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.
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.
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.
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.
We investigated the treatment of 146 men, mean age 62 years, and 54 women, mean age 69 years, with acute ST-segment elevation myocardial infarction (STEMI) in a university medical center. Coronary revascularization or thrombolytic therapy was given to 143 men (98%) and 52 women (96%) [P = not significant (NS)]. Antiplatelet therapy and antithrombotic therapy were given to 146 men (100%) and 54 women (100%) (P = NS). Beta-blockers were given to 133 men (91%) and 45 women (83%) (P = NS). Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were given to 122 men (84%) and 42 women (78%) (P = NS). Statins were given to 128 men (88%) and 43 women (80%) (P = NS). Nitrates were given to 94 men (64%) and 36 women (67%) (P = NS). Diuretics were given to 97 men (66%) and 37 women (69%) (P = NS). Calcium channel blockers were given to 26 men (18%) and 12 women (22%) (P = NS). There was no significant difference in the treatment of men versus women with acute STEMI.
The in vitro metabolism of ciclesonide, a novel inhaled nonhalogenated glucocorticoid for the treatment of asthma, was compared in cryopreserved hepatocytes from mice, rats, rabbits, dogs, and humans. Incubations of C-ciclesonide with individual hepatocyte suspensions revealed similar metabolite profiles in all 5 in vitro systems used. Ciclesonide was rapidly converted to its active metabolite, desisobutyryl-ciclesonide (des-CIC). Des-CIC was then extensively metabolized to pharmacologically inactive metabolites through oxidation and reduction, followed by glucuronidation. A total of 12 groups of metabolites derived from des-CIC were characterized and identified by liquid chromatography/radioactivity monitor/mass spectrometry. Oxidation occurred on both the cyclohexane ring and the steroid moiety. Hippuric acid formation by cleavage of the cyclohexylmethyl moiety of ciclesonide, followed by aromatization of the cyclohexane ring through multiple steps of hydroxylation, dehydration, and conjugation with glycine, was found in rat, rabbit, and human hepatocyte incubations. The results indicated that ciclesonide and its active metabolite, des-CIC, were extensively metabolized in vitro in animal and human hepatocytes and that the metabolite profiles in mouse, rat, rabbit, and dog hepatocytes were similar to the profiles in human hepatocytes.
[4S-[4alpha,7alpha(R*),12bbeta]]-7[[2-(acetylthio)-1-oxo-3-phenylpropyl]amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a]benzazepine-4-carboxylic acid (M100240) is an acetate thioester of MDL 100,173-a dual angiotensin-converting enzyme/neutral endopeptidase inhibitor currently in phase II development. The mass balance of [(14)C]M100240 was assessed following oral administration of [(14)C]M100240. Healthy male subjects were given a single 25-mg dose of [(14)C]M100240 (50 microCi) as an oral solution under fasting conditions. Blood samples and excreta were collected postdose. (14)C-radioactivity was measured by liquid scintillation counting. Plasma concentrations of M100240 and MDL 100,173 were determined by LC/MS/MS methods. Pharmacokinetic parameters were calculated. About 98% of the total radioactive dose was recovered within 7 days of oral administration, with most of the radioactivity recovered within 72 hours. Of the recovered radioactive dose, 49.4% and 48.5% were recovered in the urine and feces, respectively. Unchanged M100240 and MDL 100,173 were not detected in the excreta. On average, 76% of the total radioactivity in the blood was associated with the plasma fraction. M100240 accounted for less than 0.06% of the (14)C-radioactivity in plasma and MDL 100,173 accounted for 15.8% (AUC( infinity )) of (14)C-radioactivity in plasma after oral dosing. These data suggest that the drug was absorbed but rapidly converted to its metabolites either presystemically or postsystemically. Up to 78% of the total radioactivity was identified as MDL 100,173. The apparent terminal elimination half-life of MDL 100,173 was longer than that of (14)C-radioactivity, attributable to assay sensitivity and the saturable binding phenomenon commonly associated with angiotensin-converting enzyme inhibitors. M100240 undergoes extensive metabolism in humans, and its metabolites are excreted relatively equally in feces and urine.
