. One of the most prominent of these, dating from the early eighteenth century, was the action of platinum black on hydrogen observed in 1823 by Johann Wolfgang Döbereiner (1780-1849), Professor of Chemistry and Technology at the Universität Jena (1810-1849), who is regarded as the discoverer of platinum catalysis. His startling discovery led to his invention of the widely used pneumatic gas lighter (Döbereinersches Feuerzeug) and was cited by Berzelius in his formulation of the concept of catalysis.

Pretreatment with SR48692 has different effects on central neurotensin-induced gastric mucosal defense and inhibition of gastric acid secretion in rats.

Neurotensin is a tridecapeptide present in the brain and gastrointestinal tract. Administration of neurotensin into the brain results in responses in the gastrointestinal tract, suggesting a role for neurotensin in the interrelationships that comprise the brain-gut axis. Intracerebroventricular (i.c.v.) administration of neurotensin protects the gastric mucosa against injury caused by cold water restraint (CWR) and also inhibits gastrin-stimulated gastric acid secretion. The hypothesis tested was that these two actions of neurotensin are mediated via its high-affinity receptor. Rats were given neurotensin (60 microgram, i.c.v.) prior to CWR or pylorus ligation after pretreatment with SR48692, a nonpeptide antagonist of the high-affinity neurotensin receptor (0.25 or 2.5 microgram, i.c.v., or 10, 100, or 500 microgram kg-1, i.p.). Neurotensin reduced cold water restraint (CWR)-induced gastric mucosal injury and inhibited gastrin-stimulated acid secretion. Pretreatment with SR48692 (2.5 microgram, i.c.v., or 100 microgram kg-1, i.p.) prior to CWR blocked neurotensin's protection of the gastric mucosa against injury. In contrast, pretreatment with 2.5 microgram SR48692, i.c.v., did not block neurotensin-induced inhibition of acid secretion, whereas 500 microgram kg-1, i.p., partially blocked the inhibition. SR48692 (2.5 microgram, i.c.v.) inhibited acid secretion, suggesting that SR48692 has agonist activity in this system. These results suggest that central neurotensin protects the gastric mucosa against CWR-induced injury via its high-affinity receptor. The receptor that mediates central neurotensin-induced inhibition of gastric acid secretion does not appear to be the high-affinity receptor since the neurotensin receptor antagonist SR48692, when given i.c.v., had agonist activity, inhibiting stimulated acid secretion. High-affinity neurotensin receptors in the periphery appear to play a role in inhibition of stimulated gastric acid secretion.

Mesolimbic expression of neurotensin and neurotensin receptor during stress-induced gastric mucosal injury.

Neurotensin is a neurotransmitter present in the brain and gastrointestinal tract. Intracerebroventricular injection of neurotensin protects rats from gastric mucosal injury caused by cold water restraint (CWR). Direct injection of neurotensin into the nucleus accumbens (NACB), part of the mesolimbic dopamine system, reduces gastric mucosal injury, suggesting that neurotensin confers protection on the mucosa through interaction with the mesolimbic system. The hypothesis is that the concentration of neurotensin in the mesolimbic system decreases during CWR, affecting the expression of neurotensin and the neurotensin receptor. After 1 h of CWR, neurotensin concentration significantly decreased 41% in the NACB and returned toward control concentrations after 2 h of CWR. The concentration of neurotensin mRNA significantly decreased 46% after 1 h CWR and returned toward control after 2 h. In contrast, neurotensin binding sites in the NACB increased from 159 to 228 fmol/mg protein after 1 h of CWR and increased significantly to 280 fmol/mg protein after 2 h CWR, whereas the level of neurotensin receptor mRNA significantly decreased 51 and 50% at 1 and 2 h, respectively. These studies show that neurotensin concentration within the mesolimbic system is transiently reduced by CWR stress and that the number of neurotensin binding sites increases, presumably in response to the decrease in neurotensin.

Stress, the brain, and the gastric mucosa.

