OBJECTIVES: Amiodarone (AMI) has proven to be a potent anti-arrhythmic compound. Due to the structural similarity between AMI and thyroid hormone, it is possible that the drug could inhibit the activity of the 5'-thyroxine-deiodinase. METHODS: AMI analogues resulting from (1) dealkylation, (2) deiodination and (3) deamination were synthesised and used as inhibitors in an in vitro biotransformation reaction of thyroxine (T4) to 3,3',5'-triiodothyronine (T3). Using high-performance liquid chromatography and ultraviolet detection for quantifying T3, it was found that the 5'-T4 deiodinase type I was involved in the reaction. On separate occasions, AMI or an AMI analogue was added to the reaction as an inhibitor. RESULTS: All studied AMI analogues inhibited 5'-T4 deiodination competitively (Ki value range 25-360 microM). In the concentration range of 1-1000 microM, AMI and its N-desethylated, deiodinated analogues inhibited 5'-T4 deiodination very weakly. AMI analogues with a hydroxyl group at the 4-position were strong inhibitors. Moreover, diiodo-AMI analogues inhibited 5'-T4 deiodination more strongly than their corresponding monoiodo- or deiodinated derivatives. CONCLUSION: It is likely that the degraded products of AMI could be responsible for thyroid dysfunction toxicosis in AMI therapy.

Amiodarone↗

PubMedDate not supplied

Calcium channel blockers in treatment of hypertension.

Calcium channel blockers (CCBs) are among the most often prescribed drugs for the treatment of hypertension, but there is still uncertainty regarding the risks and benefits of their use as first-line drugs in the treatment of hypertension. Compared with placebo, dihydropyridine CCBs (long-acting nifedipine and nitrendipine) reduce the risk for cardiovascular endpoints, and in a pooled analysis of available studies on treatment of hypertension, significantly decrease the risk for strokes and cardiovascular and total mortality. This also holds true for patients with diabetes who have a clearly reduced risk when treated with CCBs as compared with placebo. However, compared with other active treatments in mixed study populations, CCBs are associated with a small risk increase for myocardial infarction and heart failure, but for cardiovascular mortality, there is only a very small and nonsignificant trend to a risk increase, and total mortality is similar. Among patients with diabetes, compared with angiotensin-converting enzyme inhibitors in particular, available data suggest that CCB use is associated with a moderate increase in cardiac endpoints. Therefore, among patients with diabetes and those with heart failure, angiotensin-converting enzyme inhibitors are preferable as first-line drugs; among the large fraction of patients without these conditions, there is no convincing evidence that long-acting dihydropyridine or nondihydropyridine CCBs are inferior to other blood pressure-lowering drugs. In these patients, the choice of blood pressure-lowering medication can be based on the expected tolerability, costs, and personal preferences.

Age Factors↗

PubMedDate not supplied

Primary angiosarcoma of the pulmonary arteries: dynamic contrast-enhanced MRI.

PURPOSE: Our goal was to assess the MR appearance and histologic correlation of primary pulmonary artery angiosarcoma. METHOD: Four patients with tumorous masses in the pulmonary arteries were evaluated by dynamic contrast-enhanced MRI using T1- and T2-weighted SE images, GE images, as well as coronal 3D MRA in breath-hold technique. The percentage of tumor enhancement was determined by measuring regions of interest before and after Gd-DTPA administration on the 2D multiplanar spoiled GRE images. RESULTS: All four masses showed some contrast enhancement on the dynamically acquired GRE images. The degree of contrast enhancement correlated with the degree of tumor differentiation, content of myxoid matrix, and associated thrombus. Contrast-enhanced 3D MRA was useful for preoperative delineation of the peripheral pulmonary arteries to the subsegmental order. CONCLUSION: Dynamic contrast-enhanced 3D MRA of the pulmonary arteries can be used to delineate pulmonary arterial angiosarcomas preoperatively. Considerable variability of contrast agent uptake reflects the wide histologic behavior of these masses in differentiation from central pulmonary embolism.

Adult↗

PubMedDate not supplied

Reliability of antiarrhythmic drug plasma concentration monitoring.

