We evaluated the efficacy and the safety of medium-(240 mg/day) and high-dose (360 mg/day) diltiazem alone and in combination with digoxin when used for control of heart rate in 12 patients with chronic atrial fibrillation. Medium-dose diltiazem was comparable to therapeutic dose of digoxin at rest (88 ± 19 vs 86 + 12 beats/min) but superior during peak exercise (154 23 vs 170 + 20 beats/min; p < .05). High-dose diltiazem resulted in better control of heart rate than digoxin both at rest (79 17 beats/min; p < .05) and exercise (136 + 25 beats/min; p < .05) but was associated with side effects in 75% of the patients. Combined therapy of digoxin and diltiazem enhanced the effect of digoxin alone and resulted in significantly better control of heart rate at rest (67 + 16 beats/min with medium-dose and 65 + 15 beats/min with high-dose diltiazem) and during peak exercise (132 + 32 and 121 ± 24 beats/min, respectively). However, the difference in heart rate between these two doses was not significant. Reduction of heart rate combined with concomitant effect on blood pressure resulted in a significant fall in pressure-rate product at rest from 10,077 + 1708 mm Hg/min on digoxin alone to 7877 + 1818 mm Hg/min after the addition of medium-dose diltiazem (p < .05) and during exercise from 25,670 + 3606 to 18,439 4115 mm Hg/min (p < .05). Continued therapy with digoxin combined with diltiazem 240 mg/day for 21 ± 8 days in nine patients showed persistent effect on heart rate and blood pressure without any toxic manifestations or change in serum digoxin (1.5 + 0.4 vs 1.3 + 0.4 ng/ml) or plasma diltiazem concentrations (204 72 vs 232 129 ng/ml). In conclusion, medium-dose diltiazem when combined with digoxin is an effective and safe regimen for the treatment of patients with chronic atrial fibrillation and enhances digoxin-mediated control of heart rate both at rest and during exercise. Circulation 73, No. 2, 316-324, 1986. DIGITALIS has been used traditionally as a drug of choice for control of ventricular rate in patients with atrial fibrillation.1 2 Although the drug is valuable at rest, it is less effective in the control of heart rate response to exercise or other stress-related situations.3 1 4Recent studies have demonstrated that the direct effect of verapamil on slowing atrioventricular nodal conduction results in a better control of exercise heart rate in patients with atrial fibrillation.3 5,6 The

A Bayesian method for monitoring vancomycin concentrations and adjusting regimens in patients with unstable renal function by using a two-compartment population model was evaluated with a personal computer. The population model was derived from data from 12 cardiac outpatients who received single doses of vancomycin. The performance of the method was then tested in 27 acutely ill patients who received multiple doses of vancomycin. Significant renal impairment was observed in 15 patients. Renal function changed in 15 patients. The vancomycin concentrations in the patients with changing renal function were not at steady state during the observation times. Two concentrations in serum (peak and then trough, or trough and then peak) were fitted along with the population model to individualize the parameter values for each patient. All the subsequent concentrations in serum for each patient were then predicted by using the parameter values for each patient. Future concentrations of 118 serum samples were predicted. The mean absolute prediction error was 3.6 ± 4.5 ,Lg/ml, and the mean prediction error was -0.7 ± 5.3 ,Ig/ml. These results confirm that a two-compartment pharmacokinetic model can be sufficiently individualized with the knowledge of just two concentrations of drug in patient serum; it is possible to predict closely subsequent concentrations in serum, and dosing regimens for individual patients can be well adjusted to achieve the chosen therapeutic goals.Three favorable characteristics of vancomycin are the bactericidal effect, the sustained concentrations in serum achieved compared with those achieved with beta-lactam antibiotics, and the rare development of bacterial resistance (4). These traits, along with the current rise in methicillinresistant staphylococcal infections and the increasing use of prosthetic devices requiring antibiotic prophylaxis (1), have stimulated new interest in vancomycin use. In addition, the availability of more precise methods of measuring vancomycin concentrations in serum and the availability of sophisticated computer software for analyzing drug concentrationin-serum data (7, 14) now make it possible to individualize vancomycin dosage regimens that are more clinically effective, safe, and cost-effective. These factors have led to a growing demand to monitor vancomycin therapy and to interpret the meaning of its concentrations in serum.The (2,4,11,17,18,21). The controversy stems from the fact that the concentration-time profile of vancomycin in serum is not described by a monoexponential decay, as reflected by the one-compartment pharmacokinetic model used in many earlier clinical studies (3,10,18). At least two compartments are required to describe vancomycin pharmacokinetics adequately: a central serum compartment and a peripheral compartment (nonserum) (5,13,16

