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Biomedical subjects

Ronald A Siegel

Publications and source records attributed to Ronald A Siegel.

12 recordsLinked to original sources
PubMed2006

Investigation of a cellular pharmacodynamic model exhibiting sharp response sensitivity and tolerance.

The potential relevance of a kinetic model for switch-like behavior in biochemical reactions to pharmacodynamics is explored. This model, which postulates that drug acts by modulating the balance of kinase and phosphatase activities, and their effect on the phosphorylation state of an effector molecule critical in determining drug effect, predicts sharp concentration-effect profiles without explicit incorporation of cooperativity. The degree of sharpness depends on concentration of the critical effector. It is argued that such a model can account for inter-individual differences in pharmacodynamic sensitivity profiles, as well as intra-individual changes in sensitivity associated with time-varying physiological processes or disease. By augmenting the model with a kinetic description of critical effector synthesis and degradation in the nonphosphorylated and phosphorylated forms, a putative mechanism for drug tolerance is revealed. The combined model predicts that tolerance, in addition to attenuating the maximum effect, may lead to a decrease in apparent Hill coefficient.

Animals↗
PubMed2006

Theoretical and experimental exploration of rules for combining transport parameters in laminar membranes.

Permeabilities, time lags, and mean first passage times were measured in silastic (Sil) and ethylene vinyl acetate copolymer (EVAc) membranes and in the series composites Sil/EVAc and EVAc/Sil. These measurements were used to test phenomenological rules derived previously [R. A. Siegel, J. Phys. Chem. 95, 2556 (1991)] relating the parameters of the constituent membranes to the same parameters for the membrane composites. Reasonable agreement was found between experimental results and these rules. As predicted, permeability and time lag are the same in either direction of transport through the series composite, while mean first passage time is direction dependent. In addition to the experimental results, the combination rules are rederived using the partition/diffusion model of membrane transport, and certain new theoretical connections are noted.

Biological Transport↗
PubMed2006

Chemically controlled self-assembly of protein nanorings.

The exploitation of biological macromolecules, such as nucleic acids, for the fabrication of advanced materials is a promising area of research. Although a greater variety of structural and functional uses can be envisioned for protein-based materials, systematic approaches for their construction have yet to emerge. Consistent with theoretical models of polymer macrocyclization, we have demonstrated that, in the presence of dimeric methotrexate (bisMTX), wild-type Escherichia coli dihydrofolate reductase (DHFR) molecules tethered together by a flexible peptide linker (ecDHFR(2)) are capable of spontaneously forming highly stable cyclic structures with diameters ranging from 8 to 20 nm. The nanoring size is dependent on the length and composition of the peptide linker, on the affinity and conformational state of the dimerizer, and on induced protein-protein interactions. Delineation of these and other rules for the control of protein oligomer assembly by chemical induction provides an avenue to the future design of protein-based materials and nanostructures.

Binding Sites↗
PubMed2006

Enhanced permeation of diazepam through artificial membranes from supersaturated solutions.

The present work consists of studies of saturated and supersaturated solutions of diazepam (DZP) in [glycofurol (GF)/water] cosolvent systems, which are a potential dosage form for intranasal administration of DZP in rapid response to epileptic seizure emergencies. Equilibrium solubility of DZP increased in a convex manner with GF content, and also increased with temperature. Rapidly mixed supersaturated 40 mg/mL solutions displayed temporal stability, with long periods before onset of crystallization. Permeation of supersaturated DZP across polydimethylsiloxane (PDMS) membranes, chosen as an in vitro model for nasal mucosa, was shown to be well described by Theeuwes's transference equation, when DZP was formulated up to three times its solubility in a particular cosolvent vehicle. Transference and time lag were independent of vehicle composition, indicating that permeation enhancement was due virtually exclusively to enhanced driving force due to supersaturation. Implications of these results on potential intranasal DZP delivery systems based on supersaturation are discussed.

Administration, Intranasal↗
PubMed2006

A hydrogel-based implantable micromachined transponder for wireless glucose measurement.

