Home About us Contact
|
Home About us Contact | ||
|
|
||
End Points (end + point)
Kinds of End Points Selected AbstractsMigraine Management: Contrasting Patient Preferences With Current Clinical End Points: IntroductionHEADACHE, Issue 2002Peter J. Goadsby MD No abstract is available for this article. [source] Type 2 Diabetes: RENAAL and IDNT,The Emergence of New Treatment OptionsJOURNAL OF CLINICAL HYPERTENSION, Issue 1 2002Domenic A. Sica MD The Reduction in End Points in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study and the Irbesartan Diabetic Nephropathy Trial (IDNT) are two recently reported trials with hard end points, conducted in patients in advanced stages of diabetic nephropathy. Two other studies,the Irbesartan Microalbuminuria Study (IRMA)-2 and the Microalbuminuria Reduction with Valsartan study (MARVAL),were trials conducted in patients with type 2 diabetes with microalbuminuria, a cardiovascular risk factor associated with early-stage diabetic nephropathy. These trials all had a common theme,that is, does an angiotensin receptor blocker (ARB) interfere with the natural history of diabetic nephropathy in a blood pressure-independent fashion? Without question, the results of these trials legitimatize the use of the ARB class in forestalling the deterioration in renal function, which is almost inevitable in the patient with untreated diabetic nephropathy. These data can now be added to the vast array of evidence supporting angiotensin-converting enzyme (ACE) inhibitor use in patients with nephropathy associated with type 1 diabetes. It now appears a safe conclusion that the patient with diabetic nephropathy should receive therapy with an agent that interrupts the renin-angiotensin system. These studies have not resolved the question as to whether an ACE inhibitor or an ARB is the preferred agent in people with nephropathy from type 1 diabetes, though the optimal doses of these drugs remain to be determined. Head-to-head studies comparing ACE inhibitors to ARBs in diabetic nephropathy are not likely to occur, so it is unlikely that comparable information will be forthcoming with ACE inhibitors. An evidence-based therapeutic approach derived from these trials would argue for ARBs to be the foundation of therapy in the patient with type 2 diabetes and nephropathy. [source] Nonlinear Indices of Heart Rate Variability in Chronic Heart Failure Patients: Redundancy and Comparative Clinical ValueJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 4 2007ROBERTO MAESTRI M.S. Aims: We aimed to assess the mutual interrelationships and to compare the prognostic value of a comprehensive set of nonlinear indices of heart rate variability (HRV) in a population of chronic heart failure (CHF) patients. Methods and Results: Twenty nonlinear HRV indices, representative of symbolic dynamics, entropy, fractality-multifractality, predictability, empirical mode decomposition, and Poincaré plot families, were computed from 24-hour Holter recordings in 200 stable CHF patients in sinus rhythm (median age [interquartile range]: 54 [47,58] years, LVEF: 23 [19,28]%, NYHA class II,III: 88%). End point for survival analysis (Cox model) was cardiac death or urgent transplantation. Homogeneous variables were grouped by cluster analysis, and in each cluster redundant variables were discarded. A prognostic model including only known clinical and functional risk factors was built and the ability of each selected HRV variable to add prognostic information to this model assessed. Bootstrap resampling was used to test the models stability. Four nonlinear variables showed a correlation >0.90 with classical linear ones and were discarded. Correlations >0.80 were found between several nonlinear variables. Twelve clusters were obtained and from each cluster a candidate predictor was selected. Only two variables (from empirical mode decomposition and symbolic dynamics families) added prognostic information to the clinical model. Conclusion: This exploratory study provides evidence that, despite some redundancies in the informative content of nonlinear indices and strong differences in their prognostic power, quantification of nonlinear properties of HRV provides independent information in risk stratification of CHF patients. [source] Heart Rate Turbulence for Prediction of Heart Transplantation and Mortality in Chronic Heart FailureANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 3 2010Beata Sredniawa M.D. Background: Previous studies have shown conflicting results about the value of heart rate turbulence (HRT) for risk stratification of patients (pts) with chronic heart failure (CHF). We prospectively evaluated the relation between HRT and progression toward end-stage heart failure or all-cause mortality in patients with CHF. Methods: HRT was assessed from 24-hour Holter recordings in 110 pts with CHF (54 in NYHA class II, 56 in class III,IV; left ventricular ejection fraction (LVEF) 30%± 10%) on optimal pharmacotherapy and quantified as turbulence onset (TO,%), turbulence slope (TS, ms/RR interval), and turbulence timing (beginning of RR sequence for calculation of TS, TT). TO , 0%, TS , 2.5 ms/RR, and TT >10 were considered abnormal. End point was development of end-stage CHF requiring heart transplantation (OHT) or all-cause mortality. Results: During a follow-up of 5.8 ± 1.3 years, 24 pts died and 10 required OHT. TO, TS, TT, and both (TO and TS) were abnormal in 35%, 50%, 30%, and 25% of all patients, respectively. Patients with at least one relatively preserved HRT parameter (TO, TS, or TT) (n = 98) had 5-year event-free rate of 83% compared to 33% of those in whom all three parameters were abnormal (n = 12). In multivariate Cox regression analysis, the most powerful predictor of end point events was heart rate variability (SDNN < 70 ms, hazard ratio (HR) 9.41, P < 0.001), followed by LVEF , 35% (HR 6.23), TT , 10 (HR 3.14), and TO , 0 (HR 2.54, P < 0.05). Conclusion: In patients with CHF on optimal pharmacotherapy, HRT can help to predict those at risk for progression toward OHT or death of all causes. Ann Noninvasive Electrocardiol 