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Comparing modified-release formulations can be difficult using current bioequivalence criteria. Two 60-mg-once-daily nifedipine formulations are deemed bioequivalent in Canada. This study examined the validity of the assumption that these interchangeable, but different, delivery technologies are therapeutically equivalent in maintaining systolic blood pressure (SBP) control throughout the entire dosing interval. We used 24-h Ambulatory Blood Pressure Monitoring to objectively examine whether formulation switches changed population SBP >2 mmHg (reflecting 6% increased stroke mortality) and in what proportion of patients SBP changed ≥6 mmHg (risking unnecessary therapeutic alterations). When 20 patients, previously receiving 60-mg-once-daily Nifedipine-GITS, were switched to Mylan-Nifedipine-XL, population-mean ± SE 24-h SBP increased 3 ± 1.1 mmHg (P = 0.0173) and 8-h nocturnal SBP increased 4 ± 1.6 mmHg (P = 0.0098). Thus, interchange of nifedipine formulations can affect therapeutic consistency. These data support existing calls to improve criteria for establishing bioequivalence between formulations employing differing modified-release technologies.

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During the introduction of a new once-daily nifedipine 60 mg osmotic delivery tablet to Canada in 2009, several patients previously maintained at target blood pressure on regimens that included nifedipine 60 mg daily were observed to have > 10 mmHg rises in their systolic pressure during follow-up. The only difference noted in their medication and clinical status was a substitution with the new 60 mg nifedipine formulation by their pharmacists. Three patients agreed to report home blood pressure for N of 1 studies in which all clinical parameters remained the same, but their nifedipine was repeatedly switched between the original and alternate formulations each week. Of 14 recorded switches, systolic pressure was higher on the alternate formulation 13 times. In at least some patients, the alternate pump technology appears less effective. This highlights the need for better bioequivalence criteria for comparing differing delivery technologies that artificially retard absorption of the drug.

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The use of amiodarone has grown rapidly, resulting in the marketing of several generic formulations. The adequacy of the testing used to approve these formulations as bioequivalent has been questioned, and mounting clinical evidence suggests that in some patients, substitution with generic amiodarone can cause serious problems. The effects of switching amiodarone formulations may take weeks to develop, leaving the relationship between the events unrecognized. In animal models, the toxicity of desethylamiodarone, an active metabolite partly formed during amiodarone absorption, is greater than that of its parent compound. High metabolite to amiodarone ratios have been associated with clinical toxicity. Because measuring serum amiodarone and metabolite is not standard clinical practice, aberrations after switching formulations will be missed. Major changes in metabolite concentrations were documented in four patients switched to a generic formulation, suggesting that the tests used for regulatory approval failed to identify the cumulative effects of differing excipients on amiodarone metabolism during absorption. Physicians should monitor patients for several months after a switch in amiodarone formulation is made. Regulatory criteria for bioequivalence of amiodarone need to be reconsidered.

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OBJECTIVE: To report a case of hypoglycemia that occurred in a patient treated with the selective serotonin-reuptake inhibitor, sertraline. CASE SUMMARY: An 82-year-old white woman with mild cardiovascular disease and no history of glucose intolerance was seen in the emergency department for a presyncopal episode associated with a blood glucose of 32 mg/dL as measured by the ambulance attendant. She had similar symptoms the day before. Despite repeated administration of oral and intravenous glucose, the patient had recurrent episodes of hypoglycemia and was hospitalized for four days. She had started taking sertraline 50 mg once daily for mild depression 25 days prior to presentation. Other medications included furosemide 20 mg/d, ramipril 5 mg/d, clopidogrel 75 mg/d, nitroglycerin patch 0.4 mg/h, and lorazepam 1 mg taken occasionally for agitation. She had never been prescribed any oral hypoglycemic agents. Serum sertraline and desmethylsertraline concentrations measured two, three, and four days after discontinuing sertraline were within the expected range, but the rate of decline was consistent with a moderately prolonged half-life. DISCUSSION: Sertraline has been shown to blunt postprandial hyperglycemia in rats and to potentiate the hypoglycemic effects of sulfonylurea agents in humans. It has not been reported to cause hypoglycemia independently, but in this case, a nondiabetic patient experienced multiple episodes of hypoglycemia that resolved after discontinuation of sertraline. CONCLUSIONS: This report and another implicating fluoxetine in a case of hypoglycemia suggest that healthcare professionals should consider these medications among the possible causes of hypoglycemia occurring in patients receiving selective serotonin-reuptake inhibitors.

