Enzalutamide-warfarin interaction necessitating warfarin dosage adjustment: A case report of successful clinical management.

WHAT IS KNOWN AND OBJECTIVES: Enzalutamide package labeling recommends avoiding concurrent warfarin use due to potential reductions in warfarin concentrations via enzalutamide-associated hepatic enzyme induction. A case of successful management of this interaction via warfarin adjustments is reported. CASE DESCRIPTION: A 77-year-old Caucasian male, previously relatively stable on warfarin 42-45 mg weekly, reported to clinic after the recent start of enzalutamide and subsequent hospitalization with a subtherapeutic International Normalized Ratio (INR). A 50% increase in weekly warfarin dose resulted in a therapeutic INR. Enzalutamide was temporarily discontinued, and a 33% weekly warfarin dose decrease resulted in two therapeutic INRs. WHAT IS NEW AND CONCLUSION: This is the first case to highlight the clinical significance of this interaction, noting that patients taking enzalutamide may require approximately 30%-50% adjustment in their warfarin dosage to maintain a therapeutic INR.

Rifampin drug interactions.

Rifampin, an antituberculosis agent, is usually administered for nine to 12 months with other antituberculosis drugs or drugs from other classes. A potential for drug interactions often exists because this drug is a potent inducer of drug metabolism. Rifampin causes a proliferation of the smooth endoplasmic reticulum and an increase in the cytochrome P-450 content in the liver. Rifampin's enzyme-induction effect is selective; therefore, it is not always clear which agents will be affected. Studies and case reports have demonstrated that rifampin accelerates the metabolism of several drugs, including oral anticoagulants, oral contraceptives, glucocorticoids, digitoxin, quinidine, methadone, hypoglycemics, and barbiturates. Rifampin interacts with other agents, but further study is needed to demonstrate the clinical importance of these interactions. In addition to inducing drug-metabolizing enzymes, rifampin may cause alterations in absorption and hepatic uptake. Future investigations will probably identify new rifampin drug interactions.

Interaction of rifampin and digitoxin.

In a patient who had been receiving digitoxin therapy, the serum digitoxin level decreased markedly when rifampin was added to the therapeutic regimen. The serum digitoxin level returned to the pretreatment level when rifampin therapy was discontinued.

Update on rifampin drug interactions, III.

Rifampin is a potent inducer of cytochrome P-450 oxidative enzymes. Examples of well-documented, clinically significant interactions include warfarin, oral contraceptives, cyclosporine, glucocorticoids, ketoconazole, theophylline, quinidine, digitoxin, and verapamil. Recent reports have demonstrated clinically relevant interactions with protease inhibitors, zidovudine, delavirdine, itraconazole, nifedipine, midazolam or triazolam, nortriptyline, and doxycycline. To avoid reduced therapeutic response, therapeutic failure, or toxic reactions when rifampin is added to or discontinued from medication regimens, clinicians need to be cognizant of these interactions. Enhanced knowledge of known interactions will continue to develop, including research on induction of specific cytochrome P-450 isoenzymes. New rifampin interactions will be discovered with further investigations.

Update on rifampin drug interactions. II.

Rifampin is a potent inducer of hepatic P450 oxidative enzymes. Clinically important drug interactions have been documented between rifampin and numerous other drugs, such as oral anticoagulants, oral contraceptives, cyclosporine, digitalis, and ketoconazole. New, potentially clinically significant rifampin drug interactions have been reported for haloperidol, several antiarrhythmics, fluconazole, diltiazem, and select benzodiazepines. Further research has been conducted for previously reported drug interactions with rifampin involving such drugs as glucocorticoids, cyclosporine, verapamil, and oral anticoagulants. Proper management of these interactions is essential to avoid therapeutic failures on initiating rifampin therapy and potential toxic reactions after discontinuing rifampin. New rifampin drug interactions will continue to be identified with future investigations.

Update on rifampin drug interactions.

Rifampin, a potent inducer of the hepatic microsomal system, has been shown to cause clinically important interactions when combined with other drugs, including oral anticoagulants, oral contraceptives, digitoxin, methadone hydrochloride, sulfonylureas, and barbiturates. Additional literature on previously described interactions has been published recently on quinidine, glucocorticoids, digoxin, and theophylline. New rifampin interactions have been described for cyclosporine, ketoconazole, chloramphenicol, beta-blockers, verapamil, and phenytoin. These interactions seem to be of clinical significance.

Noneffect of methyldopa on urine glucose tests.

