Biomedical subjects

R L Williams

Publications and source records attributed to R L Williams.

At least 199 records · Page 11Linked to original sources

PubMed1992

Bioequivalence of topical corticosteroids: a regulatory perspective.

After reviewing the history of generic drug substitution policy in the United States, this paper discusses issues of equivalence as they apply to topical drug products. Documentation of bioequivalence of topical products has been problematic, and current methods are being re-evaluated by the Food and Drug Administration. The FDA is currently evaluating various extensions of the basic methodology of the Stoughton-McKenzie vasoconstrictor assay, in order to develop a more comprehensive pharmacodynamic methodology for documenting topical drug bioequivalence. A modern pharmacodynamic model is described, based on nonlinear dose-response relationship, a baseline effect, and a maximum or plateau effect. The Agency's goal is a bioequivalent methodology that will be simple, readily performed, and based on more objective methods of measuring the vasoconstrictor response.

Administration, Topical↗

PubMed1992

Bias and 'overcall' in interpreting chest radiographs in young febrile children.

Few studies have examined the diagnostic validity of the examination physician's interpretation of chest radiographs in young febrile children, and none (to our knowledge) the extent to which the "official" (ie, the radiologist's) reading may be biased by access to the examining physician's reading and to other clinical information. The authors studied 287 consecutive chest radiographs obtained in 286 febrile children 3 to 24 months of age without chronic cardiopulmonary disease or known asthma who presented to a children's hospital emergency department between March 1989 and August 1990. The readings by treating pediatricians, official pediatric radiologists, and a "blind" pediatric radiologist were compared. Official radiologists had access to the treating pediatricians' readings and the clinical information provided on the radiography requisition. The blind radiologist knew only that each child was 3 to 24 months of age and febrile, and he was asked to judge the presence or absence of pneumonia. Using the blind radiologist's reading as the "gold standard" for judging validity of the treating physicians' and official radiologists' readings, sensitivity (.677 vs .647), specificity (.828 vs .849), positive predictive value (PPV, .537 vs .571), and kappa index (kappa, .462 vs .475) were quite similar. By contrast, agreement by the treating physicians was considerably higher with the official radiologists' readings as gold standard: sensitivity = .756, specificity = .922, PPV = .795, and kappa = .688. When the treating physician's reading was positive, the official radiologists' positivity rate was much higher than the blind radiologist's (74.4% vs 51.8%, P less than .005), sensitivity was high (.884) but specificity was low (.436), PPV was .663, and kappa was .326.(ABSTRACT TRUNCATED AT 250 WORDS)

Fever↗

PubMed1991

Crystals of a ternary complex of human immunodeficiency virus type 1 reverse transcriptase with a monoclonal antibody Fab fragment and double-stranded DNA diffract x-rays to 3.5-A resolution.

Two crystal forms of complexes have been grown that contain human immunodeficiency virus type 1 reverse transcriptase and a monoclonal antibody Fab fragment. One of the crystal forms (form II, space group P3112, a = 168.7 A, c = 220.3 A) diffracts x-rays to 3.5-A resolution and appears suitable for moderate-resolution structure determination. The form II crystals have the unusual property that their maximum resolution of diffraction and resistance to radiation damage are enhanced by either crystallization in the presence of or soaking with double-stranded DNA primer-template mimics. These crystals may permit structural studies of catalytically relevant complexes and eventually enable us to experimentally observe successive steps in the reverse transcription process.

Antibodies, Monoclonal↗

PubMed1991

Crystallization and preliminary X-ray diffraction analysis of oucleoside diphosphate kinase from Myxococcus xanthus.