This study investigated the effects of medical therapy on incidences of myocardial infarction (MI), percutaneous coronary intervention (PCI), and coronary artery bypass graft surgery (CABG) in an academic outpatient cardiology practice. Chart reviews were performed in 1599 treated patients (1138 men and 461 women), mean age 72 years. Medications investigated included the use of statins, beta blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and aspirin. The mean follow-up was 63 months during 1977-2009. Of 1599 patients, MI occurred in 100 patients (6%), PCI occurred in 296 patients (19%), and CABG occurred in 235 patients (15%). Stepwise logistic regression analysis showed that significant independent risk factors for MI were statins [odds ratio = 0.07; 95% confidence interval (CI), 0.05-0.11, P < 0.001], beta blockers (odds ratio = 0.15, 95% CI, 0.10-0.23, P < 0.001), ACE inhibitors (odds ratio = 0.27, 95% CI, 0.16-0.45, P < 0.001), ARBs (odds ratio = 0.09, 95% CI, 0.04-0.20, P < 0.001), and aspirin (odds ratio = 0.18, 95% CI, 0.12-0.29, P < 0.001). Significant independent risk factors for PCI were statins (odds ratio = 0.15, 95% CI, 0.11-0.20, P < 0.001), beta blockers (odds ratio = 0.26, 95% CI, 0.20-0.35, P < 0.001), ACE inhibitors (odds ratio = 0.25, 95% CI, 0.18-0.34, P < 0.001), and ARBs (odds ratio = 0.18, 95% CI, 0.11-0.28, P < 0.001). Significant independent risk factors for CABG were statins (odds ratio = 0.16, 95% CI, 0.12-0.22, P < 0.001), beta blockers (odds ratio = 0.43, 95% CI, 0.32-0.58, P < 0.001), ACE inhibitors (odds ratio = 0.38, 95% CI, 0.27-0.53, P < 0.001), ARBs (odds ratio = 0.19, 95% CI, 0.11-0.31, P < 0.001), and aspirin (odds ratio = 0.45, 95% CI, 0.33-0.61, P < 0.001).
Human papillomavirus (HPV) is the most prevalent sexually transmitted disease in the United States and can cause cancer with persistent infection. The most common cancer caused by HPV is cervical carcinoma with an average of 12,000 cases reported every year in the United States. Worldwide, over 500,000 cases of cervical cancer are reported yearly with over 250,000 deaths attributed to the disease. Although much is known about the serious health risks associated with HPV infection, there is still much to be discovered about how HPV binds and enters target cells. Understanding is required on how HPV infections will lead to strategies and therapies for reducing the number of infections and HPV-related diseases, including cancers. The HPV viral particle is composed of 2 viral proteins, L1 and L2. Data suggest that binding of the viral capsid to cells is dependent on the L1 protein. We hypothesize that this initial binding to a heparan sulfate is composed of 2 independent events: the first results in a structural change that exposes a hidden portion of the L1 protein leading to a second binding event on the heparan sulfate. Our experiments tested if this "hidden" portion of L1 is necessary for infection and explored the nature of this binding. We generated a peptide with the sequence of the "hidden" portion of L1. Infection of HaCaT cells in the presence of this peptide is highly reduced. Our results suggest that the binding of the L1 C-terminal domain is dependent on amino acid sequence and is necessary for infection.
We investigated the etiologies of syncope and risk factors for mortality and rehospitalization for syncope at 17-month follow-up in a prospective study of 242 consecutive patients, mean age 69 years, hospitalized for syncope. The etiologies of syncope included the following: vasovagal syncope in 49 patients (20%), volume depletion in 39 patients (16%), orthostatic hypotension in 13 patients (5%), primary cardiac arrhythmias in 25 patients (10.3%), structural cardiac disease in 6 patients (2%), and drug overdose in 5 patients (2%). The etiology of syncope could not be determined in 84 patients (35%). Of the 242 patients, 6 (2%) were rehospitalized for syncope and 12 (5%) died. Stepwise logistic regression analysis showed that the significant independent prognostic factors for rehospitalization for syncope were drug overdose [odds ratio (OR): 11.506; 95% confidence interval (CI): 1.083-22.261]. Stepwise logistic regression analysis showed that significant independent prognostic factors for time to mortality were undetermined etiology of syncope (OR: 4.665; 95% CI: 1.002, 21.727), San Francisco Syncope Score (OR: 3.537; 95% CI: 1.472-8.496), hypertension (OR: 0.099; 95% CI: 0.019-0.504), and glomerular filtration rate (OR: 0.964; 95% CI: 0.937-0.993).