2010;15(3):230,237 [source] The intrinsic transit time of free microvascular flaps: Clinical and prognostic implicationsMICROSURGERY, Issue 2 2010Charlotte Holm M.D., Ph.D. Background: Microscope-integrated indocyanine green near-infrared videoangiography (ICGA) is a new method for the intraoperative assessment of vascular flow through microvascular anastomoses. The intrinsic transit time (ITT) describes the time period from the dye appears at the arterial anastomosis (t1) till it reaches the suture line of the venous anastomosis (t2). As the transit time reflects blood flow velocity within the flap, prolonged ITT might correlate with low blood flow and a higher rate of postoperative thrombosis. We performed a clinical trial evaluating the association between intraoperative free flap transit time and early anastomotic complications in elective microsurgery. Methods: One hundred consecutive patients undergoing elective microsurgical procedures underwent intraoperative ICG angiography (ICGA). In patients with anastomotic patency, angiograms were retrospectively reviewed and the intrinsic transit time was calculated. Postoperative outcome was registered and compared with the ITT. End points included early reexploration surgery and flap loss within the first 24 hours after surgery. Results: Fourteen patients were excluded from the study due to technical anastomotic failure. The overall flap failure rate was 6% (5/86); the incidence of early re-exploration surgery was 10% (9/86). With a median of 31 seconds patients with an uneventful postoperative course showed significantly shorter ITTs than patients with flap loss or early postoperative reexploration (median: >120 seconds). An optimal cut-off value of ITT > 50 seconds was determined to be strongestly associated with a significantly increased risk of at least one positive end point. Conclusions: This study demonstrates a significant predictive value of the intrinsic flap transit time for the development of flap compromise and early re-exploration surgery. © 2009 Wiley-Liss, Inc. Microsurgery, 2010. [source] A small dose of droperidol decreases postoperative nausea and vomiting in adults but cannot improve an already excellent patient satisfactionACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 4 2001A. Hechler Background: We evaluated whether or not 1) a routine prophylaxis with 20 ,g ,· ,kg,1 body weight of droperidol would efficiently prevent postoperative nausea and vomiting (PONV) after elective surgery in adults and 2) an efficient prophylaxis would improve patient satisfaction. Methods: With approval of the local ethics committe and after having obtained informed written consent, 1334 patients in a randomised, single-blinded fashion either received droperidol (group 1, n=665) or saline intravenously (group 2, n=669) 20 min before the end of a standard O2/N2O/fentanyl/isoflurane anaesthesia of at least 30 min duration. End points: incidence of PONV during the first 24 h; individual episodes of nausea or vomiting, overall patient satisfaction with the procedure. Results: Compared to saline, intravenous injection of droperidol substantially and significantly reduced the incidence of PONV from 30% to 20% (P<0.0001). Women suffered three times more frequently from PONV (10.5% vs. 30%, P<0.0001). Droperidol significantly reduced the incidence of PONV from 35.4% to 24.4% in women (relative risk reduction: 31%, P=0.0002), but not in men (13.1% vs. 8.2%, relative risk reduction: 37%, P=0.159) , without impact on overall patient satisfaction (98.8% vs. 97.1%, P=0.439). Distribution of surgical procedures, sex, age, height, weight and anaesthetic duration were not different between groups. To prevent one woman from suffering PONV, nine had to be treated prophylactically at an individual drug cost (German prices) of about 0.80 per woman. Conclusion: Routine PONV prophylaxis with 20 ,g ,· ,kg,1 body weight of droperidol is cost-efficient and appropriate in women but not in men. [source] Phase II study of bryostatin 1 and vincristine for aggressive non-Hodgkin lymphoma relapsing after an autologous stem cell transplant,AMERICAN JOURNAL OF HEMATOLOGY, Issue 8 2009Paul M. Barr Bryostatin 1, isolated from a marine bryozoan, enhances the efficacy of cytotoxic agents through modulation of the protein kinase C pathway and is active in combination with vincristine for diffuse large B-cell lymphoma. Further, the apoptotic frequency of peripheral blood T lymphocytes as determined by flow cytometry may predict which patients will respond to this combination. We tested the efficacy and safety of bryostatin 1 50 ,g/m2 given over 24 hr and vincristine 1.4 mg/m2 on days 1 and 15 every 28 days in aggressive B-cell non-Hodgkin lymphoma (NHL) relapsing after autologous stem cell transplantation. End points included tumor response, toxicity, and survival. Responses were correlated with an increase in apoptotic frequency of CD5+ cells by flow cytometry using annexin V staining. Fourteen patients were enrolled with 13 being evaluable for a response. The overall response rate was 31% with two patients achieving a complete response. The most common toxicities were Grade 3 lymphopenia (seven patients), Grade 3 to 4 neutropenia (two patients), and Grade 3 hypophosphatemia (two patients). Median progression-free and overall survivals for all patients were 5.7 and 21.4 months, respectively. One patient demonstrated an increase in T-cell apoptotic frequency, also achieving a complete response. Bryostatin 1 and vincristine have efficacy in select patients with aggressive NHL. Future investigations of agents targeting the protein kinase C pathway may benefit from early response assessment using flow cytometry to evaluate T-cell apoptosis. Am. J. Hematol., 2009. © 2009 Wiley-Liss, Inc. [source] Follow-Up Recommendations for Benign Breast BiopsiesTHE BREAST JOURNAL, Issue 5 2006Susanna Shin MD Abstract: Histologically proven benign breast disease increases a woman's relative risk for subsequent cancer development. Yet follow-up guidelines for mammogram and clinical breast examination after a benign breast biopsy are