Nucleoside diphosphate (NDP) kinase catalyzes the transfer of the gamma-phosphate from a nucleoside triphosphate to a nucleoside diphosphate. Human and rodent forms of this enzyme have been shown to be suppressors of metastasis. Crystals that diffract X-rays to high resolution have been obtained for the recombinant Myxococcus xanthus NDP kinase expressed in and purified from Escherichia coli. Two crystal forms have been obtained. Both forms are orthorhombic, space group I222 (or I2(1)2(1)2(1)) with a = 267.1 A, b = 74.0 A and c = 75.1 A for form I and a = 53.5 A, b = 74.0 A and c = 75.1 A for form II. Form I appears to have five molecules in the asymmetric unit approximately related to each other by a translation of 0.2 along the a axis. Diffraction data have been recorded to 1.9 A for form I and to 2.2 A for form II.

Crystallization↗

PubMed1991

Influence of food on the oral absorption and bioavailability of moricizine.

Moricizine, a unique Class I antiarrhythmic agent, was orally administered with and without a meal to 24 healthy male subjects to determine the effect of food on moricizine absorption and bioavailability. Relative to the fasting state, a standardized breakfast delayed the time to peak plasma moricizine concentration (1.2 vs. 0.9 hr; P less than .03) and lowered peak plasma moricizine concentration by 24% (0.55 vs. 0.72 microgram/mL; P less than .03). Bioavailability, as measured by area under the plasma moricizine concentration versus time curve, was not significantly altered by the meal.

Administration, Oral↗

PubMed1991

Development of a new controlled-release formulation of chlorpheniramine maleate using in vitro/in vivo correlations.

Development of a controlled-released formulation of chlorpheniramine maleate is described, using in vitro/in vivo correlates, according to a process that has been termed "biorelevant dissolution". The process begins with simulations using several possible input rates combined with known disposition parameters of chlorpheniramine maleate. Based on desired plasma concentrations, an input rate is selected for further development which consists of a combination of clinical bioequivalence studies and further in vitro testing and simulations. The method is designed to reduce the requirements for trial and error clinical bioequivalence testing of a new controlled-release formulation.

Administration, Oral↗

PubMed1991

Development of a health habits scale.

The present study is based on the assumption that health habits assessment can make a significant contribution to our understanding of physical and psychological well-being. Thus, the purpose of this study was to develop an easily administered, conceptually sound, and psychometrically adequate health habits scale for use in nursing and health research. A self-report scale consisting of 5 positive health items and 5 negative items was administered initially to a sample of more than 1500 American adults. Subsamples of this group were used in various psychometric evaluations of the scale. A second sample of more than 700 college and noncollege adults also completed the new health habits scale and a number of additional inventories thought to be related conceptually to the new scale. In general, the health scale showed high content validity, good agreement between self- and other-ratings, strong test-retest reliability, and consistent evidence of concurrent and divergent validity. The strengths of the scale are its inclusion of both disease-preventive and health-promoting behaviors, its brevity, and its psychometric development.

Adolescent↗

PubMed1991

Empirical solvation models can be used to differentiate native from near-native conformations of bovine pancreatic trypsin inhibitor.

Several hydration models for peptides and proteins based on solvent accessible surface area have been proposed previously. We have evaluated some of these models as well as four new ones in the context of near-native conformations of a protein. In addition, we propose an empirical site-site distance-dependent correction that can be used in conjunction with any of these models. The set of near-native structures consisted of 39 conformations of bovine pancreatic trypsin inhibitor (BPTI) each of which was a local minimum of an empirical energy function (ECEPP) in the absence of solvent. Root-mean-square (rms) deviations from the crystallographically determined structure were in the following ranges: 1.06-1.94 A for all heavy atoms, 0.77-1.36 A for all backbone heavy atoms, 0.68-1.33 A for all alpha-carbon atoms, and 1.41-2.72 A for all side-chain heavy atoms. We have found that there is considerable variation among the solvent models when evaluated in terms of concordance between the solvation free energy and the rms deviations from the crystallographically determined conformation. The solvation model for which the best concordance (0.939) with the rms deviations of the C alpha atoms was found was derived from NMR coupling constants of peptides in water combined with an exponential site-site distance dependence of the potential of mean force. Our results indicate that solvation free energy parameters derived from nonpeptide free energies of hydration may not be transferrable to peptides. Parameters derived from peptide and protein data may be more applicable to conformational analysis of proteins. A general approach to derive parameters for free energy of hydration from ensemble-averaged properties of peptides in solution is described.

