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Biomedical subjects

D L Phillips

Publications and source records attributed to D L Phillips.

At least 19 recordsLinked to original sources
PubMed1999

The effects of antirhino- and enteroviral vinylacetylene benzimidazoles on cytochrome P450 function and hepatic porphyrin levels in mice.

In an ongoing effort to identify an orally bioavailable compound for the treatment of rhino- and enteroviral infections, a series of vinylacetylene benzimidazoles was recently examined. Previous studies demonstrated the potential for these compounds to possess both good in vitro antiviral activity as well as acceptable oral plasma concentrations in mice. Optimization of these properties led to four compounds as candidates for further evaluation. In view of the recognized potential for certain acetylenic drugs both to inhibit cytochrome P450 enzymes by mechanism-based inactivation and to possibly perturb heme metabolism, information regarding drug effects on cytochromes P450 and hepatic porphyrin levels was sought. In an initial single-dose pharmacokinetic study, the four selected compounds were given orally to mice, and both plasma concentrations and porphyrin levels were determined. Two of the compounds, 4 and 5, caused a pronounced increase in liver porphyrin levels whereas compounds 6 and 7 exhibited almost no effect on porphyrin levels. Analysis of plasma concentrations showed that only 4 and 5 gave significant exposure and that 6 and 7 produced negligible levels of drug in the plasma even at the highest dose tested (500 mg/kg). A multiple dose study was then initiated in which compounds 4 and 5 were given for 1 week in daily oral doses to mice. Upon completion of dosing, liver was analyzed for cytochrome P450-dependent 7-ethoxyresorufin O-deethylase (EROD) and benzphetamine N-demethylase (BND) activities, total cytochrome P450 content, and porphyrin levels. Both vinylacetylenes showed dose dependent inhibitory and induction effects on EROD and BND activities. In addition, these compounds caused a marked increase in hepatic porphyrin levels. Therefore, while all four selected compounds displayed potent antiviral activity and two of the compounds exhibited acceptable pharmacokinetic properties, the hepatic effects of these latter two compounds suggest the potential for drug induced porphyria with multidose therapeutic use.

Acetylene↗
PubMed1998

Synthesis and pharmacology of conformationally restricted raloxifene analogues: highly potent selective estrogen receptor modulators.

The 2-arylbenzothiophene raloxifene, 1, is a selective estrogen receptor modulator (SERM) which is currently under clinical evaluation for the prevention and treatment of postmenopausal osteoporosis. In vivo structure-activity relationships and molecular modeling studies have indicated that the orientation of the basic amine-containing side chain of 1, relative to the stilbene plane, is an important discriminating factor for the maintenance of tissue selectivity. We have constructed a series of analogues of 1 in which this side chain is held in an orientation which is orthogonal to the stilbene plane, similar to the low-energy conformation predicted for raloxifene. Herein, we report on the synthesis of these compounds and on their activity in a series of in vitro and in vivo biological assays reflective of the SERM profile. In particular, we describe their ability to (1) bind the estrogen receptor, (2) antagonize estrogen-stimulated proliferation of MCF-7 cells in vitro, (3) stimulate TGF-beta3 gene expression in cell culture, (4) inhibit the uterine effects of ethynyl estradiol in immature rats, and (5) potently reduce serum cholesterol and protect against osteopenia in ovariectomized (OVX) rats without estrogen-like stimulation of uterine tissue. These data demonstrate that one of these compounds, LY357489,4, is among the most potent SERMs described to date with in vivo efficacy on bone and cholesterol metabolism in OVX rats at doses as low as 0.01 mg/kg/d.

Animals↗
PubMed1997

Discovery and synthesis of [6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]b enzo[b]thiophene: a novel, highly potent, selective estrogen receptor modulator.

Raloxifene,[2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl] [4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride (2), is representative of a class of compounds known as selective estrogen receptor modulators (SERMs) that possess estrogen agonist-like actions on bone tissues and serum lipids while displaying potent estrogen antagonist properties in the breast and uterus. As part of ongoing SAR studies with raloxifene, we found that replacement of the carbonyl group with oxygen ([6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]b enzo[b]thiophene hydrochloride, 4c) resulted in a substantial (10-fold) increase in estrogen antagonist potency relative to raloxifene in an in vitro estrogen dependent cell proliferation assay (IC50 = 0.05 nM) in which human breast cancer cells (MCF-7) were utilized. In vivo, 4c potently inhibited the uterine proliferative response to exogenous estrogen in immature rats following both sc and oral dosing (ED50 of 0.006 and 0.25 mg/kg, respectively). In ovariectomized aged rats, 4c produced a significant maximal decrease (45%) in total cholesterol at 1.0 mg/kg (p.o.) and showed a protective effect on bone relative to controls with maximal efficacy at 1.0 mg/kg (p.o.). These data identify 4c as a novel SERM with greater potency to antagonize estrogen in uterine tissue and in human mammary cancer cells compared to raloxifene, tamoxifen or ICI-182,780.

