American Journal of Therapeutics

We present the case of a 22-year-old patient who was successfully treated with intravenous fat emulsion for severe and refractory cardiac depression after an overdose with a tricyclic antidepressant and beta-blocker.

The in vitro metabolism of the selective M1 muscarinic agonist CDD-0102-J was evaluated in heterologous systems expressing individual human cytochrome P-450 (CYP) isoenzymes and also in suspensions of cryopreserved human hepatocytes. In all experiments, the metabolism of CDD-0102-J was characterized based on its rate of disappearance using an HPLC assay since no metabolites have as yet been characterized. The human CYP isoenzymes used were CYP1A2, 2A6, 2B6, 2C8, 2C19, 2D6, and 3A4. Measurable decreases in CDD-0102-J concentrations over time were detectable only in systems containing either CYP2D6 or CYP2C8, although the unbound in vitro clearance was more than 20 times larger for CYP2D6 (7.6 mL h(-1) nmol(-1)) than for CYP2C8 (0.35 mL h(-1) nmol(-1)). When scaled to in vivo hepatic clearance based on just CYP2D6 and CYP2C8, the projected hepatic clearance for CDD-0102-J was 7.7 L h(-1), which corresponded closely with the hepatic clearance of 8.4 L h(-1) scaled from experiments using cryopreserved human hepatocytes.

The efficacy and safety of a polyherbal preparation E-OA-07 was compared against placebo in patients with moderate to severe symptoms of osteoarthritis (OA) of the knee, in a double-blind, randomized, parallel groups study. Male or female subjects with American Rheumatism Association functional class II/III and Kellgren Lawrence grade 2 or 3 OA of the knee, who had moderate to severe OA symptoms as recorded by a score of at least 60 on the modified version of the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index, and an overall pain score of at least 70 mm on a 100 mm Visual analogue (VAS) scale were studied. Subjects received 2 capsules of E-OA-07 or placebo twice daily for 12 weeks and paracetamol up to 2 gm per day as rescue medication. Efficacy outcome measures were WOMAC and VAS scores, functional tests for joint mobility and gait, consumption of rescue medication, investigator's global assessment and subjects' opinion. Safety was assessed through incidence of adverse events and subject's assessment of tolerability. After 12 weeks of treatment, there was a significant reduction of WOMAC scores in the E-OA-07 group as compared with placebo (P < 0.01). Mean (±SEM) reductions in WOMAC scores of pain, stiffness, and physical function for E-OA-07 versus placebo were 8.86 (1.77) versus 2.50 (0.76), 3.00 (0.65) versus 0.75 (0.45), and 30.00 (5.22) versus 10.87 (2.18). Significant between-group differences were also observed for VAS scores of pain and stiffness. The symptom alleviating effect of E-OA-07 persisted over a follow-up period of 4 and 6 weeks as VAS pain and stiffness scores continued to remain statistically lower (P < 0.01) in the E-OA-07 group than placebo. Subject's opinion was significantly greater in favor of E-OA-07 than placebo, whereas both groups received favorable responses from investigator. Consumption of rescue medication and tolerability ratings were similar between the 2 groups. One E-OA-07 subject was hospitalized due to accidental fall and withdrawn from the study. No other serious adverse event occurred. The effect of E-OA-07 in relieving moderate to severe symptoms of OA of the knee is well tolerated, superior, and more persistent than placebo.

MK-0703 is a selective cyclooxygenase-2 inhibitor investigated for the treatment of acute pain and inflammation. The purpose of this single-dose, randomized, double-blind, double-dummy, placebo-controlled, parallel-group study was to compare MK-0703 12.5, 50, and 100 mg with ibuprofen 400 mg or placebo in patients who experienced moderate to severe pain after surgical removal of at least 2 third molars. Overall analgesic effect, duration of analgesic effect, time to onset of analgesic effect, peak analgesic effect, and tolerability were assessed over a 24-hour postdose period. The primary endpoint of this study was total pain relief over 8 hours postdose. The study included 121 patients (mean age, 23 yr); 16, 31, 28, 31, and 15 patients enrolled in the placebo, MK-0703 12.5 mg, MK-0703 50 mg, MK-0703 100 mg, and ibuprofen 400 mg groups, respectively. Both MK-0703 50 and 100 mg were significantly more effective than placebo for all endpoints (P < 0.01) and comparable with ibuprofen 400 mg. The onset of analgesic effect in the MK-0703 50 mg and 100 mg and ibuprofen 400 mg groups did not differ significantly from each other (P > 0.20). MK-0703 was generally well tolerated in single doses up to 100 mg. In summary, MK-0703 50 and 100 mg were efficacious in the treatment of postoperative dental pain and were indistinguishable from the active comparator, ibuprofen 400 mg.