Animals↗

PubMed1991

Nitroglycerin absorption from transdermal systems: formulation effects and metabolite concentrations.

We recently compared plasma concentrations of nitroglycerin and its two dinitrate metabolites in 16 healthy male subjects after application of two controlled-release transdermal formulations of the drug. Analysis of the resulting plasma concentration-time curves indicated that the two formulations did not produce equivalent concentrations of parent drug or either of the dinitrate metabolites during the initial period of dosing. In addition, both formulations produced concentrations of the two dinitrate metabolites that exceeded the concentration of the parent drug by severalfold. Even if the pharmacologic effect of the dinitrate metabolites is low compared to that of nitroglycerin, these higher concentrations may contribute to the effect of nitroglycerin. Scrutiny of the ratio of 1,2-glyceryl dinitrate to 1,3-glyceryl dinitrate in the 16 subjects confirmed previous observations that preferential formation of the 1,2-glycerol dinitrate metabolite may occur depending on the route of administration. This ratio may thus be indicative of the bioavailability of nitroglycerin following transdermal application. Additional data suggesting racial differences in nitroglycerin absorption after transdermal application are presented.

Administration, Cutaneous↗

PubMed1991

Expression of v-src induces aberrant development and twinning in chimaeric mice.

The role of the proto-oncogene c-src in mouse development has been investigated by studying the consequences of expressing its viral homologue, v-src. Embryonic stem (ES) cell lines with differing levels of v-src tyrosine kinase activity have been used to generate chimaeric mice. Whereas a low level of v-src expression is compatible with embryogenesis, chimaeras derived from ES clones with high levels of v-src activity develop abnormally and die on the 8th-9th day of gestation. These abnormalities are characterized by the formation of twin or multiple embryos within the same Reichert's membrane, and by the arrest of embryonic development at the late egg cylinder stage, accompanied by relative expansion of the visceral yolk sac (VYS) and hyperplasia of the VYS endoderm. These results demonstrate for the first time that deregulated expression of the src protooncogene product can induce developmental abnormalities during early embryogenesis.

Animals↗

PubMed1990

Absorption and disposition of a new low-dose combination formulation of hydrochlorothiazide and triamterene.

Two studies are reported that assess the bioequivalence of a new half-strength drug combination containing 25 mg hydrochlorothiazide and 37.5 mg triamterene compared to a full-strength formulation containing 50 mg hydrochlorothiazide and 75 mg triamterene. The first study (I) compared the absorption and disposition of the two drugs after administration of two tablets of the half-strength product as a single dose compared to a single dose of the full-strength product. The second study (II) assessed the bioavailability of the new product given as a single tablet on two occasions separated by an interval of 12 h compared to the full-strength product given as a single dose. Urine parameters in the first study indicated bioequivalence of the half-strength to the full product for both rate and extent of absorption. When given in divided doses, the half-strength product demonstrated bioequivalence to the full-strength product for extent of absorption. Additional data from the second study suggest that absorption of triamterene is greater when given in smaller divided doses and when given at night.

Biological Availability↗

PubMed1990

Ab initio self-consistent field and potential-dependent partial equalization of orbital electronegativity calculations of hydration properties of N-acetyl-N'-methyl-alanineamide.