Animals↗
PubMed1997

Structure-activity relationships of selective estrogen receptor modulators: modifications to the 2-arylbenzothiophene core of raloxifene.

The 2-arylbenzothiophene raloxifene, 1, is a selective estrogen receptor modulator which is currently under clinical evaluation for the prevention and treatment of postmenopausal osteoporosis. A series of raloxifene analogs which contain modifications to the 2-arylbenzothiophene core have been prepared and evaluated for the ability to bind to the estrogen receptor and inhibit MCF-7 breast cancer cell proliferation in vitro. Their ability to function as tissue-selective estrogen agonists in vivo has been assayed in a short-term, ovariectomized (OVX) rat model with end points of serum cholesterol lowering, uterine weight gain, and uterine eosinophil peroxidase activity. These studies have demonstrated that (1) the 6-hydroxy and, to a lesser extent, the 4'-hydroxy substituents of raloxifene are important for receptor binding and in vitro activity, (2) small, highly electronegative 4'-substituents such as hydroxy, fluoro, and chloro are preferred both in vitro and in vivo, (3) increased steric bulk at the 4'-position leads to increased uterine stimulation in vivo, and (4) additional substitution of the 2-aryl moiety is tolerated while additional substitution at the 4-, 5-, or 7-position of the benzothiophene results in reduced biological activity. In addition, compounds in which the 2-aryl group is replaced by alkyl, cycloalkyl, and naphthyl substituents maintain a profile of in vitro and in vivo biological activity qualitatively similar to that of raloxifene. Several novel structural variants including 2-cyclohexyl, 2-naphthyl, and 6-carbomethoxy analogs also demonstrated efficacy in preventing bone loss in a chronic OVX rat model of postmenopausal osteopenia, at doses of 0.1-10 mg/kg.

Adenocarcinoma↗
PubMed1997

Predictive factors for respiratory complications after tonsillectomy and adenoidectomy in children.

OBJECTIVE: To determine risk factors predictive of outcomes to aid in the cost-effective preoperative evaluation and postoperative management of patients who are undergoing tonsillectomy and adenoidectomy for obstructed breathing during sleep. DESIGN: A historical cohort study with a nested case-control analysis that examined risk factors associated with postoperative respiratory complications. SETTING: Children's Medical Center of Dallas, Dallas, Tex, which is a pediatric referral hospital for secondary and tertiary pediatric care with both private and university-appointed physicians. PATIENTS: A convenience sample of 355 patients who were undergoing tonsillectomy and adenoidectomy for obstructed breathing during sleep throughout a 1-year period. INTERVENTION: None. MAIN OUTCOME MEASURE: The occurrence of postoperative complications, including airway obstruction, apneas with oxygen desaturations, airway interventions (e.g., endotracheal intubation), or administration of supplemental oxygen, as they related to associated medical conditions (e.g., cerebral palsy or prematurity) and diagnostic tests (e.g., chest x-ray film and electrocardiogram). RESULTS: Five associated medical conditions (cerebral palsy; seizures; age, < or = 3 years; congenital heart disease; and prematurity) were identified as important predictors of a complicated postoperative course using stepwise logistic regression analysis. Those children with an abnormal chest x-ray film or electrocardiogram were also identified as having an associated medical condition that was predictive of postoperative complications. CONCLUSIONS: Children with 1 or more of the associated risk factors identified should be considered candidates for postoperative inpatient observation. A preoperative chest x-ray film and electrocardiogram were found to be of little predictive value, and they are probably not cost-effective screening tests for postoperative respiratory complications.

Adenoidectomy↗
PubMed1997

Nocturnal digestion, cloacal excretion, and digestion-related thermogenesis in pigeons (Columba livia).

Two indicators of nocturnal digestive activity were identified in pigeons. Experiment 1 showed that a sizable amount of food empties from the crop while pigeons are inactive during the night. Experiment 2 showed that the number and volume of cloacal droppings during the night were directly related to the volume of food consumed during the day. The temporal pattern of cloacal droppings in the night was systematically related to features of the nocturnal body temperature (Tb) curves, suggesting that excretory activity is thermogenic in its own right and/or that it is a marker for a thermogenic process in the upper digestive tract. Questions about the relationship between digestion-related thermogenesis and shivering thermogenesis during the night in birds are highlighted by these findings.