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PURPOSE: To establish a HPLC assay for plasma losartan and its active metabolite EXP3174 to facilitate clinical pharmacokinetic studies. METHODS: the HPLC system consisted of a 250 x 2 mm i.d. C18 reversed phase column preceded by a 4 x 4 mm guard column, a UV detector set at 254 nm, and an integrator. The mobile phase was a mixture of 0.01 M ammonium phosphate: acetonitrile: methanol (6:3:1) containing 0.02 % sodium azide and 0.04% TEA, with pH adjusted to 3.2. The system was operated isocratically at ambient temperature at a flow rate of 0.3 ml/min. Losartan and its active metabolite EXP3174 were extracted from plasma using C2 bonded silica gel standard solid phase extraction. RESULTS: recoveries of losartan and EXP3174 from plasma were greater than 70%. Using 0.5 ml of plasma sample, standard curves were linear from 10 to 300 ng/ml (r2 = 0.996 and 0.997 for losartan and EXP 3174, respectively). Sensitivity of the assay was < 10 ng/ml. Intra-and inter-assay variations were < 10 and 15%. respectively. The assay has been successfully applied to measuring plasma concentrations of losartan and EXP3174 in patients receiving a daily dose of losartan (50-100 mg). CONCLUSION: The HPLC assay has adequate sensitivity, reproducibility, and specificity for clinical pharmacokinetic studies.

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BACKGROUND: Although the new atypical antipsychotic, quetiapine fumarate, is growing in popularity over its progenitor, clozapine, clinical experience with overdose of this agent remains limited. Observation of an overdose situation provided a unique opportunity to define the safety, clinical effects, and pharmacokinetics of this medication more clearly. METHODS: A patient admitted immediately after ingesting an overdose of 30 tablets of 100 mg of quetiapine was observed carefully to document effects of the medication. These observations were compared with the only two other published cases of overdose, to the known pharmacology of the drug, and to serial measurements of serum drug concentrations obtained to document the time course of elimination of the drug. RESULTS: Consistent with the two previously published cases, the main clinical effects of overdose were hypotension, tachycardia, and somnolence as predicted by its known alpha-adrenergic receptor and histamine receptor blockade. These effects were managed with fluid resuscitation and supportive measures. No cardiac arrhythmias other than tachycardia have been reported, but the tachycardia was of an unexpectedly long duration in this case. Decline in serum quetiapine concentration followed a biexponential pattern with a terminal elimination half-life of 22 hours. Unexpectedly low peak serum concentrations in three patients with overdose suggest that absorption is highly reduced, either by the effects of the overdose or by the activated charcoal administered. CONCLUSIONS: Quetiapine appears to have greater safety in overdose than traditional antipsychotic agents. Its toxicity is consistent with its receptor pharmacology. Elevated serum concentrations associated with this overdose remained above the limit of detection long enough to document a terminal elimination half-life of 22 hours in this patient. This is much more consistent with previously noted duration of clinical effects and detectable serum concentrations after overdose than the published half-life of 6 hours. Physicians should be aware that any new drug that is active at low concentrations may have had its half-life underestimated during preclinical development because of the difficulty in detecting the drug after the distribution phase has ended.

