PubMed Health⌕ Search

Biomedical subjects

P M Dunn

Publications and source records attributed to P M Dunn.

At least 19 recordsLinked to original sources
PubMed1998

The action of blocking agents applied to the inner face of Ca(2+)-activated K+ channels from human erythrocytes.

The actions of clotrimazole and cetiedil, two drugs known to inhibit the Gardos channel, have been studied on single intermediate conductance calcium-activated potassium (IKCa) channels in inside out patches from human red blood cells, and compared with those of TEA and Ba2+ applied to the cytoplasmic face of the membrane. TEA produced a fast block which was observed as a reduction in the amplitude of the single channel current. This effect was weakly voltage dependent with the fraction of the membrane potential sensed by TEA at its binding site (delta) of 0.18 and a Kd at 0 mV of 20.5 mM. Ba2+ was a very potent blocker of the channel, breaking the single channel activity up into bursts, inter-spersed with silent periods lasting several seconds. The effect of Ba2+ was very voltage sensitive, delta = 0.44, and a Kd at 0 mV of 0.15 microM. Clotrimazole applied to the inner face of the membrane at a concentration < or = 1 microM produced a slow block resulting in bursts of channel activity separated by quiescent periods lasting many seconds. The effect of clotrimazole was mimicked by a quaternary derivative UCL 1559, in keeping with an action at the cytoplasmic face of the channel. A high concentration of cetiedil (100 microM) produced only a weak block of the channel. The kinetics of this action were very slow, with burst and inter-burst intervals lasting several minutes. While inhibition of the Gardos channel by cetiedil is unlikely to involve an intracellular site of action, if clotrimazole is able to penetrate the membrane, part of its effect may result from binding to an intracellular site on the channel.

Azepines↗
PubMed1998

A prospective study of the efficacy of the physician order form for life-sustaining treatment.

OBJECTIVES: The Physician Orders for Life-Sustaining Treatment (POLST), a comprehensive, one-page order form, was developed to convey preferences for life-sustaining treatments during transfer from one care site to another. This study examined the extent to which the POLST form ensured that nursing home residents' wishes were honored for Do Not Resuscitate (DNR) and requests for transfer only if comfort measures fail. DESIGN: The study used chart record data to follow prospectively a sample of nursing home residents with the POLST. SETTING: Eight geographically diverse, long-term, adult-care facilities in Oregon in which the POLST was in use. PARTICIPANTS: Nursing home residents (n = 180), who had a POLST recording DNR designation and who indicated a desire for transfer only if comfort measures failed, were followed for 1 year. MEASUREMENTS: For all subjects: treatment and disposition after significant health status changes; orders for narcotics and for provision or limitation of aggressive interventions. For hospitalized subjects: diagnosis, medical interventions, and DNR orders. For those who died: cause and location of death, life-sustaining treatments attempted, and comfort measures provided. RESULTS: No study subject received CPR, ICU care, or ventilator support, and only 2% were hospitalized to extend life. Of the 38 subjects who died during the study year, 63% had an order for narcotics, and only two (5%) died in an acute care hospital. A total of 24 subjects (13%) were hospitalized during the year. Hospitalized subjects' mean length of stay was 4.9 days, and the mean rate of hospitalizations for all subjects was 174 per 1000 resident years. In 85% of all hospitalizations, patients were transferred because the nursing home could not control suffering. In 15% of hospitalizations (n = 4), the transfer was to extend life, overriding POLST orders. CONCLUSIONS: POLST orders regarding CPR in nursing home residents in this study were universally respected. Study subjects received remarkably high levels of comfort care and low rates of transfer for aggressive life-extending treatments.

Advance Care Planning↗
PubMed1996

Synthesis, molecular modeling, and K+ channel-blocking activity of dequalinium analogues having semirigid linkers.