Methyldopa has been reported to cause a false-positive urine glucose test by the copper reduction method (Clinitest). We investigated the effect of methyldopa on urine glucose tests in 30 patients by comparing commonly used glucose oxidase methods to Clinitest. The results of our study indicate that methyldopa does not interfere with the copper reduction method for urine glucose determination.

Noneffect of isoniazid on urine glucose tests.

Isoniazid has been shown by in vitro study to reduce Clinitest tablets. The effect of isoniazid on urine glucose tests was investigated in 30 patients by comparing commonly used glucose oxidase methods to Clinitest. Study results indicate that isoniazid does not cause clinically significant interference with the copper reduction method for urine glucose determination.

Effects of calcium channel blockers on the pharmacokinetics of propranolol stereoisomers.

Diltiazem and verapamil inhibit oxidative drug metabolism both in vivo and in vitro. We compared their effects on the stereoselective pharmacokinetics and protein binding of propranolol in 12 subjects. After 6 days of coadministration with racemic propranolol, diltiazem caused decreases of 27% and 24% in d-propranolol and 1-propranolol oral clearances, respectively (p less than 0.05 versus control). With verapamil, d-propranolol oral clearance decreased 32% (p less than 0.05), and 1-propranolol oral clearance decreased 26% (p less than 0.05). The unbound fraction of d-propranolol was higher than that of 1-propranolol (p less than 0.05), but the protein binding was not altered by diltiazem or verapamil. Both drugs therefore decreased the unbound oral clearance of each propranolol enantiomer (p less than 0.05). Verapamil caused a stereoselective effect and increased the d/l ratio of propranolol serum concentrations (p less than 0.05) and decreased the d/l ratio of oral clearance (p less than 0.05).

Effect of calcium channel blockers on theophylline disposition.

Twelve healthy subjects received a single oral dose of theophylline, 5 mg/kg alone, and after 7 days of oral verapamil, 120 mg every 8 hours, diltiazem, 90 mg every 8 hours, and nifedipine, 20 mg every 8 hours, in randomized crossover fashion. Mean theophylline oral clearance decreased 18% and 12% after verapamil and diltiazem, respectively (p less than 0.05). No significant change in theophylline oral clearance was observed after nifedipine. Increases in mean theophylline half-life were observed after verapamil (10.8 +/- 3.2 hours) and diltiazem (9.9 +/- 2.4 hours) (p less than 0.05) but not after nifedipine (8.6 +/- 2.4 hours) when compared with control (8.6 +/- 1.9 hours). Apparent volume of distribution was unchanged. Urinary excretion data showed that the relative formation rate constants of 3-methylxanthine and 1,3-dimethyluric acid were decreased during verapamil and diltiazem (p less than 0.05) but not during nifedipine. No change in 1-methyluric acid excretion was observed. Increases in urinary elimination of unchanged theophylline were observed after verapamil, diltiazem, and nifedipine. The modest reduction in theophylline clearance observed after verapamil and diltiazem is not likely to produce clinically significant increases in theophylline concentrations in most patients.

Impact of genetic polymorphisms of the beta2-adrenergic receptor on albuterol bronchodilator pharmacodynamics.

OBJECTIVE: To determine whether genetic polymorphisms of the beta2-adrenergic receptor gene affect the relationship between albuterol (INN, salbutamol) plasma concentrations and the forced expiratory volume in 1 second (FEV1) in subjects with moderate asthma. METHODS: Sixteen clinically stable patients with moderate asthma who participated in a pharmacokinetic-pharmacodynamic study of albuterol volunteered to provide a blood sample for determination of beta2-adrenergic receptor genotype. FEV1 and plasma concentrations of albuterol were determined at various times after administration of an oral solution that contained 8 mg albuterol. Patients withheld inhaled beta2-agonist and corticosteroid therapy 12 and 24 hours, respectively, before the study. beta2-Adrenergic receptor genotype was determined by polymerase chain reaction with allele-specific oligonucleotide hybridization. RESULTS: Albuterol-evoked FEV1 was higher and the response was more rapid in Arg16 homozygotes compared with the cohort of carriers of the Gly16 variant: Maximal percentage increase in FEV1 (%deltaFEV1), 18% versus 4.9% (P < .03); area under FEV1 albuterol concentration curve, 194%.mL/ng versus 30%.mL/ng (P < .05); initial slope (dE/dC), 1.43%.mL/ng versus 0.55%.mL/ng (P < .003). CONCLUSIONS: The beta2-adrenergic receptor gene polymorphism is a major determinant of bronchodilator response to albuterol. Future pharmacodynamic studies of beta2-agonists should include determination of 02-adrenergic receptor genotype.

Nocturnal asthma uncontrolled by inhaled corticosteroids: theophylline or long-acting beta2 agonists?