In this paper, we report on the design and characterization of a new hydrogel-based implantable wireless glucose sensor. The basic device structure is a passive [inductor/capacitor (LC)] micromachined resonator coupled to a stimuli-sensitive hydrogel, which is confined between a stiff nanoporous membrane and a thin glass diaphragm. As glucose molecules pass through the nanoporous membrane, the hydrogel swells and deflects the flexible glass diaphragm, which is the movable plate of the variable capacitor in the totally integrated passive LC resonator. The corresponding change in resonant frequency can be remotely detected. A glucose- sensitive phenylboronic acid-based hydrogel was loaded into the microtransponder, and its sensitivity and time response were measured. Prior to hydrogel loading, the sensitivity of the pressure sensor to applied air pressure was measured to be -222 kHz/kPa over the frequency range 51-->42 MHz. The sensor showed a sensitivity of -34.3 kHz/mM over the glucose concentration range 0-20 mM (at pH 7.4), and a response time of 90 min. The dynamic response, although unacceptable at such values, can be easily improved by decreasing the hydrogel thickness and reducing the sensor and porous membrane thicknesses. The transponder's overall dimensions were 5x5x0.8 mm3, small enough for subcutaneous implantation.

Biosensing Techniques↗
PubMed2004

Hard and soft micromachining for BioMEMS: review of techniques and examples of applications in microfluidics and drug delivery.

Recent development in microfabrication (micromachining, microelectromechanical systems, MEMS) permits the integration of hard and soft structures, and enables the design of controllable microfluidic systems, which may be applied to drug delivery. In this paper, we present a tutorial review of both classical "hard" and more recent "soft" micromachining techniques. We then provide examples where these techniques are combined to produce hydrogel-based microfluidic control systems. The most complex of these systems utilizes a very small hydrogel based on phenylboronic acid to control the flow of an insulin solution in response to changes in glucose concentration.

Drug Delivery Systems↗
PubMed2002

New mode of drug delivery: long term autonomous rhythmic hormone release across a hydrogel membrane.

This note demonstrates a novel mode of rhythmic drug delivery, which is independent of external modulation or physiological stimulation. Rhythmic behavior is attributed to negative, nonlinear feedback between the swelling state of a hydrogel membrane and the enzymatic conversion of glucose to hydrogen ion. The system pulsates in the presence of a constant level of glucose, thus distinguishing it from insulin delivery devices that respond to changes in glucose concentration. As an example, gonadotropin-releasing hormone (GnRH) was released in short, repetitive pulses over 1 week.

Biological Transport↗
PubMed2002

Multipulse drug permeation across a membrane driven by a chemical pH-oscillator.

Chemical pH-oscillators provide a potential means for modulating the delivery of acidic or basic drugs across lipophilic membranes. Previous attempts to exploit this notion were not completely successful due to quenching of the pH oscillator in the presence of the drug, most likely by a buffering mechanism. Here we show that multiple, periodic pulses of drug flux across a membrane can be achieved when the concentration of drug is sufficiently low. Advantage is taken of a pH oscillator system whose periodicity is slower than that of previously considered oscillators.

Diffusion Chambers, Culture↗
PubMed2002

Ionizable drugs and pH oscillators: buffering effects.

It has been proposed that chemical pH oscillators may form a basis for periodic, pulsed drug delivery of weak acids and bases across lipophilic membranes. However, drugs have been shown to interfere with the ability of the chemical systems to oscillate, and rhythmic delivery of drugs by this means has been demonstrated only under constrained circumstances. Herein, we provide evidence that low concentrations of acidic drugs can attenuate and ultimately quench chemical pH oscillators, by a simple buffering mechanism. A model system consisting of the bromate-sulfite-marble pH oscillator in a continuous stirred tank reactor is used, along with acidic drugs of varying concentration and acid dissociation constant, pK(D). A published kinetic model for this oscillator is modified to account for the presence of acidic drug, and the results of this model are in qualitative agreement with the experimental results.

Acetic Acid↗