Painful episodes are the most frequent complaints of patients with sickle cell disease. The Emergency Department (ED) has provided management for acute events using the usual triage format for emergencies. A prospective study evaluated the role of the ED in the care of adults with sickle cell disease (SCD). The protocol, thus, addressed issues of acute events related to SCD and provided better care for patients with SCD in the ED. Approximately 37% of ED visits were for painful events. An inciting cause was identified in 35% of painful events and 75% of these required admission to the hospital. A 15-year follow-up prospectively showed similar results and that uncomplicated pain crisis can be treated with ED protocols. Outpatient clinics and urgent centers could reduce these visits. Absolute indications for admission include sepsis, fever >102 degreeF, white cell counts >20 000, worsening anemia, hypoxemia, acute chest syndrome and new CNS events. Patient database in the ED must be revised annually to avoid extensive workup in the ED and a complete history/physical examination, and a CBC could be sufficient for triage in an uncomplicated pain crisis. An acceptable protocol for care should be available at all EDs and a registry and information system for SCD will discourage overutilization of investigational tests and visits to multiple EDs.
The discovery of the anesthetic properties of chloroform by Sir James Simpson is one of the therapeutic triumphs of the 19th century. Queen Victoria requested chloroform anesthesia for the birth of her second son, Prince Leopold, and from then until the end of century chloroform was the most popular general anesthetic for obstetrics and surgery. Chloroform was so pleasant to inhale that it became a drug of abuse and was involved in all sorts of criminal activity. Despite its wide usage, chloroform was not thought to be part of the brutal murder of 3-year-old Saville Kent on the night of June 30, 1860, outside his manor house in southwest England. The events surrounding and after the murder have recently been documented by Kate Summerscale in a book entitled, "The Suspicions of Mr. Whicher," the Detective Inspector assigned to the case by Scotland Yard. According to Ms Summerscale's records, Mr Whicher ignored the possibility that chloroform was involved in Saville's death. However, evidence supports the view that chloroform played a critical role in the crime and indicates that the guilty plea by Samuel Kent's daughter, Constance, for which she spent 20 years to the day in prison, was as inaccurate as it was incomplete.
A comparative study was made of the utilization of cardiovascular drugs in a long-term-care facility for the aged for 1987 and 1992 during which the age and sex distributions and incidence of usage were similar. There were statistically significant declines in the usage of diuretics and potassium supplementation, digoxin, antihypertensives, antiarrhythmics, and beta blockers and a rise in the use of calcium-channel blockers. There was a slight fall in the use of antianginal drugs. The ACE inhibitors introduced after 1987 were taken by 6.1%. The dosages of digoxin and diuretics decreased as management was adequate and toxicity avoided and usage of digoxin reduced in accordance with the concept that digoxin is useful in failure only when left ventricular output is impaired.
Drug-related illness in the United States factors substantially in health care costs, although often these illnesses and their attendant costs are preventable. One strategy for minimizing adverse drug reactions is to provide drug information to consumers in the form of prescription counseling at pharmacies. The Omnibus Budget Reconciliation Act of 1990 (OBRA 1990) contained provisions for mandating such counseling to Medicaid patients. OBRA 1990 was implemented in 1993, but most states acted quickly to extend counseling services to all patients receiving prescription drugs. We looked at the extent and quality of prescription counseling available in community pharmacies 1 decade after OBRA 1990 was written. We evaluated the counseling services afforded at large chain pharmacies, independent community pharmacies, and on-line pharmacies for a hydrochlorothiazide prescription. We found that most (69%) pharmacies offered to provide prescription counseling service, and that average counseling index scores, a measure of the quality or extent of information provided as determined by a Rasch analysis, were generally satisfactory. Our observations based on a single prescription for hydrochlorothiazide, along with other studies, suggest that there is a positive upward trend in the number of pharmacies providing prescription drug information, and that the extent of information provided suggests that the objectives of OBRA 1990 and related legislation to reduce ADRs are being fundamentally satisfied.
