A 64-year-old woman presented to the emergency department with a 12-day history of nausea, vomiting and diarrhea, along with a six-month history of progressive shortness of breath. Atrial fibrillation had been diagnosed seven months earlier, at which time she had started taking amiodarone (400 mg twice daily) and warfarin (1 mg daily). Her medical history included hypertension, peripheral vascular disease, degenerative disc disease and a 30-year history of smoking. Aside from amiodarone and warfarin, her medications included meloxicam (15 mg daily), oxycodone (as needed) and alendronate (70 mg weekly). In the preceding four days, she had started tetracycline (250 mg four times daily) for suspected respiratory tract infection and paroxetine (20 mg daily) for depression.Our patient was admitted to a community hospital for investigation of gastrointestinal complaints and dyspnea, described above. Shortly after admission, sinus bradycardia developed with ectopic beats and a prolonged corrected QT interval greater than 690 ms. Subsequent cardiac arrest caused by torsades de pointes required cardiopulmonary resuscitation and cardioversion. Abnormalities in her laboratory profile included the following: leukocyte count 12.7 (normal 4-10) × 10 9 /L, potassium level 3.1 (normal 3.5-5.0) mmol/L, alanine transaminase level 166 (normal ≤ 33) U/L, aspartate transaminase level 295 (normal < 32) U/L, alkaline phosphatase level 120 (normal 33-104) U/L and γ-glutamyltransferase level 84 (normal < 31) U/L. Her thyroid-stimulating hormone level was reduced at 0.182 (normal 0.27-4.20) mIU/L, with an elevated free thyroxine level of 38 (normal 10-24) pmol/L. Her chest radiograph showed prominent interstitial markings with a nodular opacity in the right upper lobe. Amiodarone toxicity was suspected in the differential diagnosis of pulmonary interstitial disease because of the constellation of hepatic, thyroid and electrophysiologic findings in the context of overexposure to amiodarone. She was transferred to the coronary care unit in our tertiary care hospital, where amiodarone was discontinued and an isoproterenol infusion started.Our patient's stay in hospital was complicated by worsening shortness of breath and hypoxemia with high oxygen requirements. A computed tomographic scan of her thorax showed emphysema as well as dense consolidations in the right and left upper lobes, dense atelectasis in the lower lobes and dense attenuation of the liver, suggestive of amiodarone exposure and possible toxicity. Her thyroid studies and radioactive iodine uptake scan were consistent with amiodarone-induced hyperthyroidism, and she was given methimazole. Her liver enzymes returned to normal several weeks following the discontinuation of amiodarone. DiscussionOur patient presented with multisystem amiodarone toxicity including cardiac, pulmonary, thyroid and hepatic toxicity following inadvertent continuation of her loading dose of amiodarone, 400 mg twice daily, for seven months; the usual loading period is seven days. Her total cumulative do...

Four healthy, Helicobacter-negative volunteers were studied to determine the effect of omeprazole on the movement of metronidazole across the gastric mucosa into the gastric lumen. Each received a 500-mg intravenous infusion of metronidazole and repeated serum, and gastric juice samples were obtained concomitantly over an 8-hr study via indwelling intravenous catheter and nasogastric tube. The same protocol was repeated following one week of oral omeprazole 20 mg twice daily. Metronidazole concentrations were measured by high-performance liquid chromatography. The results demonstrated that: metronidazole moves rapidly from serum into gastric juice; omeprazole causes a marked reduction in total metronidazole concentrations in gastric juice, completely accounted for by pH-related shifts in the proportion of ionized metronidazole, but does not alter concentrations of nonionized metronidazole, which remain above the MIC level against H. pylori; and even under conditions where no pH-related drug trapping occurs (pH > 4), concentrations of metronidazole were higher in gastric juice than in serum during most of the study, indicating that a special transport mechanism may be operational. The practical implication of this effect of omeprazole in combination therapy with metronidazole remains to be established.

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Despite potential adverse effects, clinical use of amiodarone is increasing because of its efficacy in treating arrhythmias. Thus there is a continued need for a rapid, practical amiodarone assay to better study the relationship between serum concentrations and clinical effects and to guide safer dosing. Because the most widely used internal standard, L8040, is no longer available, a systematic comparison of potential alternatives was undertaken based on physicochemical and chromatographic characteristics. All amiodarone assays indexed on Medline were reviewed to produce a list of alternatives and five other potential substances considered based on previous experiences. An isocratic high-performance liquid chromatographic method was modified to allow simultaneous resolution of multiple compounds. The internal standard was expected to perform well in the solid-phase extraction of small sample volumes. No commercially available substances were able to duplicate all the advantages of L8040. Tamoxifen, the most acceptable alternative, was used to develop an assay to measure amiodarone and desethylamiodarone at concentrations as low as 0.25 mg/L in 100 microliters of serum (5 ng detected in a 20 microliters injection). Standard curves were linear over the range of concentrations found in our patients (0.25 to 8 mg/L), within-run coefficients of variation (CVs) averaged 5.3% for amiodarone and 2.9% for desethylamiodarone, and between-run CVs were 4.5% for amiodarone and 1.6% for desethylamiodarone.