Providing patients with pharmacogenetic test results affects adherence to statin therapy: results of the Additional KIF6 Risk Offers Better Adherence to Statins (AKROBATS) trial.

Despite the clinical benefit of statin therapy and the numerous strategies used to improve adherence, no strategy has used direct communication of genetic test results to the patient as an adherence and persistence motivator. We investigated in a real-world setting the effect of a process of providing KIF6 test results and risk information directly to 647 tested patients on 6-month statin adherence (proportion of days covered (PDC)) and persistence compared with concurrent non-tested matched controls. Adjusted 6-month statin PDC was significantly greater in tested patients: 0.77 (95% confidence interval (CI) 0.72-0.82) vs controls 0.68 (95% CI 0.63-0.73), P<0.0001. Significantly more tested patients were adherent (PDC⩾0.80) (63.4% (59.6-67.1%) vs 45.0% (41.1-48.8%), P<0.0001) and persisted on therapy (69.1% (65.4-72.5%) vs 53.3% (49.4-57.1%), P<0.0001). Similar results were observed in a secondary comparison with 779 unmatched patients who declined testing. The Additional KIF6 Risk Offers Better Adherence to Statins trial provides the first evidence that pharmacogenetic testing may modify patient adherence.

Effectiveness and economic impact associated with a program for outpatient management of acute deep vein thrombosis in a group model health maintenance organization.

BACKGROUND: Controlled clinical trials have demonstrated that outpatient administration of low-molecular-weight heparin to patients with acute deep vein thrombosis (DVT) provides safety and efficacy equivalent to that of traditional inpatient therapy with unfractionated heparin. Whether favorable results reported in controlled clinical trials are achievable in clinical practice is an important consideration. METHODS: Appropriate patients with objectively diagnosed DVT were treated as outpatients with low-molecular-weight heparin and warfarin sodium according to an approved guideline. The primary end point for analysis consisted of objectively diagnosed symptomatic recurrent thromboembolism or major bleeding within a 90-day evaluation period. The incremental cost incurred by the organization while using the outpatient DVT treatment guideline was determined. Incremental cost savings of the outpatient DVT treatment program were determined based on the cost that would have accrued had the patient been admitted to the hospital for treatment with unfractionated heparin. RESULTS: We enrolled 391 patients (91.4%) in the outpatient DVT treatment program. Of these, 373 (95.4%) completed 90 days of therapy without reaching the primary end point. The percentage of patients reaching the primary outcome measure (4.6%) fell within the range of patients enrolled in controlled clinical trials (3.5%-9.4%). During the 2-year program evaluation, total cost savings of $1,108,587 were realized. CONCLUSIONS: Outpatient treatment of acute DVT can be managed safely and effectively in clinical practice. The potential savings associated with outpatient DVT treatment are substantial. Arch Intern Med. 2000;160:2926-2932

Low-molecular-weight heparins in the treatment of pulmonary embolism.

More than 621 patients diagnosed with a PE have been treated with LMWH. This review included five randomized clinical trials (> 433 patients treated with LMWH) comparing LMWH with UFH. The remainder of the clinical studies were dose-response trials, noncomparative trials, or trials that included a subset of patients diagnosed with a PE. Additionally, 138 patients diagnosed with a PE were included in the group of 510 patients with venous thromboembolism and were subsequently treated with an LMWH. The data available suggest that LMWHs may be safe and effective in the treatment of submassive PE. However, the current data on LMWHs are limited by small sample size, inadequate patient description, and inadequate follow-up. The majority of studies fail to provide concurrent disease state information (e.g., renal disease), thus limiting their usefulness. The results of these trials must be confirmed in comparative studies using different LMWHs (since they may not be interchangeable) in various patient populations before LMWHs are considered to be a safe and effective alternative to UFH in the management of submassive PE.

Predictive performance of ten equations for estimating creatinine clearance in cardiac patients. Iohexol Cooperative Study Group.

