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Biomedical subjects

R E White

Publications and source records attributed to R E White.

At least 55 records · Page 3Linked to original sources
PubMed1996

Prodrugs of BMS-183920: metabolism and permeability considerations.

The oral bioavailability of BMS-183920, a diacidic, potent angiotensin II receptor antagonist, is low in rats (approximately 11%). In vivo studies in bile duct-cannulated rats indicated that BMS-183920 was metabolically stable and that the low bioavailability was due to incomplete intestinal absorption. Five acyl-ester prodrugs were synthesized which were 5-15 times more permeable than BMS-183920 through Caco-2 cells. However, limited studies in rats indicated that the oral bioavailability of BMS-183920 was improved only 2-fold, in the best case. The lack of a substantial increase in bioavailability was apparently due to presystemic prodrug hydrolysis or metabolism via N-glucuronidation. Bioavailability of BMS-183920 after oral dosing of a tetrazole-ester prodrug averaged 37%, the most significant improvement within this prodrug series. Interestingly, in vitro studies indicated that the tetrazole-ester prodrug was a substrate for glucuronosyl transferase; however, its rate of bioactivation (hydrolysis) was sufficiently high to provide a substantial increase in bioavailability of BMS-183920. Therefore, while prodrug modification of BMS-183920 improved Caco-2 cell permeability and oral absorption in vivo, the relative extents of hydrolysis (bioactivation) vs metabolism of the prodrug determined whether a substantial improvement in bioavailability was achieved.

Angiotensin Receptor Antagonists↗
PubMed1996

Therapeutic options and results for the management of minimally invasive carcinoma of the breast: influence of axillary dissection for treatment of T1a and T1b lesions.

BACKGROUND: Axillary dissection has maintained a role of primacy for the surgical therapy of invasive carcinoma of the breast for many years. More recently, early (T1) minimally invasive carcinoma of the breast has been diagnosed with increasing frequency, and the necessity of axillary dissection for sampling purposes in these small tumors has been questioned, based primarily on the finding of low rates of axillary metastases. STUDY DESIGN: The Rhode Island State Tumor Registry records of 1,126 patients with T1a or T1b tumors were examined to assess the effect of axillary dissection on patient outcome. These data span 9 years (1985 to 1992) with a median follow-up duration of 64 months. Five-year overall, disease-free, and breast cancer-specific (determinate) survival were determined according to treatment modality. Axillary node positivity was calculated for patients with minimally invasive carcinoma of the breast who underwent axillary dissection. Multivariate statistical methods were used to provide adjustment for known confounding prognostic variables. RESULTS: Omission of axillary dissection occurred in 157 cases and correlated with reductions in overall, disease-free, and breast cancer-specific survival (p < .001 in all cases). Nodal status significantly influenced disease-free survival in minimally invasive carcinoma of the breast (90 percent node-negative compared with 76 percent node-positive, p = .02). Nodal positivity was evident in 18.2 percent of patients undergoing axillary dissection for minimally invasive carcinoma of the breast (9.8 percent for T1a, 19.4 percent for T1b, p = .01). In multivariate analysis, the performance of axillary dissection with breast conservation or modified radical mastectomy were independent predictors of overall survival, as well as disease-free and breast cancer-specific survival. CONCLUSIONS: A significant number of patients with small (less than or equal to 1 cm) invasive tumors of the breast will have axillary metastases at the time of diagnosis. Omission of axillary dissection in these patients was associated with significant impairment of overall, disease-free, and breast cancer-specific survival. Axillary dissection should continue to be a standard approach for the surgical therapy of all patients with invasive carcinoma of the breast, regardless of tumor size.

Adenocarcinoma, Mucinous↗
PubMed1995

Prevalence estimates of alcohol problems in a Veterans Administration outpatient population: AUDIT vs. MAST.

Prior reports have indicated that the prevalence of alcohol-related problems in VA patients is significantly higher than that found in the general population. Prevalence rates, however, are likely to be affected by the screening instrument employed. A sample of 722 VA outpatients awaiting general medical and urgent care treatment was asked to complete two screening questionnaires: the World Health Organization's AUDIT and the brief MAST. Of 508 completed AUDITs, 55 (11%) scored above the cut-offs of 11 for harmful consumption, and 85 (17%) above the more liberal cut-off score of 8; whereas of 501 completed MASTs, 104 (21%) scored above the cut-off. Differences in identification rates are discussed.

Adolescent↗
PubMed1995

A three-dimensional model of aromatase cytochrome P450.