Using a recently developed parallel computation algorithm, ab initio self-consistent field (SCF) calculations were carried out to estimate the relative hydration energies for 12 low-energy conformations of N-acetyl-N'-methyl-alanineamide. The requisite SCF calculations were carried out using 6-31G and 6-31G* basis sets, both in the absence and presence of a perturbing potential arising from a model solvent. The alpha R, alpha L, polyproline II (PII), and pi helical conformations were preferentially stabilized by the solvent potential, whereas conformations with intramolecular hydrogen-bonding C5 and C7 were preferred in the gas phase. Average vicinal nmr coupling constants (JNH-C alpha H), calculated using the total energies of the various solvated conformations, were consistent with observed coupling constants for this peptide in aqueous solution. Substantial alteration of the solute charge density occurred upon equilibration with the reaction field, as was exemplified in changes both in the molecular dipole moments and in atom-centered multipoles, when the molecule was transferred from a medium of low dielectric constant to one of high dielectric constant. In order to model these changes in charge density with an empirical scheme, we have implemented a novel monopolar representation of the solute charge density based on a potential-dependent form of partial equalization of orbital electronegativities (PDPEOE). In the atom-centered point charge PDPEOE representation, charge flows from one region of the solute to another in response to external fields. Hydration energies calculated using the PDPEOE representation are similar to those calculated by the SCF procedure. Also, the PDPEOE calculations yielded changes in molecular dipole moments upon solvation that agreed closely with the changes in the calculated ab initio SCF dipole moments.

Alanine↗

PubMed1990

Isolation of embryonic stem (ES) cells in media supplemented with recombinant leukemia inhibitory factor (LIF).

The isolation of pluripotent murine embryonic stem (ES) cells has previously been achieved by coculturing the ES cells with fibroblast feeder cells. In this report we demonstrate that ES cell lines can be isolated from murine 129/Sv He blastocysts in the absence of feeder cells in culture medium supplemented with recombinant leukemia inhibitory factor (LIF). Three of the ES cell lines (MBL-1, MBL-2, and MBL-3) were isolated by directly explanting blastocysts, whilst two ES cell lines (MBL-4 and MBL-5) were isolated from blastocysts pretreated by immunosurgery. Three of the ES cell lines contained the Y chromosome (MBL-1, MBL-2, and MBL-5) with a high proportion of the cells displaying a normal diploid karyotype with a modal chromosome number of 40. All of the ES cell lines tested expressed the stem cell markers ECMA-7 and alkaline phosphatase, which were lost on removal of LIF when the ES cells differentiated into a variety of cell types. The full developmental potential of the ES cells was determined by injecting cells from two of the independently derived ES cell lines, MBL-1 and MBL-5, into C57BL/6J blastocysts. A high proportion of the pups born were chimeric as judged by coat pigmentation. Subsequent breeding established that the ES cells had contributed to the germ line. These results demonstrate that feeder cells are not essential for the isolation of pluripotent ES cell lines.

Animals↗

PubMed1990

Formation of germ-line chimeras from embryonic stem cells maintained with recombinant leukemia inhibitory factor.

Murine embryonic stem (ES) cells can be maintained as stem cells in vitro only in the presence of feeder cells or a soluble factor produced by a number of cell lines. We have previously demonstrated that leukemia inhibitory factor (LIF) is the molecule which prevents ES cell differentiation in culture. In this report we demonstrate that recombinant LIF can substitute for feeder cells in maintaining the full developmental potential of ES cells. The totipotent D3 ES cell line, previously isolated and maintained on growth-arrested primary embryo fibroblasts, was transferred to media supplemented with 1000 U/ml (10 ng/ml) recombinant LIF. In the presence of LIF the ES cells were maintained for over 2 months as undifferentiated cells in the absence of any feeder cells. When injected into blastocysts the ES cells which had been maintained in LIF-supplemented media efficiently formed germ-line chimeras.

Animals↗

PubMed1990

Prevalence of sleep apnea in men with erectile dysfunction.

Sleep studies were performed on 1,025 patients complaining of erectile dysfunction. In addition to standard measures of sleep stage and nocturnal penile tumescence, respiratory activity was evaluated. The number of episodes of sleep apnea per hour (Apnea Index--AI) was calculated for each patient. The overall prevalence of sleep apnea activity in this sample was: 43.8 percent with AI greater than or equal to 5; 27.9 percent with AI greater than or equal to 10; and 19.6 percent with AI greater than or equal to 15. These results confirm that sleep apnea activity is common in men with erectile dysfunction. This high prevalence also indicates that further study is needed to elucidate pathophysiology of erectile failure in men with sleep apnea.