The Prescription Drug User Fee Act of 1992 (PDUFA) authorizes the US Food and Drug Administration (FDA) to levy user fees on manufacturers who submit applications to the agency. Revenues are dedicated to the achievement of a set of specific performance goals, documented by the FDA Commissioner and referenced in the Act. The FDA currently credits PDUFA with the agency's success in reducing new drug review times and eliminating the formidable new drug application (NDA) backlog. To provide an independent assessment of PDUFA's impact on the new drug development process, the Tufts Center for the Study of Drug Development established an annual user fee survey of over 50 major pharmaceutical and biotechnology firms with operations in the United States. As of December 31, 1996, survey data have been collected for fiscal years 1994, 1995, and 1996. Data from a cohort of user fee drugs approved in 1993-1996 were compared with data from all non-user fee drugs approved in 1990-1992. Whereas the mean approval phase (NDA submission to approval) for the user fee drugs was considerably shorter than that for the non-user fee drugs (14.5 versus 31.0 months, respectively), the mean clinical phase (investigational new drug application filing to NDA submission) was somewhat longer (88.0 versus 81.1 months, respectively). As a result, the total time from the start of clinical testing to drug approval (total phase) was only marginally shorter for the user fee drugs (102.0 versus 112.1 months, respectively). These results highlight the need for efforts to reduce lengthy drug development times.
Growing concern within Congress, the pharmaceutical industry, and the Food and Drug Administration (FDA) over the excessive time and cost required to develop new drugs and bring them to market has led to several initiatives designed to speed the drug development process, e.g., the Prescription Drug User Fee Act of 1992 and recent efforts at legislative reform of the agency. To assess the impact of these initiatives, it is useful to examine recent trends in new drug development and review. This report is the fourth in a series in which we analyze new chemical entities (NCEs) recently approved by the FDA. In 1993, 1994, and 1995, the FDA approved 75 new drugs, 67 of which met the Tufts Center's definition of an NCE. Of the 67, 31 (46%) received priority review, 13 (19%) had orphan drug status, and 5 (7%) were approved under the accelerated approval regulations. For the 67 NCEs, the mean length of the clinical phase (investigational new drug filing to new drug application submission) was 7.1 years, and the approval phase (new drug application submission to approval) was 2.0 years. The mean approval phase for the 31 priority NCEs (1.5 years) was 38% shorter than that for the 36 standard NCEs (2.5 years). Compared with similar values for the previous 3-year period, the mean clinical phase for all NCEs increased by 16%, whereas the mean approval phase decreased by 23%. Of the 66 NCEs for which foreign marketing data were available, 34 (52%) were available in foreign markets one or more years prior to U.S. approval, with a mean of 7.7 years of earlier foreign marketing.
This research investigates US Food and Drug Administration review intervals in the United States from 1997 through 2002 for three main categories new drugs applications: new drug application (NDA), the supplemental new drug application (SNDA), and the abbreviated new drug application (ANDA). Review interval for each application was the basis for evaluation and was calculated based on the difference between approval date and the application date. The median review time for all applications was 13.5 months (1.1 years). The median review intervals for ANDAs, NDAs, and SNDAs were 19.1, 12.0, and 10.0 months (1.6, 1.0, and 0.8 years), respectively, during the period. It was found that the median review period for an ANDA was significantly longer than that for an NDA and SNDA. Comparison of application class medians revealed significant differences for all 3 pairwise comparisons (all P < 0.001, Tukey HSD). Within each application category, we compared differences between years. The year effect was not statistically significant for ANDAs or NDAs. NDA median review times were 13.7, 12.0, 12.0, 10.8, 12.5, and 11.7 months (1.14, 1.00, 1.00, 0.90, 1.04, and 0.98 years), while ANDA median review times were 20.4, 19.1, 19.9, 18.6, 18.4, and 21.5 months (1.70, 1.59, 1.66, 1.55, 1.53, and 1.79 years) for 1997, 1998, 1999, 2000, 2001, and 2002, respectively. Year differences were significant for SNDAs (P < 0.001). The primary source of this difference was a lower median review time during 1997, but there was little difference in median review times for the remaining years.
