The pharmacokinetics, pharmacodynamics, and safety of pravastatin, a new selective 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, were evaluated during monotherapy and with subsequent concomitant cholestyramine therapy in 33 patients with primary hypercholesterolemia in this randomized study. After 4 weeks, pravastatin monotherapy (5 mg, 10 mg, and 20 mg twice daily) significantly decreased total cholesterol by 17% to 24% (p less than 0.001 versus baseline) and low-density lipoprotein cholesterol by 23% to 35% (p less than 0.001). High-density lipoprotein cholesterol increased by 8% to 9%, and triglycerides decreased by 6% to 9%. The area under the serum concentration-time curve and maximum serum concentration of pravastatin showed dose-proportionality; time to maximum serum concentration and serum elimination half-life were independent of dose. When added to pravastatin therapy, cholestyramine enhanced the lipid-lowering effects of pravastatin. After 4 weeks of combination therapy, total cholesterol was reduced by 32% to 38% (p less than 0.001 versus baseline), and low-density lipoprotein cholesterol was reduced by 47% to 56% (p less than 0.001). High-density lipoprotein cholesterol increased by 11% to 18% (p less than 0.05). Pravastatin was well tolerated; no clinical adverse events directly attributable to the drug were reported.

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Background Opioid induced chest wall rigidity was first described in the early 1950s during surgical anesthesia and has often been referred to as fentanyl induced rigid chest syndrome (FIRCS). It has most commonly been described in the setting of procedural sedation and bronchoscopy, characterized by pronounced abdominal and thoracic rigidity, asynchronous ventilation, and respiratory failure. FIRCS has been infrequently described in the setting of continuous analgesia in critically ill adult patients. We postulate that FIRCS can occur in this setting and is likely under recognized, leading to increased morbidity and mortality. Methods Patients admitted to the intensive care unit with suspected FIRCS were included in this retrospective analysis. The objective of this analysis is to describe the clinical presentation and treatment strategies for FIRCS. Results Forty-two patients exhibiting symptoms of FIRCS were included in this analysis. Twenty-two of the forty-two patients with descriptive documentation had evidence of thoracic or abdominal rigidity on examination (52.4%). Twelve of sixteen (75%) patients treated solely with naloxone had documented ventilator compliance following intervention, compared to six of eleven (55%) managed with cisatracurium alone. Nine of twelve patients who ultimately received naloxone after initial treatment with cisatracurium had documented ventilator compliance following naloxone administration (75%). Standard interventions, including sedation optimization and ventilator adjustments were attempted to rule out and treat other potential causes of dyssynchrony. In most cases, the administration of naloxone resulted in appropriate compliance with both ventilator and patient-initiated breaths, suggesting the ventilator dyssynchrony was due to fentanyl. Conclusions This is the largest case series to date describing FIRCS in the intensive care setting. Recognition and prompt management is necessary for improved patient outcomes. Research is needed to increase awareness and recognition, identify patient risk factors, and analyze the efficacy and safety of interventions.

We have shown that activin A, a cytokine implicated in regulating B-cell proliferation, is severely deficient in alveolar macrophages from patients with pulmonary alveolar proteinosis (PAP), an autoimmune disorder characterized by surfactant accumulation and neutralizing autoantibodies to granulocyte-macrophage colony stimulating factor. Mechanisms of activin regulation in alveolar macrophages are not well understood. Based on previous gene array results from PAP bronchoalveolar lavage cells suggesting deficiencies in vitamin D target genes, and on recent evidence of vitamin D receptor elements (VDREs) in the human activin A gene promoter, we investigated the effects of 1,25-dihydroxyvitamin D (vitamin D(3)) on activin A expression in alveolar macrophages from healthy individuals and PAP patients. Activin A expression was stimulated by LPS in cultures of either healthy control or PAP alveolar macrophages; in contrast, vitamin D(3) increased activin A only in healthy controls but not in PAP. Compared to healthy controls, freshly obtained (uncultured) PAP alveolar macrophages displayed healthy intrinsic vitamin D receptor expression but deficient expression of vitamin D target genes, cathelicidin and thioredoxin interacting protein. PAP patients also demonstrated a relative insufficiency of circulating vitamin D. Investigation of activin A in murine alveolar macrophages confirmed a lack of functional response to vitamin D as anticipated since murine activin A does not contain VDREs. Results suggest that mechanisms of activin A deficiency in PAP alveolar macrophages may involve dysregulation of a novel species-specific vitamin D-activin A pathway.

Twelve patients underwent hemodialysis using dialysate containing 130 mEq/L sodium, and, on a separate occasion, dialysis using a dialysate of constantly decreasing sodium concentration (from 150 to 133 mEq/L). Hydrostatic ultra-filtration during dialysis was performed at a constant rate (900 ml/hr) during both treatments, and was continued until a substantial drop in mean arterial pressure (-15%) or symptoms were observed. A double-blind comparison of the two treatment modalities was thus achieved. At the end of ultrafiltration, significantly more fluid had been removed using decreasing sodium dialysate (2.9 +/- 0.3 kg) than when using the low-sodium dialysate (1.9 +/- 0.2 kg, P<0.001). Plasma sodium concentration at the end of ultrafiltration using decreasing sodium dialysate was not significantly different from the predialysis level. Hydrostatic ultrafiltration using a dialysate of decreasing sodium level may prove to be a useful means of removing excess fluid asymptomatically from dialysis patients.