Amiodarone-liposome interaction: a multinuclear NMR and X-ray diffraction study.

Amiodarone, a potent antiarrhythmic drug, is widely used in cardiology. Its electrophysiological effects, as well as many of its side effects, seem to involve lipids. We report here a multinuclear NMR and X-ray diffraction study of amiodarone in egg phosphatidylcholine liposomes and lipid multilayers. In proton NMR experiments, amiodarone alters the signal from the lipid trimethyl ammonium group for pH values ranging from 3.2 to 8.4; cholesterol does not cause this alteration. The addition of SCN- changes both the proton and phosphorus NMR spectra of liposomes containing amiodarone. For both proton and carbon NMR, amiodarone modifies the signal from the lipid methylene groups, but to a far lesser extent than does cholesterol. Incorporation of amiodarone in EPC bilayers also modifies the low-angle X-ray diffraction patterns, decreasing the lamellar repeat period at low water contents, but swelling the fluid spaces between bilayers at high water contents. Electron density profiles and modeling studies using the X-ray data indicate that amiodarone decreases the bilayer thickness and adds electron density at the interfacial region of the bilayer. Our analysis of the NMR and X-ray data indicates that the iodine atoms of amiodarone are located near the hydrocarbon/water interface and that the tertiary amine of amiodarone is in the headgroup region of the bilayer.

Plasma norepinephrine in exercise-induced ventricular tachycardia.

The relation between plasma norepinephrine levels and the occurrence of ventricular tachycardia during exercise testing was prospectively evaluated in 17 patients. Ten patients had reproducible ventricular tachycardia exclusively during exercise or recovery, or both; 7 patients had ventricular tachycardia only during ambulatory electrocardiographic monitoring. The two groups did not differ in age, exercise duration, left ventricular ejection fraction at rest, heart rate throughout the exercise protocol, rest QTc interval, change in QTc interval during exercise, the presence of coronary artery disease or exercise-related myocardial ischemia. Furthermore, there was no difference between groups in plasma norepinephrine levels at rest, peak exercise or in the recovery period. Myocardial ischemia was detectable by thallium perfusion scan in only 2 of the 10 patients with exercise-induced ventricular tachycardia. The 10 patients with exercise-induced ventricular tachycardia underwent repeat exercise testing immediately after maximal intravenous beta-adrenergic blockade with propranolol. Although they had no change in exercise duration, ventricular tachycardia did not occur in 9 of these 10 patients. Plasma norepinephrine levels were significantly decreased compared with levels before beta-adrenergic blockade (p less than 0.0002). Thus, plasma norepinephrine levels do not distinguish patients with reproducible exercise-induced ventricular tachycardia from otherwise comparable patients. Propranolol is highly effective in abolishing this arrhythmia and this effect is associated with decreased norepinephrine levels.

A randomized multicenter trial of crotalinae polyvalent immune Fab (ovine) antivenom for the treatment for crotaline snakebite in the United States.

BACKGROUND: Current therapy for crotaline snakebite includes antivenin (Crotalidae) polyvalent, an antivenom with numerous adverse effects. We compared the efficacy and safety of 2 dosing regimens with a new antivenom, Crotalinae polyvalent immune Fab (Fab AV). METHODS: A single dose of Fab AV alone (as-needed [PRN] group) was compared with an initial dose plus repeated treatments during 18 hours (scheduled group) in a multicenter randomized trial. The study included patients with minimal or moderate envenomation by a crotaline snake within the preceding 6 hours, aged 10 years or older, in whom worsening of the envenomation syndrome was observed before Fab AV treatment. After treatment with Fab AV to achieve initial control, patients were randomized to the scheduled or PRN treatment group. Scheduled group patients received additional doses of Fab AV every 6 hours for 3 doses. The PRN group received no planned additional doses of antivenom. RESULTS: The mean severity score of the 31 patients decreased from 4.35 to 2.39 points (P<.001); there was no difference between scheduled and PRN groups. No patient in the scheduled group received unplanned Fab AV doses, but 8 of 16 patients in the PRN group received unplanned doses (P =.002). Acute reactions occurred in 6 patients (19%), and serum sickness occurred in 6 (23%) of 26 patients who returned for follow-up. CONCLUSIONS: In the first randomized trial of antivenom in the United States, Fab AV effectively terminated venom effects. Since the unplanned use of Fab AV in the PRN group was common, the treatment regimen may require more than 1 initial dose.

