Background Intravenous hydralazine is approved for the treatment of hypertensive emergency and widely used for hypertension associated with toxemia of pregnancy. As we had observed increased off-label use of this agent in area hospitals, we studied its use in a University teaching hospital. Methods Patients were identified prospectively between April and October 2010 from all hospitalized patients who had an order for intravenous hydralazine entered into the computerized physician order entry system. Clinician prescribers were unaware that this study was being conducted. Demographic and clinical information, including pre-treatment blood pressure (BP), change in BP and heart rate (HR) within 2 hours post-administration of hydralazine, concurrent and follow-up antihypertensive medications, and adverse events were obtained. Results There were 94 patients (mean age, 69 ± 18 years, 48% women, 89% with chronic hypertension) who received 201 intravenous hydralazine doses (mean dose of 11.4 ± 4.3 mg). Only 4 (2%) of patients had evidence of an urgent hypertensive condition (e.g., symptoms, target organ injury). Baseline BP was 175/82 ± 25/16 mmHg and following hydralazine was reduced by 24/9 ± 29/15 mmHg while HR increased by 4 ± 13 beats/min. Changes from baseline in BP were related to baseline BP: change in BP in the lower baseline range was −3 ± 20 mmHg while change observed in those with the highest range of baseline blood pressure was −35 ± 25 mmHg. Seventeen patients experienced an adverse event, the most common being hypotension (n=11). Conclusions Intravenous hydralazine is commonly prescribed for non-urgent cases of hypertension in the hospitalized patient. Changes in systolic BP, while related to baseline BP values, are nevertheless, highly variable. There is risk of hypotension associated with its use. There is evidence that this agent is not useful for many patients with hypertension in the hospital setting and may cause harm if used inappropriately.

Candida albicans and Candida glabrata cause fungal bloodstream infections that are associated with significant mortality. As part of an effort to develop potent and selective antifolates that target dihydrofolate reductase (DHFR) from Candida species, we report three ternary crystal structures of Candida albicans DHFR (CaDHFR) bound to novel propargyl-linked analogs. Consistent with earlier modeling results, these structures show that hydrophobic pockets in the binding site may be exploited to increase ligand potency. The crystal structures also confirm that loop residues Thr 58- Phe 66, which flank the active site and influence ligand potency and selectivity, adopt multiple conformations. To aid the development of a dual Candida spp. inhibitor, three new crystal structures of C. glabrata DHFR (CgDHFR) bound to similar ligands as those bound in the ternary structures of CaDHFR are also reported here. Loop residues 58-66 in CgDHFR and human DHFR are 1 Å and 3 Å closer to the folate binding site, respectively, than loop residues in CaDHFR, suggesting that a properly size ligand could be a potent and selective dual inhibitor of CaDHFR and CgDHFR.

Atrial fibrillation (AF) is well known as one of the leading causes of stroke and systemic embolism. Anticoagulation therapy is recommended in all patients at moderate-to-high risk of stroke. The vitamin K antagonist warfarin has traditionally been used in these patients but presents challenges in dosing and monitoring in these patients. The oral direct thrombin inhibitor dabigatran etexilate (Pradaxa®; Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA) was recently approved for use in the US for preventing stroke and systemic embolism in patients with nonvalvular AF. Clinical trials have shown it to reduce the risk of stroke and systemic embolism when compared with warfarin (goal international normalized ratio [INR] 2-3) with a similar risk for severe bleeding. It can be given twice daily, with the dose adjusted for renal function. It does not have any dietary restrictions, has few drug interactions (except involving permeability [P]-glycoprotein [P-gp] agents), and does not require routine laboratory monitoring. Patients may experience significant dyspepsia with its use. Compared with warfarin there is increased risk for gastrointestinal bleeding and perhaps myocardial infarction. Currently, no reversal agent exists for use in situations of overdose or severe bleeding although some strategies have been suggested. Despite its high acquisition cost compared with warfarin, analysis using theoretical models has shown it to be cost-effective. Dabigatran offers a unique alternative to warfarin in patients with nonvalvular AF and can be beneficial in patients requiring anticoagulation therapy.

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