Biomedical subjects

D A Edwards

Publications and source records attributed to D A Edwards.

At least 37 records · Page 2Linked to original sources

PubMed1997

Large porous particles for pulmonary drug delivery.

A new type of inhalation aerosol, characterized by particles of small mass density and large size, permitted the highly efficient delivery of inhaled therapeutics into the systemic circulation. Particles with mass densities less than 0.4 gram per cubic centimeter and mean diameters exceeding 5 micrometers were inspired deep into the lungs and escaped the lungs' natural clearance mechanisms until the inhaled particles delivered their therapeutic payload. Inhalation of large porous insulin particles resulted in elevated systemic levels of insulin and suppressed systemic glucose levels for 96 hours, whereas small nonporous insulin particles had this effect for only 4 hours. High systemic bioavailability of testosterone was also achieved by inhalation delivery of porous particles with a mean diameter (20 micrometers) approximately 10 times that of conventional inhaled therapeutic particles.

Administration, Inhalation↗

PubMed1997

Deafferentation of the olfactory bulbs of male rats reduces erection to remote cues from females.

If male rats are paired with a receptive, soliciting female rat in a setting that prevents physical contact, but permits auditory, visual, and olfactory contact, some will have erections of the penis--noncontact erections (NCE). Surgical deafferentation of the olfactory bulbs from all the known chemosensory systems of the nasal septum renders rats anosmic, decreases sexual performance in copulation tests with females, and substantially reduces the frequency of NCE. Thus, NCE appear to be primarily regulated though the olfactory perception of volatile chemosensory cues from receptive females.

Animals↗

PubMed1997

A theoretical model of erosion and macromolecular drug release from biodegrading microspheres.

A theoretical model is outlined for predicting the time evolution of total mass, mean molecular weight, and drug release for the case of a spherical bulk-eroding microsphere, prepared by a double emulsification procedure and containing a hydrophilic drug, such as a protein or peptide. Explicit analytical formulae are derived for calculating the time evolution of measurable macroscopic characteristics, such as drug release or mean molecular weight. Microsphere hydration, polymer erosion, and drug release phases are each described. Results indicate that polymer degradation by only random-chain scission or only end scission (or unzipping) cannot explain experimentally observed kinetics of particle mass loss and molecular weight change; thus, a combined model (incorporating both random and end scission) is proposed. A general methodology for determining the microscopic transport coefficients (such as polymer degradation rate constant or drug diffusion coefficient) from erosion and release data is outlined. This paradigm is applied to the specific case of 50:50 poly(D,L-lactic-co-glycolic acid (PLGA) microspheres encapsulating glycoprotein 120 (gp 120), a candidate AIDS vaccine. Predictions permit comparisons with experimental data for mean weight- and number-averaged molecular weights, as well as for mass loss and protein release. Other comparisons are made with data appearing in the literature for release of tetanus toxoid from PLA and PLGA microspheres of variable molecular weight. Agreement between theory and experiment is observed.

AIDS Vaccines↗

PubMed1996

The nucleation of receptor-mediated endocytosis.

A theory of the mechanical origins of receptor-mediated endocytosis shows that a spontaneous membrane complex formation can provide the stimulus for a local membrane motion toward the cytosol. This motion is identified with a nucleation stage of receptor-mediated endocytosis. When membrane complexes cluster, membrane deformation is predicted to be most rapid. The rate of growth of membrane depressions depends upon the relative rates of approach of aqueous cytosolic and extracellular fluids toward the cell membrane. With cytosolic and extracellular media characterized by apparent viscosities, the rate of growth of membrane depressions is predicted to increase as the extracellular viscosity nears the apparent viscosity of the cytosol and then to decrease when the extracellular viscosity exceeds that of the cytosol. To determine whether these trends would be apparent in the overall endocytosis rate constant, an experimental study of transferrin-mediated endocytosis in two different cell lines was conducted. The experimental results reveal the same dependence of internalization rate on extracellular viscosity as predicted by the theory. These and other comparisons with experimental data suggest that the nucleation stage of receptor-mediated endocytosis is important in the overall endocytosis process.

Biophysical Phenomena↗

PubMed1996

Variable responses of species and strains to white mineral oils and paraffin waxes.

Recent dietary studies on mineral hydrocarbon (MHC) white oils and waxes have shown inflammatory effects in Fischer 344 (F-344) rats, but not in other rat strains or dogs. Histopathologic effects seen in F-344 rats include mesenteric lymph node histiocytosis, liver granulomas, and inflammation of the mitral valve (only seen with paraffin waxes). Human ingestion of MHC can result in noninflammatory lipogranulomas (oil droplets) in tissues which are regarded as clinically unimportant. It is speculated that inherent interspecies differences in pharmacokinetics and/or immune function may contribute to the differential response to MHC seen in F-344 rats. The F-344 rat retains greater amounts of MHC in target tissues compared to other rat strains and dogs and appears to be more sensitive immunologically to MHC than other species, including humans. This strain may be predisposed to these effects as indicated by a high background incidence of inflammatory granulomatous lesions in control female F-344 rats. Because of its apparently unique sensitivity, relevance of effects seen in F-344 rat to human health is questionable and requires further investigation.

