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Biomedical subjects

C F Starmer

Publications and source records attributed to C F Starmer.

At least 73 records · Page 4Linked to original sources
PubMed1986

pKa does not predict pH potentiation of sodium channel blockade by lidocaine and W6211 in guinea pig ventricular myocardium.

During diastole, tertiary amine local anesthetic molecules may exit cardiac sodium channels quickly through the membrane if they are neutral, or more slowly through the aqueous channel pore if they are charged. Extracellular acidosis potentiates sodium channel blockade by these drugs, and drug pKa should be a potent predictor of the degree of response of drug dissociation kinetics to changes in extracellular pH. To test this hypothesis, we measured kinetics of recovery from drug-induced channel blockade in guinea pig papillary muscle exposed to lidocaine (pKa 7.86) and to W6211 (pKa 6.29) using Vmax as a measure of peak sodium current. Both compounds, which are physicochemically very similar in respects other than pKa, delayed Vmax recovery in a pH-dependent fashion. As pH was lowered from 7.9 to 6.5, the recovery time constant rose from 86 to 230 msec for lidocaine and from 53 to 154 msec for W6211. We revised an earlier kinetic scheme of drug-channel interaction to incorporate newer concepts of drug trapping and ionization within the channel, and the resulting analytic expressions fit the data well. Important implications of the new scheme are that the pKa of the drug-receptor complex may differ from the drug pKa, and that deprotonation of channel-bound charged drug molecules may be a rate-limiting process.

Acidosis↗
PubMed1985

Mechanisms of apparent affinity variation of guarded receptors.

Studies of interactions between blocking agents such as antiarrhythmic drugs and gated ion channels have suggested apparent variations in binding site affinity. In this report, we develop a model by which these properties of ion channels can be explained simply on the fact that blocking agent access to the channel receptor is regulated by the channel gating apparatus. We view ion channel blockade as a two stage process: diffusion of drug to a region near the channel binding site and coupling of drug to the binding site resulting in a non-conducting, drug complexed channel. We define a guarded receptor as a receptor where binding site access is regulated by some process such as gated control of the ligand diffusion path. Relationships for equilibrium properties of guarded receptors differ from those of traditional unguarded receptors. With periodic activation of channel gates, as in cardiac muscle, a true equilibrium may never be reached due to transient receptor access. Lack of equilibrium can complicate analysis. For gated ion channels we derive equilibrium block properties under conditions of no stimulation. We show that a fixed affinity guarded receptor appears as an apparent variable affinity receptor in gated channels. These results are consistent with observations of apparent variations in receptor affinity derived from studies of local anesthetics in cardiac muscle. Furthermore, by separating drug diffusion and receptor binding, this description may facilitate quantitative characterization of local anesthetics and antiarrhythmia drugs in excitable membranes.

Animals↗
PubMed1985

Phasic ion channel blockade. A kinetic model and parameter estimation procedure.

For excitable membranes, use and frequency dependence represent a progressive incorporation of drug into gated ion channels with repetitive stimulation. In contrast to receptors where access to ligand is continuous in time, we define guarded receptors, such as gated ion channels, as receptors whose access to the ligand pool is transient and controlled by the channel-gating process. During repetitive stimulation, the fraction of ligand-bound channels (ion channel blockade) follows an exponential time course, determined by the interstimulus interval, channel-gating processes, drug concentration, and the forward and reverse rate coefficients characteristic of the binding process. Based on a first order model of ligand-receptor binding, we derive a characterization of ion channel blockade via a single diffusion path under conditions of repetitive phasic stimulation. Extension to multiple diffusion paths and multiple drugs leads to a more complex scheme, but these generalizations are straightforward. For the case of one diffusion path, we derive the steady state level of channel blockade for guarded receptors as a function of stimulus rate and develop a data analysis strategy suitable for characterizing ion channel-blocking agents such as local anesthetics and antiarrhythmic drugs. We show that as receptor access time increases, the transient and steady state properties of guarded receptors become equivalent to those derived from the standard continuous access ligand-receptor model. The analysis tools presented simplify the quantitative description of the functional properties of many ion channel blockers and appear to have general applicability to characterization of periodically accessible receptors.

Animals↗
PubMed1984

Mechanisms of use-dependent block of sodium channels in excitable membranes by local anesthetics.