lacking. Our objective was to determine if increased surveillance is indicated following a benign breast biopsy. Following institutional review board approval, a retrospective database review was conducted of prospectively gathered patients who had a benign breast biopsy (core or excisional) for an abnormality detected on mammogram, ultrasound, or clinical breast examination. Follow-up, for all subjects, was a clinical breast examination and mammogram or ultrasound at 6 months, 1 year, and 2 years after benign breast biopsy by a breast surgeon. End points were the need for additional biopsies or cancer detection. Statistical analysis was performed using chi-squared analysis. From January 2000 to July 2003, 156 patients age 18,86 years had a benign breast biopsy. During the 2 year follow-up, 20 patients (13%) required a subsequent biopsy. No significant difference was observed in mean age, race, menarche, menopause, parity, age at first live birth, use of oral contraceptives, history of prior biopsy, or the pathology of the initial lesion between those who needed a subsequent biopsy and those who did not. Seven excisional biopsies were performed (one at 6 months, four at 1 year, and two at 2 years follow-up) for growth of the benign breast biopsy lesion, and pathology remained concordant with the original diagnosis. Thirteen biopsies were done for new findings on mammogram or ultrasound. Three of these (1.9%) yielded a cancer diagnosis (one at 6 months, one at 1 year, and one at 2 years follow-up). No new lesions were identified on follow-up by clinical breast examination alone. Increased surveillance following a benign breast biopsy is necessary because of the increased need for subsequent biopsy or risk of cancer development. This should include imaging (mammography or ultrasound) and a clinical breast examination 6 months, 1 year, and 2 years after a benign breast biopsy. [source] P53 and Ki-67 as Outcome Predictors for Advanced Squamous Cell Cancers of the Head and Neck Treated With Chemoradiotherapy,THE LARYNGOSCOPE, Issue 11 2001Pierre Lavertu MD Abstract Hypothesis P53 and Ki-67 status will predict response to treatment, organ preservation, and survival in patients with advanced squamous cell cancers of the head and neck treated with chemoradiotherapy (CRT). Study Design Retrospective analysis of p53 and Ki-67 status from the CRT arm of a randomized, controlled trial (n = 50) and from patients receiving the same treatment but not enrolled in the trial (n = 55). Methods P53 and Ki-67 status were established from archived tissue samples using immunohistochemical (IHC) staining. Tumors were positive for p53 (p53+) when more than 2% of cells stained for p53 and were positive for Ki-67 (Ki-67+) when any cell stained for Ki-67. End points were tumor response, tumor recurrence, survival status, and organ preservation at last follow-up, and time to events. Predictive models were calculated for each outcome. Results Neither marker predicted tumor response to treatment. P53+ status was associated with tumor recurrence (P = .003) and locoregional recurrence (P = .003). Adjusting for time to event, p53+ status was significantly related to a lower recurrence-free survival (P = .004), lower disease-specific survival (P = .04), lower overall survival with primary site preservation (P = .03), and lower disease-specific survival with primary site preservation (P = .003). Multivariate analysis revealed that p53+ status was significantly related to a lower recurrence-free survival (P = .01, risk ratio [RR] = 3.65) and lower disease-specific survival with organ preservation (P = .02, RR = 3.41). Ki-67+ status was not related to any variables. However, multivariate analysis revealed that Ki-67+ was significantly related to a lower overall survival (P = .05, RR = 2.03). The combination of both markers negative (p53-/Ki-67-) was associated with a lower incidence of tumor recurrence (P = .02), lower locoregional recurrence (P = .01), and fewer second primary lesions (P = .04). Adjusting for time to event, p53-/Ki-67- status was significantly related to a higher recurrence-free survival (P = .02), higher disease-specific survival with primary site preservation (P = .02), and higher overall survival with primary site preservation (P = .02). Multivariate analysis revealed that p53-/Ki-67- status was significantly related to a higher overall survival with site preservation (P = .01, RR = 2.78). Conclusions P53 and Ki-67 status appear to be related to the various survival end points considered in this study. However, this relation does not seem to be sufficient to warrant treatment modifications. Closer follow-up may be justified in both p53+ and Ki67+ patients to detect recurrence or a second primary at an earlier stage, possibly improving survival. [source] LY2439821, a humanized anti,interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: A phase I randomized, double-blind, placebo-controlled, proof-of-concept studyARTHRITIS & RHEUMATISM, Issue 4 2010M. C. Genovese Objective We undertook this study to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of LY2439821, a humanized anti,interleukin-17 (anti,IL-17) monoclonal antibody, in a first in-human trial in rheumatoid arthritis (RA) patients taking oral disease-modifying antirheumatic drugs (DMARDs). Methods This randomized, double-blind, placebo-controlled study consisted of 2 parts. In part A, 20 patients received 1 intravenous (IV) dose of LY2439821 (0.06, 0.2, 0.6, or 2.0 mg/kg, escalating) or placebo followed by 8 weeks of evaluation. End points included safety, tolerability, and pharmacokinetics. In part B, 77 patients received 1 IV dose of LY2439821 (0.2, 0.6, or 2.0 mg/kg) or placebo every 2 weeks for a total of 5 doses, with a total evaluation period of 16 weeks. End points included safety, tolerability, pharmacokinetics/pharmacodynamics, and efficacy (Disease Activity Score in 28 joints [DAS28] and percentages of patients meeting American College of Rheumatology 20%, 50%, or 70% improvement criteria [achieving an ACR20, ACR50, or ACR70 response]). The primary efficacy end point was the