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BACKGROUND: Amiodarone is an increasingly popular and uniquely effective antiarrhythmic agent for which population pharmacokinetic parameters in patients receiving long-term oral therapy have not been defined previously. METHODS: We collected 605 observations of serum amiodarone and desethylamiodarone metabolite concentrations from 77 patients (mean follow-up, 2 years). Mixed-effects modeling (NONMEM) was used to determine the typical population pharmacokinetic parameters, their respective variabilities, and a simple oral dosing regimen to rapidly achieve and maintain a target concentration of 1.5 mg/L. Individual serum concentration versus time curves were simulated for the study population based on regimens outlined in the product monograph and were compared with those for the proposed dosing regimen. The relationship between the duration of amiodarone therapy and the rate of decrement in serum concentration after discontinuation was explored. RESULTS: Amiodarone concentrations were best described by a two-compartment model with the typical parameters +/- interindividual coefficients of variation (where applicable) as follows: volumes of distribution/bioavailability (V1/F = 882 L; V2/F = 12,700 L +/- 58%) and clearances/bioavailability (CL1/F = 229 L/day +/- 31%; and CL2/F = 599 L/day +/- 56%). Rapid distribution half-life was 17 hours, and terminal half-life was 55 days. A practical dosing regimen of 1600 mg/d for 2 days, 1,200 mg/d for 5 days, 1,000 mg/d for 7 days, 800 mg/d for 7 days, 600 mg/d for 7 days, and 400 mg/d for 62 days followed by a maintenance dose of 343 mg/d (400 mg/d for 6 of 7 days) is proposed. After steady state is reached, cessation of dosing produces a 25% serum concentration decrement in 3 days and 50% in 36 days. CONCLUSIONS: Population pharmacokinetics confirm that amiodarone has an extraordinarily long half-life. The slow elimination rate makes anticipating the timing of adjustments in amiodarone therapy to avoid toxicity unusually perplexing. However, based on the estimated variability, the proposed dosing regimen would produce steady-state concentrations within the therapeutic window for 90% of patients.

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The history of antiarrhythmic therapy reveals these agents to be associated with a high incidence of toxicity. Although several agents have ocular effects, amiodarone is the most widely recognized for producing adverse effects in the eyes. Corneal microdeposits are almost ubiquitous in patients being treated with amiodarone. However, they are, for the most part, benign and produce no changes in visual acuity. Lack of microdeposits should prompt the physician to investigate whether there is a problem with drug absorption or adherence to therapy. Other effects on the eye have been reported including optic neuropathy, but no causal link has been proved with amiodarone. The population of patients treated with amiodarone often have ischemic disease and/or diabetes, which affect retinal and optic nerve health. Many antiarrhythmic agents also affect lung function. The frequent association of procainamide with a lupus-like syndrome, where half the cases develop pleural-pericardial involvement, may require discontinuation of that drug. Although beta blockers and to a lesser degree, calcium antagonists, may cause bronchospasm in some patients, this is not usually a major clinical problem. Again, it is amiodarone that has the most widespread reputation for causing pulmonary toxicity. Although infrequent (< 1% incidence), it generates the most fear as it is sometimes fatal. Because of the lack of a diagnostic "gold standard," it is often overdiagnosed, placing patients at risk from overlooked congestive heart failure and infections and from recurrent arrhythmias after drug withdrawal. Patients with pre-existing pulmonary disease appear to be more at risk. Common features include indolent onset of cough, malaise and fever associated with patchy peripheral infiltrates, and severely decreased diffusion capacity. Several cases of pulmonary toxicity have had inordinately high serum desethylamiodarone to amiodarone ratios. Most cases recover with cessation of amiodarone therapy. Steroids are commonly used, but are of unproved efficacy. In terms of its toxicity, amiodarone remains the most feared of the antiarrhythmic agents. In the future, a better understanding of its pharmacokinetics, mechanisms of toxicity, and optimal dosing regimens should provide a possibility of better strategies for avoidance, early diagnosis, and more directed therapy of toxicities associated with amiodarone.