Exposure of rats to 2 hours of cold water restraint is associated with both macroscopic and microscopic gastric mucosal injury. Administration of neurotensin into the lateral ventricle or into the nucleus accumbens, one of the mesolimbic dopamine system nuclei, is associated with protection when given before exposure to cold water restraint. Under conditions of cold water restraint, pretreatment with central neurotensin is associated with maintenance of gastric mucosal blood flow and an increase in endogenous gastric mucosal PGE2 activity. In addition, pretreatment with 6-hydroxy dopamine into the mesolimbic nuclei, which depletes them of endogenous dopamine, prior to exposure to cold water restraint, ameliorates the protective effect of central neurotensin. Centrally administered neurotensin inhibits basal, pentagastrin-, carbachol-, and 2-deoxy-D-glucose-induced but not histamine-induced gastric acid secretion. This antisecretory effect is ameliorated by parenteral pretreatment with haloperidol and domperidone. Taken together, these observations support the hypothesis that centrally administered neurotensin, particularly into the nuclei of the mesolimbic dopamine system, confers protection against gastric mucosal injury produced by 2 hours of cold water restraint. This affect may be due, in part, to inhibition of acid secretion and maintenance of mucosal blood flow mediated by an increase in gastric mucosal PGE2 activity.

Increased intestinal permeability in rats with graft versus host disease.

BACKGROUND/AIMS: The study of graft versus host disease of the intestine has significant clinical relevance and may also be a model for other immune mediated intestinal diseases. There presently is no simple non-invasive test that can be used to evaluate graft versus host disease induced intestinal injury in humans or animal models. This study tested the hypothesis that graft versus host disease leads to an increase in host bowel permeability as assessed by the relative urinary excretion of orally administered lactulose and rhamnose. METHODS: The urinary excretion ratio of orally administered lactulose and rhamnose was determined daily for two weeks in (Lewis x Brown-Norway) F1 rats with graft versus host disease caused by either the transplantation of parental (Lewis) small bowel or the intraperitoneal injection of parental (Lewis) splenic lymphocytes. RESULTS: Significant twofold to fourfold increases in the lactulose to rhamnose ratio were seen in both small bowel transplant and splenic lymphocyte transfer animals suffering from graft versus host disease during the second postoperative week. This effect occurred sooner in small bowel transplant than in splenic lymphocyte transfer animals (postoperative day 7 versus 11, respectively). The signs of graft versus host disease, including splenomegaly and altered intestinal mucosal architecture, as well as the increased lactulose to rhamnose ratio were significantly attenuated in small bowel transplant animals treated with cyclosporine A (10 mg/kg/day). CONCLUSIONS: Graft versus host disease is associated with an increase in the lactulose to rhamnose clearance ratio reflecting an increase in host bowel permeability. This increase, along with the signs of systemic graft versus host disease, can be significantly ameliorated by cyclosporine A. The lactulose to rhamnose clearance ratio is a non-invasive technique that can be used to assess the intestinal effects of graft versus host disease and the associated increase in intestinal permeability.

Comparison of rest thallium-201 imaging and rest technetium-99m sestamibi imaging for assessment of myocardial viability in patients with coronary artery disease and severe left ventricular dysfunction.