Animals↗
PubMed1997

Evaluation of the major metabolites of raloxifene as modulators of tissue selectivity.

Raloxifene (LY139481 HCl) is a selective estrogen receptor modulator (SERM) which blocks the effects of estrogen on some tissues, such as the breast and uterus, while mimicking estrogen in other tissues, such as bone. To study the origins of this unique pharmacology, we have prepared the major metabolites of raloxifene as chemical probes for examining the estrogen receptor function in vitro and in vivo. In human breast cancer cell (MCF-7) related assays, these glucuronide conjugates show little affinity for the estrogen receptor and are more than two orders of magnitude less potent at inhibiting cell proliferation than raloxifene. In non-traditional estrogen target tissue, such as bone, these metabolites are less effective than the parent at inhibiting cytokine-stimulated bone resorbing activity in rat osteoclasts or producing transforming growth factor beta-3 (TGF-beta3). In animal models, tissue distribution studies with radiolabelled metabolite indicate that conversion to raloxifene occurs readily in a variety of tissues including the liver, lung, spleen, kidney, bone and uterus. Differential conversion of metabolite in target organs, such as bone and the uterus, is not observed indicating that the origin of raloxifene's pharmacology does not result from tissue-selective deconjugation of metabolite to parent.

Adenocarcinoma↗
PubMed1997

Hypocholesterolemic activity of raloxifene (LY139481): pharmacological characterization as a selective estrogen receptor modulator.

After once-daily oral dosing in ovariectomized rats, raloxifene (LY139481) hydrochloride produced dose- and time-dependent reductions in serum cholesterol and high-density lipoprotein-cholesterol. Paired-feeding studies demonstrated that effects of raloxifene on serum lipids were not secondary to effects on food consumption. Maximal reductions in serum cholesterol occurred within 4 days of raloxifene administration or sooner, depending on the administered dose. The ED50 for 50% reduction in serum cholesterol by raloxifene was 0.13 +/- 0.04 mg/kg/day (mean +/- S.E.M., n = 17); maximal cholesterol reduction by raloxifene (68%) was significantly less than that produced by estrogen (17 alpha-ethinylestradiol; 89%) after 4 to 7 days of daily dosing. Dose-response curves for cholesterol lowering by raloxifene were generated in the presence of varying doses of 17 alpha-ethinylestradiol; two-way analysis of variance revealed significant interactions between estrogen and raloxifene with respect to cholesterol lowering (P < .001). Furthermore, a high dose of raloxifene (10 mg/kg/day) prevented further reduction of serum cholesterol by estrogen (1-100 micrograms/kg/ day) beyond that produced by raloxifene alone. For a series of closely related structural analogs of raloxifene, log(ED50) values for cholesterol lowering were highly correlated with log(relative binding affinity) for the estrogen receptor (r = 0.93; P < .0001). Thus, cholesterol lowering by raloxifene in ovariectomized rats is mediated primarily via partial agonist effects at estrogen receptors. Taken together with previous observations in uterine tissue of estrogen antagonism by raloxifene in the absence of significant agonism, the present findings support the classification of raloxifene as a selective estrogen receptor modulator.

Animals↗
PubMed1997

Quality systems for unit-use testing devices.

Unit-use testing or single-test-system analysis has existed for many years. Quality-control and quality-assurance procedures have generally used conventional methods and lyophilized or aqueous control materials. Because these materials were readily available and generally accepted, they became part of the quality-assurance program for many early unit-use test systems such as the DuPont aca. Over the years, these control products became standard and are now required as part of good laboratory practice. Technically speaking, however, conventional quality-control methods and materials cannot completely control the test system when used in a unit-use or single-test-system device. When conventional control material is run on a unit-use single-test system, only that testing unit is checked. One cannot test every unit with control material because by definition these are single-test systems: Once the control has been run, the patient's sample cannot be run. Conventional quality-assurance and quality-control methods do not, of themselves, assure quality. A one-size-fits-all, or "two levels per day of use" as outlined in the CLIA '88 regulations, is not appropriate. The divergence between HCFA-approved practices and those of the deemed agencies, coupled with the financial aspects of this quality-control method, led to the formation of the Subcommittee on Unit Use Testing of the National Committee on Clinical Laboratory Standards to develop guidelines for manufacturers, users, and regulators to use in developing new quality systems.

Autoanalysis↗
PubMed1996

Correlation of clinical sinusitis signs and symptoms to imaging findings in pediatric patients.