Measurement of drug levels is becoming increasingly popular to optimise the dosage of various drugs. In the case of antiarrhythmic drugs, the narrow therapeutic margin of most of these agents and a direct relationship between their pharmacological effects and plasma concentrations would justify more widespread use of monitoring. Optimum plasma concentration ranges have been described for lignocaine (lidocaine), procainamide, quinidine and, more recently, also for disopyramide, mexiletine, tocainide and other new antiarrhythmics. A critical analysis of the original data shows, however, that therapeutic and toxic levels are not so well defined as often assumed: small numbers of patients, marked interindividual variability, sometimes inadequate documentation of arrhythmias and lack of standardised blood sampling characterise many of these studies. Uncertainty about the reliability of concentration-effect relationships also arises when active drug metabolites are identified or there are marked concentration-dependent changes of drug protein-binding. In addition, abolition of various types of arrhythmias might require different drug concentrations. Nevertheless, therapeutic monitoring can be of practical value in patients with life-threatening ventricular arrhythmias and can also greatly facilitate dosage adjustment in cases with renal hepatic or severe cardiac failure. For a correct interpretation of drug levels, the time of blood sampling, dosage regimen, duration of treatment, pharmacokinetic principles, and the clinical condition of the patient must be taken into account. Further studies are needed to define the optimum therapeutic range for several drugs and to evaluate the usefulness of plasma concentration measurements in routine antiarrhythmic treatment.

Amiodarone↗

PubMedDate not supplied

Rapid prediction of individual dosage requirements for lignocaine.

The mean and standard deviation of lignocaine (lidocaine) pharmacokinetic parameters in a patient population were determined on the basis of 327 serum concentration measurements obtained in 42 patients treated for ventricular arrhythmias. The application of a Bayesian forecasting method, which uses the estimates of the population parameters and 1 or 2 serum concentration measurements as feedback information, was tested retrospectively in 17 of the 42 patients (group I, 32 levels), and prospectively in 10 additional patients (group II, 20 levels). With 1 individual feedback concentration, sampled 2 to 4 hours after the start of lignocaine infusion, serum concentrations at 12 and 24 hours could be accurately predicted. The prediction error (measured minus predicted concentration) ranged between -1.2 and +1.6 (mean -0.03) mg/L in group I, and from -0.7 to +1.5 mg/L (mean +0.13) mg/L in group II; the correlation coefficient of measured and predicted levels were 0.92 and 0.86, respectively. In contrast, a prediction of lignocaine concentrations in these patients using only population parameters without feedback was poor: range of the prediction error = -3.1 to +3.0 mg/L (mean = +0.001 mg/L, r = 0.63, groups I and II, n = 52). The results demonstrate that with the Bayesian forecasting technique, accurate assessment of individual dosage requirements can be obtained within a few hours after starting lignocaine therapy.

Adult↗

PubMedDate not supplied

Serum level monitoring of antibacterial drugs. A review.

Serum concentration measurements of antibacterial agents are increasingly used to optimise drug dosage regimens. However, this approach is only justified for drugs with a low therapeutic index and poor predictability of serum concentrations, such as the aminoglycosides, chloramphenicol and vancomycin, whereas the penicillins and cephalosporins can safely be applied well above their minimum inhibitory concentrations. Wide interpatient variation in distribution and elimination are the main reasons for the unpredictability of aminoglycoside serum concentrations. It has been shown that in patients with normal creatinine clearance, the apparent elimination half-life of gentamicin varies from 0.4 to 7.6 hours. The pharmacokinetics of the aminoglycosides are most adequately described by a 3-compartment open model where the slow terminal half-life reflects elimination from the deep tissue compartment. The accumulation of the aminoglycosides in this compartment, which includes the kidneys and inner ear, is probably an important factor in their potential toxicity in these organs. Careful serum level monitoring may reduce, but cannot totally avoid, the risk of side effects. However, maintenance of effective drug levels appears to be at least an equally important goal of aminoglycoside serum level monitoring. Chloramphenicol is also a potentially toxic antibacterial agent. Its therapeutic range is usually considered to be 15 to 25 mg/L. The most important side effects are the 'grey baby syndrome' and bone marrow toxicity. Chloramphenicol is metabolised to several microbiologically inactive products. It also shows wide interpatient variability of its pharmacokinetics, especially in young children, and serum levels should therefore be followed in these patients. Vancomycin, a highly effective agent for staphylococcal and enterococcal infections, may also exhibit nephrotoxic and ototoxic side effects. A well-defined therapeutic range has not yet been established but in view of its minimum inhibitory concentrations it seems reasonable to maintain vancomycin serum concentrations between 15 and 50 mg/L. Since this drug is excreted unchanged in the urine, serum levels should particularly be monitored in patients with impaired renal function. The advances in routine therapeutic drug monitoring are directly related to rapid developments in technologies associated with the quantification of these agents. Microbiological plate diffusion assays are now often replaced by more specific immunoassays (radioimmunoassay, enzyme immunoassay, and fluorescence immunoassay) and chromatographic techniques.