P450 hemeproteins comprise a large gene superfamily that catalyzes monooxygenase reactions in the presence of a redox partner. Because the mammalian members are, without exception, membrane-bound proteins, they have resisted structure-function analysis by means of X-ray crystallographic methods. Among P450-catalyzed reactions, the aromatase reaction that catalyzes the conversion of C19 steroids to estrogens is one of the most complex and least understood. Thus, to better understand the reaction mechanism, we have constructed a three-dimensional model of P450arom not only to examine the active site and those residues potentially involved in catalysis, but to study other important structural features such as substrate recognition and redox-partner binding, which require examination of the entire molecule (excepting the putative membrane-spanning region). This model of P450arom was built based on a "core structure" identified from the structures of the soluble, bacterial P450s (P450cam, P450terp, and P450BM-P) rather than by molecular replacement, after which the less conserved elements and loops were added in a rational fashion. Minimization and dynamic simulations were used to optimize the model and the reasonableness of the structure was evaluated. From this model we have postulated a membrane-associated hydrophobic region of aliphatic and aromatic residues involved in substrate recognition, a redox-partner binding region that may be unique compared to other P450s, as well as residues involved in active site orientation of substrates and an inhibitor of P450arom, namely vorozole. We also have proposed a scheme for the reaction mechanism in which a "threonine switch" determines whether oxygen insertion into the substrate molecule involves an oxygen radical or a peroxide intermediate.

Amino Acid Sequence↗
PubMed1995

Estrogen relaxes coronary arteries by opening BKCa channels through a cGMP-dependent mechanism.

Women rarely suffer cardiovascular dysfunction before menopause, but by the age of 65 a woman becomes as vulnerable to cardiovascular mortality as a man. It has been proposed that estrogens protect against cardiovascular disease; however, the physiological basis of estrogen protection is unknown. In the present study the mechanism of estrogen-induced relaxation of coronary arteries was investigated at the tissue, cellular, and molecular levels. Tissue studies demonstrate that 17 beta-estradiol relaxes porcine coronary arteries by an endothelium-independent mechanism involving K+ efflux, and subsequent studies employing the patch-clamp technique confirmed that estrogen stimulates K+ channel gating in coronary smooth muscle. Perforated-patch recordings from metabolically intact coronary myocytes revealed that 17 beta-estradiol more than doubles steady state outward currents in these cells at positive voltages. Studies of on-cell patches demonstrated a potent stimulatory effect of 17 beta-estradiol on the gating of the large-conductance, Ca(2+)- and voltage-activated K+ (BKCa) channels, while 17 alpha-estradiol had no effect. Furthermore, blocking BKCa channels in intact arteries inhibited estrogen-induced relaxation. The effect of 17 beta-estradiol on BKCa channels was blocked by inhibiting cGMP-dependent protein kinase (PKG) activity and was mimicked by exogenous cGMP or by stimulating PKG activity. Therefore, we propose that 17 beta-estradiol relaxes coronary arteries by opening BKCa channels via cGMP-dependent phosphorylation. This novel mechanism could account for the hypotensive effect of estrogens and help explain, at least in part, why postmenopausal estrogen therapy lowers the risk of cardiovascular disease.

Animals↗
PubMed1995

Effects of bioflavonoids on hepatic P450 activities.

1. The effects of tangeretin, green tea flavonoids, and other flavonoids on 7-ethoxyresorufin-O-deethylase (EROD; 450 1A), 7-pentoxyresorufin-O-dealkylase (PROD; P450 2B), p-nitrophenol hydroxylase (PNPH, P450 2E1), and erythromycin-N-demethylase (ERDM; P450 3A) were examined in induced rat liver microsomes. EROD, PNPH, ERDM, and nifedipine oxidase (NIFO; P450 3A4) were examined in human liver microsomes. 2. All flavonoids tested inhibited EROD activity at higher concentrations in liver microsomes. Flavone and tangeretin were potent inhibitors of EROD, with IC50's of 0.7 and 0.8 microM respectively in rat liver microsomes and 0.15 and 16 microM respectively in human liver microsomes. The green tea flavonoid (-)-epicatechin-3-gallate (ECG) was the most potent inhibitor of EROD in human liver microsomes (IC50 = 75 microM). The effect of the green tea flavonoids on EROD was complex; in addition to inhibition at high concentrations of flavonoid, moderate activation was seen at lower concentrations. 3. 450 2B-, 2E1- and 3A-dependent activities in rat and human liver microsomes were only moderately inhibited by any of the flavonoids tested, and, in general, ECG was the most potent inhibitor for these activities with IC50's ranging from 75 to 300 microM. 4. Tangeretin inhibited EROD activity (P450 1A2) in human liver microsomes in a competitive manner with a Ki = 68 nM. Tangeretin inhibited NIFO activity (P450 3A4) in human liver microsomes in an uncompetitive manner with Ki = 72 microM.

Animals↗
PubMed1994

Photoaffinity labeling of cytochrome P450 2B4: capture of active site heme ligands by a photocarbene.