We retrospectively evaluated the ability of equations with in vivo population binding parameters of our previous study (Method 1) or an average unbound fraction of 0.25 of Pynnönen (Method 2) to predict the unbound serum carbamazepine (CBZ) concentration in 35 serum samples from 18 adult patients with epilepsy receiving polytherapy. In 9 serum samples from 6 patients, the ability of equations for unbound serum carbamazepine-10,11-epoxide (CBZ-E) concentration prediction was also determined in predictive performance with in vivo population binding parameters of our previous study (Method A) or an average unbound fraction of 0.5 of Pynnönen (Method B). Mean prediction error, mean absolute prediction error (MAE), and root mean squared error (RMSE) were calculated for each method, and these values served as a measure of prediction bias and precision. Method 1 shows a bias to underpredict unbound serum CBZ. The MAE and RMSE were smaller in Method 2 (MAE = 0.454 &mgr;m/L, RMSE = 0.597 &mgr;m/L) than Method 1 (MAE = 0.597 &mgr;m/L, RMSE = 0.721 &mgr;m/L). Method 2 is superior to Method 1 in accuracy and precision. The effects of antiepileptic comedications on predictive performance of Methods 1 and 2 were determined in each group of serum samples with (n = 18, Group 1) or without (n = 17, Group 2) valproic acid (VPA) comedication. The results obtained by Method 1 show a bias to underprediction in Group 1 and no bias to over- or underprediction in Group 2. Results obtained by Method 2 show no bias to over- or underprediction in Groups 1 and 2. The effects of VPA comedication on predictive performance of unbound serum CBZ are relatively larger in Method 1 than Method 2. There was a weak but significant positive relationship between age and unbound serum CBZ fraction by simple regression analysis (n = 35, r = 0.368, p = 0.0297). The determined coefficient indicated that only about 14% of variations in unbound serum CBZ fraction can be explained by age, however. In each of Groups 1 and 2, no significant relationship was observed between age and unbound serum CBZ fraction. The effects of age on predictive performance of unbound serum CBZ are relatively small in patients receiving polytherapy. For unbound CBZ-E prediction, each of Methods A and B has no bias to over- or underprediction. The MAE was larger in Method B (MAE = 0.311 &mgr;m/L) than Method A (MAE = 0.233 &mgr;m/L). The differences in RMSE were small between Methods A (RMSE = 0.349 &mgr;m/L) and B (RMSE = 0.333 &mgr;m/L), however. Each of Methods A and B may have similar accuracy and precision.

A simple method to estimate antimalarial drug-related fall in hematocrit (FIH) after treatment of Plasmodium falciparum infections in the field is described. The method involves numeric estimation of the relative difference in hematocrit at baseline (pretreatment) and the first 1 or 2 days after treatment begun as numerator and the corresponding relative difference in parasitemia as the denominator, and expressing it per 1000 parasites cleared from peripheral blood. Using the method showed that FIH/1000 parasites cleared from peripheral blood (cpb) at 24 or 48 hours were similar in artemether-lumefantrine and artesunate-amodiaquine-treated children (0.09; 95% confidence interval, 0.052-0.138 vs 0.10; 95% confidence interval, 0.069-0.139%; P = 0.75) FIH/1000 parasites cpb in patients with higher parasitemias were significantly (P < 0.0001) and five- to 10-fold lower than in patients with lower parasitemias suggesting conservation of hematocrit or red cells in patients with higher parasitemias treated with artesunate-amodiaquine or artemether-lumefantrine. FIH/1000 parasites cpb were similar in anemic and nonanemic children. Estimation of FIH/1000 parasites cpb is simple, allows estimation of relatively conserved hematocrit during treatment, and can be used in both observational studies and clinical trials involving antimalarial drugs.