Many local anesthetics promote reduction in sodium current during repetitive stimulation of excitable membranes. Use-, frequency-, and voltage-dependent responses describe patterns of peak INa when pulse width, pulse frequency, and pulse amplitude are varied. Such responses can be viewed as reflecting voltage-sensitive shifts in equilibrium between conducting, unblocked channels and nonconducting, blocked channels. The modulated-receptor hypothesis postulates shifts in equilibrium as the result of a variable-affinity receptor and modified inactivation gate kinetics in drug-complexed channels. An alternative view considers drug blocking in the absence of these two features. We propose that drug binds to a constant-affinity channel receptor where receptor access is regulated by the channel gates. Specifically, we view channel binding sites as guarded by the channel gate conformation, so that unlike receptors where ligands have continuous access, blocking agent access is variable during the course of an action potential. During the course of an action potential, the m and h gates change conformation in response to transmembrane potential. Conducting channels with both gates open leave the binding site unguarded and thus accessible to drug, whereas nonconducting channels, with gates in the closed conformation, act to restrict drug access to unbound receptors and possibly to trap drug in drug-complexed channels. We develop analytical expressions characterizing guarded receptors as "apparently" variable-affinity binding sites and predicting shifts in "apparent" channel inactivation in the hyperpolarizing direction. These results were confirmed with computer simulations. Furthermore, these results are in quantitative agreement with recent investigations of lidocaine binding in cardiac sodium channels.

Action Potentials↗
PubMed1984

A method for quantitating antifibrillatory effects of drugs after coronary reperfusion in dogs: improved outcome with bretylium.

We developed a quantitative approach to assess the antifibrillatory effects of short-term interventions in a canine preparation of ventricular fibrillation caused by coronary reperfusion, and applied it to evaluate the antifibrillatory effects of bretylium tosylate. Twenty-five dogs were given 10 mg/kg infusions of bretylium over 10 min, subjected to a 20 min proximal left anterior descending coronary artery ligation followed by sudden release, and compared with 25 animals given saline placebo. Drug infusion was begun 90 min before reperfusion to avoid evaluation of outcome during the phase of drug-induced catecholamine release and to allow adequate time for bretylium uptake in the myocardium. The relationship between the likelihood of ventricular fibrillation during reperfusion and the amount of myocardium perfused by the occluded vessel (myocardium at risk) was analyzed with the logistic risk-regression model. This model was developed to control for the effects of amount of myocardium at risk on outcome. For both the bretylium and the placebo groups the incidence of ventricular fibrillation correlated significantly with amount of myocardium at risk. However, animals treated with bretylium had an improved outcome for a given amount of myocardium at risk. In other words, the curve relating outcome to myocardium at risk was shifted significantly to the right. The amount of myocardium at risk required for half the placebo-treated animals to fibrillate was 20.3 g and that required for half the bretylium-treated animals to fibrillate was 27.9 g, or 37% more than that for the placebo group. This logistic risk-regression analysis format permits quantification of treatment effects while accounting for variability in amount of myocardium at risk.

Animals↗
PubMed1984

Lipid solubility modulates pH potentiation of local anesthetic block of Vmax reactivation in guinea pig myocardium.

Current theories envision recovery from local anesthetic block of sodium channels via slow hydrophilic and fast hydrophobic paths. Extracellular pH reduction which increases cationic/neutral anesthetic form should especially prolong recovery kinetics of highly lipid soluble compounds that could readily exit via the hydrophobic pathway at normal extracellular pH. To test this hypothesis, we compared the effects of three related compounds with similar pKa on the time course of Vmax reactivation in guinea pig papillary muscle at pHo 7.4 and 6.95. The compounds were lidocaine and its two desethylation products, monoethylglycinexylidide and glycinexylidide. Judged from the octanol:water partition coefficient, lidocaine was the most lipid soluble (log partition coefficient 2.39 +/- 0.10), followed by monoethylglycinexylidide (log partition coefficient 1.32 +/- 0.09) and glycinexylidide was the least lipid soluble (log partition coefficient 0.41 +/- 0.09). At 30 microM and pHo 7.4, the potency order for Vmax depression at zero diastolic interval was lidocaine (53 +/- 6%), monoethylglycinexylidide (17 +/- 3%), and then glycinexylidide (7.8 +/- 1.9%). The decay of Vmax block appeared monoexponential, and the time constant of recovery was dose independent. Most important is the fact that there were significant differences in the tau r increase with extracellular pH reduction (P less than 0.05; Scheffé contrasts). The increase was greatest with lidocaine [73 +/- 28% (mean +/- SD)], less with monoethylglycinexylidide (42 +/- 15%), and least with glycinexylidide (13 +/- 17%). The simplest interpretation of the differences in extracellular pH-dependence of recovery kinetics was that recovery from block due to the neutral form of these ionizable local anesthetics depended on lipid solubility, whereas recovery from block due to the protonated form depended on molecular weight.