Asthma is an inflammatory disease of the airways that is frequently characterised by marked circadian rhythm. Nocturnal and early morning symptoms are quite common among patients with asthma. Increased mortality and decreased quality of life are associated with nocturnal asthma. Although numerous mechanisms contribute to the pathophysiology of nocturnal asthma, increasing evidence suggests the most important mechanisms relate to airway inflammation. According to international guidelines, patients with persistent asthma should receive long term daily anti-inflammatory therapy. A therapeutic trial with anti-inflammatory therapy alone (without a long-acting bronchodilator) should be assessed to determine if this therapy will eliminate nocturnal and early morning symptoms. If environmental control and low to moderate doses of inhaled corticosteroids do not eliminate nocturnal symptoms, the addition of a long-acting bronchodilator is warranted. Long-acting inhaled beta2 agonists (e.g. salmeterol, formoterol) are effective in managing nocturnal asthma that is inadequately controlled by anti-inflammatory agents. In addition, sustained release theophylline and controlled release oral beta2 agonists are effective. In patients with nocturnal symptoms despite low to high doses of inhaled corticosteroids, the addition of salmeterol has been demonstrated to be superior to doubling the inhaled corticosteroid dose. In trials comparing salmeterol with theophylline, 3 studies revealed salmeterol was superior to theophylline (as measured by e.g. morning peak expiratory flow, percent decrease in awakenings, and need for rescue salbutamol), whereas 2 studies found the therapies of equal efficacy. Studies comparing salmeterol to oral long-acting beta2 agonists reveal salmeterol to be superior to terbutaline and equivalent in efficacy to other oral agents. Microarousals unrelated to asthma are consistently increased when theophylline is compared to salmeterol in laboratory sleep studies. In addition to efficacy data, clinicians must weigh benefits and risks in choosing therapy for nocturnal asthma. Long-acting inhaled beta2 agonists are generally well tolerated. If theophylline therapy is to be used safely, clinicians must be quite familiar with numerous factors that alter clearance of this drug, and they must be prepared to use appropriate doses and monitor serum concentrations. Comparative studies using validated, disease specific quality of life instruments (e.g. Asthma Quality of Life Questionnaire) have shown long-acting inhaled beta2 agonists are preferred to other long-acting bronchodilators. Examination of costs for these therapeutic options reveals that evening only doses of long-acting oral bronchodilators are less expensive than multiple inhaled doses. However, costs of monitoring serum concentrations, risks, quality of life and otheroutcome measures must also be considered. Long-acting inhaled beta2 agonists are the agents of choice for managing nocturnal asthma in patients who are symptomatic despite anti-inflammatory agents and other standard management (e.g. environmental control). These agents offer a high degree of efficacy along with a good margin of safety and improved quality of life.

Interaction of rifampin and warfarin.

A 72-year-old man who had been taking rifampin daily for several months was concurrently administered warfarin daily for ten weeks. During this period, the prothrombin time (PT) rose remarkably little as the dosage of warfarin was increased. With difficulty, satisfactory anticoagulation was achieved by giving warfarin 20 mg daily. On discontinuation of rifampin therapy, the PT increased significantly, and subsequent stabilization of the PT within therapeutic range required treatment with warfarin 7.5 mg daily.

Interaction of rifampin and chlorpropamide.

A 62-year-old man who had been taking 250 mg of chlorpropamide daily for several years received rifampin concomitantly and had a subsequent increased dosing requirement of chlorpropamide. When rifampin was discontinued several months later, the serum chlorpropamide concentration rose dramatically.

Inhaled albuterol and oral prednisone therapy in hospitalized adult asthmatics. Does aminophylline add any benefit?

STUDY OBJECTIVE: To determine the efficacy of intravenous aminophylline in the treatment of adult patients hospitalized for exacerbation of asthma. DESIGN: Randomized, double-blind, placebo-controlled trial throughout the study. SETTING: University Hospital Clinical Research Center. PATIENTS: Forty-four patients admitted from the emergency room with a primary diagnosis asthma; 39 patients completed the study. INTERVENTIONS: Patients received either intravenous aminophylline or placebo in addition to frequent nebulized albuterol; prednisone 0.5 mg/kg body weight every 6 h orally; and supplemental oxygen. Aminophylline infusion rates were adjusted to achieve serum theophylline concentrations of 10 to 20 micrograms/ml. Changes were made in placebo infusion rates to maintain the double blind design. MEASUREMENTS AND RESULTS: Forced expiratory volume in 1 s (FEV1) and other spirometric measurements every 8 h by a blinded investigator or trained respiratory therapist. Subjective patient response and duration of hospitalization were compared. No difference in spirometric measurements was observed between the two groups at any time point. On admission to the study, FEV1 in the placebo group was 41.5 (+/- 2.9) percent predicted and in the aminophylline group 34.7 (+/- 2.3) percent predicted (p = 0.08). At discharge, FEV1 was 70.4 (+/- 2.9) percent predicted in the placebo group and 63.7 (+/- 2.8) percent predicted in the theophylline group (p = 0.10). There was no difference in subjective patient rating or duration of hospitalization between the two groups (placebo 1.95 days and aminophylline 1.78 days, p = 0.51). CONCLUSIONS: Our results suggest that aminophylline therapy does not add significant benefit to other standard therapies in hospitalized adult asthmatic patients. Because of the risks and cost of aminophylline treatment in the hospital setting, further research is needed to determine if there are subgroups of adult asthmatics who may benefit from the addition of aminophylline to other standard optimal therapies.