OBJECTIVE: The predictive performance of 10 equations used to estimate creatinine clearance (Clcr) was assessed retrospectively from data collected on 420 patients. DESIGN: This study is a retrospective data analysis of information collected on hemodynamically stable patients awaiting coronary angiography during the Iohexol Cooperative Study. SETTING: The Iohexol Cooperative Study was a multicenter study that compared nephrotoxicity of high- and low-osmolar contrast media in patients undergoing coronary angiography. Data used for this analysis were preangiography 24-hour urine collections that were primarily collected in hospitalized patients. PATIENTS: Patients selected from the Iohexol Cooperative Study database for analysis were participants categorized into one or more of six subgroups: elderly (n = 222), hypoalbuminemic (n = 25), chronic renal insufficiency (n = 128), low serum creatinine (n = 115), obese (n = 208), and diabetic (n = 191) who had baseline urine collections of at least 24 hours. OUTCOME MEASURES: Predictive performance was assessed using bias, precision, slopes, and y-intercepts. RESULTS: The Salazar-Corcoran equation was unbiased in the entire group as well as in five of the subgroups. The Cockcroft-Gault equation was unbiased in three of the subgroups. All other equations were biased in predicting Clcr in the entire group as well as in at least four of the subgroups. Precision was generally poor. All slopes were significantly different than one and all y-intercepts were significantly different than zero (p < 0.01). Correlation coefficients were between 0.63 and 0.79 with the exceptions of the low serum creatinine subgroup (r values 0.35-0.64) and the Davis-Chandler equation (r values 0.35-0.71 across groups). CONCLUSIONS: Of the equations studied, Salazar-Corcoran and Cockcroft-Gault appear to be the best for predicting Clcr.

Acute pain management: operative or medical procedures and trauma.

OBJECTIVE: To review the topics presented in the Agency for Health Care Policy and Research (AHCPR) Clinical Practice Guideline for Acute Pain Management and provide updated information on therapeutic issues as necessary. DATA SOURCES: AHCPR Clinical Practice Guideline for Acute Pain Management: Operative or Medical Procedures and Trauma. A MEDLINE search (1990 to June 1996) of English-language literature pertaining to pain assessment and management was performed. Reference lists from relevant articles also served as a literature source. STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data sources were evaluated. Relevant information, as determined by the authors, was included in the review. DATA SYNTHESIS: Inadequate acute pain management continues to be recognized as a problem due to limited health professional education on the treatment of pain, inadequate patient empowerment, negative connotations associated with opioid analgesics (e.g., fear of "addiction"), federal regulations associated with prescribing opioid analgesics, and difficulty in assessing pain. The widespread inadequacy in pain management prompted the development of the AHCPR Clinical Practice Guideline for Acute Pain Management, which was published in 1992. In addition to reviewing the pain guideline, this article includes updated information on ketorolac tromethamine, tramadol, local anesthetics, sedation, regional anesthetic techniques, and the management of opioid adverse effects. CONCLUSIONS: The AHCPR Clinical Practice Guideline for Acute Pain Management is a comprehensive, yet functional, review for clinicians. Most issues relating to acute pain assessment and management are adequately discussed. Overall, this guideline is a worthwhile general resource to clinicians. It is important, however, for clinicians managing acute pain issues to supplement this guideline with more detailed and current information.

Is the volume of distribution of digoxin reduced in patients with renal dysfunction? Determining digoxin pharmacokinetics by fluorescence polarization immunoassay.

