Influence of grapefruit juice on caffeine pharmacokinetics and pharmacodynamics.

The influence of grapefruit juice (GFJ) on caffeine's metabolism and the hemodynamic effects of this potential food interaction were studied in 10 normotensive volunteers. In this crossover study, caffeine (3.3 mg/kg) and water or caffeine and GFJ were given to participants. Nine serum caffeine concentrations were determined within 24 hours of each phase. In another phase of this study, caffeine was given with multiple GFJ doses to 6 of the 10 participants. Ambulatory blood pressure (BP) monitors were used for 12 hours to assess treatment hemodynamic effects. The mean area under the serum caffeine concentration-time curve (AUC0-infinity) values +/- SD for the caffeine with water group, caffeine with GFJ group, and caffeine with multiple GFJ group were 47.0 +/- 10.8, 48.7 +/- 15.2, and 49.6 +/- 7.0 micrograms/ml.hr, respectively (NS). There was no significant difference on the ambulatory systolic BP, diastolic BP, percentage of the time with a diastolic BP greater than 90 mm Hg, or heart rate area under the effect curves. We conclude that grapefruit juice had no effect on caffeine pharmacokinetics or hemodynamic effects.

Is there a therapeutic or pharmacokinetic rationale for amphotericin B dosing in systemic Candida infections?

OBJECTIVE: To review the literature regarding the dosage of amphotericin B in Candida infections. The correlation or rationale of current dosing practices is assessed in light of the literature. DATA SOURCES: A MEDLINE search encompassing the years 1968-1995 was used to identify pertinent literature. Additional references were obtained from the articles retrieved from MEDLINE. STUDY SELECTION: Studies that directly assessed amphotericin B dosage and/or duration, pharmacokinetic literature dealing with plasma concentrations and amphotericin B disposition, and literature dealing with dose and/or concentration as well as clinical outcome were selected for inclusion. Additional relevant citations were used in the introductory material and discussion. DATA EXTRACTION: Although there was a large number of articles related to amphotericin B, surprisingly few large studies were designed to address the issues in question. The description of the methods and results of these heterogeneous articles are the basis of this review. Although additional controlled studies with more subjects need to be performed, the results to date provide a foundation from which to make some inferences regarding optimal use of this therapeutic modality until more definitive data become available. DATA SYNTHESIS: Despite numerous articles addressing the pharmacokinetics of amphotericin B, little is known about its tissue distribution, the rate of transfer of the drug from vascular to peripheral sites, or its terminal disposition. Less information is available regarding the relevance of pharmacokinetic parameters or serum concentrations to clinical outcome. Most of the articles mentioning dosing provide little or no justification for the doses employed. The variety of the dosages used and the heterogeneity of the populations studied make determination of dose-outcome relationships difficult. CONCLUSIONS: From the available clinical data, it appears that early initiation of amphotericin B therapy is crucial to a favorable outcome. Daily dosing initially followed by every-other-day administration of twice the daily dose is better tolerated by the patient than daily dosing and produces a similar therapeutic outcome. The drug should be continued until therapeutic endpoints have been achieved, rather than until a specific total dosage has been administered. The nephrotoxicity that occurs with amphotericin B administration is apparently reversible and should not be used as an endpoint for therapy if total dosages do not exceed 4 g. Additional well-designed, controlled trials evaluating standardized dosing methods of amphotericin B with predetermined dosing regimens and/or definitive therapeutic endpoints are needed to determine the optimal dosing approach for this agent.

Clinical and medicoeconomic impact of the cyclosporine-diltiazem interaction in renal transplant recipients.

The effect of the diltiazem-cyclosporine interaction on cyclosporine pharmacokinetics, pharmacodynamics, and pharmacoeconomics was studied in 10 recipients of renal allografts. Each subject was studied while receiving diltiazem 60 mg twice/day and while not taking the drug. After achieving steady-state conditions, cyclosporine and metabolite concentrations were determined in whole blood from samples drawn after the morning cyclosporine dose. After pharmacokinetic analysis, all patients were followed for 6 months during treatment with cyclosporine plus diltiazem or cyclosporine alone. Cyclosporine blood clearance decreased significantly after treatment with diltiazem (18.0-11.0 ml/min.kg; p = 0.008). The apparent volume of cyclosporine distribution also decreased significantly (4.26-2.62 L/kg; p < 0.05). After 6 months, diltiazem had no effect on renal function indexes, and no apparent effect on immunosuppression. Alterations in cyclosporine clearance and apparent volume of distribution secondary to diltiazem result in dosage reduction and potential cost savings in transplant pharmacotherapy. The mean decrease in cyclosporine dosage requirements would produce a cost saving of $1520 or 28% per patient per year.

