Investigation of the Applicability of Ion Exchange Resins as a Sustained Release Drug Delivery System Forpropranolol Hydrochloride

The purpose of this study was to investigate the application of six strongly acidic cation exchange resins as a sustained release drug delivery system. Propranolol hydrochloride was chosen as the model drug to study the in vitro adsorption and desorption characteristics of the resins because of its chemical structure and pharmacokinetie properties which make it a good candidate for a sustained release formulation. The exchange rate constants and diffusion coefficients for the adsorption and desorption experiments were determined for each resin using the equations derived by Boyd, Adamson and Myers. Only one cation exchange resin showed potential as a sustained release drug delivery system for propranolol hydrochloride.     

Allosteric gating of a large conductance Ca-activated K+ channel

Large-conductance Ca-activated potassium channels (BK channels) are uniquely sensitive to both membrane potential and intracellular Ca2+. Recent work has demonstrated that in the gating of these channels there are voltage-sensitive steps that are separate from Ca2+ binding steps. Based on this result and the macroscopic steady state and kinetic properties of the cloned BK channel mslo, we have recently proposed a general kinetic scheme to describe the interaction between voltage and Ca2+ in the gating of the mslo channel (Cui, J., D.H. Cox, and R.W. Aldrich. 1997. J. Gen. Physiol. In press.). This scheme supposes that the channel exists in two main conformations, closed and open. The conformational change between closed and open is voltage dependent. Ca2+ binds to both the closed and open conformations, but on average binds more tightly to the open conformation and thereby promotes channel opening. Here we describe the basic properties of models of this form and test their ability to mimic mslo macroscopic steady state and kinetic behavior. The simplest form of this scheme corresponds to a voltage-dependent version of the Monod-Wyman-Changeux (MWC) model of allosteric proteins. The success of voltage-dependent MWC models in describing many aspects of mslo gating suggests that these channels may share a common molecular mechanism with other allosteric proteins whose behaviors have been modeled using the MWC formalism. We also demonstrate how this scheme can arise as a simplification of a more complex scheme that is based on the premise that the channel is a homotetramer with a single Ca2+ binding site and a single voltage sensor in each subunit. Aspects of the mslo data not well fitted by the simplified scheme will likely be better accounted for by this more general scheme. The kinetic schemes discussed in this paper may be useful in interpreting the effects of BK channel modifications or mutations.     

Interaction between proteins containing homeodomains associated to leucine zippers from sunflower

A strategy based on the use of PCR with one degenerate oligonucleotide deduced from conserved sequences and lambda gt10 primers was used to isolate homeobox containing sequences from sunflower stem and root cDNA libraries. Six different partial cDNAs coding for the first 48 amino acids of homeodomains and amino terminal sequences were analyzed and found to be members of the HD-Zip superfamily, which contain a homeobox linked to a leucine zipper coding region. A full-length cDNA clone, Hahb-10, was isolated and characterized. The leucine zipper portions of Hahb-10 and of the previously reported Hahb-1 have been utilized to construct fusions with the N-terminal domain of the lambda repressor. These fusions were tested for their ability to bind to lambda promoters in vivo. The expression of a protein containing an active dimerization domain, but not capable of DNA binding, exerts a dominant negative effect on the ability of repressor-zipper fusions to bind to its target DNA. From these experiments, it was concluded that Hahb-1 and -10, when co-expressed, form preferentially homodimers. Exchange of conserved threonines and leucines at positions a1 and d1 of both zippers reduces dimerization efficiency and allows the formation of heterodimers, suggesting that these residues are, among others, determinants of the specificity of interaction, most likely through changes in hydrophobic packing interactions at the dimer interface. The results imply that a great number of interacting molecular entities compose this protein superfamily which is presumably involved in regulating plant developmental responses.     

Ultrasonic vocalization behavior differs between lines of ethanol-preferring and nonpreferring rats

To further understand the relationship between emotional state and alcohol intake in rats, the tendency to emit ultrasonic vocalizations in response to an aversive, but nonpainful, air puff stimulus was tested in several rat lines. Included in this group were Maudsley Reactive (MR) and Non-Reactive (MNR) rats, and several lines of rats with either high ethanol preference or a low ethanol preference: Preferring, (P), Alko-Alcohol (AA), and Fawn-Hooded (FH) animals; and Non-Preferring (NP), Alko-Non-Alcohol (ANA), and Flinders Resistant Line (FRL). MR rats emitted fewer ultrasonic vocalizations (USVs) and showed less preference for ethanol than did MNR animals. An overall analysis that included the P, NP, FH, FRL, AA, and ANA groups demonstrated a significant negative correlation between the total number of USVs emitted and ethanol consumption. NP, FRL, and especially ANA rats (low ethanol-preferring) emitted the most USVs--to an extent similar to that typically found for normal rats. The duration of vocalizing was higher only in the NP and the FRL rats the relative to their P and FH comparison groups, respectively. In the ethanol-preferring and nonpreferring lines, the numbers of USVs emitted correlated positively with the duration of vocalizing, but not with the latency to vocalize, which in turn did not correlate strongly with ethanol intake. The latency to vocalize did not correlate significantly with ethanol intake across all drinking lines or MR or MNR rats, but was found to be higher in FH and AA rats relative to their nondrinking comparison groups. These associations suggest that the relationship between emotional state and ethanol drinking is complex and cannot be attributed to a simple elevated state of anxiety or emotionality. Further examination of the central nervous system mechanisms mediating the difference in USVs between paired lines of ethanol-preferring and nonpreferring rats may identify neurochemical factors that predict ethanol preference.     

The haematological management of patients with cyanotic congenital heart disease. A time for consensus?

AIMS: Recurrent venesection of patients with cyanotic congenital heart disease may be detrimental, with an increased risk of cerebrovascular events and symptomatic iron-deficiency. The aim of this study was to determine the venesection policies as practised in hospitals within a U.K. region and to determine if these policies followed current recommendations. METHODS AND RESULTS: Fifty-eight consultants (56% response rate) in cardiac specialties completed self-assessment questionnaires regarding the indications for and practice of venesection. Sixty-one percent of those responding were involved directly in the care of patients with cyanotic congenital heart disease and of these clinicians 97% used venesection. Indications for venesection varied, with 51% of those responding using an elevated haemoglobin per se (6.5-21.0 g. dl-1); 78% an elevated haematocrit (0.55-0.75) and 83% symptoms. Desired maintenance haemoglobin and haematocrit levels also varied greatly. Fifty percent of the consultants responding routinely screened their patients for iron deficiency and 23% felt there was no indication for investigating a low mean corpuscular volume. Only 18% of the policies described followed any evidence based principles. CONCLUSIONS: The practice of venesecting patients with congenital cyanotic heart disease varies greatly. Policies in many hospitals do not reflect the minimal benefits and considerable risks associated with recurrent venesection.