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PURPOSE: To determine the steady-state plasma concentrations of diltiazem (DTZ) and hemodynamic effect in humans at rest and during exercise. METHODS: Healthy volunteers (10 F, mean age 22, and 11 M, mean age 24) were recruited. Prior to receiving DTZ, each volunteer performed two 3-minute stages of treadmill exercise according to the Bruce protocol. Intra-arterial BP and ECG recordings were obtained before, during and immediately post exercise. Each volunteer then received DTZ 60 mg qid for one week. The same exercise protocol was repeated 1 h after the last dose. Steady-state plasma concentrations of DTZ were determined by a previously reported HPLC. RESULTS: DTZ decreased resting DBP from 84 +/- 13 to 79 +/- 10 mmHg (p > 0.05), and HR from 89 +/- 11 to 82 +/- 13 bpm (p < 0.05). During exercise, an average of 32 and 10% increase in SBP and DBP, respectively, and a 47% increase of HR was found (p < 0.05). DTZ limited these increases to 21% for SBP, 5% for DBP, and 44% for HR (p < 0.05 for drug effect). Steady-state plasma DTZ concentrations were 141 +/- 56 ng/ml. CONCLUSION: DTZ significantly decreased resting HR but not BP in health volunteers. It decreased both hemodynamic variables during exercise. Thus, the hemodynamic effects of diltiazem are more profound during exercise, and may be more useful surrogate markers for calcium antagonists and other cardiovascular agents in healthy volunteer studies.

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The distribution of plasma lipids was studied in 18 patients receiving amiodarone for 18 months, confirming that amiodarone is associated with a 17% elevation in total cholesterol and, for the first time, documenting increases in high-density lipoprotein cholesterol. The increase in high-density lipoprotein was proportionately greater than that of low-density lipoprotein cholesterol, suggesting that the impact of changes in the predicted risk of coronary heart disease are less important than if the elevation consisted of low-density lipoprotein cholesterol alone.

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OBJECTIVES: To review the historical development of amiodarone and the changing perceptions of the drug, and discuss its electrophysiologic, pharmacologic, and pharmacokinetic properties. METHODS: Review of relevant literature. RESULTS: In the 1970s and 1980s a plethora of new antiarrhythmic agents, including amiodarone, was introduced. Amiodarone is predominately a class III antiarrhythmic, but also possesses class I, II, and IV effects. By 1977 it was described as the ideal antiarrhythmic agent. However, clinicians underestimated potential difficulties caused by misunderstanding its variable absorption, slow initial response at nonloading dosages, and extended half-life. Elevated dosages also produced frequent adverse effects. Thus, early enthusiasm for the drug's efficacy was gradually replaced by a focus on its toxicity. The 1990s witnessed reacceptance of the agent as more logical initial regimens and lower maintenance dosages decreased adverse effects, and amiodarone emerged as one of the few drugs effective in suppressing and preventing arrhythmias that does not increase mortality. Remaining challenges include delineation of an optimal oral regimen, identification of markers useful in clinical monitoring, and elucidation of the relationship between dose-tissue concentration and response and dose-toxicity associations. CONCLUSION: Amiodarone is an increasingly valuable component of today's antiarrhythmic therapy.

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OBJECTIVES: To review the clinical efficacy and role of amiodarone in the management of supraventricular and ventricular arrhythmias and its effects on mortality. METHODS: Review of relevant studies and reports. RESULTS: Amiodarone exerts significant effects on atrial tissue. In most studies it was completely or partly effective in preventing recurrences of atrial fibrillation or flutter in up to 80% of patients. Amiodarone may be superior to class Ia agents for maintaining normal sinus rhythm. Large randomized trials indicate that it is a potent suppressor of ventricular arrhythmia and reduces arrhythmic death after myocardial infarction. In patients with cardiomyopathy, it suppresses asymptomatic arrhythmias and increases left ventricular ejection fraction. Meta-analysis of relevant studies indicated that amiodarone reduces the risk of arrhythmic and sudden death by 29% in high-risk patients with recent myocardial infarction or congestive heart failure. This translates into an overall 13% reduction in total mortality. CONCLUSION: Because of its effectiveness against a broad range of arrhythmias, amiodarone is a valuable addition to the antiarrhythmic pharmacopeia.