The purpose of this study was to determine the correlation between signs and symptoms of upper respiratory tract disease and sinus images in a convenience sample of sixty pediatric patients scheduled for computed tomography or magnetic resonance imaging of the head for non-sinus diagnoses over a 2-year period. The study was carried out in a tertiary pediatric referral center. Each patient underwent rhinoscopy and otoscopy just prior to imaging, and each patient's parent was asked to fill out a questionnaire regarding recent symptoms of upper respiratory tract infection; a blinded comparison was then made between respiratory signs and symptoms and images of the paranasal sinuses. Forty-seven percent of patients had abnormalities of their sinus images, and a significant (P < 0.05) correlation was found between the presence of absence of respiratory signs and symptoms and the presence or absence of abnormalities of sinus images, especially in younger patients. In conclusion, a large percentage of pediatric patients undergoing imaging procedures of the head for non-sinus diagnoses have sinus image abnormalities. In the population studied these imaging abnormalities appear to reflect ongoing or resolving upper respiratory tract viral or allergic inflammation.

Adolescent↗
PubMed1996

Environmental estrogens: effects on cholesterol lowering and bone in the ovariectomized rat.

Representative non-steroidal estrogens, from common environmental sources such as plants, pesticides, surfactants, plastics, and animal health products, demonstrated an ability to lower serum cholesterol and prevent bone loss. Specifically, select environmental estrogens (coumestrol, genistein, methoxychlor, bisphenol A, and zeranol) effectively lowered total serum cholesterol in an estrogen-dependent animal model, the ovariectomized rat. Of these entities, coumestrol, methoxychlor, and zeranol prevented ovariectomy-induced bone loss. In an in vitro environment, these compounds competed with 17beta-estradiol for estrogen receptor binding and stimulated cell proliferation in a human breast cancer cell line (MCF-7). In addition to their well-documented effects on reproductive tissue, various environmental estrogens can dramatically affect non-reproductive parameters such as cholesterol lowering and bone metabolism.

Adenocarcinoma↗
PubMed1996

Comparison of HPLC and GC-MS for measurement cocaine and metabolites in human urine.

High-performance liquid chromatography (HPLC) was compared with gas chromatography-mass spectrometry (GC-MS) for quantitation of cocaine, benzoylecgonine, norcocaine, and cocaethylene in urine. Calibration standards were prepared in human urine, and bupivacaine was added as the internal standard for quantitation. After solid-phase extraction, the reconstituted samples were divided into aliquots for analysis by HPLC and GC-MS. The analytical performance of the two methods were compared with regard to sensitivity, precision, and dynamic range. Results of GC-MS and HPLC analyses of nine urine specimens previously confirmed as positive for benzoylecgonine were compared. Analytical results by HPLC were comparable to GC-MS. Therefore, for many laboratories, HPLC is a useful alternative to GC-MS for measuring cocaine and metabolites in urine.

Chromatography, High Pressure Liquid↗
PubMed1995

Stimulatory effects of cocaine and its metabolites on IM-9 human B-lymphoblastoid cells.

This study examined the effect of cocaine and its metabolites benzoylecgonine, norcocaine, and cocaethylene on human B-cell proliferation using IM-9 cells. Cells were incubated with 0.01-10 micrograms/ml of cocaine or metabolite in serum-free medium or medium containing 2% FBS for 24 and 48 h, and [3H] thymidine incorporation into DNA was measured using liquid scintillation counting. Results showed incubation with cocaine and metabolites significantly increased IM-9 cell proliferation. With cocaine, maximal stimulation of 148% (compared to drug-free control) occurred at 1.0 micrograms/ml in serum-free medium at 48 h. Benzoylecgonine and norcocaine showed maximal stimulation at 0.1 micrograms/ml with 170% and 150% stimulation, respectively. Cocaethylene showed maximal stimulation of 146% at 10 micrograms/ml. Drug stability was monitored under incubation conditions using high-performance liquid chromatography (HPLC). We have shown that cocaine and its major metabolites have an immunomodulatory effect on B-cell proliferation at concentrations equivalent to serum levels produced during cocaine use in humans. Since the cocaine metabolites also show an immunomodulatory effect, the immune consequences of cocaine use may be significantly prolonged.

B-Lymphocytes↗
PubMed1995

Financial justification of alternate site testing.

Fixed costs are higher and variable costs lower for clinical laboratory testing than for alternate-site testing (AST). For AST to become cost-effective, variable costs must be reduced. Four models for accounting for the costs of clinical laboratory testing and AST are compared. A common error is to omit some of the indirect costs of a cost-per-test analysis for AST, thereby providing false claims. For a cost-per-test analysis, we recommend that identical categories be used for both the central laboratory and for AST. However, cost-per-test data alone do not completely represent institutional costs or savings associated with laboratory testing at any site.

Centralized Hospital Services↗