STUDY OBJECTIVE: To determine digoxin pharmacokinetics in subjects with different degrees of renal function using fluorescence polarization immunoassay (FPIA), which is associated with less interference from digoxin-like immunoreactive substances (DLIS) than radioimmunoassay. SETTING: University hospital clinical research center. PARTICIPANTS: Eighteen subjects (mean age 44 yrs) with different degrees of renal function: group 1, creatinine clearance (Clcr) below 10 ml/minute; group 2, Clcr 10-50 ml/minute; and group 3, Clcr greater than 50 ml/minute (6 patients in each group). INTERVENTION: Over 5-7 days, 15 serum samples were collected after a single intravenous dose of digoxin 7 or 10 micrograms/kg actual body weight (WT) for serum concentration measurements by FPIA. Two-compartment pharmacokinetic parameters (zero-time intercept of the concentration-time curve of the initial distribution phase [A], zero-time intercept of the concentration-time curve of the terminal elimination phase [B], initial distribution phase constant [alpha], terminal elimination rate constant [beta], volume of distribution in the central compartment [Vc] and at steady state [Vss], total body clearance [Cl], mean residence time [MRT], area under the concentration-time curve [AUC]) were determined using a nonlinear least squares regression program. MEASUREMENTS AND MAIN RESULTS: No significant differences were found among groups for A, B, alpha, beta, beta-half-life Vc/WT, MRT, AUC, and Cl/WT. Significant differences were observed in Vss/WT (4.8 +/- 1.0, 6.6 +/- 0.5, 6.4 +/- 0.7 L/kg) between group 1 versus group 2 and group 1 versus group 3 (p < 0.01). Measured Clcr was correlated with Cl (r2 = 0.40, p < 0.01), Cl/WT (r2 = 0.29, p < 0.05), Vss (r2 = 0.35, p = 0.01), and Vss/WT (r2 = 0.24, p < 0.05). CONCLUSION: This study confirmed that Vss is smaller in patients with chronic renal failure (Clcr < 10 ml/min) than those without chronic renal failure. Therefore, previous recommendations that lower digoxin loading doses should be administered in patients with renal failure are applicable to digoxin serum concentration monitoring using FPIA.

The effect of timing of single-dose transplacental ampicillin-sulbactam therapy for prevention of neonatal group B streptococcal colonization and bacteremia in a rabbit model.

OBJECTIVE: Our purpose was to evaluate the effect of maternal administration of ampicillin-sulbactam on group B streptococcal colonization and bacteremia in newborn rabbits. STUDY DESIGN: Before induction of labor, timed pregnant New Zealand White rabbits on day 29 of a 31-day gestation received no therapy or ampicillin-sulbactam 50 mg/kg intramuscularly as a single dose 2 to 8 hours before delivery. Labor was induced with oxytocin. After delivery, the oropharynx of each pup was inoculated with 10(9) cfu of type la group B Streptococcus. Cultures of each pup were taken from the oropharynx and anorectum daily and from the heart at death or after 96 hours. Ampicillin-sulbactam concentrations were determined at delivery in both mothers and pups. RESULTS: Thirteen animals were assigned to no therapy and 14 animals to ampicillin-sulbactam. Untreated pups had 100% oropharyngeal colonization at 24 hours. Pups treated with antibiotic were significantly less likely to have positive oropharyngeal cultures at 24 and 48 hours after birth than did untreated pups (24 hours 47% vs 100%, p < 0.0001; 48 hours 68% vs 91%, p = 0.0006). For anorectal cultures treated pups were significantly less likely to have positive culture results. Heart cultures were also less likely to have positive results for treated animals at 48 and 72 hours than for untreated animals (48 hours 30% vs 96%, p = 0.0001; 72 hours 31% vs 71%, p = 0.03). Treated pups had higher rates of survival at 48 hours (89% vs 62%, p < 0.0001). When neonatal oropharyngeal colonization at 24 hours after birth was compared with length of time from maternal antibiotic injection to delivery, there was a significant polynomial relationship (r = 0.78, p < 0.05). Ampicillin-sulbactam serum concentrations were highest 3 to 5 hours after injection. An inverse relationship existed between the rate of neonatal oropharyngeal colonization with group B streptococci at 24 hours after birth and neonatal ampicillin serum concentrations near birth (r = 0.733). CONCLUSION: Transplacental treatment with a single intramuscular dose of ampicillin-sulbactam significantly decreased neonatal colonization and bacteremia after oral inoculation with type la group B Streptococcus. An effect of ampicillin-sulbactam was evident as early as 2 hours but maximal 3 to 5 hours after injection.

Reversal of tumor-associated hyperglucagonemia as treatment for cancer cachexia.