Adult↗

PubMed1990

Diabetes, erectile dysfunction, and sleep-related erections.

Sleep-related erections were assessed in conjunction with polysomnography in 100 diabetic and 400 nondiabetic men with complaints of erectile problems. We also measured bulbocavernosus reflex latency, heart rate response to deep breathing, postural-related blood pressure changes, penile arterial sufficiency, and brachial blood pressures. To investigate the relationship between diabetes and erectile capacity, the results obtained from men with and without diabetes were compared. Men with diabetes had fewer sleep-related erections, less tumescence time, diminished penile circumference increase, and lower penile rigidity than nondiabetic men. These diabetes-related differences were found regardless of the maximum penile rigidity observed. The diabetic group had less heart rate response to deep breathing and lower penile blood pressures than the nondiabetic group, but only among men with maximum penile rigidity less than 500 g. These data indicate that both neurological and vascular mechanisms are involved to a greater degree in organic diabetic impotence than in the organic erectile dysfunction that occurs in nondiabetic men. Finally, the pattern of lower values for measures of nocturnal tumescence among diabetic men, compared to nondiabetic men, occurred in all age groups, except the oldest. Among impotent men, age 65 years or older, no difference was found between men with and without diabetes. This suggests that diabetes may foreshadow some of the age-related pathophysiological processes associated with erectile dysfunction.

Adult↗

PubMed1990

The safety and pharmacokinetics of GLQ223 in subjects with AIDS and AIDS-related complex: a phase I study.

A phase I dose-escalation study was performed to evaluate the safety and pharmacokinetics of a single intravenous infusion of GLQ223 in subjects with AIDS and AIDS-related complex (ARC). The active ingredient in GLQ223 is trichosanthin. Trichosanthin, imported from China, is the active drug in community-initiated treatment programs for patients with HIV infection. Eighteen subjects were enrolled, 10 with AIDS and eight with ARC. All subjects were monitored for tolerance and toxicity. Immunological and virological parameters were also followed. GLQ223 administration was not associated with notable toxicity with the exception of one subject who experienced a severe neurological adverse reaction. No consistent or sustained changes in CD4+ lymphocyte populations or HIV antigen levels were observed. Serum concentrations of GLQ223 that were comparable to concentrations shown to have antiviral activity in vitro were achieved transiently but may not have been maintained for a sufficient duration to exert antiretroviral effects. Further studies are indicated to determine pharmacodynamic properties of GLQ223, its optimal dosing schedule, and whether GLQ223 or related molecules will be useful in the treatment of HIV infection.

AIDS-Related Complex↗

PubMed1990

Sympathetic hyperplasia and neuroblastomas in transgenic mice expressing polyoma middle T antigen.

Transgenic mice carrying a cDNA to the polyoma virus middle T (mT) antigen linked to the thymidine kinase promoter were generated to study the consequences of deregulated expression of mT-associated tyrosine kinase activity in a wide variety of tissues. Four independent transgenic founder animals were obtained, from one of which was established a transgenic line. This mouse and all its offspring developed multiple neuroblastomas between 2 and 3 months of age. Expression of the transgene (assayed by tyrosine kinase assay and in situ hybridization) was restricted to the neurons of the central and peripheral nervous tissue, probably because of a positional effect of the transgene integration. Characteristic preneoplastic lesions in the sympathetic ganglia and in the adrenal medulla were identified from which the neuroblastomas originated. The tumors arising in these mice show striking analogies to human neuroblastomas, including the sites of development of the tumors, their histological and ultrastructural appearance, and the expression of diagnostic markers, such as synaptophysin, and high expression of the N-myc oncogene. This animal model thus provides a unique tool for studying growth control in sympathetic neuroblasts and the pathogenesis of neuroblastoma.

Adrenal Medulla↗