DAS28 at week 10. Results Baseline characteristics were similar across all groups. Changes in the DAS28 were significantly greater in the 0.2 mg/kg, 2.0 mg/kg, and all-LY2439821,combined groups (,2.3, ,2.4, and ,2.3, respectively) than in the placebo group (,1.7) at week 10 (P , 0.05), and these differences were significant as early as week 1. Percentages of ACR20, ACR50, and ACR70 responses as well as improvements in the ACR core set of measures were greater in LY2439821-treated patients than in placebo-treated patients at multiple time points. There was no apparent dose-response relationship in treatment-emergent adverse events. Conclusion LY2439821 added to oral DMARDs improved signs and symptoms of RA, with no strong adverse safety signal noted. This first evaluation of LY2439821 supports neutralization of IL-17 as a potential novel goal for the treatment of RA. [source] MQX-503, a novel formulation of nitroglycerin, improves the severity of Raynaud's phenomenon: A randomized, controlled trial,ARTHRITIS & RHEUMATISM, Issue 3 2009Lorinda Chung Objective Raynaud's phenomenon (RP) affects 3,9% of the general population and >90% of patients with systemic sclerosis. Nitrates are often prescribed for the treatment of RP, but currently available formulations are limited by side effects, particularly headaches, dizziness, and skin irritation. The purpose of this study was to evaluate the tolerability and efficacy of a novel formulation of topical nitroglycerin, MQX-503, in the treatment of RP in an ambulatory setting. Methods We conducted a multicenter, randomized, placebo-controlled study with a 2-week single-blind run-in period to determine baseline severity, followed by a 4-week double-blind treatment phase. Two hundred nineteen adult patients with a clinical diagnosis of primary or secondary RP received 0.9% MQX-503 gel or matching placebo during the treatment period. Gel was applied immediately before or within 5 minutes of the beginning of an episode of RP (maximum of 4 applications daily). End points included the change in the mean Raynaud's Condition Score (RCS; scale 0,10), the frequency and duration of episodes, and subjective assessments at the target week (the week during the treatment phase that most closely matched the run-in period in terms of ambient temperature) compared with baseline. Results The mean (%) change in the RCS at the target week compared with baseline was significantly greater in the MQX-503 group (0.48 [14.3%]) than that in the placebo group (0.04 [1.3%]; P = 0.04). Changes in the frequency and duration of RP episodes and subjective assessments were not statistically different between the groups. MQX-503 had a side effect profile similar to that of placebo. Conclusion MQX-503 is well tolerated and more effective than placebo for the treatment of RP. [source] Transcatheter versus Surgical Closure of Secundum Atrial Septal Defect in Adults: Impact of Age at Intervention.CONGENITAL HEART DISEASE, Issue 3 2007A Concurrent Matched Comparative Study Abstract Objectives., To compare the short- and mid-term outcomes of surgical (SUR) vs. transcatheter closure of secundum atrial septal defect (ASD) using Amplatzer septal occluder (ASO) in adults with a very similar spectrum of the disease; and to identify predictors for the primary end point. Design., Single-center, concurrent comparative study. Surgically treated patients were randomly matched (2:1) by age, sex, date of procedure, ASD size, and hemodynamic profile. Setting., Tertiary referral center. Patients., One hundred sixty-two concurrent patients with ASD submitted to ASO (n = 54) or SUR closure (n = 108) according with their preferences. Main Outcome Measures., Primary end point was a composite index of major events including failure of the procedure, important bleeding, critical arrhythmias, serious infections, embolism, or any major cardiovascular intervention-related complication. Predictors of these major events were investigated. Results., Atrial septal defects were successfully closed in all patients, and there was no mortality. The primary event rate was 13.2% in ASO vs. 25.0% in SUR (P = .001). Multivariate analysis showed that higher rate of events was significantly associated with age >40 years; systemic/pulmonary output ratio <2.1; and systolic pulmonary arterial pressure >50 mm Hg; while in the ASO group the event rate was only associated with the ASD size (>15 cm2/m2; relative risk = 1.75, 95% confidence interval 1.01,8.8). There were no differences in the event-free survival curves in adults with ages <40 years. Conclusions., The efficacy for closure ASD was similar in both groups. The higher morbidity observed in SUR group was observed only in the patients submitted to the procedure with age >40 years. The length of hospital stay was shorter in the ASO group. Surgical closure is a safe and effective treatment, especially in young adults. There is certainly nothing wrong with continuing to do surgery in countries where the resources are limited. [source] Treatment of Anemia With Darbepoetin Alfa in Heart FailureCONGESTIVE HEART FAILURE, Issue 3 2010William T. Abraham MD Anemia is common in heart failure (HF) patients. A prespecified pooled analysis of 2 randomized, double-blind, placebo-controlled studies evaluated darbepoetin alfa (DA) in 475 anemic patients with HF (hemoglobin [Hb], 9.0,12.5 g/dL). DA was administered subcutaneously every 2 weeks and titrated to achieve and maintain a target Hb level of 14.0±1.0 g/dL. By week 27, mean (SD) Hb concentrations did not increase with placebo but increased with DA from 11.5 (0.7) to 13.3 (1.3) g/dL. Hazard ratios (HRs) for DA compared with placebo for all-cause death or first HF hospitalization (composite end point), all-cause death, and HF hospitalization by month 12 were 0.67 (95% confidence interval [CI], 0.44,1.03; P=.067), 0.76 (95% CI, 0.39,1.48; P=.419), and 0.66 (95% CI, 0.40,1.07; P=.093), respectively. Incidence of adverse events was similar in both groups. In post hoc analyses, improvement in the composite end point was significantly associated with the mean Hb change from baseline (adjusted HR, 0.40; P=.017) with DA treatment. There was no increased risk of all-cause mortality or first HF hospitalization with DA in patients with reduced renal function or elevated baseline B-type natriuretic peptide, a biomarker of worse HF. These results suggest that DA is well tolerated, corrects HF-associated anemia, and may have favorable effects on clinical outcomes., Congest Heart Fail. 2010;16:87,95. © 2010 Wiley Periodicals, Inc. [source] Risk factors for relapse after remission with repetitive transcranial magnetic stimulation for the treatment of depressionDEPRESSION AND ANXIETY, Issue 7 2009Roni B. Cohen M.D. Abstract Background: Several studies have shown that repetitive transcranial magnetic stimulation (rTMS) treatment is associated with a significant antidepressant effect that can last for several months. Methods: To investigate the mean remission time and the predictors associated with its duration; we performed a large retrospective, naturalistic study with 204 patients who underwent treatment with rTMS. During the periods from 2000 to 2006, we identified and collected the data on 204 patients who underwent rTMS treatment for major depression and who remitted their depression (defined as Hamilton Depression Rating Scores less or equal to 7). Patients were followed up to 6 months after this therapy. Results: Event-free remission with the end point defined as relapse (Hamilton Depression Rating Scores higher than 8) was 75.3% (73.7) at 2 months, 60.0% (74.5) at 3 months, 42.7% (74.8) at 4 months, and 22.6% (74.5) at 6 months. According to a multivariate analysis, only the age and number of sessions were independent predictors of outcome. Although depression severity and use of tricyclics also showed a significant relationship with remission duration, the model including these variables was not adequate to explain our data. Conclusions: The results of this study suggest that young age and additional rTMS sessions are associated with a ong duration of rTMS effects and therefore future trials investigating the effects of maintenance rTMS treatment need to explore further the implication of these factors for depression remission. Depression and Anxiety, 2009. © 2009 Wiley-Liss, Inc. [source] A double-blind study of the efficacy of venlafaxine extended-release, paroxetine, and placebo in the treatment of panic disorderDEPRESSION AND ANXIETY, Issue 1 2007Mark H. Pollack M.D. Abstract To date, no large-scale, controlled trial comparing a serotonin,norepinephrine reuptake inhibitor and selective serotonin reuptake inhibitor with placebo for the treatment of panic disorder has been reported. This double-blind study compares the efficacy of venlafaxine extended-release (ER) and paroxetine with placebo. A total of 664 nondepressed adult outpatients who met DSM-IV criteria for panic disorder (with or without agoraphobia) were randomly assigned to 12 weeks of treatment with placebo or fixed-dose venlafaxine ER (75,mg/day or 150,mg/day), or paroxetine 40,mg/day. The primary measure was the percentage of patients free from full-symptom panic attacks, assessed with the Panic and Anticipatory Anxiety Scale (PAAS). Secondary measures included the Panic Disorder Severity Scale, Clinical Global Impressions,Severity (CGI-S) and ,Improvement (CGI-I) scales; response (CGI-I rating of very much improved or much improved), remission (CGI-S rating of not at all ill or borderline ill and no PAAS full-symptom panic attacks); and measures of depression, anxiety, phobic fear and avoidance, anticipatory anxiety, functioning, and quality of life. Intent-to-treat, last observation carried forward analysis showed that mean improvement on most measures was greater with venlafaxine ER or paroxetine than with placebo. No significant differences were observed between active treatment groups. Panic-free rates at end point with active treatment ranged from 54% to 61%, compared with 35% for placebo. Approximately 75% of patients given active treatment were responders, and nearly 45% achieved remission. The placebo response rate was slightly above 55%, with remission near 25%. Adverse events were mild or moderate and similar between active treatment groups. Venlafaxine ER and paroxetine were effective and well tolerated in the treatment of panic disorder. Depression and Anxiety 24:1,14, 2007. © 2006 Wiley-Liss, Inc. [source] Results of a Survey of 5,700 Patient Monopolar Radiofrequency Facial Skin Tightening Treatments: Assessment of a Low-Energy Multiple-Pass Technique Leading to a Clinical End Point AlgorithmDERMATOLOGIC SURGERY, Issue 8 2007FRCP, FRCPC, JEFFREY S. DOVER MD INTRODUCTION Monopolar radiofrequency is an effective means of nonsurgical facial skin tightening. OBJECTIVE The objective of this study was to determine whether using larger tips at lower energy and multiple passes, using patient feedback on heat sensation and treating to a clinical end point of visible tightening, would yield better results than single passes with small tips at high energy, as measured by patient and physician satisfaction. METHODS Fourteen physicians from four specialties were surveyed to determine the answers to the following three questions. (1) Is patient's feedback on heat sensation a valid and preferred method for optimal energy selection? (2) Do multiple passes at moderate energy settings yield substantial and consistent efficacy? (3) Is treating to a clinical end point of visible tightening predictable of results? RESULTS A total of 5,700 patient treatments were surveyed. Comparisons were made using the original algorithm of high-energy, single pass to the new algorithm of lower energy and multiple passes with visible tightening as the end point of treatment. Using the original treatment algorithm, 26% of patients demonstrated immediate tightening, 54% observed skin tightening 6 months after treatment, 45% found the procedure too painful, and 68% of patients found the treatment results met their expectations. With the new multiple-pass algorithm, 87% observed immediate tightening, 92% had the tightening six months after treatment, 5% found the procedure too