Intravenous magnesium therapy in acute myocardial infarction.

OBJECTIVE: To review the methods and summarize the findings of clinical trials evaluating the use of intravenous magnesium (Mg2+) in acute myocardial infarction (AMI); to discuss serum Mg2+ in AMI and the potential mechanisms by which intravenous Mg2+ may be effective. Tables are used extensively to provide detailed information about the various trials. DATA SOURCES: A MEDLINE search was used to identify pertinent literature. Additional references were obtained from the articles retrieved from that search. STUDY SELECTION: Studies randomized and/or placebo-controlled were selected for review. Additional relevant citations were used in the introductory material and discussion. DATA EXTRACTION: There were surprisingly few large, placebo-controlled trials. All clinical trials available at the time of publication were reviewed. Only eight trials enrolled sufficient numbers of patients and/or were of adequate design to make meaningful interpretations. The description of the methods and results of these articles are the basis of this review. Although additional controlled studies with more subjects are needed, the results to date form a foundation from which to make inferences regarding the utility of this therapeutic modality. DATA SYNTHESIS: Intravenous Mg2+ has been demonstrated, albeit inconclusively, to reduce immediate and long-term morbidity and mortality when given in the immediate postinfarction period. Six of the eight controlled trials discussed report a decrease in the overall incidence of arrhythmia or in the frequency of arrhythmia requiring treatment. Four of the eight reported statistical significance. Five of the six trials evaluating mortality reported a decrease in the mortality rate from intravenous Mg2+ administered post-MI. Four of the five reported statistical significance. The favorable effect of intravenous Mg2+ on the mortality rate appears to occur in the first 30 days post-MI and is maintained through at least one year. The effects appear to be independent of concurrent therapy and do not appear to relate to baseline serum Mg2+ concentrations. Intravenous Mg2+ appears to be safe and well tolerated. Flushing, hypotension, and atrioventricular (AV) node conduction abnormalities occur on occasion and seem related to the rate of administration. The exact dosage in this setting remains to be determined. CONCLUSIONS: Additional, well-designed, multicenter, controlled trials evaluating intravenous Mg2+ in AMI are needed. The pending Fourth International Study of Infarct Survival, with an anticipated 400,000 subjects, should clarify a number of unresolved issues regarding this therapy. Based on the information available to date, however, intravenous Mg2+ as a significant therapeutic modality for AMI shows promise. Pending further investigation, however, it should be avoided in patients with significant sinoatrial or AV conduction disturbances.

Magnesium homeostasis and clinical disorders of magnesium deficiency.

OBJECTIVE: To survey the causes of clinical hypomagnesemia and Mg deficiency. The relationship of hypomagnesemia to digitalis toxicity, congestive heart failure, arrhythmias, and acute myocardial infarction is discussed, as is the clinical interrelationship of Mg and K concentrations, the principal intracellular cations. DATA SOURCES: A MEDLINE search and retrieval was used to identify relevant references. STUDY SELECTION: Clinical reports, as well as studies, were selected for this review. DATA EXTRACTION: There were very few placebo-controlled clinical studies. Clinical observations were related primarily to compilation of series in which Mg was administered and clinical results reported. In addition, conclusions derived from review articles on the subject of clinical Mg depletion were used. DATA SYNTHESIS: Clinical diagnosis of Mg deficiency is ascertained most expeditiously by estimating serum Mg concentrations. Although available on order by physicians, the lack of routine serum Mg analysis as part of the "electrolyte panel" impedes the diagnosis of clinical Mg deficiency. Renal loss of Mg resulting from the widespread use of loop diuretics is responsible for significant numbers of patients with Mg deficiency and hypomagnesemia. Life-threatening cardiac arrhythmias and seizures represent the most serious manifestations of clinical hypomagnesemia and Mg depletion. In the most critically ill patients, treatment with intravenous Mg is recommended. Oral repletion of Mg is reserved for the less critically ill hospitalized patients and ambulatory patients. Close attention must be paid to optimizing K replenishment in hypokalemic patients by concurrent treatment of any accompanying hypomagnesemia to avoid the problem of refractory K repletion. CONCLUSIONS: Hypomagnesemia is one of the most frequent serum electrolyte abnormalities in current clinical practice. Routine inclusion of serum Mg analysis in the electrolyte panel will enhance the clinical recognition and treatment of hypomagnesemic Mg-depleted patients. Failure to respond to treatment of recurrent ventricular tachycardia/fibrillation to usual antiarrhythmic therapy in patients with acute myocardial infarction, idiopathic dilated cardiomyopathy, and congestive heart failure should alert the clinician to consider administering intravenous Mg. Repair of coexisting hypomagnesemia in hypokalemic patients is essential to avoid the problem of refractory K repletion caused by coexisting Mg depletion. More controlled clinical studies of Mg deficiency are necessary to ascertain the cost-effectiveness of Mg replacement therapy.