A pharmacoscintigraphic study was conducted to compare the dose deposition of HMR 1031 from the existing nebulizer formulation and the new Ultrahaler device to help determine the doses for future phase 2 trials. This was a single-dose, open-label, randomized, two-way crossover study in which HMR 1031 (3 mg) was delivered by the Ultrahaler and the Pari LC Star nebulizer to 12 healthy male subjects. For both treatments, the formulations were radiolabeled with technetium-99m pertechnetate such that a maximum of 10 MBq was delivered on each study day. Scintigraphic images were acquired immediately after dosing to estimate the percentage of the dose delivered to the lungs and oropharynx. Serial plasma samples were collected up to 12 hours post-dose on each occasion and analyzed for HMR 1031 by a LC/MS/MS method with a lower limit of quantitation of 10 pg/mL (0.01 ng/mL). Pharmacokinetic parameters were calculated for HMR 1031 using noncompartmental methods. No serious adverse events were reported. The systemic absorption of HMR 1031 following inhalation administration was relatively rapid, with median T(max) values of 0.5 hours and 1.0 hours post-dose after administration via Ultrahaler and nebulizer, respectively. The mean plasma AUC(0-12) (Ultrahaler, 15.8 ng*h/mL; nebulizer, 11.1 ng*h/mL) and C(max) (Ultrahaler, 4.96 ng/mL; nebulizer, 2.28 ng/mL) values were approximately 42% and 118% higher for the Ultrahaler compared with the nebulizer. The mean terminal half-life of HMR 1031 was similar after administration from both devices (2.91 and 3.18 hours). Based on the scintigraphic data, the lung deposition of HMR 1031 after administration by Ultrahaler (24.6% of the administered dose) was approximately 37% higher compared with the lung deposition from the nebulizer (18.0% of the administered dose). This observation was in agreement with the relative difference in the plasma AUC values achieved after administration of the two formulations. The in vivo results based on the scintigraphic data were also comparable with those from in vitro studies for the Ultrahaler. Based on the ratio of the dose delivered by both the formulations, the required doses for the future Ultrahaler formulation can be predicted.

During a 33-month follow-up of 1038 consecutive patients who had implantable cardioverter-defibrillators, appropriate shocks occurred in 329 of 1038 patients (32%). Appropriate shocks occurred in 101 of 380 patients (27%) treated with beta-adrenergic blockers alone; in 31 of 95 patients (33%) treated with amiodarone alone; in 39 of 149 patients (26%) treated with beta-blockers plus amiodarone; in 11 of 28 patients (39%) treated with sotalol alone; and in 147 of 386 patients (38%) treated with no beta-blockers, amiodarone, or sotalol (P < 0.001 comparing patients treated with beta-adrenergic blockers alone with patients treated with no beta-blockers, amiodarone, or sotalol; and P < 0.01 comparing patients treated with beta-blockers plus amiodarone with patients treated with no beta-blockers, amiodarone, or sotalol). In conclusion, patients having implantable cardioverter-defibrillators should also be treated with beta-adrenergic blockers to reduce the frequency of appropriate shocks.

The interleukins function as intercellular hormones, possessing the ability to alter the activity of a target cell population. Interleukin-4, secreted by activated T-cells, has shown antitumor activity in vitro against multiple myelomas, lymphoma, chronic myelomonocytic leukemia, and some solid tumors. Early promising clinical studies have shown the efficacy of IL-4 in decreasing the malignant lymphocyte count and in normalizing hematologic parameters in patients with CLL and in inducing transient clinical responses in patients with non-Hodgkin's lymphoma. Interleukin-6 possesses immunomodulating properties including enhancement of NK cell activity and induction of cytotoxic T-cell activity. IL-6 has shown antitumor activity in mice injected with weakly immunogenic syngeneic tumors and has been shown to inhibit in vitro human breast carcinoma and leukemia/lymphoma proliferation through a direct tumor inhibitory effect. Clinical studies investigating the antitumor activity of IL-6 are currently in phase II clinical trials. IL-6 and IL-11 have demonstrated thrombopoietic enhancing activity in primate models and early clinical trials. These agents have a potential application in ameliorating the thrombocytopenia associated with myeloablative chemotherapy. Yet to enter clinical trials, IL-12 has been shown to enhance the lytic activity of nonspecific NK/LAK cells and appears to be more efficient than IL-2 or IFN's in enhancing NK cytotoxicity. IL-12 has also been shown to enhance specific allogeneic human CTL responses and to induce the secretion of IFN-gamma from both resting and activated T and NK cells. In summary, these interleukins are now promising agents under investigation as effective treatment strategies in the oncologic setting.