painful, while 94% found the treatment results met their expectations. CONCLUSIONS Patient feedback on heat sensation is a valid, preferable method for optimal energy selection in monopolar radiofrequency skin-tightening treatments. [source] Life-cycle exposure of fathead minnows (Pimephales promelas) to an ethinylestradiol concentration below 1 ng/L reduces egg fertilization success and demasculinizes malesENVIRONMENTAL TOXICOLOGY, Issue 2 2005Joanne L. Parrott Abstract Forty-eight hours after fertilization, fathead minnow (Pimephales promelas) eggs were exposed to the synthetic estrogen 17,-ethinylestradiol (EE2) at nominal concentrations of 0.32 and 0.96 ng/L and measured concentrations of 3.5, 9.6, and 23 ng/L. The fish were observed through the larval, juvenile, and adult stages. Growth, secondary sex characteristics, the liver somatic index, the gonadosomatic index, and fecundity were examined after several lengths of exposure. No significant changes were seen in fry or juvenile growth from 8 to 30 days posthatch (dph). An increase in the ovipositor index (a female secondary sex characteristic) was the most sensitive early response at 60 dph and was seen in fish exposed to EE2 concentrations , 3.5 ng/L. Continuation of the EE2 exposure until 150 dph, through maturation and reproduction, allowed measurement of two sensitive end points: decreased egg fertilization and sex ratio (skewed toward females), both of which were significantly affected at the lowest EE2 concentration tested, 0.32 ng/L. The next most sensitive end point was demasculinization (decreased male secondary sex characteristic index) of males exposed to an EE2 concentration of 0.96 ng/L. The effects of low concentrations of EE2 (0.32 and 0.96 ng/L) were manifested in male fish (decreased male sex characteristics and reduced egg fertilization success), whereas female fish showed no changes in the gonadosomatic index. Exposure to higher EE2 concentrations negatively affected females, as shown by a reduced gonadosomatic index at 150 dph in fish exposed to ,3.5 ng/L EE2. Although there were some end points that showed changes at 60 dph, the reproductive end points and external sex characteristics measured in mature fish at 150 dph were more sensitive, with response thresholds of EE2 ranging from 0.32 to 0.96 ng/L. The concentrations of EE2 that negatively affected fathead minnows were similar to or lower than those detected in many municipal wastewater effluents. In conclusion, life-cycle exposure of fathead minnows proved to be a very sensitive bioassay, and responses were seen at concentrations of less than 1 ng/L, which are environmentally relevant concentrations of EE2. © 2005 Government of Canada. Exclusive worldwide publication rights in the article have been transferred to John Wiley & Sons, Inc. Environ Toxicol 20: 131,141, 2005. [source] Response of the charophyte Nitellopsis obtusa to heavy metals at the cellular, cell membrane, and enzyme levelsENVIRONMENTAL TOXICOLOGY, Issue 3 2002Levonas Manusad, ianas Abstract The responses of the freshwater macroalga Nitellopsis obtusa to heavy metal (HM) salts of Hg, Cd, Co, Cu, Cr, and Ni were assessed at different levels: whole-cell mortality (96-h LC50), in vivo cell membrane (45-min depolarization of resting potential, EC50), and enzyme in plasma membrane preparations (K+, Mg2+ -specific H+ -ATPase inhibition, IC50). To measure ATPase activity, a novel procedure for isolation of plasma membrane,enriched vesicles from charophyte cells was developed. The short-term ATPase inhibition assay (IC50 from 6.0 × 10,7 to 4.6 × 10,4 M) was slightly more sensitive than the cell mortality test (LC50 from 1.1 × 10,6 to 2.6 × 10,3 M), and the electrophysiological test with the end point of 45-min depolarization of resting potential was characterized by less sensitivity for HMs (EC50 from 1.1 × 10,4 to 2.2 × 10,2 M). The variability of IC50 values assessed for HMs in the ATPase assays was close to that of LC50 values in the mortality tests (CVs from 33.5 to 83.5 and from 12.4% to 57.7%, respectively), whereas the EC50 values in the electrophysiological tests were characterized by CVs generally below 30%. All three end points identified two separate HM groups according to their toxicity to N. obtusa: Co, Ni, and Cr comprised a group of less toxic metals, whereas Hg, Cu, and Cd comprised a group of more toxic metals. However, the adverse effects within each group were discriminated differently. For example, the maximum difference between the highest and lowest LC50 for the group of less toxic metals in the long-term mortality test was approximately 60% of the response range, whereas the corresponding difference in IC50 values in the ATPase assay was 30%. In contrast, the LC50 values of the more toxic metals occupied only 10% of the response range, whereas the IC50 values were spread over 70%. Further investigation should be done of the underlying mechanism or mechanisms responsible for the observed differences in the dynamic range of a particular end point of the groups of toxicants of varying strength. © 2002 Wiley Periodicals, Inc. Environ Toxicol 17: 275,283, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/tox.10058 [source] Effects of the estrogen agonist 17,-estradiol and antagonist tamoxifen in a partial life-cycle assay with zebrafish (Danio rerio)ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 1 2007Leo T. M. van der Ven Abstract A partial life-cycle assay (PLC) with zebrafish (Danio rerio) was conducted to identify endocrine-disrupting effects of 17,-estradiol (E2) and tamoxifen (TMX) as reference for estrogen agonist and antagonist activity. Adult zebrafish were exposed for 21 d and offspring for another 42 d, allowing differentiation of gonads in control animals. The assessed end points included reproductive variables (egg production, fertilization, and hatching), gonad differentiation of juveniles, histopathology, and vitellogenin (VTG) expression. With E2, the most sensitive end points were feminization of offspring (at 0.1 nM) and increased VTG production in males (at 0.32 nM). At 1 nM, decreased F1 