Animals↗

PubMed1996

Androgen receptor immunoreactivity and mating-induced Fos expression in forebrain and midbrain structures in the male rat.

The distribution of androgen receptor immunoreactive-neurons, mapped with the PG21 anti-androgen receptor antibody, was compared in male rat brains with the distribution of Fos-immunoreactive neurons induced by mating. In gonadally intact, but not in castrated male rats, substantial numbers of androgen receptor-containing neurons were present in a variety of forebrain and midbrain regions. The PG21 antibody apparently had a higher affinity for occupied than for non-occupied androgen receptors. Androgen receptor-immunoreactive regions included the medial preoptic area and other forebrain areas previously identified as containing androgen receptors, the dorsal and ventral periaqueductal gray, and a midbrain region that included the lateral part of the central tegmental field, part of the caudal zona incerta, the subparafascicular nucleus of the thalamus and the peripeduncular nucleus. Fos-expressive neurons were essentially absent in non-mated males but were present in the brains of rats which mated to ejaculation. All brain regions in which androgen receptor-immunoreactive neurons were counted also expressed Fos immunoreactivity after mating, and there was considerable overlap between the distributions of androgen receptor- and Fos-immunoreactive neurons. In a second experiment, we used immunofluorescent techniques to document the intraneuronal co-localization of Fos with androgen receptor immunoreactivity in the medial preoptic area, medial amygdala, and central tegmental field. In these regions mating-induced Fos immunofluorescence was exclusively localized in androgen receptor-immunofluorescent neurons. However, not all androgen receptor neurons were Fos expressive, suggesting that only some androgen-sensitive neurons were activated during mating. These results are consonant with the view that hormone actions on forebrain and midbrain structures influence the neuronal activity correlated with mating.

Animals↗

PubMed1996

Spontaneous vesicle formation at lipid bilayer membranes.

Unilamellar vesicles are observed to form spontaneously at planar lipid bilayers agitated by exothermic chemical reactions. The membrane-binding reaction between biotin and streptavidin, two strong transmembrane neutralization reactions, and a weak neutralization reaction involving an "antacid" buffer, all lead to spontaneous vesicle formation. This formation is most dramatic when a viscosity differential exists between the two phases bounding the membrane, in which case vesicles appear exclusively in the more viscous phase. A hydrodynamic analysis explains the phenomenon in terms of a membrane flow driven by liberated reaction energy, leading to vesicle formation. These results suggest that energy liberated by intra- and extracellular chemical reactions near or at cell and internal organelle membranes can play an important role in vesicle formation, membrane agitation, or enhanced transmembrane mass transfer.

Bacterial Proteins↗

PubMed1996

Hypothalamic and olfactory control of sexual behavior and partner preference in male rats.

Sexually active male rats prefer a sexually receptive female to a nonreceptive female, and partner-preference tests provide one way of studying sexual motivation. Surgical deafferentation of the olfactory bulbs from all the known chemosensory systems of the nasal septum renders rats anosmic. In Experiment 1, we show that, although bulb deafferentation of male rats decreases some aspects of sexual performance, most deafferented males copulate and partner preference is not affected. In Experiment 2, we show that large excitotoxin lesions of the preoptic hypothalamus eliminate copulation, an effect that is correlated with damage to the anterior portions of the medial and lateral preoptic area. Lesions also decrease partner preference, an effect that is correlated (r = 0.82) with damage to a small part of the bed nucleus of the stria terminalis. Most males who do not copulate after hypothalamic lesions show a persistent, albeit reduced, preference for receptive females over nonreceptive females. This preference appears to depend on olfactory ability because bulb deafferentation of lesioned, noncopulating males virtually eliminates partner preference.

Animals↗

PubMed1996

Hydrogels with enhanced mass transfer for transdermal drug delivery.

The sonophoretic transport rates of monomeric insulin and vasopressin across human skin in vitro in the presence of a 20 kHz ultrasound field are shown to differ substantially depending on whether molecules enter the skin from a saline solution or from a viscous ultrasonic coupling medium (specifically, a methyl cellulose hydrogel or viscous sol). Theoretically, the reduction in sonophoretic transport caused by the hydrogels can be explained by boundary layers that form within the hydrogel owing to the relatively rapid rate of molecular transport across the (ultrasonically) permeated stratum corneum as well as poor diffusive mass transfer between the skin and gel. The results of in vitro experiments performed with an ac current accompanying the ultrasound show that the mass-transfer barrier posed by the hydrogel can be eliminated for both vasopressin and insulin by suppressing the diffusive boundary layers, indicating that relatively high rates of sonophoretic molecular transport across human skin are achievable when hydrogels are used as the ultrasound coupling medium as long as method is used to induce molecular mixing within the gel.