Clinical pharmacology, pharmacodynamics and interactions with esmolol.

The clinical pharmacology and pharmacodynamic data from several clinical trials are summarized. The pharmacokinetic profile of esmolol alone and in the presence of digoxin, morphine and warfarin was studied. Conversely the effect of esmolol on these drugs was monitored. No clinically important effects were observed on vital signs, blood chemistry or hematology. The pharmacokinetic interactions associated with administration of these drug combinations were statistically significant in several cases, but they were not considered to be of clinical importance.

Effects of nifedipine and verapamil on isometric and dynamic exercise in normal subjects.

Effects of single- and multiple-dose nifedipine and verapamil in 10 healthy men were compared with the effect of placebo during static and dynamic physical activity. Blood pressure (BP), heart rate (HR), and plasma catecholamine and plasma potassium levels were assessed and quantified at rest and at peak levels of 50% handgrip and at rest and peak treadmill activity during placebo, single- and at 2 multiple-dose levels of each of the drugs. Peak BP responses were blunted by a maximal dosage of 120 mg of verapamil administered twice daily during static activity. No blunting of HR response was observed. BP and HR did not change significantly at any dosage level of nifedipine during static exercise. During isotonic exercise the only significant alteration was a progressive decrease in the peak exercise HR with both verapamil and nifedipine. The plasma potassium level increased with both static and dynamic activity but to no greater level than that seen with placebo. Plasma norepinephrine concentration increased at rest after administration of maximal dosage of nifedipine during both isometric and isotonic phases of the study. This is probably related to the underlying mild to moderate increase in sympathetic tone induced by nifedipine. Overall, the hemodynamic responses to exercise are not blunted with calcium-channel antagonists at the dosages studied.

T wave inversion associated with severe theophylline toxicity.

Adverse cardiovascular effects are commonly seen in severe theophylline poisoning. Primary ST-T wave changes have not been described previously. We report T wave inversion associated with severe theophylline toxicity in a 33-year-old woman with no evidence of organic heart disease. The T wave inversion resolved after treatment. Physicians should be alerted to possible T wave abnormalities in patients with severe theophylline poisoning.

A multicenter evaluation of variables affecting the predictability of creatinine clearance.

Data from 722 urine collections (627 patients) from 14 medical facilities were used to compare measured creatinine clearance values with clearance estimates calculated using three "urine-free' mathematical formulas. The influence of two patient weight variables (actual weight, lean body weight) and the level of renal function on clearance prediction was assessed. In addition, site parameters (region, facility), time parameters (month, day, day of the week), and patient parameters (age, sex, height, weight, diagnoses) were evaluated for their statistical influence on the relationship between measured clearance and estimates calculated with one of the methods. Strong, statistically significant correlations were observed between clearance values estimated with each prediction method and measured clearances. Although statistical differences were noticed between mean values predicted with each method, these differences were clinically insignificant. Use of lean body weight for calculation of creatinine excretion produced clearance estimates that were significantly lower than those obtained with actual weight and substantially closer to measured clearance values. Among patient variables, age and two specific diagnoses (congestive heart failure and pregnancy), were statistically associated with variability in the relationship between measured and predicted clearance. Interregional and interfacility differences in the measured-predicted clearance relationship, variability associated with the day of the week of collection, and tendency of the urine-free formulas to over-predict clearance support potential inaccuracy of measured clearance determination. The results suggest that inaccuracies in clearance determination, rather than inadequacies of urine-free prediction methods, account for the majority of the observed variability in the relationship.

Polyclonal anti-tumor necrosis factor-alpha Fab used as an ancillary treatment for severe malaria.

Single doses (250, 500, 1,000, or 2,000 units/kg) of an ovine polyclonal-specific Fab fragment directed against tumor necrosis factor-alpha (TNF-alpha) were given to 17 adult patients with severe falciparum malaria immediately before treatment with artesunate in a pilot study to assess safety and optimal dosage with a view to future studies. Clinical and laboratory variables were compared with 11 controls. In the groups given Fab, there was a tendency for a faster resolution of clinical manifestations and reduction of fever but also a tendency towards longer parasite clearance times. Adverse events were more common in the control group and no early anaphylactic or late serum sickness reactions occurred in the Fab treated patients. On admission all patients had markedly elevated levels of TNF-alpha (85-1,532 ng/L) and interleukin-6 (IL-6) (30-27,500 ng/L). Also, 86% had elevated interferon-gamma (IFN-gamma) levels, 75% had increased IL-2 levels, 36% had increased IL-8 levels, and 21% had increased IL-1beta levels. Antibody treatment reduced IFN-gamma concentrations in a dose-related manner, but had no obvious effects on levels of other cytokines in this small study, although unbound TNF-alpha was undetectable after Fab treatment. Circulating concentrations of soluble E-selectin, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were not affected by Fab treatment. The Fab exhibited a two-compartment, dose-proportional kinetics with an average elimination half-life of 12.0 hr, with about 20% being excreted renally. These results encourage a randomized, placebo-controlled trial in patients with cerebral malaria and provide some guidance about dosage.