BACKGROUND: The tumor-bearing state is associated with increased circulating glucagon levels that may play an etiologic role in cancer cachexia. The secretion of glucagon can be inhibited with long-term somatostatin analogs, and, in combination with insulin, should maximally reverse the low insulin/glucagon ratio seen in cancer cachexia. The goal of this study is to examine the effect of somatostatin (octreotide) and insulin in a model of cancer cachexia and to determine whether inhibition of glucagon secretion will reverse some of the abnormalities in carbohydrate metabolism to selectively benefit host versus tumor metabolism. METHODS: Sixty-seven female Lewis rats were subcutaneously inoculated with 1 x 10(6) metastasizing mammary adenocarcinoma tumor cells. On day 30 the animals were randomized into four groups to receive (1) tumor-bearing control (saline injections); (2) octreotide, 150 microgram/kg intraperitoneally twice a day; (3) neutral protamine Hagedorn insulin, 5 units/kg subcutaneously twice a day; or (4) both insulin and octreotide injections. A fifth group of non-tumor-bearing controls was included. The animals received treatment for 5 days and were then killed. RESULTS: The tumor-bearing state was found to be associated with an increase in glucagon levels and a significant decrease in the insulin/glucagon ratio. The combination of somatostatin+insulin resulted in a 23-fold increase in the insulin/glucagon ratio without causing significant host morbidity from hypoglycemia. This increased insulin/glucagon ratio was associated with increased carcass weight, increased muscle weight, increased muscle protein, increased liver cellular protein, increased liver microsomal P-450 content, and decreased tumor protein content compared with the tumor-bearing controls. These results were not seen with insulin or somatostatin alone. Hepatic lactate dehydrogenase, glucose-6-phosphatase, and fructose-1, 6-diphosphatase activities were increased as a result of combination hormone treatment. CONCLUSIONS: Combination hormone treatment with somatostatin and insulin results in a marked increase in the insulin/glucagon ratio and a selective nutritional benefit to the host. The inhibition of tumor-associated hyperglucagonemia should be considered in the treatment of cancer cachexia.

Effects of renal function on recainam pharmacokinetics and pharmacodynamics.

OBJECTIVES: To investigate the pharmacokinetics and pharmacodynamics of recainam, an investigational class I antiarrhythmic agent, in subjects with various degrees of renal function. METHODS: This single-dose open-label study was carried out at the Clinical Research Center of the University of Pennsylvania Hospital. Twenty-six volunteers participated in the study (group 1, glomerular filtration rate [GFR] < 15 ml/min; group 2, GFR 15 to 50 ml/min; group 3, GFR > 50 ml/min). After a single 400 mg oral dose, plasma samples were collected for the following 48 hours. Recainam pharmacokinetic parameters of apparent volume of distribution (Varea/F), apparent clearance (CL/F), elimination rate constant (ke), absorption rate constant (ka), lag-time (tlag), time to peak (tmax), and maximum concentration (Cmax) were determined with a least-squares regression program. The relationship between recainam concentrations and electrocardiographic intervals were determined with the sigmoidal maximum effect model. Measured GFR was correlated to CL/F with regression analysis. RESULTS: There were no significant differences found among groups in ka, tlag, tmax, and Varea/F. Significant differences were found in CL/F (114.4 +/- 32.7, 319.4 +/- 129.2, and 795.9 +/- 341.8 ml/min, group 1 versus group 3 and group 2 versus group 3, p < 0.05), Cmax (3.54 +2- 0.81, 1.77 +/- 0.53, and 1.63 +/- 0.66 micrograms/ml, group 1 versus group 2 and group 1 versus group 3, p < 0.01), and ke (0.074 +/- 0.025, 0.137 +/- 0.124, and 0.352 +/- 0.300, group 1 versus group 3, p < 0.05). Recainam CL/F was highly correlated with GFR (r = 0.67, p = 0.001). Approximately 8.9% +/- 3.8% of a recainam dose was eliminated during a 4-hour hemodialysis period. There was a trend (but not statistically significant) of increasing maximum percentage change in PR interval and the effective recainam concentration that produces half of its maximum effect (EC50) in group 1. CONCLUSION: Recainam dosing adjustment is required in renal impairment. Recainam is not dialyzed to a significant extent. Further studies are required to fully characterize the pharmacodynamic profile of recainam.