Anticholinergic syndrome may present with a wide variety of signs and symptoms. Central manifestations range from excitatory symptoms including delirium and agitation to central nervous system depression, stupor and coma. Anticholinergic syndrome was once a common phenomenon after general anesthesia because of the frequent administration of the anticholinergic agents atropine and scopolamine. Now that these agents are rarely administered, anesthesia-related anticholinergic syndrome is currently infrequently reported. Still, many prescription and over the counter medications as well as many anesthetic agents possess anticholinergic activity, and this diagnosis should be considered in patients with altered mental status following general anesthesia. We report a case of prolonged somnolence following general anesthesia for an MRI. A rapid improvement of mental status with physostigmine confirmed the diagnosis of anticholinergic syndrome. This case is unique in that anticholinergic syndrome-related respiratory depression was promptly reversed with physostigmine.

This report describes the normalization of left ventricular ejection fraction and resolution of signs and symptoms of chronic and severe heart failure in both male and female patients (mean age 54 years) treated with standard medical therapy. These observations were made in 11 patients with idiopathic dilated cardiomyopathy treated in a single cardiology practice, who had evidence of myocardial "viability" (dysfunctional but noncontractile myocardium that has the potential for improvement in function) as assessed by cardiac magnetic resonance imaging, low-dose dobutamine echocardiography, or nuclear imaging. These patients were treated with standard available therapies including beta-blockers, angiotensin-converting enzyme inhibitors, digoxin, and potassium and non-potassium-sparing diuretics. The average ejection fraction at presentation was 17% +/- 9% which improved to 59% +/- 5%. All patients improved to New York Heart Association functional class I with available therapy. The majority of patients received micronutrient supplementation with coenzyme Q10, vitamin B1, and amino acids, which target the pathways of cardiac metabolism and may aid in the restoration of cardiac function. This case series demonstrates that normalization of cardiac function is possible with standard therapy and the importance of assessing myocardial viability in all patients with heart failure and reduced ejection fraction. Given the unique metabolic needs of the failing heart, the role of micronutrients in combination with standard therapy warrants further investigation.

Irinotecan (CPT-11) is a derivative of the chemotherapeutic agent camptothecin. CPT-11 inhibits the nuclear enzyme topoisomerase I. It has demonstrated a broad spectrum of antitumor activity in preclinical tumor model systems. Significant advances have been made toward the understanding of the pharmacokinetics and schedule dependency of this agent. CPT-11 has demonstrated significant clinical activity in the treatment of patients with gastrointestinal, pulmonary, gynecologic, and lymphoid malignancies. Further study of this agent to determine its role in combination chemotherapeutic regimens is currently underway.

There is a rising worldwide prevalence of diabetes, especially type 2 diabetes mellitus (T2DM), which is one of the most challenging health problems in the 21st century. The associated complications of diabetes, such as cardiovascular disease, peripheral vascular disease, stroke, diabetic neuropathy, amputations, renal failure, and blindness result in increasing disability, reduced life expectancy, and enormous health costs. T2DM is a polygenic disease characterized by multiple defects in insulin action in tissues and defects in pancreatic insulin secretion, which eventually leads to loss of pancreatic insulin-secreting cells. The treatment goals for T2DM patients are effective control of blood glucose, blood pressure, and lipids (if elevated) and, ultimately, to avert the serious complications associated with sustained tissue exposure to excessively high glucose concentrations. Prevention and control of diabetes with diet, weight control, and physical activity has been difficult. Treatment of T2DM has centered on increasing insulin levels, either by direct insulin administration or oral agents that promote insulin secretion, improving sensitivity to insulin in tissues, or reducing the rate of carbohydrate absorption from the gastrointestinal tract. This review presents comprehensive and up-to-date information on the mechanism(s) of action, efficacy, pharmacokinetics, pleiotropic effects, drug interactions, and adverse effects of the newer antidiabetic drugs, including (1) peroxisome proliferator-activated-receptor-γ agonists (thiazolidinediones, pioglitazone, and rosiglitazone); (2) the incretin, glucagon-like peptide-) receptor agonists (incretin-mimetics, exenatide. and liraglutide), (3) inhibitors of dipeptidyl-peptidase-4 (incretin enhancers, sitagliptin, and vildagliptin), (4) short-acting, nonsulfonylurea secretagogue, meglitinides (repaglinide and nateglinide), (5) amylin anlog-pramlintide, (6) α-glucosidase inhibitors (miglitol and voglibose), and (7) colesevelam (a bile acid sequestrant). In addition, information is presented on drug candidates in clinical trials, experimental compounds, and some plants used in the traditional treatment of diabetes based on experimental evidence. In the opinion of this reviewer, therapy based on orally active incretins and incretin mimetics with long duration of action that will be efficacious, preserve the β-cell number/function, and block the progression of diabetes will be highly desirable. However, major changes in lifestyle factors such as diet and, especially, exercise will also be needed if the growing burden of diabetes is to be contained.