Subcutaneous interferon beta-1a is a recognized treatment of relapsing multiple sclerosis, and it may delay the onset of definite multiple sclerosis in patients with a first clinical demyelinating episode. Interferon beta-1a exerts beneficial effects on cognitive functioning via both short-term and long-term mechanisms. The beneficial effect is thought to be a result of immune modulation, with inhibition of leukocyte proliferation and antigen presentation and an increased amount of interleukins. The systemic side effects of interferon beta-1a are flu-like syndrome and development of neutralizing antibodies, the clinical significance of which is not known. There have been concerns about the rare development of an acute demyelinating disease after interferon beta-1a therapy as a result of upregulation of inflammatory mediators. In the clinical trials, there is evidence of development of mild anemia with a hemoglobin level below 10 g/dL only in 3% of the patients. There has been no reported case of development of aplastic anemia in patients being treated with interferon beta-1a. Described here is a case of development of aplastic anemia with interferon beta-1a in a patient with multiple sclerosis. Our patient underwent a complete hematologic evaluation to rule out other causes of aplastic anemia. Association with interferon beta-1a was highly suspected.
ABT-761 is a second-generation 5-lipoxygenase inhibitor for the treatment of asthma. The effects of ABT-761 on the pharmacokinetics of theophylline were assessed in 15 adult volunteers in a phase I, multiple-dose, open-label, one-period study. Subjects received a single 400-mg dose of theophylline on days 1 and 8 and 200-mg oral doses of ABT-761 once daily beginning on day 3 and continuing through day 9. The pharmacokinetic parameters of theophylline after administration of theophylline alone and concomitantly with ABT-761 were compared using a paired t-test. No statistically significant differences were observed between the pharmacokinetic parameters of theophylline administered alone and theophylline with concomitant administration of ABT-761. The 95% confidence interval for the ratio of the mean with ABT-761 dosing to the mean for theophylline alone was 0.970 to 1.127 for area under the plasma concentration-time curve and 0.887 to 1.036 for maximal plasma concentration. The lack of an inhibition effect by ABT-761 on theophylline clearance suggested that ABT-761 may have a low affinity for the cytochrome P450 1A2 isozyme, the primary isozyme responsible for theophylline metabolism.
The effect of misoprostol on interleukin-1beta (IL-1beta)-mediated phospholipid metabolism, arachidonic acid release, and prostaglandin E(2) (PGE(2)) production was examined using normal skin fibroblasts and synovial fibroblasts from patients with osteoarthritis. We found that both IL-1beta and misoprostol induced arachidonic acid release, suggesting enhanced phospholipase A(2) activation. Both Il-1beta and IL-1beta/misoprostol, but not misoprostol alone, induced a significant increase in PGE(2) levels compared with controls. Even though PGE(2) production was not significantly increased by misoprostol alone, misoprostol synergistically enhanced IL-1beta-mediated cyclooxygenase activity (sixfold to eightfold) and PGE(2) synthesis in normal fibroblasts but not in OA synovial fibroblasts. Additionally, misoprostol dramatically affected the arachidonate-labeling of triglyceride and cholesterol ester pools; the significance of this is as yet unclear. Together, the results suggest that misoprostol may upregulate the conversion of arachidonic acid to PGE(2) by enhancing the IL-1beta-induced activation/synthesis of cyclooxygenase.
Interleukin-1 induced the expression of cyclooxygenase II in renal mesangial cells. This effect was similar to that seen by phorbol myristate accetate which also induced the message for COX II. Cycloheximide superinduced the message for COX II in the presence of IL-1beta. While the message for COX II when stimulated by PMA was completely inhibited by dexamethasone with concentrations of dexamethasone which inhibited PGE(2) formation, dexamethasone only partially inhibited the message for COX II by Northern analysis. Genistein, an inhibitor of tyrosine phosphorylation completely inhibited the ability of IL-1beta to induce the COX II message. Immunocytochemical studies confirmed the ability of IL-1beta to selectively induce the COX II protein without any effect on COX I protein. These studies confirm the dependency of tyrosine phosphorylation in the IL-1beta induced expression of COX II message and protein.
Interleukin-1 (IL-1) is involved in a broad range of biological activities that affect immunological, inflammatory, and nonimmunological responses. Although the role of the IL-1 proteins in normal physiological responses in vivo remains incompletely defined, there is substantial evidence that excessive production of IL-1 contributes to the pathogenesis of many illnesses with autoimmune or inflammatory components, including rheumatoid and osteoarthritis, type I diabetes mellitus and atherosclerosis. Despite numerous reports on IL-1 regulation, very little is known regarding the molecular details of IL-1 production, particularly at the transcription level. This review will focus on our studies of transcriptional regulation of the murine IL-1beta gene and, where appropriate, comparison to similar studies of the human IL-1beta gene. A basic understanding at this level should lead to effective pharmacological intervention and, ultimately, to control of inflammatory disease.