Spiro[adamantane-2,2'-diazirine], which produces adamantyl carbene upon photolysis, binds tightly to P450 2B4 (KS = 3.2 microM), giving a normal substrate binding difference spectrum. Irradiation of 2-[3H]adamantane diazirine at 365 nm in the presence of native, ferric P450 2B4 resulted in first-order photolysis (t1/2 = 1.8 min). The main product was 2-[3H]adamantanol, with about 6% of the radioactivity covalently bound to P450 2B4. With the ferrous carbonyl form of P450 2B4, 2-adamantanol production decreased and protein labeling increased to 12%. When ferric cyanide 2B4 was used, 2-adamantanecarbonitrile was formed in addition to 2-adamantanol. The nitrile appears to have resulted from capture of the iron-bound cyanide ligand by the carbene. The use of multiple cycles of photolysis increased the percentage of protein labeling to 76%. Photolabeling was inhibited by known 2B4 substrates and inhibitors. Also, N-demethylation of benzphetamine and generation of a substrate binding difference spectrum by benzphetamine were both inhibited stoichiometrically with the fraction of radiolabeled protein. The labeled protein was permanently converted to the high-spin state, as indicated by the characteristic change in the absorbance spectrum, demonstrating irreversible occupation of the substrate binding site by the adamantyl residue. Mild acid hydrolysis of radiolabeled 2B4 at the five Asp-Pro bonds generated a 2-kDa peptide which carried 78% of the radioactivity. These results are interpreted as the result of the active site carbene reacting by three competing pathways: capture of the heme sixth ligand to yield either 2-adamantanol or 2-adamantanecarbonitrile, capture of an unbound active site water molecule to yield adamantanol, and covalent attachment to a protein residue. Thus, the P450 2B4 active site appears to contain at least one unbound water molecule in addition to the heme aquo sixth ligand, even when substrate is present.

Adamantane↗
PubMed1993

Potassium channel stimulation by natriuretic peptides through cGMP-dependent dephosphorylation.

Natriuretic peptides inhibit the release and action of many hormones through cyclic guanosine monophosphate (cGMP), but the mechanism of cGMP action is unclear. In frog ventricular muscle and guinea-pig hippocampal neurons, cGMP inhibits voltage-activated Ca2+ currents by stimulating phosphodiesterase activity and reducing intracellular cyclic AMP; however, this mechanism is not involved in the action of cGMP on other channels or on Ca2+ channels in other cells. Natriuretic peptide receptors in the rat pituitary also stimulate guanylyl cyclase activity but inhibit secretion by increasing membrane conductance to potassium. In an electrophysiological study on rat pituitary tumour cells, we identified the large-conductance, calcium- and voltage-activated potassium channels (BK) as the primary target of another inhibitory neuropeptide, somatostatin. Here we report that atrial natriuretic peptide also stimulates BK channel activity in GH4C1 cells through protein dephosphorylation. Unlike somatostatin, however, the effect of atrial natriuretic peptide on BK channel activity is preceded by a rapid and potent stimulation of cGMP production and requires cGMP-dependent protein kinase activity. Protein phosphatase activation by cGMP-dependent kinase could explain the inhibitory effects of natriuretic peptides on electrical excitability and the antagonism of cGMP and cAMP in many systems.

Animals↗
PubMed1993

Kallmann's syndrome and anorexia nervosa: a diagnostic dilemma.

Kallmann's syndrome is a rare cause of primary amenorrhea, with impairment of release of gonadotropin-releasing hormone and anosmia. We present a case in which Kallmann's syndrome had been diagnosed, but who also fulfilled the diagnostic criteria for anorexia nervosa. We discuss the diagnostic dilemma.

Adult↗
PubMed1993

Data-driven performance improvement in health care: the Joint Commission's Indicator Measurement System (IMSystem).

BACKGROUND: Since 1986, the Joint Commission has worked to create an evaluation system that would remain standards based but would accent an organization's performance as well as its capability to provide care. One component is the Indicator Measurement System (IMSystem), which involves continuous data collection and periodic feedback about specific performance measures, or indicators. An indicator is a quantitative measure of an aspect of patient care. It is not a direct measure of quality; rather it is a screen or flag which indicates areas for more detailed analysis. METHODOLOGY: Sets of indicators, each set related to specific important health care functions such as perioperative care, are established by expert task forces and are then subject to two phases of testing. Alpha testing addresses face validity and feasibility of data collection and may result in indicator revision. In the beta phase, a large group of organizations test the indicators for validity, reliability, and usefulness in improving performance. OPERATIONAL ISSUES: In 1994, the IMSystem will contain ten indicators and participation by hospitals will be voluntary. Once the value of these data in the accreditation process has been demonstrated--possibly as early as 1996--participation will become an integral component of accreditation. Hospitals will transmit indicator data to the Joint Commission but no patient or physician identifiers will leave the hospital. The system will provide organizations with information they can use to monitor and improve their performance, while helping meet external needs for performance measurement.