Clinical pharmacology education in a division of cardiology.

A working model of how clinical pharmacology education can be interwoven into the matrix of an academic cardiology program that includes didactic teaching, clinical research, and patient care has been presented. Essential to the success of such a program is the commitment and dedication of both its full-time and voluntary faculty. Moreover, a comprehensive plan of organization and allocation of efforts is vital to the success of such a complex undertaking. As we look to the future, the discipline of clinical pharmacology will be increasingly relevant to the practicing cardiologist.

Esmolol-digoxin drug interaction.

An open-label baseline-controlled study was conducted in 11 healthy male subjects to study the possible interaction between the cardioselective, short-acting beta blocker esmolol and digoxin when administered concurrently under steady-state conditions. Steady-state concentration, elimination half-life, and the total body clearance of esmolol were not changed significantly (P greater than .05) by digoxin. Digoxin peak concentration and the time to reach the peak concentration were not affected by esmolol. However, the digoxin AUC during the six-hour esmolol infusion increased from 2.60 +/- 0.59 to 2.88 +/- 0.75 ng.hr/mL (P less than .05). There were no clinically significant changes in the heart rate and blood pressure during this drug interaction study. The PR intervals were similar between digoxin monotherapy and esmolol plus digoxin combined treatment. Although digoxin did not influence the kinetics of esmolol, the small increase seen in digoxin serum concentration during the combination therapy warrants that caution be exercised during concurrent administration of esmolol and digoxin to patients.

Impact of cost problems on morbidity in a hypertensive population.

Researchers disagree about the extent to which limited access to health services negatively affects health. In this study, we investigated the association of health status with access to high blood pressure medication among hypertensive respondents drawn from two random household surveys conducted in the state of Georgia during 1981 and 1983. We compared hypertensive respondents reporting difficulties in paying for medication (n = 616) with hypertensive respondents not reporting cost problems (n = 616) who were matched on race, sex, age (+/- 3 years), and per capita family income (+/- $3,000). Because questions were not identical in the 1981 and 1983 surveys, we compared responses of the matched groups separately for each year in the analysis. In the 1981 comparison, a significantly higher (P less than .05) percentage of hypertensive individuals experiencing cost problems reported being in fair or poor health (60.5%) and having had a stroke (11.4%) than those without cost problems (39% for fair or poor health status and 5% for occurrence of stroke). Those with cost problems also reported a higher frequency of cardiac problems (24.6%) than those without cost problems (18.1%), although these differences are not statistically significant (P greater than .05). In the 1983 survey, a significantly larger number of those with cost problems (57.4%) reported being in fair or poor health than those without cost problems (43.1%, P less than .05).

The pharmacology of adenosine.

Adenosine is a purine nucleoside present in every cell of the human body. It is released into the extracellular space under physiologic and pathophysiologic conditions characterized by increased oxygen demand:supply ratio. Adenosine can exert a wide spectrum of effects in various organs and tissues. Exogenous adenosine has a wide spectrum of effects in experimental animal models as well as humans. The pharmacokinetics, pharmacodynamics, and the interaction of adenosine with other drugs are reviewed.

Prediction of hyperkalemia in dogs from electrocardiographic parameters using an artificial neural network.