This study investigated whether a fixed-dose combination of 40 mg of the angiotensin II antagonist telmisartan plus 12.5 mg of the diuretic hydrochlorothiazide (HCTZ) was superior to 40 mg telmisartan in patients with mild to moderate hypertension who failed to respond adequately to 40 mg telmisartan monotherapy. One hundred forty-six patients were withdrawn before randomization. Nonresponders (n = 327) were double blind and randomized to 40 mg telmisartan + 12.5 mg HCTZ (n = 160) or 40 mg telmisartan (n = 167). After 8 weeks of treatment, 40 mg telmisartan + 12.5 mg HCTZ lowered diastolic blood pressure (DBP) by an additional 3.5 mm Hg (P <.01) and systolic blood pressure (SBP) by 7.4 mm Hg (P <.01) compared with 40 mg telmisartan. Most of the additional effect of the combination was seen after 4 weeks of treatment. At week 8, blood pressure was normalized (SBP <140 mm Hg and DBP <90 mm Hg) in 51.6% of patients on 40 mg telmisartan + 12.5 mg HCTZ compared with 23.5% on 40 mg telmisartan (P <.05). The combination of 40 mg telmisartan + 12.5 mg HCTZ normalized DBP in 64.8% of patients, whereas 40 mg telmisartan normalized DBP in 40.1% (P <.05). SBP decreased by > or =10 mm Hg from baseline in 63.5% of patients receiving the fixed-dose combination compared with 42.6% of those receiving 40 mg telmisartan (P <.05). Both treatments were well tolerated. Adverse events were predominantly mild, transient, and considered unrelated to therapy. These findings indicate that a fixed-dose combination of 40 mg telmisartan + 12.5 mg HCTZ is clinically and statistically superior to 40 mg telmisartan in patients with mild to moderate hypertension failing to respond to 40 mg telmisartan alone.

Information on the pharmacokinetic behavior of a new anticonvulsant agent (CGP 33101) was obtained after oral administration of ascending doses to male epileptic patients maintained on existing antiepileptic drug (AED) therapy, as well as to healthy male subjects. Single doses of 400, 800 and 1200 mg were administered to 12 of the 16 epileptic patients participating in the clinical trial and all 3 healthy subjects; the remaining patients received placebo doses on each dosing occasion. The study's primary objectives were to obtain single-dose add-on tolerability information, as well as preliminary pharmacokinetic data for the drug candidate. Either placebo or 400, 800 and 1200 mg of the compound, administered as 200-mg tablets, were coadministered with enzyme-inducing antiepileptic medications to the patients participating in the trial. These AEDs dilantin, tegretol, depakote, mysoline and tranxene) were administered individually or as combination therapy of two or three, with each patient being on the existing therapy for a minimum of 3 weeks prior to receiving the drug candidate (CGP 33101) as an add-on. Three healthy male subjects were included in the study to provide concurrent pharmacokinetic data at equivalent doses, as well as additional safety data in the absence of concomitant medication. Plasma concentrations of the new drug candidate were determined in samples obtained predose through 120-h postdose, with a 5-day washout period between doses. Preliminary pharmacokinetic parameters, such as peak plasma concentrations (C(max), times to peak levels (T(max)), areas under the plasma concentration-time curve (AUC) and terminal half-lives (T(1/2)), were determined in both epileptic patients and healthy subjects following all three doses. The mean T(max) values were similar for all three dose levels in both patients and subjects, indicating that the rate of absorption was comparable. Mean C(max) values increased in a dose-related manner with increasing dose in epileptic patients. The corresponding values showed a dose-proportional relationship in healthy subjects. The relationship between C(max) values and the administered dose did not change in patients or subjects when the data was corrected for dose and/or body weight. After the peak, plasma levels declined, but were still quantifiable in most patients and subjects at 36 h following all three doses. The mean AUC values increased in a dose-proportional manner with increasing dose in healthy subjects. The corresponding mean patient data appeared to increase in a dose-related manner. The relationship between AUC values and size of the administered dose did not change in either patients or subjects when the data was corrected for dose and/or body weight. The terminal elimination half-lives (T(1/2)) were apparently shorter in patients compared to the healthy subjects and were independent of the close administered.