Comparison of MS-DOS and Macintosh pharmacokinetic analysis programs using a two-compartment, two-infusion dosing scheme.

Pharmacokinetic values derived by three nonlinear least-squares regression computer programs for sets of serum drug concentration data were compared. The three programs selected for comparison were the MS-DOS-based programs PCNONLIN and ADAPT and the Macintosh program BOOMER. Data on serum recainam hydrochloride concentration in 10 patients given an i.v. loading dose followed by a maintenance infusion were fitted by the appropriate models in each program. Samples had been subjected to reverse-phase isocratic high-performance liquid chromatography with ultraviolet light detection; intraday and interday coefficients of variation were less than 8% over the range of concentrations measured. A two-compartment model was used for all regressions. Each program was given identical initial estimates, and the simplex minimization algorithm of each program was used to fit the model to the data. An identical weighting scheme was used for all three programs. The mean pharmacokinetic values estimated by each program for the 10 data sets were essentially identical. Slightly larger rate constants and smaller volume terms were derived by BOOMER. BOOMER yielded the lowest weighted sum of squares and the highest correlation coefficient. A mean concentration-time plot showed that the programs all produced values that described the data very well. The three computer programs used in this analysis derived essentially the same pharmacokinetic values to describe sets of serum drug concentration data. The BOOMER program provides an acceptable alternative to MS-DOS-based programs for pharmacokinetic analysis.

Using estimated creatinine clearance for individualizing drug therapy: a reassessment.

Estimates of renal function are frequently used to design individual dosing regimens. The accuracy of these estimates naturally influences their ability to predict certain pharmacokinetic parameters and appropriate drug dosages. Creatinine clearance is the most widely used estimate of renal function. Many formulas have been developed to provide a quick, relatively accurate prediction of creatinine clearance and, supposedly, the glomerular filtration rate (GFR). However, an understanding of the limitations associated with creatinine clearance estimations raises questions concerning their reliability as an aid in individualizing drug therapy. Many factors such as disease states, age, diet, analytical variations, and drug interactions affect the relationship between estimates and measures of creatinine clearance and GFR. As a result, creatinine clearance estimates using these formulas are often poor reflections of measured creatinine clearance or GFR. Also, studies comparing measured creatinine clearance with more accurate methods of assessing renal function (i.e., inulin) reveal errors that are often exaggerated as renal function declines. Therefore, estimated creatinine clearance is twice removed from the associated pharmacokinetic parameter. Despite these limitations, no other clinically relevant and convenient assessment of renal function is available. The authors recommend that the appropriate caveats be considered when using these tools clinically. For drugs with narrow therapeutic indices, estimates of creatinine clearance should only be used to establish initial dosing regimens, with subsequent therapy based on parameters generated from concentration determinations.

Toxic carbamazepine concentrations following cardiothoracic surgery and myocardial infarction.

Carbamazepine is being used more frequently in the U.S. as an initial agent of choice to treat generalized tonic-clonic, mixed, and partial seizures with complex symptomatology. Carbamazepine is extensively metabolized in the liver; however, there is little information available on its pharmacokinetics in patients following surgery or myocardial infarction, or in those with liver disease. We report a case of a patient who attained toxic carbamazepine serum concentrations (ranging from 18.2 to 21.5 micrograms/mL) two days after cardiothoracic surgery and an intraoperative myocardial infarction, and experienced lethargy, diplopia, dysarthria, diaphoresis, and horizontal and downgaze nystagmus. These alterations in serum carbamazepine concentration normalized ten days after surgery. They may have been due to a combination of changes in protein binding and decreased elimination due to altered intrinsic hepatic clearance. With carbamazepine achieving a more prominent place in anticonvulsant therapy, the influence of various procedures and disease processes on the pharmacokinetics and pharmacodynamics of carbamazepine, as well as the clinical consequences of such changes, need further investigation.

Stability of cisplatin and etoposide in intravenous admixtures.