OBJECTIVES: We prospectively compared myocardial uptake of thallium-201 (201Tl) at rest with rest technetium-99m (99mTc) sestamibi uptake in the same patients, using quantitative singlephoton emission computed tomography (SPECT). BACKGROUND: Because of only slightly delayed redistribution, 99mTc-sestamibi uptake at rest may be less than 201Tl uptake, thereby underestimating the extent of viability. METHODS: Twenty patients (2.25 stenoses per patient) with a mean left ventricular ejection fraction of 33 +/- 2% underwent early and 3-h delayed rest 201Tl SPECT, rest 99mTc-sestamibi SPECT and two-dimensional echocardiography. RESULTS: The 280 scan segments were classified as either a normal, mild reduction in viability, defined as delayed 201Tl uptake < or = 75% and > or = 5%, or a severe reduction in viability, defined as delayed 201Tl uptake < 50%. Mild and severe defects were further classified as fixed or having rest 201Tl redistribution. Comparisons by patients were made using repeated measures analysis of variance and Dunnett's multiple comparisons test to compare 99mTc-sestamibi with initial rest 201Tl and delayed 201Tl uptake. Twenty patients had at least one mild fixed defect (95 total segments). The average percent uptake in these defects for initial 201Tl, delayed 201Tl and 99mTc-sestamibi was 62.5 +/- 2.7%, 63.1 +/- 7.1% and 67.3 +/- 9.7%, respectively (p = NS). Twelve patients (27 segments) had mild redistribution defects on serial rest 201Tl imaging. The average percent uptake was 61.6 +/- 5.2% for initial 201Tl, 67.0 +/- 9.1% for delayed 201Tl and 67.7 +/- 12.4% for 99mTc-sestamibi defects. Technetium-99m sestamibi uptake was not significantly different than that for delayed 201Tl but was significantly greater than initial 201Tl uptake. Seventeen patients (52 segments) had severe fixed 201Tl defects. The average percent uptake was 38.9 +/- 7.3% for initial 201Tl, 38.3 +/- 12.2% for delayed 201Tl and 42.7 +/- 14.2% for 99mTc-sestamibi defects in these patients (p = NS). Ten patients (19 segments) had severe redistribution defects on rest 201Tl imaging. The average percent uptake was 37.0 +/- 8.5% for initial 201Tl, 42.9 +/- 8.6% for delayed 201Tl and 44.5 +/- 11.3% for 99mTc-sestamibi defects. As was seen for mild 201Tl redistribution defects, 99mTc-sestamibi uptake was significantly higher than initial 201Tl uptake, but not significantly different than delayed 201Tl uptake in these severe defects. CONCLUSIONS: Technetium-99m sestamibi uptake after injection at rest is comparable to 201Tl uptake after injection at rest in patients with severe coronary artery disease and left ventricular dysfunction, suggesting comparable worth for viability assessment.

Intracerebroventricular secretin enhances pancreatic volume and bicarbonate response in rats.

BACKGROUND: Although secretin has been found within the brain, its central role in pancreatic exocrine function has not been previously addressed. The hypothesis that intracerebroventricular secretin enhances pancreatic volume and bicarbonate output at doses that have no effect when given intravenously was tested. METHODS: Sprague-Dawley rats had a cannula stereotactically placed into the left lateral cerebral ventricle 24 hours before study. At laparotomy the bile and pancreatic ducts were separately cannulated and excluded for tared collections and bicarbonate assay. RESULTS: Increasing doses of intracerebroventricular secretin (0.005, 0.05, and 0.5 microgram/1.0 microliter) induced a significant dose-related increase in bicarbonate output (2.95, 3.32, and 4.02 microEq/30 min, respectively) above basal (2.62 microEq/30 min) compared with control or intracerebroventricular saline treated animals. Pancreatic volume increased to 59.7 microliters at the lowest intracerebroventricular dose and increased (p < 0.025) to 65.8 microliters at the 0.05 intracerebroventricular secretin dose when compared with basal (59.4 microliters). To show that this was not a systemic effect of secretin, intravenous infusion of secretin at 0.005 and 0.05 microgram/kg/hr failed to stimulate either volume or bicarbonate output compared with that observed with intracerebroventricular secretin over the same dose range. CONCLUSIONS: These observations indicate that intracerebroventricular secretin stimulates pancreatic volume and bicarbonate output and suggest that central secretin may play a role in the regulation of exocrine pancreatic secretion.

Awake epidural anesthesia is associated with improved natural killer cell cytotoxicity and a reduced stress response.

BACKGROUND: Laparotomy under general anesthesia is associated with depressed natural killer cell cytotoxicity (NKCC) and compromised clearance of tumor cells. We tested the hypothesis that awake epidural anesthesia (AEA) improves NKCC compared to conventional general endotracheal anesthesia (GEA). PATIENTS AND METHODS: Preoperative, perioperative, and postoperative (day 3) NKCC, plasma epinephrine, norepinephrine, cortisol levels, and 24-hour urinary cortisol levels were measured in 20 patients undergoing open colectomy under either AEA or GEA. RESULTS: Preoperative and postoperative measurements were not significantly different in the two groups. Patients receiving GEA had a significant reduction in NKCC from 36% +/- 4% preoperatively to 22% +/- 4% perioperatively (P = 0.02). Patients receiving AEA had no significant change in NKCC. Perioperative plasma epinephrine and cortisol levels were higher with GEA than AEA. The perioperative 24-hour urinary cortisol excretion values were significantly higher in the group receiving GEA, suggesting a greater stress hormone response in this group compared to AEA patients. CONCLUSIONS: Compared to GEA, AEA appears to preserve perioperative NKCC. This effect may be related to an attenuated stress hormone response associated with AEA. Cancer patients may have improved killing of embolized tumor cells during surgery performed under AEA.