survival, increased F1 body length and weight, VTG-related edema and kidney lesions, and inhibited spermatogenesis were observed. Oocyte atresia occurred at even higher concentrations. Exposure to TMX resulted in specific effects at an intermediate test concentration (87 nM), including oocyte atresia with granulosa cell transformation and disturbed spermatogenesis (asynchrony within cysts). In F1, decreased hatching, survival, and body weight and length as well as decreased feminization were observed. Decreased vitellogenesis and egg production in females and clustering of Leydig cells in males occurred at higher concentrations. Toxicological profiles of estrogen agonists and antagonists are complex and specific; a valid and refined characterization of endocrine activity of field samples therefore can be obtained only by using a varied set of end points, including histology, as applied in the presented PLC. Evaluation of only a single end point can easily produce under- or overestimation of the actual hazard. [source] Generic Products of Antiepileptic Drugs (AEDs): Is It an Issue?EPILEPSIA, Issue 10 2007Meir Bialer Summary:, The availability of generic products of antiepileptic drugs (AEDs) has raised the following concerns: (1) Do generic AEDs work as well as brand AEDs in terms of their efficacy, safety and quality? (2) Can generic AEDs be used as substitutions for brand AEDs? and (3) Can generic products of AEDs be used interchangeably? The traditional average bioequivalence analysis addresses concern 1 but does not provide a complete adequate response to concerns 2 and 3. Drug interchangeability can be classified as drug prescribability or drug switchability. Drug prescribability refers to the situation where a patient is treated for the first time so that either a brand or a bioequivalent generic AED can be chosen. Drug switchability refers to the situation in which a brand AED is switched to a bioequivalent generic product of the same AED. The traditional average bioequivalence approach is sufficient to evaluate the prescribability of generic products, but does not ensure the switchability between prescribable formulations. The necessity of assuring switchability of two formulations can be addressed by individual bioequivalence. While the switch to generic AEDs is well tolerated by many patients and in general cost-effective, seizure control should not be sacrificed on the basis of cost alone, as the major end point in treating epilepsy with AEDs is seizure control without side effects. Until we have individual (within patient) bioequivalence data on generic AEDs and/or the tools to a priori identify the subset of patients susceptible to the generic switch, a switch of AED products in seizure-free patients is not recommended. [source] Eslicarbazepine Acetate: A Double-blind, Add-on, Placebo-controlled Exploratory Trial in Adult Patients with Partial-onset SeizuresEPILEPSIA, Issue 3 2007Christian Elger Summary:,Objective: To explore the efficacy and safety of eslicarbazepine acetate (BIA 2-093), a new antiepileptic drug, as adjunctive therapy in adult patients with partial epilepsy. Methods: A multicenter, double-blind, randomized, placebo-controlled study was conducted in 143 refractory patients aged 18,65 years with ,4 partial-onset seizures/month. The study consisted of a 12-week treatment period followed by a 1-week tapering off. Patients were randomly assigned to one of three groups: treatment with eslicarbazepine acetate once daily (QD, n = 50), twice daily (BID, n = 46), or placebo (PL, n = 47). The daily dose was titrated from 400 mg to 800 mg and to 1,200 mg at 4-week intervals. The proportion of responders (patients with a ,50% seizure reduction) was the primary end point. Results: The percentage of responders versus baseline showed a statistically significant difference between QD and PL groups (54% vs. 28%; 90% CI =,,, ,14; p = 0.008). The difference between the BID (41%) and PL did not reach statistical significance (90% CI =,,, ,1; p = 0.12). A significantly higher proportion of responders in weeks 5,8 was found in the QD group than in the BID group (58% vs. 33%, respectively, p = 0.022). At the end of the 12-week treatment, the number of seizure-free patients in the QD and BID groups was 24%, which was significantly different from the PL group. The incidence of adverse events was similar between the treatment groups and no drug-related serious adverse events occurred. Conclusion: Eslicarbazepine acetate was efficacious and well tolerated as an adjunctive therapy of refractory epileptic patients. [source] Pharmacodynamic Analysis of the Interaction between Tiagabine and Midazolam with an Allosteric Model That Incorporates Signal TransductionEPILEPSIA, Issue 3 2003Daniël M. Jonker Summary: ,Purpose: The objective of this study was to characterize quantitatively the pharmacodynamic interaction between midazolam (MDL), an allosteric modulator of the ,-aminobutyric acid subtype A (GABAA) receptor, and tiagabine (TGB), an inhibitor of synaptic GABA uptake. Methods: The in vivo concentration,response relation of TGB was determined through pharmacokinetic/pharmacodynamic (PK/PD) modeling. Rats received a single intravenous dose of 10 mg/kg TGB in the absence and the presence of a steady-state plasma concentration of MDL. The EEG response in the 11.5- to 30-Hz frequency band was used as the pharmacodynamic end point. Results: Infusion of MDL resulted in a mean steady-state plasma concentration of 66 ± 3 ng/ml. A significant pharmacokinetic interaction with TGB was observed. MDL inhibited TGB clearance by 20 ± 7 ml/min/kg from the original value of 89 ± 6 ml/min/kg. However, no changes in plasma protein binding of both drugs were observed. The concentration,EEG relation of TGB was described by the sigmoid- Emax model. The pharmacodynamic parameter estimates of TGB were: Emax = 327 ± 10 ,V, EC50 = 392 ± 20 ng/ml, and nH = 3.1 ± 0.3. These values were not significantly different in the presence of MDL. Factors that may explain the lack of synergism were identified by a mechanism-based interaction model that separates the receptor