The stability of various concentrations of etoposide and cisplatin in intravenous admixtures under various storage conditions was studied. Admixtures containing etoposide (200 and 400 micrograms/mL) with cisplatin (200 micrograms/mL) were prepared in 0.9% sodium chloride injection and in 5% dextrose and 0.45% sodium chloride injection. The admixtures were stored in either polyvinyl chloride bags or glass bottles. Mannitol and potassium chloride were added to selected admixtures. Half of the admixtures were protected from light, while the other half were exposed to fluorescent light. All admixtures were stored at room temperature. Samples were visually inspected and assayed for etoposide and cisplatin content by high-performance liquid chromatography within 15 minutes after admixture preparation and after 8, 24, and 48 hours of storage. Etoposide and cisplatin concentrations decreased less than 10% from the initial concentration after eight hours of storage. At 24 hours, the admixtures containing etoposide 400 micrograms/mL and cisplatin 200 micrograms/mL (with additives) in 0.9% sodium chloride injection precipitated. The decrease in etoposide concentrations during the first 24 hours in the rest of the admixtures was less than 10% of the initial concentration. The change in etoposide concentration was related to the type of i.v. solution and the presence of additives. After 24 hours, the change in cisplatin concentrations was less than 10% of the initial concentration, except in the admixtures that precipitated. For cisplatin, the presence of light was related to an increased loss of cisplatin concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

The disposition of recainam hydrochloride during and after intravenous loading and maintenance infusion in cardiac patients.

Recainam hydrochloride is a newly synthesized propylurea compound demonstrating potent antidysrhythmic effects. Recainam was administered as a loading dose of 3 mg/kg/40 minutes followed by a continuous infusion of 0.9 mg/kg/hr for 23 hours and 20 minutes to ten patients with cardiac disease and frequent PVCs (more than 30/hr). A total of 15 plasma samples were drawn over 36 hours during and after the infusion. Plasma recainam concentration was determined by high performance liquid chromatography (HPLC). The mean (+/- SD) postload and 24-hour plasma concentrations were 5.19 +/- 0.51 and 3.41 +/- 0.71 micrograms/mL, respectively. The data were best described by a two-compartment model yielding the following mean (+/- SD) pharmacokinetic parameters: lambda 1 = 2.62 +/- 0.68 hr-1, lambda 2 = 0.144 +/- 0.014 hr-1, t1/2 lambda 2 = 4.84 +/- 0.46 hr, CLT = 0.268 +/- 0.057 L/hr/kg, CLR = 0.143 +/- 0.052 L/kg/hr, CLNR = 0.125 +/- 0.041 L/hr/kg, Vdss = 1.3 +/- 0.19 L/kg, and Vd lambda 2 = 1.9 +/- 0.43 L/kg. There were no adverse reactions. Based on these data, recainam can be safely administered as a loading dose followed by a continuous infusion in patients with stable cardiac disease without significant ventricular dysfunction.

Effect of maturation on drug disposition in pediatric patients.

Maturational changes in the physiologic processes that govern drug disposition in pediatric patients are described, and evaluation of data from pediatric drug studies is discussed. Gastrointestinal absorption depends on gastric pH, gastric emptying time, intestinal transit time, and gastrointestinal enzymatic activity; the overall effect of age-related alterations in these variables is poorly understood. Maturational changes in the skin affect percutaneous absorption. Distribution of drugs is affected by alterations in vascular perfusion, body composition, tissue binding, and plasma protein binding. For most water-soluble drugs, volume of distribution is increased in neonates. Age-related changes in biotransformation are complex because the rate of development of phase 1 and phase 2 metabolic pathways varies and metabolic pathways may be induced by in utero exposure to inducing agents. For most drugs, biotransformation is decreased in the neonate, increases from one to five years of age, and decreases after puberty to adult values. The kidneys of neonates are inefficient at drug elimination, leading initially to prolonged elimination half-lives of many drugs. Clearance of some drugs may be greater in infants than in older children and adults because of disproportionate development of renal filtration and secretion in relation to reabsorption. Few data on maturational changes in physiologic processes that affect drug disposition are available for any one drug in a specific pediatric population. In the development of research protocols, careful attention should be paid to the design limitations of published studies.

Recainam, a potent new antiarrhythmic agent: effects on complex ventricular arrhythmias.