Water-clear cell adenoma of the parathyroid. A case report with immunohistochemistry and electron microscopy.

We report a water-clear cell adenoma of the parathyroid gland, a lesion which to our knowledge has not been described previously. Like its rare but well-described hyperplastic counterpart, water-clear cell hyperplasia, this adenoma is composed of cells with abundant foamy-to-granular cytoplasm and mild nuclear pleomorphism. The cells form glandular structures and cell nests separated by fine fibrovascular septae. The tumor cells stain positively with anti-parathyroid hormone and show characteristic glassy and flocculate material by electron microscopy. Unlike water-clear cell hyperplasia, water-clear cell adenoma is a solitary lesion that compresses the residual nonneoplastic parathyroid gland.

Comparison of the costs associated with medical and surgical treatment of obesity.

BACKGROUND: We compared the long-term costs and outcomes of gastric bypass versus medical therapy (very low-calorie diet plus weekly behavioral modification) for obese patients. METHODS: A successful outcome was defined as the loss of at least one third of excess weight that was maintained for the duration of the study. A minimal cost was assigned: $3000 for medical and $24,000 for surgical treatment. A cost per pound of weight lost for all patients successfully monitored was calculated. The Federal Trade Commission recently asked all weight loss programs to report this cost for patients at least 2 years after therapy. RESULTS: A total of 201 patients entered surgical and 161 entered medical therapy. The surgical group was initially heavier (mean body mass index [kg/m2] +/- SE = 49.3 +/- 0.6 versus 41.2 +/- 0.7, p < 0.01), but each group's lowest mean body mass index was similar (31.8 versus 32.1, respectively). A significantly higher percentage of patients in the surgical versus the medical group were still successful at year 5: 89% versus 21%. The cost per pound lost for medical therapy exceeded the cost of surgical therapy in the sixth posttreatment year (both more than $250/pound). CONCLUSIONS: Surgical treatment appears to be more cost-effective at producing and maintaining weight loss. It is imperative that long-term follow-up studies be funded to definitely establish this finding.

Graft-versus-host disease after small bowel transplantation is associated with host colonic injury.

The present studies were undertaken to evaluate the histologic effects of graft-versus-host disease on the host colon after small bowel transplantation. Graft-versus-host disease was produced in six Lewis x Brown Norway F1 rats by performing vascularized, out-of-continuity small bowel transplants from parental Lewis donors. Host proximal and distal colon were sampled 14 days after operation when signs of graft-versus-host disease, including weight loss and splenomegaly, were present. Tissue was assessed histologically by blinded observer and compared to eight sham-operated controls. Three histologic features were noted to be statistically increased in diseased animals: (1) mucin loss; (2) crypt abscesses; and (3) large lymphoid aggregates in the mucosa and submucosa. These features were more commonly noted in the distal rather than the proximal colon. Another group of five grafted animals treated with cyclosporine A (10 mg/kg/day intramuscularly) still lost weight but did not display overt signs of graft-versus-host disease and had normal-sized spleens. There was normal mucin content and no evidence of crypt abscesses in these treated animals, although large lymphoid aggregates were present. It is concluded that mucin loss, crypt abscesses, and large lymphoid aggregates are characteristics of graft-versus-host disease-induced colonic injury in this model and that these changes are most evident in the distal colon. Cyclosporine A therapy does not completely reverse the histological changes of colonic graft-versus-host disease. This model may be useful in studying the mechanisms by which immune mediated colitides preferentially affect the distal colon.