Data Collection↗
PubMed1992

Benzazepinone calcium channel blockers. 5. Effects on antihypertensive activity associated with N1 and aromatic substituents.

We have shown that the pyrrolidinylmethyl substituent on the lactam nitrogen (N1) of benzazepinone and benzothiazepinone calcium channel blocking agents is resistant to metabolic deamination and generally increases the duration and potency of antihypertensive activity in spontaneously hypertensive rats (SHR) relative to (N,N-dimethylamino)ethyl analogs. Additionally, compounds possessing a substituent on the fused aromatic ring are more resistant to metabolic deacylation of the C3 hydroxy function, which may explain why aromatic substituents also frequently increase the potency and/or duration of antihypertensive activity. Our data also indicate the increased antihypertensive activity associated with these structural modifications is independent of any effects of potency in vitro. Overall, we interpret these results to indicate that these structural modifications improve antihypertensive activity as a result of increased metabolic stability and, consequently, oral bioavailability.

Animals↗
PubMed1992

Benzazepinone calcium channel blockers. 2. Structure-activity and drug metabolism studies leading to potent antihypertensive agents. Comparison with benzothiazepinones.

As part of a program to discover potent antihypertensive analogues of diltiazem (3a), we prepared 1-benzazepin-2-ones (4). Benzazepinones competitively displace radiolabeled diltiazem, and show the same absolute stereochemical preferences at the calcium channel receptor protein. Derivatives of 4 containing a trifluoromethyl substituent in the fused aromatic ring show potent and long-acting antihypertensive activity. Studies of the metabolism of 4 lead to the metabolically stable antihypertensive calcium channel blockers 5a and 5c. Benzazepinone 5a is a longer acting and more potent antihypertensive agent than the second generation diltiazem analogue TA-3090 (3e).

Acetylation↗
PubMed1992

An enzymatic mechanism for potassium channel stimulation through pertussis-toxin-sensitive G proteins.

Many neurotransmitters inhibit secretion from electrically excitable cells by activating pertussis-toxin-sensitive G proteins that modulate voltage-gated ion channels. Recent electrophysiological studies of metabolically intact cells from mammalian and molluscan neuroendocrine systems have implicated protein phosphatases in this process. In this article David Armstrong and Richard White review these studies and suggest a biochemical pathway that might link one of the G proteins to protein phosphatase activity.

Animals↗
PubMed1992

Spinal epidural abscess complicating vertebral osteomyelitis: an insidious cause of deteriorating spinal cord function.

Spinal epidural abscess may complicate vertebral osteomyelitis. The purpose of this report is to discuss its course in two patients with sensory/motor and cognitive impairment and to demonstrate the need for its early detection. Delayed detection may lead to spinal cord injury or meningitis. It may also delay functional return and hinder intensive rehabilitation efforts. Two patients are presented.

Abscess↗
PubMed1992

A derivation of the underlying constructs of just-in-time management systems.

Researchers have recommended that the theoretical constructs underlying just-in-time (JIT) management systems be identified and developed if JIT is to be fully understood and its full capabilities realized. In this study, we advanced this conceptual development through an instrument based on the relevant literature and empirically deriving three underlying constructs: (1) operating structure and control, (2) product scheduling, and (3) quality implementation. We report a content analysis of these constructs and develop propositions regarding their relationships, predecessors, and outcomes.

Data Collection↗
PubMed1992

Increased occurrence of exfoliation in the male, Spanish American population of New Mexico.

Exfoliation syndrome was found to occur much more frequently in the male Spanish American population of New Mexico. This was based on a Veterans Administration Medical Center study in Albuquerque, New Mexico. The prevalence of exfoliation in the Spanish Americans was estimated to be from 3-6 percent and this is consistent with many other such studies performed in the United States and other countries. The Spanish American population is 5.8 times more likely to develop exfoliation than the non-Spanish American population of New Mexico. Exfoliation was found on such eye structures as the lens, iris, ciliary processes, posterior capsule, vitreous face, posterior corneal surface, and arterial chamber angle. Glaucoma capsulare was also studied and it was found that there was not a significant difference between the Spanish American and the non-Spanish American population for developing the condition. However, there was a strong association of glaucoma with the presence of exfoliation in both groups. Based on our results, patients with exfoliation are 22 times more likely to develop glaucoma than are their age-matched controls. Also, 40 percent of the exfoliation patients had glaucoma compared with only 5 percent of the age-matched controls (p less than .001). The patients with glaucoma capsulare were found to have a more medically resistant type of glaucoma, which was consistent with other reports of this condition. There are two theories we propose for the existence of exfoliation in the Spanish American population of New Mexico. The first is a geographic climatic theory that relates exfoliation to greater solar radiation levels due to a high overall altitude and sunny weather in New Mexico.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