Xanthine interference with dipyridamole-thallium-201 myocardial imaging.

Both theophylline and caffeine have been shown to antagonize adenosine and are associated with false-negative test results with dipyridamole-T1-201 imaging. This has led to recommendations for theophylline and caffeine abstinence for at least 24 hours prior to dipyridamole-T1-201 imaging. Because pentoxifylline and its metabolites are structurally similar to theophylline and caffeine, and pentoxifylline has adenosine antagonistic properties, one might presume that pentoxifylline may also attenuate the diagnostic yield of dipyridamole-T1-201 imaging. To the best of our knowledge, the pharmacodynamic interaction between pentoxifylline and dipyridamole and its effects on dipyridamole-T1-201 imaging in patients have never been studied adequately. However, a single study in 7 dogs does suggest that there may be no significant interaction. In addition, we must also consider the nonacute nature of the clinical use of pentoxifylline in peripheral vascular disease and the critical need for accurate dipyridamole-T1-201 imaging results and the cost associated with this procedure. Until such information is available in humans, it would be prudent to discontinue pentoxifylline, in addition to caffeinated foods, caffeine-containing drug products, and theophylline, at least 24 hours prior to dipyridamole-T1-201 imaging.

The effect of insulin-like growth factor-1 on protein metabolism and hepatic response to endotoxemia in parenterally fed rats.

To determine the influence of insulin-like growth factor-1 (IGF-1) on nitrogen loss and hepatic response to critical illness, 34 male Sprague-Dawley rats (190-230 g) were randomized to receive parenteral nutrition (PN) only (Ctrl), PN plus continuous infusion of Escherichia coli 026:B6 lipopolysaccharide at 6 mg/kg/day (LPS), or PN plus LPS plus rhIGF-1 (IGF-1) at 3 mg/kg/day for 48 hr. Prior to randomization, all animals underwent iv cannulation and 30 hr of adaptation to PN. All animals received isocaloric and isonitrogenous PN (glucose 170 kcal/kg/day and nitrogen 1.1 g/kg/day) and were kept NPO except for water ad libitum. [15N]glycine was infused in all animals for determination of liver fractional synthetic rate. Cumulative nitrogen balance during endotoxemia was significantly different from each other (+72 +/- 42, -217 +/- 131, -114 +/- 137 mg/kg/48 hr for the Ctrl, LPS, and IGF-1 groups, respectively; ANOVA, P < 0.001). Endotoxin significantly increased the urinary 3-methylhistidine/creatinine ratio (0.24 +/- 0.05, 0.55 +/- 0.12, 0.48 +/- 0.17 for the Ctrl, LPS, and IGF-1 groups, respectively; ANOVA, P < 0.001); however, IGF-1 did not significantly reduce the ratio. Endotoxin induced a significant increase in liver fractional synthetic rate (29 +/- 8, 56 +/- 18, 64 +/- 12%/day for the Ctrl, LPS, and IGF-1 groups, respectively; ANOVA, P < 0.01) and depressed hepatic cytochrome P450 concentration (0.54 +/- 0.19, 0.22 +/- 0.07, 0.19 +/- 0.07 nmol/mg protein, respectively; ANOVA, P < 0.05) and ethoxycoumarin O-deethylase (ECOD) activity (103 +/- 73, 29 +/- 13, 17 +/- 11, pmol/mg/min, respectively; ANOVA, P < 0.01); however, rhIGF-1 did not significantly alter these hepatic variables during endotoxin infusion. Recombinant human insulin-like growth factor-1 significantly improved nitrogen balance without compromising hepatic response as measured by liver fractional synthetic rate, cytochrome P450 concentration, and ECOD activity in endotoxemic parenterally fed rats.

A significant methotrexate-glutamine pharmacokinetic interaction.