I-125 labeled SP4 is a synthetic oligopeptide derived from apolipoprotein B of low-density lipoprotein that has been shown to localized in atherosclerotic plaques in experimental animals. However, its biodistribution and mechanism of localization need to be further elucidated. Twenty-four cholesterol-fed (CF) and 20 normal (NL) New Zealand White rabbits were injected with I-125-SP4 and killed 15 to 30 min (6 NL; 6 CF) or 2 h (14 NL; 18 CF) later. We obtained aortic autoradiograms and activity concentrations (% injected dose/gm) in aortic segments and other tissues. The uptake of I-125-SP4 was higher in CF than in NL rabbits in all aortic segments (p < 0.05). I-125-SP4 was cleared rapidly in both CF and NL rabbits with 60 to 70% of the injected dose cleared from the blood by 1 h. No statistically significant differences in radiotracer biodistribution were observed between NL and CF rabbits although activity tended to be higher in the liver, gallbladder, and intestine in NL rabbits and in the kidney and spleen in CF rabbits. Silver grains were distributed mainly on foam cells of the fatty streaks in aortic microautoradiograms from two additional rabbits that had been injected with I-125-SP4. There were 23,518 plus minus 15,878 (SD) grains/mm(2) in fatty plaques but only 14,669 plus minus 11,035 grains/mm(2) in media muscle (p < 0.0001 [9 sections, 17 areas evaluated] in an atherosclerotic animal) in injected animals and 13,439 plus minus 5,565 grains/mm(2) in media muscle (two sections, four areas) in the normal control animals (NS versus media of atherosclerotic animal). I-125-SP4 specifically localizes in aortic atherosclerotic plaques in CF rabbits. There is no significant difference in tissue distribution between normal and CF rabbits except in the aorta. Preliminarily, it appears that the site of tracer uptake is on foam cells and this suggests the possibility of relative specificity for fatty plaque.

The pharmacokinetic and pharmacodynamic properties of a new calcium channel blocker MPC-1304 (MPC) were examined following a single 10 mg oral dose of MPC in six hypertensive subjects. Blood samples for measurement of MPC and its active metabolite (MPC-Keto-H(2)) were obtained, and blood pressure was measured just before and at 1, 2, 4, 6, 8, 12 and 24 h after administration. Plasma concentrations of MPC-Keto-H(2) were significantly higher than those of MPC at every observation point. The value of maximum plasma concentration of MPC-Keto-H(2) was 10 times greater than that of MPC. The antihypertensive effect of MPC was observed at 4 h after administration and persisted up to 8 h. A plot of plasma concentrations of MPC versus reductions in blood pressure showed an anticlockwise hysteresis loop. These results suggest that the active metabolite MPC-Keto-H(2) contributes in part to the antihypertensive action of MPC, the delayed distribution of MPC into the effector site, or both.

HFA-134a blood levels from four clinical studies were combined to give a preliminary description of its population pharmacokinetics. HFA-134a was absorbed promptly and was eliminated with a half-life of 5.1 min.

Of 136 patients, mean age 72 years, receiving digoxin in the hospital or in the medical clinic, 47 (35%) had heart failure with reduced left ventricular ejection fraction and symptoms despite optimal medical therapy, 82 (60%) had persistent atrial fibrillation (AF), and 7 (5%) had paroxysmal AF. The prevalence of inappropriate use of digoxin was 5%. Of 89 patients with persistent or paroxysmal AF, 70 (79%) were being treated with warfarin to maintain an International Normalized Ratio between 2.0 and 3.0, 15 (17%) were being treated with aspirin 325 mg daily, and 4 (4%) were not being treated with warfarin or aspirin. The prevalence of nonuse of warfarin or aspirin in patients with persistent or paroxysmal AF was 4%.