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Antibiotics which are actively secreted into gastric fluid may be more efficacious in the eradication of Helicobacter pylori in peptic ulcer disease. Other agents used in the treatment of this disease such as omeprazole or other anti-secretory agents may alter the secretion and/or distribution characteristics of antibiotics. In order to test the applicability of these concepts to metronidazole, a sensitive and specific high performance liquid chromatography (HPLC) assay was developed to quantitate omeprazole in plasma, and metronidazole in plasma and gastric fluid. The HPLC system consisted of a multi-phase column combining anion exchange and reversed phase separation (OmniPac Pax-500, Dionex), and a variable wavelength UV detector set at 254 nm. The mobile phase was a mixture of 0.1 M sodium phosphate buffer:methanol:acetonitrile (60:20:20) with final pH adjusted to approximately 7.0. Metronidazole and omeprazole were extracted by adsorption onto a C2-bonded silica gel solid phase extraction column, and eluted with methanol. The extract was dried, reconstituted in a solution of acetyl salicylic acid (ASA), and then injected into the HPLC system. Under these conditions, metronidazole, omeprazole and ASA were well separated and recoveries in plasma were greater than 80%. Omeprazole could not be measured in gastric fluid because of rapid decomposition. Using 0.3 ml of sample, the assay sensitivity was less than 0.1 microgram ml-1 and linear up to 10 micrograms ml-1. Both intra- and inter-assay CV were greater than 15%. It was applied successfully in determining metronidazole concentrations in clinical samples of plasma and gastric fluid.

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A 68-year-old man receiving long-term therapy with oral sustained-release theophylline 450 mg twice/day was admitted to the hospital after failing treatment with azithromycin for an acute exacerbation of obstructive lung disease. Peak serum theophylline concentration was 20 microg/ml (normal 10-20 microg/ml). Azithromycin was discontinued and the theophylline dosage reduced by 33%. The subsequent 80% decrease in serum theophylline to 4.6 microg/ml was unexpectedly large. Two rechallenges produced similar transient depressions of serum theophylline concentrations after withdrawal of azithromycin, suggesting an interaction. Withdrawal of azithromycin may leave an increased number of active enzyme sites available as the drug is cleared from the system. In some circumstances, it may be useful for pharmacokinetic interaction studies to continue measuring concentrations after the suspected interacting agent is stopped.

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To determine the clinical effect of diltiazem on the metabolism of adenosine, and its importance in ischemic heart disease, arterial plasma concentrations of the purine metabolites were determined in 21 healthy volunteers (10 female and 11 male) and 19 patients with effort angina (8 female and 11 male) before, during, and immediately after standard treadmill exercise tests conducted before and after they had taken 60 mg diltiazem (Cardizem; Hoechst Marion Roussel, Laval, QC, Canada) four times a day for 1 week. The results showed that the cardiac patients had significantly lower mean plasma concentrations of uric acid (46.82 +/- 25.51 versus 95.47 +/- 35.41 micrograms/ml, p 0.05), inosine (0.25 +/- 0.19 versus 0.84 +/- 0.17 microgram/ml, p < 0.05), and hypoxanthine (0.28 +/- 0.35 versus 0.50 +/- 0.27 microgram/ml, p < 0.05). Diltiazem decreased the mean resting plasma concentrations of uric acid in patients (uric acid 43.47 +/- 22.26 versus 46.82 +/- 25.51 micrograms/ml, p < 0.05) and healthy volunteers (uric acid 85.68 +/- 26.71 versus 95.47 +/- 35.41 micrograms/ml, p < 0.05). There was no statistically significant change in the plasma concentrations of the purine metabolites during exercise (p < 0.05). Female subjects had significantly lower plasma concentrations of uric acid than males (patients, 34.87 +/- 26.93 versus 55.78 +/- 21.25 micrograms/ml; healthy volunteers, 84.79 +/- 32.07 versus 104.22 +/- 37.05 micrograms/ml; p < 0.05 for both). Results of the study suggest that normal therapeutic doses of diltiazem may modulate the metabolism of adenosine and that some of the purine metabolites may be useful markers for specific types of ischemic heart disease.