The antiarrhythmic efficacy and safety of intravenous recainam, a newly synthesized compound displaying potent class I antiarrhythmic activity, were tested in 10 hospitalized patients with frequent (greater than 30/h) complex ventricular ectopic beats. There were seven men and three women of average age 57 years (range 21 to 74); five had ischemic heart disease, three had cardiomyopathy and two had valvular heart disease. Recainam was given as a 3.0 mg/kg per 40 min loading infusion followed by a 0.9 mg/kg per h maintenance infusion over a 24 hour observation period. Arrhythmia response was assessed both in the short term (comparing 2 hours before and 1 hour after drug loading) and in the long term (comparing 48 hours before drug loading and 23 hours of maintenance infusion). The median frequency of total premature ventricular complexes decreased in the short term by 99.6% (from 392.5 to 1.5/h, p less than 0.005) and in the long term by 99.7% (from 435 to 1.3/h, p less than 0.01). Repetitive beats were suppressed by a median of 100% both in the short term (p less than 0.006) and during 24 hour infusion (from 80.9 to 0/h, p less than 0.003). More than 90% suppression of repetitive beats occurred in all 10 patients (100%) and more than 90% suppression of total arrhythmias occurred in 9 patients (90%) during the maintenance period. Electrocardiographic PR and QRS intervals increased by 19% (p less than 0.001) and 24% (p less than 0.003), respectively, during therapy, but the JTc interval decreased (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Initial and long-term outpatient experience with pirmenol for control of ventricular arrhythmias.

Pirmenol, a new class IA antiarrhythmic agent, has shown promise in short-term trials, but long-term efficacy has not been documented. We thus evaluated 11 patients with frequent (greater than or equal to 60/h) premature ventricular complexes (PVC) given oral pirmenol for 25-727 days. Ten of 11 patients entering the long-term open trial had shown greater than or equal to 70% (mean 83%) PVC suppression during in-hospital pirmenol dose ranging. Long-term pirmenol was given in divided doses of 100-600 mg/day. Mean PVC frequency during baseline was 13,078/24 h (range, 3,218-32,718); couplets averaged 481/24 h (1-2,829) and runs 45/24 h (0-334). Ambulatory monitoring was performed at 1, 3, 6, and 12 months, then semiannually. Mean absolute PVC suppression at 1 month averaged 75% (p less than or equal to 0.02). Median individual percentage PVC suppression was 94%. During the first 3 months, 8 patients (73%) continued to show a favorable response (greater than or equal to 70% suppression), and 3 had arrhythmia recurrence and were dropped. One responder was withdrawn after the onset of paroxysmal atrial fibrillation, and another early responder was withdrawn after 3 months because of arrhythmia relapse. Six patients have been treated for over 1 year, with 99% mean PVC suppression. Mean couplet and run frequencies at 1 month decreased by means of 76% (p less than or equal to 0.05) and 92% (p = 0.001) respectively. At 1 year, couplets were suppressed 99.8% and runs by 99.7% in the 6 patients remaining on pirmenol.(ABSTRACT TRUNCATED AT 250 WORDS)

Initial and long-term outpatient experience with lorcainide for suppression of malignant and potentially malignant ventricular arrhythmias.

There is a need for effective, well-tolerated antiarrhythmic agents, particularly those effective by both intravenous and oral routes. Lorcainide, a new antiarrhythmic drug with such properties, was given long-term orally to 24 patients controlled initially with intravenous therapy--19 with frequent (greater than 1/min) complex premature ventricular complexes (PVCs) on a baseline 24-hour Holter monitor and five with ongoing sustained ventricular tachycardia (VT) or frequent paroxysmal sustained VT, for a mean of 13 months (range 0.03 to 39.4 months). Long-term lorcainide was given in divided doses of 200 to 800 mg/day (median 260, mean 269 +/- 90 mg/day). Response to long-term lorcainide therapy was assessed at a mean of both 26 days and 12.2 months. Frequency of PVCs on baseline averaged 13,490/24 hours (median 10,578, range 2,115 to 61,716); couplets averaged 309/24 hours (median 166, range 0 to 5,686), and runs averaged 33/24 hours (median 30, range 0 to 2,951). Median frequency of PVCs decreased by 94% (p much less than 0.001) and 97% (p less than 0.01) at the first and second lorcainide efficacy assessments, respectively. Couplets decreased by a median of 99% (p much less than 0.001) and 100% (p less than 0.005) at the first and second assessments, respectively. Runs were suppressed by a median of 100% at both evaluations (p much less than 0.001). Only three (16%) of the patients with complex PVCs failed to respond to therapy. No recurrence during lorcainide has been noted in the five patients with ongoing sustained VT or recurrent episodes of VT.(ABSTRACT TRUNCATED AT 250 WORDS)