Previous studies indicate that glutamine-supplemented diets decrease the enterocolitis associated with methotrexate administration. The influence of glutamine on the pharmacokinetics of methotrexate and the formation of its major hepatic metabolite, 7-hydroxy-methotrexate was examined in 36 adult, female Lewis rats. Animals were randomly assigned to receive either a 3% glycine-supplemented solid diet (GLY; 25.0% protein; 17.6 kJ/g, or 4.2 kcal/g) or a 3% glutamine-supplemented solid diet (GLN; 25.0% protein; 17.6 kJ/g, or 4.2 kcal/g) ad libitum for 35 days. Animals were separated into two groups (serum methotrexate pharmacokinetics, n = 20; or methotrexate renal elimination, n = 16) and given a 10 mg/kg dose of methotrexate. There was a 25% decrease in mean methotrexate total serum clearance in the GLN group compared with the control group (0.63 +/- 0.09 L.h-1.kg-1 and 0.47 +/- 0.13 L.h-1.kg-1, respectively, p = 0.01). Renal methotrexate elimination was decreased by 65%. There was no significant difference in methotrexate volume of distribution or half-life between the two groups. Glutamine decreases methotrexate systemic clearance, thus exposing the host as well as the tumor to greater methotrexate concentrations.

Possible inhibition of hepatic metabolism of quinidine by erythromycin.

OBJECTIVE: To present and analyze a patient case illustrating a possible drug interaction between quinidine and erythromycin. METHODS: This is a case report of one hospitalized patient. The setting for this analysis was a university hospital. Through a MEDLINE search of all English medical literature (1966 to 1994) documenting possible interactions between quinidine and erythromycin, retrospective patient chart review, and analysis of the relationship between serum quinidine concentrations and significant clinical events, deduce the possibility of a quinidine and erythromycin pharmacokinetic and pharmacodynamic interaction in this particular patient case. RESULTS: This case demonstrated a probable erythromycin-quinidine pharmacokinetic interaction that led to a decrease in quinidine apparent clearance, an increase in quinidine serum concentrations, and a possible quinidine toxicity. CONCLUSION: Serum quinidine concentrations, electrocardiograms, and other factors that may predispose patients to torsades de pointes, such as hypokalemia and hypomagnesemia, should be monitored closely if quinidine is coadministered with erythromycin.

The effect of parenteral nutrition on hepatic cytochrome P-450.

BACKGROUND: Total parenteral nutrition (TPN) has been shown to affect liver function tests. Additional investigations in animals and humans have demonstrated that hepatic cytochrome P-450 content and enzyme activity are also affected. METHODS: To review the literature on the effect of TPN on hepatic cytochrome P-450, an English-language literature search was performed using MEDLINE (1966 through 1993). RESULTS: Studies in laboratory rats show that administration of dextrose, with or without amino acids, decreases the cytochrome P-450 content and the in vitro or in vivo microsomal oxidation rates of various drugs. The addition of lipid emulsions to TPN decreases oxidation rates for meperidine demethylase but does not affect ethoxyresorufin deethylase. Using immunoquantitation, it was shown that the components of TPN selectively affect specific hepatic P-450 enzymes. In humans, dextrose decreases antipyrine clearance, whereas amino acids and possibly lipids increase antipyrine clearance. However, the effects of protein-calorie malnutrition in these studies obscure the results. CONCLUSIONS: Possible mechanisms for the reduction of hepatic cytochrome P-450 seen during TPN administration include altered gastrointestinal hormone response, mucosal barrier, and the effect of sepsis. Additional studies are needed to determine the actual mechanisms of hepatic cytochrome P-450 reduction observed during TPN.

Superiority of aztreonam/clindamycin compared with gentamicin/clindamycin in patients with penetrating abdominal trauma.