To compare the modulatory effects of different prostaglandins on collagen gene expression in human chondrocytes, PGE(2), PGE(1), misoprostol (PGE(1) analog), and PGF(2alpha) (10, 50 and 100 ng ml(minus sign1)) were added to human chondrocytes with or without interleukin-1beta (IL-1beta) in the presence of indomethacin to inhibit endogenous prostaglandin synthesis and the effects evaluated on chondrocyte morphology, collagen synthesis, and procollagen mRNA levels. The effects of prostaglandins on the expression of collagen gene regulatory sequences were examined using transient transfection assays of reporter gene constructs in human chondrocytes and BALB/c3T3 fibroblasts, PGE(1), misoprostol, and PGF(2alpha), similar to PGE(2), inhibited type I collagen gene expression in fibroblasts and promoted type II collagen gene expression in chondrocytes. PGE(2), the major inflammatory prostaglandin produced by IL-1-activated chondrocytes and fibroblasts, and PGF(2alpha) were somewhat more potent than the anti-inflammatory prostaglandins PGE(1) and misoprostol in counteracting the IL-1-induced suppression of type II collagen gene expression by chondrocytes and stimulation of type I collagen gene expression by fibroblasts. Rather than promoting degradation of the cartilage matrix in joint diseases, prostaglandins may be somewhat protective, suppressing fibrosis, and maintaining or promoting appropriate cartilage repair.
Smooth-muscle erg 1 (erg1-sm) potassium channel has been recently reported to participate in the modulation of gastrointestinal contractility. Because quinidine inhibits cardiac potassium channel and as a result augments gastrointestinal contractility, it was thought that quinidine may affect erg1-sm. Studies were undertaken to evaluate the effects of quinidine and its chiral isolates on gastrointestinal erg1-sm potassium current and correlate these effects with colon contractility. Chiral separation (high-performance liquid chromatography technique), mass spectrometry, and optical rotation determination were performed to obtain chiral isolates needed for experiments. The erg1-sm potassium channel was expressed in Xenopus oocytes, and the two-electrode patch clamp technique was employed for recording. An isolated rat colon preparation was employed to measure changes in contractility. As a result of chiral separation, two peaks were obtained with elution times of 8.31 and 8.66 minutes, both with a molecular weight of 324; the optical rotations of racemate isolates X and Y were: +258 degrees, +/-0 degrees; and +217 degrees, respectively. The percentage changes in amplitudes of colon contraction (from baseline) were determined at different concentrations of quinidine and for the two isolates in five experiments in each group. Quinidine 0.1, 1, and 10 microM increased contractility by 79 +/- 34, 125 +/- 42, and 217 +/- 51 (P < or = 0.05); for isolate X, the values were 70 +/- 20, 115 +/- 32, and 272 +/- 32 (P < or = 0.05), and for isolate Y the values were 22 +/- 12, 46 +/- 17, and 59 +/- 22. The inhibition of erg1-sm currents by quinidine was 19 +/- 4, 21 +/- 5, and 48 +/- 6 (P < or = 0.05), respectively; that by isolate X was 20 +/- 4, 23 +/- 5, and 39 +/- 7 (P < or = 0.05), and that by isolate Y was 22 +/- 4, 21 +/- 4, and 31 +/- 6. One chiral isolate and quinidine markedly augmented contractility, whereas quinidine and the two chiral isolates inhibited the erg1-sm potassium currents to a similar extent. These results suggest that erg1-sm inhibition does not explain gastrointestinal contractile augmentation caused by the quinidine racemate and its chiral isolates.
The authors investigated the effects of 2,4,6-trihydroxy-alpha-p-methoxyphenylacetophenone (compound D-58), a potent inhibitor of protein tyrosine kinases SYK and Bruton's tyrosine kinase (BTK), on IgE receptor/FcepsilonRI-triggered mast cell-mediated acute allergic responses in vitro and in vivo. Compound D-58 abrogated IgE receptor/FcepsilonRI-mediated SYK and BTK activation as well as calcium mobilization in mast cells. Mast-cell degranulation and leukotriene (LT) C(4) release was inhibited by compound D-58 in a concentration-dependent fashion. Notably, compound D-58 prevented the mast cell mediator-induced vascular hyperpermeability in an in vivo murine model of passive cutaneous anaphylaxis as measured by the prevention of extravasation of systemically administered Evans blue dye. The results uniquely indicate that compound D-58 has potent antiallergic properties. Therefore, further development of compound D-58 may provide the basis for new and effective treatment programs for severe allergic disorders.