Action Potentials↗
PubMed1984

Spurious hypertension in the obese patient. Effect of sphygmomanometer cuff size on prevalence of hypertension.

We used standard, large adult, and thigh-size cuffs in random order to take BPs in 470 patients. The prevalences of definite high BP [( HBP]), greater than or equal to 160/95 mm Hg) and borderline HBP [( BHBP ], greater than or equal to 140/90 less than 160/95 mm Hg) were the same with all three cuffs in patients with an arm circumference less than 35 cm, a body mass index less than 34, and a weight of less than 95 kg. The large adult and thigh cuffs did not underestimate the prevalence of HBP in these nonobese patients. The prevalences of HBP and BHBP were twofold greater with the standard cuff than with the large adult or thigh cuffs in obese patients (arm circumference greater than or equal to 35 cm or body mass index greater than or equal to 34 or weight greater than or equal to 95 kg). Routine use of the large adult cuff will provide accurate BP measurement and avoid unneeded evaluation and treatment.

Adolescent↗
PubMed1983

BP control. Improvement in a university medical clinic by use of a physician's associate.

Many hypertensive patients, especially those in outpatient clinics at large teaching hospitals, do not achieve BP control. We incorporated a physician's associate into an existing house staff medical clinic and evaluated whether this improved BP control. In patients with moderate or severe hypertension, BP control was achieved in 56% of patients observed by both the physician's associate and the house staff and in 32% of patients observed solely by house staff. Possible contributing factors were more frequent follow-up, simplification of drug regimens, reduced waiting time, more time spent with the patients, and overall greater satisfaction with the physician's associate. We conclude that the addition of a physician's associate to an outpatient clinic is an effective method for enhancing BP control. This can be achieved without establishing a separate hypertension clinic or depriving house staff of experience in the management of hypertension.

Blood Pressure↗
PubMed1983

Unitary sodium channels in isolated cardiac myocytes of rabbit.

Transmembrane ionic movements are thought to occur through special membrane areas or channels. Until recently, it has not been possible to study the properties of individual ionic channels, directly. We have used the extracellular patch clamp technique to resolve unitary sodium channels in enzyme-dissociated rabbit ventricular myocytes. Depolarizing voltage clamp steps elicited rectangular inward current fluctuations representing open-closed transition of the channels. Probability of channel opening increased with depolarization. Single channel current amplitude ranged from 0.6 to 1.9 pA. Channel open time increased with depolarization. Sodium channels could be distinguished from calcium channels by their insensitivity to cadmium and inactivation voltage range. First-event latency histograms suggest multiple-closed states. The patch clamp technique can be readily applied to the study of sodium channels in adult cardiac myocytes.

Action Potentials↗
PubMed1982

A recursively interpreted data structure for representing clinical entities.

Clinical investigations generate a spectrum of data and data relationships that no longer fit simple data structures. To build a data management facility sufficiently flexible to deal with this spectrum of structures is thus an important problem. A general table-based data structure is presented that provides the clinical investigator with a means of tailoring the data structure to the experimentally derived data. The use of such a general structure appears limited to settings where deletion of instances of data is infrequent. This restriction poses no serious constraint in most clinical investigations.

Clinical Trials as Topic↗
PubMed1982

A data-based approach to assessing clinical interventions in the setting of chronic disease.

Accurately assessing the effect of a clinical intervention is a complex task based on observing patients and their outcomes. Two strategies, the randomized trial and the observational data bank, represent different approaches toward detecting an outcome gradient across treatments. The observational data base is rooted on prospective data collected on an unselected group of patients with continuous surveillance of outcome events. As such, this approach captures a broad spectrum of patients within which prognostically important factors can be identified. In addition, the ongoing nature of the observational approach provides a means for capturing the dynamics of the disease process as well as the dynamics of the surrounding technology. These factors are particularly useful in the study of chronic illness where time frames of years to decades are encountered. In assessing treatment effects, both the randomized trial and the observational data base are subject to inferential errors due to multiple comparisons. In this paper, we describe some of the complexity associated with the study of chronic illness and demonstrate the multiple comparison problem. We have found multivariate models helpful in attenuating multiple comparison problems, but it still seems that independent confirmatory studies are required to establish confidence in a questionable intervention.