OBJECTIVE: To predict severe hyperkalemia from single electrocardiogram (ECG) tracings. METHODS: Ten conditioned dogs each underwent this protocol three times: Under isoflurane anesthesia, 2 mEq/kg/hr of potassium chloride was given intravenously until P-waves were absent from the ECG and ventricular rates decreased > or =20% in < or =5 minutes. Serum potassium levels (K(+)) were measured at regular intervals with concurrent digital storage of lead II of the surface ECG. A three-layer artificial neural network with four hidden nodes was trained to predict K(+) from 15 separate elements of corresponding ECG data. Data were divided into a training set and a test set. Sensitivity, specificity, and diagnostic accuracy for recognizing hyperkalemia were calculated for the test set based on a prospectively defined K(+) = 7.5. RESULTS: The model produced data for 189 events; 139 were placed in the training set and 50 in the test set. The test set had 37 potassium levels at or above 7.5 mmol/L. The neural network had a sensitivity of 89% (95% CI = 75% to 97%) and a specificity of 77% (95% CI = 46% to 95%) in recognizing these. The positive likelihood ratio was 3.87. Overall accuracy of this model was 86% (95% CI = 73% to 94%). Mean (+/-SD) difference between predicted and actual K(+) values was 0.4 +/- 2.0 (95% CI = -0.2 to 1.0). CONCLUSIONS: An artificial neural network can accurately diagnose experimental hyperkalemia using ECG parameters. Further work could potentially demonstrate its usefulness in bedside diagnosis of human subjects.

Chronic stability of bipolar epicardial plunge electrodes in dogs.

We constructed and surgically implanted 114 chronic bipolar epicardial plunge electrodes for programmed left ventricular stimulation in closed chest dogs; 88 electrodes could be analyzed in animals surviving infarct surgery. Electrode plunges were constructed of silver wire, with conduction strands of silver-plated copper wire, in medical grade silicone tubing. Electrodes were implanted epicardially through left thoracotomy and secured with prolene. Wires exited the fifth intercostal space and were tunneled subcutaneously and secured at the dorsal aspect of the neck. Baseline thresholds (mA) were recorded at a paced cycle length of 300 ms and pulse duration of 1 ms. At least 5 days after implantation, under light Nembutal sedation, thresholds were reassessed before programmed stimulation. Each lead was tested repeatedly over 5-177 (mean 28) days. The number of leads decreased with time due to animal attrition from ventricular arrhythmias. Mean pacing threshold at implantation was 0.25 mA. Mean and median threshold values reached plateau after 1 week and showed little change thereafter for the duration of the study. More than 50% of the leads maintained thresholds less than 1.5 mA through the entire study. In animals that survived, 86% of the electrodes remained useful for the duration of the protocol. These data support the use of this electrode system as effective and reliable for chronic electrophysiologic studies in dogs.

Encainide dosing in patients with severe renal dysfunction: report of a case and literature review.

Dosage of encainide for patients with lethal ventricular arrhythmias is based on pharmacodynamic effects and efficacy of arrhythmia suppression, coupled with metabolizer phenotype and extent of renal and hepatic dysfunction. Decreased clearance in patients with renal dysfunction necessitates a reduction in dosage to avoid toxic and dose-related proarrhythmic effects. This case represents a patient with severe renal dysfunction and sustained ventricular tachycardia who achieved electrophysiologically guided suppression of induced ventricular tachycardia at a steady-state encainide dose of only 25 mg daily, significantly lower than package insert or compendial recommendations for initial dosage in patients with renal insufficiency. Documented "therapeutic" metabolite concentrations correlated to electrophysiologic response. Literature review illustrates the complexity of encainide dosage in such individuals and underscores the need for therapeutic drug monitoring to individualize dosage.

Intravenous magnesium is ineffective in adult asthma, a randomized trial.

Intravenous magnesium sulphate (MgSO4) has been tried in the emergency department treatment of asthma since the mid-1980s, but published reports vary as to its efficacy. The literature suggests that it may be effective in the more severely ill asthmatic. We evaluated i.v. MgSO4 in adult asthmatics having a moderate to severe exacerbation. The study was performed in a convenience sample of adult asthmatics between the ages of 18 and 55 presenting to the emergency department with a peak expiratory flow (PEF) of < 100 l/min or < 25% of predicted flow. Patients received either 2.0 grams of MgSO4 or placebo in a randomized, double-blind fashion. All patients received inhaled bronchodilators and i.v. steroids. Outcome variables were: improvement in PEF, subjective respiratory distress as measured by the Borg dyspnoea scale (BDS) and hospital admission. The first visits of 42 patients presenting with acute asthma exacerbations were evaluated, 18 receiving MgSO4 and 24 receiving placebo. The t = 60 peak flow in the MgSO4 group was 174 l/min versus 212 l/min in placebo, p = 0.04. Controlling for age, heart rate, initial PEF and initial BDS in ordinal logistic regression, the t = 60 Borg scale of subjective dyspnoea had an odds ratio of 1.54 in favour of more dyspnoea in MgSO4 (95% C.I., 0.36-6.67; p = 0.56). Five of 18 patients (28%) receiving MgSO4 were admitted compared with 5 of 24 (21%) receiving placebo (p = 0.72). In moderately severe adult asthmatics, 2.0 grams of MgSO4 i.v. resulted in less improvement in peak expiratory flow compared with placebo. MgSO4 did not appear to decrease subjective dyspnoea or the hospital admission rate. This evidence does not support the use of MgSO4 in the treatment of acute asthma.