Is theophylline use justified in acute exacerbations of asthma?

Despite widespread use of theophylline in the hospital management of asthma, supportive data justifying its use are sparse. Clinical research in the 1980s has forced a serious new examination of the drug's role in acute exacerbations of asthma. Because of the morbidity, mortality, questionable value, and overall cost of theophylline therapy, this reevaluation is of particular importance. Enhanced knowledge of the value of treatment with intensive inhaled beta agonists, systemic glucocorticoids, and inhaled ipratropium should prompt elimination of the routine, initial use of theophylline in emergency room care of most asthmatics. Further research is necessary to justify the routine, initial use of the drug in hospitalized asthmatics.

Reassessing the therapeutic range for theophylline on laboratory report forms: the importance of 5-15 micrograms/ml.

The therapeutic status of theophylline has changed dramatically over the last decade. As part of this change, a different view of the most appropriate therapeutic range for serum theophylline concentration (STC) has emerged. The National Institutes of Health Expert Panel Report, "Guidelines for the Diagnosis and Management of Asthma," suggests a conservative approach of aiming for STC of 5-15 micrograms/ml. This truly landmark document along with several studies in the literature, recently prompted us to change our hospital's laboratory report form for the medical record to read that the therapeutic range for STC is 5-15 micrograms/ml. We encourage hospital laboratories or other clinical laboratories who have not already made this change to do so.

Effects of gender and race on albuterol pharmacokinetics.

We evaluated the effects of race and gender on albuterol pharmacokinetics in 30 patients with moderate asthma (15 blacks, 15 whites, 16 men, 14 women). Subjects received a single dose of albuterol 8 mg oral solution and had blood samples collected at various times for 12 hours after the dose. Albuterol plasma concentrations were determined by HPLC with fluorescence detection, and pharmacokinetics were determined by compartmental analysis. The apparent volume of distribution of albuterol was significantly higher in men than in women (631+/-171 and 510+/-109 L, respectively, p<0.05). Consequently, the maximum concentration was lower in men than women (10.3+/-2.1 and 12.0+/-1.9 ng/ml, respectively, p<0.05). Elimination rates were 0.136+/-0.008 and 0.160+0.012 hour(-1), respectively (p<0.10). When corrected for ideal body weight, apparent volume of distribution was not different by gender. No differences between blacks and whites other than lag time were noted in albuterol kinetics. The greater apparent volume of distribution in men is likely explained by differences in ideal body weight or lean body mass.

Gender differences in metered-dose inhaler-spacer device technique.

STUDY OBJECTIVE: To determine whether gender affects the correct use of a metered-dose inhaler (MDI)-spacer device. DESIGN: Prospective, observational study. SETTING: University classrooms. PATIENTS: Eighty-three students in their third year of a Doctor of Pharmacy program. INTERVENTION: Students were given the device and received 20 minutes of education on its use. They then were asked to perform the technique. Assessment and retraining were done, as necessary, by clinicians who were experienced with the device. Students returned 1 week later to perform the technique again. MEASUREMENTS AND MAIN RESULTS: The performance of men versus women was analyzed with chi 2 tests and the Student's t test. Power analysis indicated that 30 students were needed in each group. CONCLUSION: There were no significant differences between men and women in proper MDI-spacer technique.

Nortriptyline absorption in short bowel syndrome.

Severe short bowel syndrome usually requires a period of parenteral nutrition support until gastrointestinal hypertrophy occurs. Because of the shortened length of the gastrointestinal tract, oral drug therapy can be compromised secondary to decreased absorption. In the case presented, a patient with short bowel syndrome who required parenteral nutrition was able to achieve therapeutic nortriptyline serum concentrations while receiving the drug via the oral route.