The pharmacokinetics of various drugs may be profoundly altered during different stages of pregnancy, parturition, and lactation. Gastrointestinal absorption or bioavailability of drugs may vary due to changes in gastric secretion and motility. Various haemodynamic changes such as an increase in cardiac output, blood volume, and renal plasma flow may affect drug disposition and elimination. The increase in blood volume and total body water which occurs during pregnancy can alter the volume of distribution for various drugs. Although exact quantifications are not easy, these changes in pharmacokinetic parameters should be considered when dosing antiarrhythmic agents in pregnant women. Plasma protein concentrations and drug binding capacity are altered in the mother and fetus as pregnancy advances. With highly protein bound drugs, these changes may be clinically significant, as the pharmacological efficacy and toxicity are presumed to be related to the concentration of free drug in both the mother and fetus. In some instances, the fetus may be susceptible to greater drug toxicity as free drug concentrations may be underestimated by measurement of total drug concentrations. Changes in maternal drug metabolism and metabolism by the fetoplacental unit also contribute to alterations in the pharmacokinetics of drugs. As the placenta contains many metabolising enzymes, biotransformation of drugs at this site could potentially convert a drug into an active metabolite, or prevent fetal exposure to a toxic drug. Placental transfer of drugs, leading to toxicity in the fetus, is a major concern in the pharmacological management of the pregnant patient. The passage of individual drugs will vary depending on their apparent volumes of distribution, degree of protein binding the rates of metabolic conversion and excretion within the placenta and fetus, the pH difference between the maternal and fetal fluids, and maternal haemodynamic changes. Drug properties such as lipid solubility, protein binding characteristics, and ionisation constant (pKa) also influence the placental passage of drugs. For weakly basic antiarrhythmic agents, the fetal drug concentration may potentially exceed the maternal plasma concentration when the fetal pH is lowered as in the case of fetal acidosis; this is due to 'ion trapping'. Additionally, higher free drug concentrations of these basic drugs may exist, due to decreased alpha 1-acid glycoprotein concentration and binding affinity in the fetus. Lignocaine (lidocaine) has been shown to enter fetal plasma rapidly with fetal-maternal concentration ratios in the range of 0.52 to 0.66.(ABSTRACT TRUNCATED AT 400 WORDS)

Introduction: Many warfarin-related genotypes have shown to impact the average daily warfarin (ADW) dose requirements; however, information in non-Caucasian populations is limited. Objectives: To identify the frequencies of 4 warfarin-related gene polymorphisms in an ethnically diverse patient population and to examine their impact with other clinical variables on ADW dose requirements. Methods: Patients were recruited from 2 anticoagulation clinics in the Los Angeles area. Blood samples were collected and genotyped for vitamin K epoxide reductase (VKORC1), CYP2C9*2, CYP2C9*3, and CYP4F2 after informed consent. Charts were reviewed to collect demographic, clinical, and warfarin dosing data. Results: A total of 291 patients were included (120 Caucasians, 127 Hispanics, and 44 Asians). In patients with wild-type genotypes for VKORC1, CYP2C9*2, CYP2C9*3, and CYP4F2, the highest warfarin requirement was found in Caucasians, lower in Hispanics, and lowest in Asians. Homozygous VKORC1 variant carriers were detected in 15%, 15%, and 79% in Caucasians, Hispanics, and Asians, respectively. Progressive lowering of ADW doses were associated with each VKORC1 variant in Caucasians and Hispanics, but the results in wild-type/ heterozygote Asians were unclear. CYP2C9 variants were associated with lower ADW doses; frequencies of CYP2C9*2 and CYP2C9*3 mutations were higher in Caucasians than in Hispanics but rare to none in Asians. The frequencies of CYP4F2 variant were similar across all ethnicities, but their impact on warfarin dose requirement were insignificant. Clinical factors such as age, body surface area, history of coronary artery disease, deep vein thrombosis or atrial fibrillation, and concomitant amiodarone or HMG-CoA reductase inhibitors had varying impact on the ADW requirements in the ethnicities studied. Conclusions: Our study demonstrated differences among 3 ethnic groups in terms of ADW dose requirements and the impact of associated clinical variables. The results suggest that a single model for all ethnicities may not provide the best performance in predicting warfarin dose requirements.

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