Biological Transport↗

PubMed1995

A mechanistic study of ultrasonically-enhanced transdermal drug delivery.

Although ultrasound has been shown to enhance the transdermal transport of a variety of drugs, the mechanisms underlying this phenomenon are not clearly understood. In this paper, we evaluate the roles played by various ultrasound-related phenomena, including cavitation, thermal effects, generation of convective velocities, and mechanical effects, in the ultrasonic enhancement of transdermal drug delivery (sonophoresis). Our experimental findings suggest that among all the ultrasound-related phenomena evaluated, cavitation plays the dominant role in sonophoresis using therapeutic ultrasound (frequency range, 1-3 MHz; intensity range, 0-2 W/cm2). Furthermore, confocal microscopy results indicate that cavitation occurs in the keratinocytes of the stratum corneum upon ultrasound exposure. It is hypothesized that oscillations of the cavitation bubbles induce disorder in the stratum corneum lipid bilayers, thereby enhancing transdermal transport. Evidence supporting this hypothesis is presented using skin electrical resistance measurements. Finally, a theoretical model is developed to predict the effect of ultrasound on the transdermal transport of drugs. The model predicts that sonophoretic enhancement depends most directly on the passive permeant diffusion coefficient, rather than on the permeability coefficient through the skin. Specifically, permeants passively diffusing through the skin at a relatively slow rate are expected to be preferentially enhanced by ultrasound. The experimentally measured sonophoretic transdermal transport enhancement for seven permeants, including estradiol, testosterone, progesterone, corticosterone, benzene, butanol, and caffeine, agree quantitatively with the model predictions. These experimental and theoretical findings provide quantitative guidelines for estimating the efficacy of sonophoresis in enhancing transdermal drug delivery.

Administration, Cutaneous↗

PubMed1994

Brainstem auditory evoked response development in preterm and term baboons (Papio hamadryas).

Brainstem auditory evoked responses were recorded longitudinally from 11 neonatal baboons (Papio hamadryas), 6 of which were preterm. Recordings were made in unsedated animals from day 161 to day 362 after conception (term = 182 days). The pattern of development of both waveform morphology and of wave latency was consistent with that seen in the human neonate, with a rapid maturation of the response during the perinatal period, and then a slower development to adult values. Brainstem conduction time was measured from the wave I to wave IV interval, and this demonstrated a similar pattern, with a rapid decrease in latency up to term, and then decreasing more slowly to reach adult values by 4 months of age in the baboon.

Aging↗

PubMed1994

A linear theory of transdermal transport phenomena.

A theory of charge, fluid-mass, and solute (including macromolecular) transport through porous media is applied to describe transport phenomena across the external layer of mammalian skin. Linear relationships are derived between transport fluxes and applied fields. These relationships introduce six effective transdermal transport coefficients. Formulas for each of these coefficients are provided. The practical relevance of these parameters is emphasized in the specific context of transdermal drug delivery. By employing typical physiological values for the various geometrical and physicochemical parameters that appear in the formulas for the transdermal transport coefficients, predictions are made for transport rates of charge, fluid mass, and solute species across a uniform-thickness skin sample contained within a diffusion-cell apparatus. These results are used to explore transdermal phenomena involving forced convection, current flow, electroosmosis, iontophoresis, and molecular diffusion (including convective dispersion). Comparisons with existing transdermal drug delivery data are made. On the basis of these comparisons, the theory suggests that transdermal transport in the presence of an electrical field may occur through corneocytes of the stratum corneum. The theory confirms the importance of a shunt route for small ion transport, as well as an intercellular route of transport for passive diffusion of noncharged substances. These latter conclusions, also based on comparisons with experimental data, are consistent with previous statements in the literature. A new form of solute transport enhancement, termed transdermal convective dispersion, is included in the theory, and methods for its measurement are described. Generalizations and future applications of the theory are discussed.

Administration, Cutaneous↗

PubMed1994

Screening petrochemicals for contact hypersensitivity potential: a comparison of the murine local lymph node assay with guinea pig and human test data.

Over the last few years, the Murine Local Lymph Node Assay (MLLNA) has received considerable attention as a more quantitative, less expensive alternative to the guinea pig assays currently employed to identify potential human contact allergens. At this time, several companies are involved in both independent and joint efforts to validate the MLLNA with their products. This report describes the preliminary results of an Exxon-sponsored research effort to validate the assay with selected materials that are representative of our company's diverse chemical and petroleum product groups. Nine test materials were chosen for which there already existed guinea pig and/or human patch sensitization data. When the MLLNA results were compared to those data obtained from currently used predictive tests (guinea pig, human patch test), the MLLNA showed good agreement for moderate and strong sensitizers. However, the assay may be prone to the potential confounding effects of irritation (false positives), may be insensitive to weak sensitizers, and may be influenced by vehicle selection.