There were 73 evaluable patients entered into a prospective, double-blinded trial comparing aztreonam/clindamycin (A/C) to gentamicin/clindamycin (G/C) for the prevention of infection after penetrating abdominal trauma. Aztreonam was administered at a dosage of 2 g every 8 hours and gentamicin at 5 mg/kg for the first 24 hours and then adjusted by serum monitoring to a peak of 6 to 8 micrograms/mL and a trough of less than 2 micrograms/mL; all patients received 900 mg of clindamycin every 8 hours. Patients with colon wounds received 4 days of antibiotics, and the remaining patients received a 24-hour course. Gunshot wounds occurred in 69% of patients: 74% of all patients had some hollow viscus injury, and 26% had only solid viscus injury. The groups were well matched according to abdominal trauma index, percentage with colon injury, and transfusion requirements. Failures occurred in eight patients (11%): two wound infections, five intra-abdominal infections, and one case of necrotizing fasciitis. Seven infections occurred in 36 (19%) G/C patients compared with 1 in 37 (3%) A/C patients (p < 0.03). The hospital stay was 12 +/- 11 days for G/C patients and 8 +/- 7 for A/C patients (p < 0.12). The superiority of the A/C regimen may be partially attributable to relative underdosing of gentamicin (approximately half of the patients had inadequate levels after 24 hours) combined with a favorable pharmacokinetic profile (significantly prolonged half-life) of aztreonam in this clinical setting.

Effect of protein-calorie malnutrition on methotrexate pharmacokinetics.

Methotrexate toxicity is increased in protein-calorie malnutrition. The influence of protein-calorie malnutrition on the pharmacokinetics and binding of methotrexate (MTX) and the formation of its major hepatic metabolite, 7-hydroxy-methotrexate was examined in 30 adult, female Lewis rats. Animals were randomized to receive either a standard diet (22.0% protein; 4.20 kcal/g) or a protein-depleted diet (PD) (0.03% protein; 4.27 kcal/g) ad libitum for 35 days. Animals were then separated into two groups for either methotrexate pharmacokinetics (n = 20) or serum protein binding (n = 10) studies. The mean weight loss in the PD group was 26% of their initial body weight, as compared with a 29% weight gain in the control group. In the protein binding study, a significant decrease in serum albumin (19%), uncorrected creatinine clearance (38%), and free fraction of MTX (15%) was found in the PD group. All animals in the pharmacokinetic study received a single intraperitoneal injection of MTX (10 mg/kg), and serum MTX and 7-hydroxy-methotrexate concentrations were determined using a specific, reversed phase, high-performance liquid chromatography assay. The mean AUC0-3 in the PD group was 43.6 +/- 3.9 micrograms/mL per hour compared with 15.8 +/- 1.1 micrograms/mL per hour in the control group (p < .001). The time to peak and the peak serum concentrations were significantly greater in the PD animals, which indicated delayed absorption and clearance. These results suggest that the increase in MTX toxicity observed in protein-calorie malnutrition is associated with a decrease in MTX clearance, and is not related to changes in protein binding or formation of 7-hydroxy-methotrexate.

Propafenone-theophylline interaction.

A 63-year-old man with ventricular tachycardia (VT) refractory to drug therapy was admitted for surgical ablation of the VT with coronary artery bypass graft surgery. He developed increased theophylline concentrations with decreased calculated theophylline clearance after propafenone therapy for recurrent VT was initiated. Within 1 day after the addition of propafenone 150 mg every 8 hours to a drug regimen that included theophylline sustained-release tablets 300 mg every 12 hours, the patient demonstrated increased theophylline serum concentrations and decreased calculated theophylline clearance. Despite a decrease in theophylline dosage, theophylline concentrations continued to rise as the dosage of propafenone was increased to 300 mg every 8 hours. Theophylline was discontinued due to a rising theophylline level, improved oxygenation, and absence of wheezing. Both propafenone and theophylline are hepatically metabolized by the cytochrome P-450 enzyme system. The decrease in theophylline clearance of 25% to 69% in this patient may be due to competitive metabolism resulting in enzyme inhibition and increased theophylline concentrations. Since propafenone and 5-OH-propafenone levels were not measured, it is unknown whether propafenone clearance was affected as well. Health care practitioners should be aware of this possible drug interaction and monitor theophylline concentrations and the electrocardiogram closely if the agents are coadministered.