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The purpose of this study was to measure the blood pressure and electrocardiographic responses of a small, matched group of women (n = 8) and men (n = 9) who experienced typical, effort angina during an exercise on the treadmill (up to the second stage of a Bruce protocol). These responses were measured before and after therapy with diltiazem (60 mg four times daily for 1 week). Reports of previous studies have described significant gender differences in blood pressure responses to diltiazem in healthy volunteers tested with the same protocol. In contrast to the data in healthy individuals, gender differences in blood pressure responses to exercise before and after diltiazem administration were not observed. Results of analysis of pulse pressure responses to exercise were also similar in male and female patients with angina. A significant postexercise drop in blood pressure was observed, which was augmented by diltiazem. These data suggest that gender differences in drug action may be difficult to demonstrate in patients with vascular disease.

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OBJECTIVE: To underscore the need for caution when making dramatic changes in phenytoin dosing, and to report a possible ciprofloxacin interaction in which failure of seizure control led to inappropriately high phenytoin dosing and subsequent intoxication. CASE SUMMARY: A 61-year-old African-American man receiving long-term therapy with phenytoin 100 mg po tid for seizures secondary to a stroke was admitted for community-acquired pneumonia. His serum phenytoin concentration at admission was therapeutic at 12.6 micrograms/mL. Eight days after admission, ciprofloxacin 750 mg po bid was started for possible aspiration. Two days later he experienced a seizure; the serum phenytoin concentration was 2.5 micrograms/mL. In response to the 80% decline in phenytoin concentration, the dosage was gradually titrated upward to produce a serum concentration of 12.6 micrograms/mL. This eventually required a doubling of the original phenytoin dosage and he was discharged on 200 mg po tid. The patient subsequently developed severe ataxia and sustained a head injury for which he was seen again in the emergency department. Serum phenytoin concentration at that time was 42.8 micrograms/mL. Concentrations declined at a normal rate when phenytoin was withheld. CONCLUSIONS: It appears that a rapid decline in phenytoin concentration during the first admission was related to coadministration of ciprofloxacin, either through inhibition of absorption or induction of metabolism. In a conscientious effort to titrate phenytoin concentrations back to therapeutic values, the issue as to why this required such a dramatic change in dosage was ignored. Thus, in trying to prevent further seizures, the patient was unknowingly placed in jeopardy a second time when his usual dosage of phenytoin was doubled. As a result, phenytoin intoxication ensued after discharge when the ciprofloxacin was discontinued. This case illustrates a potentially dangerous interaction between ciprofloxacin and phenytoin, and it underscores the need to maintain a high index of clinical suspicion for drug interactions in any patient requiring a substantial change in drug dosage.

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Metronidazole is an important component of combination antimicrobial therapies used in the eradication of Helicobacter pylori, a recognized cause of gastritis and duodenal ulcer. Studies are needed to understand which pharmacokinetic factors determine the success of metronidazole therapy and what role drug monitoring plays. Such studies require a rapid, accurate assay for small volumes of sample, including gastric juice, over a 200-fold range of concentrations. Using an isocratic high-performance liquid chromatography (HPLC) method, with an 8-min run time and protein precipitation of samples, metronidazole could be measured reliably to as low as 0.5 mg/L in 100 microliters samples of serum, gastric juice, or saliva. Standard curves for serum and gastric juice were linear between 0.5 and 50 mg/L. Within-day coefficients of variation (CVs) (n = 5 at six concentrations) ranged from 1.1 to 4.8% over this range and the between-day CV (n = 7 days) was 5.8%. Neither omeprazole nor common gastroenteric and cardiac medications interfered with this assay. A pilot study, done in four healthy volunteers given intravenous metronidazole 500 mg before and after 7 days of omeprazole therapy, found metronidazole to be present in higher concentrations in gastric juice and saliva than in serum 2 h after intravenous administration. The range and accuracy of the assay proved to be suitable for carrying out pharmacokinetic studies at clinically used doses of the drug.

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