Analysis of Variance↗
PubMed1981

Problems in data management when studying chronic illness.

Chronic illness is characterized by a long response time during which many external influences can modify the system. Accurate characterization of such a system may require a large number of attributes. Such "data" complexity, in both the time and the feature domain, introduces a number of operational difficulties into the methodology for the scientific investigation of such systems. One such problem is the investigator's changing viewpoint and understanding of the system during the course of a study. Research data bases with a static attribute content are in conflict with this learning process and are of limited use when incorporated in investigation of chronic illness. Data element refinement is a tool for dealing with this problem, by providing a means for modifying an attribute's definition during the temporal life of a data base. We have been investigating means for supporting refinement of data elements in a large data base for coronary artery disease. For certain data types, we have developed a means of introducing "refined" views of particular data elements into a data base such that programs written prior to the refinement execute properly without modification during the lifetime of the data base. We will describe a data structure we have found suitable for capturing the information base from a broad range of clinical investigations, and our approach to the problem of data element refinement. Examples from ongoing clinical studies will be used to illustrate these ideas.

Chronic Disease↗
PubMed1981

Computed tomography brain scanning in alcohol withdrawal seizures. Value of the neurologic examination.

We evaluated the usefulness of computed tomography (CT) brain scanning in alcoholic patients with withdrawal seizures (n = 151) and other neurologic problems (n = 87) and compared the findings of a detailed neurologic examination to the results of CT scanning. In patients with seizures, nearly 50% of CT scans were normal, 34% showed generalized cerebral atrophy, and only 15% showed focal structural lesions. When focal neurologic deficits were present, 30% of CT scans showed focal structural lesions compared to 6% when such deficits were absent (p less than 0.0002). The frequency of potentially reversible lesions was 18% in patients with and 1% in patients without focal neurologic deficits (p less than 0.0002). Of patients treated surgically, 9% had focal neurologic deficits and 1% did not (p less than 0.03). Results were similar in alcoholic patients with other neurologic problems. Careful use of the neurologic examination adequately determines which patients need prompt CT scanning. In the absence of either focal deficits on neurologic examination or signs of acute head trauma, CT brain scanning does not improve the evaluation of patients with alcohol withdrawal seizures.

Alcoholism↗
PubMed1980

Clinical judgment and statistics. Lessons from a simulated randomized trial in coronary artery disease.

A simulated randomized clinical trial in coronary artery disease was conducted to illustrate the need for clinical judgment and modern statistical methods in assessing therapeutic claims in studies of complex diseases. Clinicians should be aware of problems that occur when a patient sample is subdivided and treatment effects are assessed within multiple prognostic categories. In this example, 1073 consecutive, medically treated coronary artery disease patients from the Duke University data bank were randomized into two groups. The groups were reasonably comparable and, as expected, there was no overall difference in survival. In a subgroup of 397 patients characterized by three-vessel disease and an abnormal left ventricular contraction, however, survival of group 1 patients was significantly different from that of group 2 patients. Multivariable adjustment procedures revealed that the difference resulted from the combined effect of small imbalances in the distribution of several prognostic factors. Another subgroup was identified in which a significant survival difference was not explained by multivariable methods. These are not unlikely examples in trials of a complex disease. Clinicians must exercise careful judgment in attributing such results to an efficacious therapy, as they may be due to chance or to inadequate baseline comparability of the groups.

Coronary Disease↗
PubMed1980

On the complexity of investigating chronic illness.

Chronic diseases are in many ways more complex than acute diseases. In chronic diseases, response times to environmental effects are long, and confounding variables are numerous and may fluctuate with time. Treatment schedules are complicated and may be unique to the individual patient. Controlled trials deal with rigid hypotheses and permit control of error rates; prospective registries permit access to homogeneous subgroups. There is now a need for a new methodology for the study of the treatment of chronic diseases, which combines the merits of both approaches.

Chronic Disease↗