The introduction of over-the-counter histamine2 -receptor antagonists (H2 -RAs) makes it important to characterize these agents in terms of their different times to onset of action and magnitude of effect. The time to onset of action and the degree of gastric acid inhibition of the H2 -RAs famotidine and cimetidine at dosage levels approved for over-the-counter use (10 mg famotidine and 200 mg cimetidine) were compared. Twenty-four subjects with a history of heartburn of at least 2 months duration received 10 mg famotidine, 200 mg cimetidine, or placebo in a randomly assigned sequence of three treatment periods. Each period began with an overnight fast, followed by insertion of an intragastric pH probe during a 1-hour baseline monitoring phase, and, 1 hour later, administration of the test medications and monitoring of intragastric pH for an additional 2-hour period. The onset of acid inhibition occurred approximately 35 minutes after administration of either famotidine or cimetidine. Famotidine provided a significantly greater degree of efficacy on all three parameters monitored: percentage of time that gastric pH values were greater than 3.0, mean area-under-the-pH-curve-versus-time curve, and median pH (obtained at 5-minute intervals). Clearly, the over-the-counter dosage of famotidine (10 mg) provided gastric pH elevations that were as rapid and of superior degree than those induced by cimetidine 200 mg.
Several medical and economic factors affect the process of development and introduction of new drugs and the disappearance of various medical agents from the drug market. There are no data in the existing literature on quantitative and qualitative changes in the drug market. We assessed changes in the drug market in Israel over 14 years, focusing on drug groups that, in our subjective opinion, are mainly used in primary care medicine: pain medications, lipid lowering agents, drugs for diabetes, and antihypertensives. We assessed volume of drugs and changes and trends in terms of therapeutic efficacy and safety in selected drugs in each of the groups over the study time period. We used the Medic Compendium for the analyses. Medic contains a listing of drugs that are approved and available for use in Israel. It is updated every 2 months. In 2000, there were 253 available drugs in the study groups that contained 124 active agents. In contrast, in 2013, there were 278 available drugs that contained 130 active agents. Over the study years, there was an increase in the number of drugs that are effective, "user friendly," and have a high safety profile. Our study provides the first data on quantitative and qualitative changes that have taken place in selected groups of drugs. Although the availability of the drugs in different countries is determined by multiple factors, we assumed that there are other countries with a similar situation in terms of their drug markets.
The quality of clinical data submitted by manufacturers to support Food and Drug Administration cardiovascular device premarket approval (PMA) applications varies widely and formal quality assessment has not been previously performed. This study evaluated all original cardiovascular device PMAs with Food and Drug Administration decisions between January 1, 2000, and December 31, 2007, to assess the quality of clinical investigations submitted by manufacturers. Effectiveness and safety end points were judged high quality if they were clearly defined and associated with a specific time point for analysis. Subject accounting was high quality if 90% or greater of the original cohort was accounted for at study conclusion. In total, 88 cardiovascular device PMAs (77.3% permanent implants), 132 clinical studies, 37,328 study subjects (age 61.0 +/- 14.5 years, 33.9% women, 86.3% white), and 29,408 device recipients were analyzed. All PMAs contained clinical data. Primary effectiveness end points, primary safety end points, and subject accounting were deemed high quality in 81.8%, 60.2%, and 77.3% of pivotal studies, respectively. Key cardiovascular comorbidities (coronary artery disease 51.1%, diabetes 36.6%, hypertension 35.2%, heart failure 37.5%, tobacco use 31.8%) and race (14.8%) were infrequently reported, and studies rarely included patients younger than 18 years of age (10.2% of studies). Poorly defined safety and effectiveness end points, poor patient accounting, and incomplete collection of important patient comorbidities make device safety and effectiveness assessments more challenging. Women, pediatric, and nonwhite populations are underrepresented in premarket cardiovascular clinical trials. Manufacturers, regulators, and the clinical community should collaborate to address these study shortcomings to ensure that patients are treated with reliable, safe, and clinically useful medical devices.