This analysis focused on three objectives: 1) to measure packed red blood cell (pRBC) use across different critical care settings; 2) to characterize transfused and nontransfused critically ill patients; and (3) to identify potential predictors of transfusion use. A retrospective analysis of critically ill patients from 139 hospitals across the United States was conducted. Hospital administrative and laboratory data were collected for patients 18 years of age and older admitted to the intensive care unit (ICU) (including coronary care unit and intermediate care units) from January 1, 2004, to May 31, 2005. Multivariate analyses controlling for patient and hospital heterogeneity evaluated the association between pRBC transfusions and patients' ICU or hospital length of stay. A total of 180,221 patients met all inclusion criteria, with 29,331 (16.3%) receiving pRBCs during their ICU stay. There was differential use of pRBCs by ICU/coronary care unit setting (ie, 23% of general ICU patients versus 7% of intermediate coronary care unit patients). Increasing age [odds ratio (OR), 1.007; 95% confidence interval (CI), 1.006-1.008], declining hemoglobin concentrations (OR, 2.315; 95% CI, 2.288-2.342), mechanical ventilation (OR, 1.338; 95% CI, 1.287-1.392), dialysis (OR, 2.071; 95% CI, 1.913-2.242), and presence of acute renal failure (OR, 1.259; 95% CI, 1.193-1.329), congestive heart failure (OR, 1.156; 95% CI, 1.106-1.208), or septicemia (OR, 1.143; 95% CI, 1.071-1.221) were associated with a higher likelihood of pRBC use. Each pRBC transfusion significantly increased hospital length of stay (1.6, 0.5, and 2.7 additional days for patients with 1, 2, and 3 or more transfusions, respectively, P < 0.0001) as compared with nontransfused patients. Multiple factors increased the likelihood of pRBC use in ICU patients. In addition, pRBC transfusion was associated with increased length of stay. Clinicians should evaluate the risk-benefit ratio and consider interventions to limit any unnecessary pRBC use in the critically ill.

Systemic lupus erythematosus (SLE) is a disease characterized by the prolonged production of high-affinity autoantibodies resulting in direct and immune complex-mediated tissue damage. Because autoantibody responses occur over several years, memory B cells are likely to be involved. Interleukin-14 (IL-14) is a cytokine implicated in the generation and maintenance of normal memory B cells. Many of the actions of IL-14, including inhibition of antibody synthesis and upregulation of IL-14 receptors (IL-14R), are dependent on the formation of prostaglandin E (PGE) and subsequently cAMP. We observed that IL-14 induces phospholipase A(2) (PLA(2))-dependent release of arachidonic acid from phosphatidylcholine and phosphatidylinositol. Production of PGE is blocked by the PLA(2) inhibitor bromophenacyl bromide. Exogenous PGE (misoprostol) induces similar inhibition of antibody synthesis and increases in IL-14R as IL-14. Lymphocytes from patients with inactive SLE were noted to spontaneously produce PGE. Lymphocytes from normal donors produced PGE only after Sac-activation and IL-14 stimulation. Peripheral B and T lymphocytes from SLE patients, but not normal donors, spontaneously produced IL-14. Increased numbers of peripheral B lymphocytes from patients with inactive SLE expressed IL-14R, when compared to normal donors. Thus, increased production of IL-14 and PGE in SLE may result in expansion of a memory B-cell population capable of long-term autoantibody production. Further study will be necessary to confirm these preliminary findings and to examine in greater depth the regulation of PGE and IL-14 in SLE patients and normal donors.

The inhibitory effects of HOE 140 (D-Arg-[Hyp(3),Thi(5),D-Tic(7), Oic(8)]bradykinin), a novel bradykinin B(2)-receptor antagonist, on mesenteric vascular bed vasodilator responses to bradykinin (BK) were investigated under constant-flow conditions in the isolated blood-perfused rat mesenteric vascular bed. During baseline conditions, injections of BK produced dose-related decreases in mesenteric arterial perfusion pressure which were reproducible with respect to time. HOE 140, in a dose of 50 &mgr;g/kg intravenously, decreased vasodilator responses to BK but had no significant effect on mesenteric vasodilator responses to albuterol, acetylcholine, levcromakalim, or to nitroglycerin. These results suggest that BK has significant vasodilator actions which are mediated by the activation of kinin B(2)-receptors in the mesenteric vascular bed of the rat. HOE 140 caused a significant increase in baseline mesenteric arterial perfusion pressure. These data indicate that HOE 140 is a highly selective, BK B(2)-receptor antagonist in the mesenteric vascular bed of the rat, and the elevation of baseline mesenteric arterial tone by HOE 140 suggests that BK plays a role in maintaining normal vascular tone in the mesenteric circulation. These results also suggest that HOE 140 is a useful probe for studying the role of BK in the mesenteric vascular bed under physiologic and pathophysiologic conditions.