Animals↗

PubMed1994

Preoptic and subthalamic connections with the caudal brainstem are important for copulation in the male rat.

Bilateral lesions of either the medial preoptic area/anterior hypothalamus (MPAH) or a subthalamic region that includes the caudal zona incerta eliminate copulation in male rats. Pathways connecting the MPAH and subthalamus with the caudal brainstem may help regulate sexual behavior. Experiment 1 showed that bilateral coronal transections of the pontine tegmentum reduce mating and that the combination of a unilateral tegmental cut with a contralateral excitotoxin lesion of either the MPAH (Experiment 2) or subthalamus (Experiment 3) virtually eliminates copulation. Asymmetric bilateral damage appears to eliminate mating through a bilateral effect common to the transection and the lesion--the destruction of connections linking the MPAH and subthalamus with the caudal brainstem. These results indicate that preoptic and subthalamic connections with the caudal brainstem are important for copulation in the male rat.

Animals↗

PubMed1993

Long-term results of treatment of peptic stricture of the oesophagus with the Angelchik prosthesis.

An Angelchik prosthesis was inserted in 43 patients with a peptic stricture above a hiatus hernia; 16 showed columnar lining of the oesophagus below the stricture. The mean preoperative bore of strictures was 8.7 mm. Within months, and without dilatation, 33 strictures shortened, 35 widened and of these 13 disappeared with a mean bore of 11.7 mm. In the long term, three more strictures resolved but three recurred. Final measurements gave a mean bore of 12.2 mm. The mean follow-up was 3.5 years. Symptomatic and radiological assessments suggested that the prosthesis was less effective when sited in the chest.

Abdomen↗

PubMed1993

Pathways linking the olfactory bulbs with the medial preoptic anterior hypothalamus are important for intermale aggression in mice.

Manipulations affecting olfaction, as well as bilateral lesions of the medial preoptic anterior hypothalamic (MPAH) continuum, decrease intermale aggression in mice. In the present study, unilateral removal of an olfactory bulb was combined with a contralateral lesion of the MPAH. This surgery, like bulbectomy and bilateral lesions of the MPAH, substantially decreased aggressive behavior. This surgery bilaterally destroys the ipsilateral links between the olfactory bulbs and the MPAH, and it is this disruption that presumably causes the decrease in aggression. The effect is not due to removal of an olfactory bulb combined with hypothalamic damage per se, because ipsilaterally lesioned/bulbectomized males continued to fight without decrement after surgery. These results provide compelling evidence that multisynaptic neural pathways linking the chemosensory systems of the olfactory bulbs with the rostral hypothalamus are involved in the regulation of intermale aggression in mice.

Aggression↗

PubMed1993

Intermale aggression in mice: does hour of castration after birth influence adult behavior?

In the mouse, perinatally present testicular androgens promote the development of the propensity for adult intermale aggression. In the newborn male mouse plasma testosterone more than doubles during the first 2 h after birth and then falls rapidly to remain relatively low for the remainder of the 24-h period after birth. To study whether this surge in plasma testosterone influences aggressiveness we castrated some male mice within 1 h after birth i.e., before the surge. We castrated other males between 1.5-6 h after birth, or 1, 6, or 12 days after birth. Males were given testosterone as adults and tested for aggression for 5 weeks. Males castrated within 1 h after birth were not clearly different from males castrated 1.5-6 h after birth with respect to aggressive behavior, although males in both groups were substantially less aggressive than males castrated later in life. Thus, the perinatal surge in plasma testosterone in the mouse does not appear to make a unique contribution to the organization of mechanisms for intermale aggression. Rather, this surge is probably the initial stimulus that begins the postnatal process by which testicular hormones promote the development of the potential for adult aggressive behavior. This process appears to be complete by 6 days after birth.

Aggression↗

PubMed1992

Parent educational attainment and adolescent cigarette smoking.

In a longitudinal design, this study examined psychosocial mediators of the effects of parental educational attainment on adolescent smoking acquisition and also examined whether smoking transition had different antecedents among adolescents from families of varying educational backgrounds. Parents' low educational attainment acted as a moderate to strong risk factor for the initial onset of smoking among middle school girls. Some of this effect was mediated by the higher smoking prevalence among both parents and friends of these adolescent girls, as well as by their lowered expectations for academic success. However, these variables only partially mediated the effect of parent education. There were few indications of differential antecedents of smoking acquisition among adolescents from less and more highly educated families. Implications for public health antismoking campaigns are discussed.

Achievement↗