Diagnosis and treatment of pediatric fever by caretakers.

Assessment of pediatric temperature is a multistep task involving both manipulative and cognitive skills. Emergency Physicians typically assume that parents possess these skills, but this assumption has never been fully tested. A prospective survey was conducted of caretakers of children < or = 36 months of age presenting to an inner city emergency department or pediatric clinic. Participants were asked to read a Fahrenheit scale mercury thermometer and to demonstrate use of that thermometer to "take" the temperature of an infant doll. They were then asked what temperature constituted a "fever" and what temperature would require antipyretic therapy. Caretakers were also asked how they would treat a fever in the child they had brought for treatment. Proportions of correct responses were tabulated and also compared by age and level of education of caretaker. Eighty-two of 92 caretakers (89.1%) possessed working thermometers in their homes. Thirty-six subjects (39.1%) were able to measure temperature appropriately using the mercury thermometer, 52 (56.5%) were able to read the mercury thermometer correctly, and 28 (30.4%) could both measure and read correctly. Sixty-seven subjects (72.8%) described correct treatment of fever. Overall, 27 subjects (29.3%) could measure, read, and treat fever appropriately. There was no statistically significant difference in age or percentage of high school graduates between caretakers who could successfully measure, read and treat and those who could not. In this inner city patient population, caretakers of any pediatric patient whose discharge instructions contain a reference to patient temperature should receive a brief refresher along with written instructions on temperature measurement and treatment.

The clinical pharmacology of antihypertensive drugs.

Antihypertensive drugs act centrally (methyldopa, clonidine, guanabenz), peripherally (prazosin, guanadrel, guanethedine, hydralazine, minoxidil), centrally and peripherally (beta-adrenergic blocking drugs) and systemically [angiotensin converting enzyme (ACE) inhibitors and diuretics]. Centrally-acting antihypertensives decrease blood pressure by diminishing sympathetic outflow from the vasomotor centre. Peripherally-acting antihypertensives act by depleting or inhibiting the release of catecholamines from the peripheral nerve ending or altering the response at alpha 1- and alpha 2-receptor sites. Beta-adrenergic blocking drugs act through a variety of mechanisms by either decreasing cardiac output, decreasing renin release, inhibiting prejunctional release of norepinephrine or through central mechanisms. Diuretics act as indirect vasodilators by depleting salt and water not only within the intravascular compartment but within the intramural portion of the arteriole, thereby diminishing its responsiveness to catecholamine and angiotensin II stimulation. ACE inhibitors such as captopril and enalapril act by inhibiting the conversion of angiotensin I to angiotensin II thereby decreasing the vasoconstrictor effect of angiotensin II and the aldosterone production secondary to angiotensin II stimulation. The main differences between captopril and enalapril is that enalapril does not possess the potentially toxic sulphydryl group and can be given twice-daily. Both drugs may show accumulation in patients with impaired renal function.

Clinical diagnosis of West Nile Fever in Equids by classification and regression tree (CART) analysis and comparative study of clinical appearance in three European countries.

This retrospective study describes risk/protection factors for the development of clinical West Nile Fever (WNF) in equids, compares clinical presentation in three European countries, France, Italy and Hungary, and creates classification and regression trees (CART) to facilitate clinical diagnosis. The peak of WNF occurrence was observed in September whatever the country. A significant difference between Italy and France was observed in the delay between initial clinical signs and veterinary consultation. No clinical sign was significantly associated with WNF. Despite similar clinical presentations in the three countries, occurrence of hyperthermia was more frequently reported in France. Classification and regression tree demonstrated the major importance of geographical locality and month to reach a diagnosis and emphasized differences in predominant clinical signs depending on the period of detection of the suspected case (epizootic or not). However, definite diagnosis requires specific serological tests. Centralized reporting system and time-space risk mapping should be promoted in every country.