Dequalinium [1,1'-(decane-1, 10-diyl)bis(2-methyl-4-aminoquinolinium)] is an effective blocker of the small conductance Ca2(+)-activated K+ channel. It has been shown that the number of methylene groups in the alkyl chain linking the two quinolinium rings of this type of molecule is not critical for activity. To further investigate the role of the linker, analogues of dequalinium have been synthesized, in which the alkyl chain has been replaced by CH2XCH2 where X is a rigid or semirigid group containing aromatic rings. The compounds have been tested for blockade of the slow after-hyperpolarization on rat sympathetic neurons. The most potent compounds have X = phenanthryl, fluorenyl, cis-stilbene, and C6H4(CH2)nC6H4, where n = 0-4. The conformational preferences of the compounds were investigated using the XED/COSMIC molecular modeling system. Although there is some dependence of the potency of the analogue on the conformational properties of the linker (X), overall, X groups having substantial structural differences are tolerated. It seems that X provides a support for the two quinolinium groups and does not interact with the channel directly. The intramolecular separation between the quinolinium rings, which is provided by rigid groups X, is not critical for activity; this may be attributed to the residual conformational mobility of the heterocycles and to the extensive delocalization of the positive charge. These two factors may permit favorable contacts between the quinolinium groups and the channel over a range of intramolecular separations.

Animals↗
PubMed1996

Synthesis and pharmacological testing of dequalinium analogues as blockers of the apamin-sensitive Ca(2+)-activated K+ channel: variation of the length of the alkylene chain.

Dequalinium is a potent and selective blocker of the small conductance Ca(2+)-activated K+ (SKCa) channel in rat sympathetic neurones. Analogues of dequalinium possessing 3-6, 8, 10, and 12 methylene groups in the linking chain have been synthesized and tested for inhibition of the afterhyperpolarization in rat sympathetic neurones. The compounds having a 5-12-carbon chain showed very little variation in their activity as SKCa channel blockers. The analogues possessing four and three methylenes exhibited 3- and 8-fold lower potency, respectively, compared with dequalinium. These results are discussed in the context of possible modes of binding of the compounds to the SKCa channel.

Action Potentials↗
PubMed1996

Synthesis and quantitative structure-activity relationship of a novel series of small conductance Ca(2+)-activated K+ channel blockers related to dequalinium.

The synthesis, pharmacological testing, and quantitative structure-activity relationship studies of a novel series of bisquinolinium small conductance Ca(2+)-activated K+ channel blockers (23) related to dequalinium are described. In this series, two quinolinium rings are linked via the 4-position to an alpha, omega-diamino alkylene chain and the ring N atom is quaternized with a methyl or benzyl group. The exocyclic N atom can be replaced by O, S, or CH2 but with some loss of potency. The quinoline groups do not have to be quaternized for blocking activity, as long as they are basic enough to be protonated at the site of action. For the quaternary compounds, there is considerable steric tolerance for the group R attached to the ring N atom of the quinoline; a benzyl group gave the optimum potency in this series. Moreover, and in contrast to previously reported results for dequalinium analogues, there is no correlation of activity to previously reported results for dequalinium analogues, there is no correlation of activity with N1 charge or EHOMO. On the other hand, a good correlation was obtained between the blocking potency of the compounds and ELUMO [pEMR = 1.16(+/-0.26)ELUMO + 5.33(+/-01.29)(n = 11, r= 0.83, s = 0.243)]. It has been possible to combine this equation with the previously reported ELUMO correlation for a series of dequalinium analogues to include all the compounds of both series [pEMR = 1.17(+/-0.15)ELUMO +5.33(+/-0.76)(n =24, r = 0.85, s = 0.249)]. A possible physical meaning for the ELUMO correlation based upon the principle of maximum hardness is discussed.

Animals↗
PubMed1996

On the concept of a bivalent pharmacophore for SKCa channel blockers: synthesis, pharmacological testing, and radioligand binding studies on mono-, bis-, and tris-quinolinium compounds.

The dissociation equilibrium constants (Kd values) of dequalinium (2) and the monoquinolinium compounds 1a and 1b have been determined from competition equilibrium radioligand binding with [125I]apamin on rat brain synaptic plasma membranes (SPMs). Dequalinium binds to the channel with 2 orders of magnitude higher affinity than 1a or 1b, suggesting that both quinolinium groups are needed for potent and selective SKCa channel blockade. The trisquinolinium compound 3 (1,1'-[5-[4-(4- aminoquinolinium-1-yl)but-1-yl]non-4-en-1,9-diyl]-bis-(4- aminoquinolinium)) has been synthesized and tested for inhibition of the afterhyperpolarization of rat sympathetic neurones and on the binding assay. Compound 3 shows approximately one order of magnitude higher potency than 2, being the most potent non-peptidic SKCa channel blocker reported so far (Kd approximately 30 nM). The higher affinity of 3 compared with 2 may be due to direct binding of the third quinolinium group to the channel or may arise from a reduction of the unfavorable entropy of binding via an increase of the "local concentration" of quinolinium groups.

Animals↗