Aminoglycosides↗

PubMedDate not supplied

[Monitoring of plasma concentrations of aminoglycosides].

Aminoglycosides are antibiotics commonly used in the management of a large number of gram- and gram+ infections but their use is limited by their potential nephrotoxicity and ototoxicity. At present, monitoring of plasma concentrations is the most reliable method for assuring adequate therapy with these antibiotics. The above paper was intended to show the importance of pharmacokinetic monitoring in order to guarantee therapeutic efficacy and control potential toxicity of aminoglycosides in a series of 90 patients.

Adult↗

PubMedDate not supplied

Relative electrophysiological potencies of quinidine, 3-OH quinidine and quinidine-N-oxide in guinea-pig heart.

The relative potencies of the quinidine metabolites, 3-OH quinidine (3OHQ) and quinidine-N-oxide (QNO), to their parent drug, quinidine, were obtained electrophysiologically using guinea-pig hearts. The items examined were QT interval of local extracellular electrogram in a Langendorff's perfused heart, effective refractory period (ERP) and action potential duration at 90% repolarization (APD90) in the right papillary muscle. Quinidine (0.125-1 mg/l) and 3OHQ (0.5-4 mg/l) prolonged QT interval in a concentration-dependent manner and the relative potency of 3OHQ to quinidine was 0.25. The effect of QNO on QT interval within the range of concentration used (up to 8 mg/l) was small and the relative potency was 0.04 at the most. An apparent additive effect of 3OHQ to that of quinidine was revealed, but QNO of 4 mg/l has no effect on the concentration-effect relationship of quinidine for prolonging QT interval. These results were quite similar to those in humans reported previously. Quinidine (0.5-4 mg/l), 3OHQ (1-8 mg/l) and QNO (2-8 mg/l) prolonged APD90 in a concentration-dependent manner. These effects were accompanied by the prolongation of ERP in similar degrees. The relative potencies of 3OHQ to Q were 0.22 for APD90 and 0.27 for ERP and those of QNO were 0.087 for APD90 and 0.084 for ERP. Quinidine (10(-5) M) depressed the maximum upstroke of action potential (Vmax) in a frequency-dependent manner. 3OHQ of the same concentration also depressed it in the same manner to a much lesser extent and QNO had no effect. In conclusion, relative potencies of quinidine metabolites to quinidine for prolonging QT interval of local extracellular electrogram represent those to prolong APD90 and ERP, suggesting the relative potencies for antiarrhythmic activity in the same order. In the physiological range of concentrations of metabolites, 3OHQ may contribute to the antiarrhythmic effect of quinidine in an additive way, but QNO may have little effect when we take into account the fact that the free fraction of 3OHQ is 2.5 times that of quinidine.

Action Potentials↗

PubMedDate not supplied

Complications in patients with cloth-covered Starr-Edwards prostheses.

Ninety-six patients were followed for an average of 45 months after insertion of cloth-covered Starr-Edwards prostheses (SE 2300, 2310, 2320, 2400, 6300, 6320, 6400). Operative mortality was 1%, hospital mortality 5.2% and late mortality (45 months) 13.5%. We observed a high incidence of valve disfunction as evidenced by a removal rate of 23% after six years. Disfunction was most reliably detected by abnormal prosthetic sounds and/or murmurs of incompetence at the prostheses. Thromboembolism occurred in 14% of the patients over 6 years and increased hemolysis was found in 18.8% of patients. It is concluded that the low incidence of thromboembolism does probably not out-weight the high incidence of valve disfunction.

Female↗