activation from the signal-transduction process. High efficiency of signal transduction and the presence of a baseline response were shown to diminish the degree of synergism. Conclusions: We conclude that the in vivo pharmacodynamic interaction between MDL and TGB is additive rather than synergistic. This strongly suggests that allosteric modulation of the antiseizure activity of a GAT-1 inhibitor by a benzodiazepine does not offer a therapeutic advantage. [source] Selection of Antiepileptic Drug Polytherapy Based on Mechanisms of Action: The Evidence ReviewedEPILEPSIA, Issue 11 2000Charles L. P. Deckers Summary: Purpose: When monotherapy with antiepileptic drugs (AEDs) fails, combination therapy is tried in an attempt to improve effectiveness by improving efficacy, tolerability, or both. We reviewed the available studies (both animal and human) on AED polytherapy to determine whether AEDs can be selected for combination therapy based on their mechanisms of action, and if so, which combinations are associated with increased effectiveness. Because various designs and methods of analysis were used in these studies, it was also necessary to evaluate the appropriateness of these approaches. Methods: Published papers reporting on AED polytherapy in animals or humans were identified by Medline search and by checking references cited in these papers. Results: Thirty-nine papers were identified reporting on two-drug AED combinations. Several combinations were reported to offer improved effectiveness, but no uniform approach was used in either animal or human studies for the evaluation of pharmacodynamic drug interactions; efficacy was often the only end point. Conclusions: There is evidence that AED polytherapy based on mechanisms of action may enhance effectiveness. In particular, combining a sodium channel blocker with a drug enhancing GABAergic inhibition appears to be advantageous. Combining two GABA mimetic drugs or combining an AMPA antagonist with an NMDA antagonist may enhance efficacy, but tolerability is sometimes reduced. Combining two sodium channel blockers seems less promising. However, given the incomplete knowledge of the pathophysiology of seizures and indeed of the exact mechanisms of action of AEDs, an empirical but rational approach for evaluating AED combinations is of fundamental importance. This would involve appropriate testing of all possible combinations in animal models and subsequent evaluation of advantageous combinations in clinical trials. Testing procedures in animals should include the isobologram method, and the concept of drug load should be the basis of studies in patients with epilepsy. [source] Permanganate Treatment of an Emplaced DNAPL SourceGROUND WATER MONITORING & REMEDIATION, Issue 4 2007Neil R. Thomson In situ chemical oxidation (ISCO) using permanganate is one of the few promising technologies that have recently appeared with the capability of aggressively removing mass from nonaqueous phase liquid (NAPL) source zones. While NAPL mass in regions of the treatment zone where delivery is dominated by advection can be removed rather quickly, the rate of mass removal from stagnant zones is diffusion controlled. This gives rise to partial mass removal and a concomitant reduction in the NAPL mass, downgradient ground water concentrations, and the dissolution rate associated with the source zone. Therefore, monitoring the performance of a permanganate ISCO treatment system is important to maintain the desired efficiency and to establish a treatment end point. In this paper, we illustrate the use of various monitoring approaches to assess the performance of a pilot-scale investigation that involved treatment of a multicomponent NAPL residual source zone with permanganate using a ground water recirculation system for 485 d. Ongoing treatment performance was assessed using permanganate and chloride concentration data obtained from extraction wells, 98 piezometers located approximately 1 m downgradient from the source, and ground water profiling. At the completion of treatment, 23 intact soil cores were extracted from the source zone and used to determine the remaining NAPL mass and manganese deposition. Based on the data collected, more than 99% of the initial NAPL mass was removed during treatment; however, remnant NAPL was sufficient to generate a small but measurable dissolved phase trichloroethene (TCE) and perchloroethene (PCE) plume. As a result of treatment, the ambient-gradient discharge rates were reduced by 99% for TCE and 89% for PCE relative to baseline conditions. The lack of complete source zone oxidation was presumed to be the result of dissolution fingers, which channeled the permanganate solution through the source zone preventing direct contact with the NAPL and giving rise to diffusion-limited mass removal. [source] Prediction of poor survival by cyclooxygenase-2 in patients with T4 nasopharyngeal cancer treated by radiation therapy: Clinical and in vitro studiesHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 6 2005Wen-Cheng Chen MD Abstract Background. This study was undertaken to determine the status of cyclooxygenase-2 (COX-2) in nasopharyngeal cancer (NPC) in Taiwanese patients and its relationship to survival after radiotherapy (RT). In addition, the effect of NS-398, a potent selective COX-2 inhibitor, was tested in vitro alone and in combination with radiation on NPC-BM1 human NPC cells as a prelude to using this drug along with RT in the treatment of patients with NPC. Methods. Thirty-seven patients diagnosed with T4N0,3M0 NPC were enrolled into this study. COX-2 expression was determined by immunohistochemical staining of formalin-fixed, paraffin-embedded tumor tissue. Patient survival was the clinical end point. The effects of COX-2 expression on cell survival and radioresistance was tested in vitro using the selective COX-2 inhibitor NS-398 in conjunction with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide (MTT) and clonogenic assays. Results. COX-2 immunoreactivity was detected in 62% of NPC tumors, and expression levels were high in 43%. Survival analysis showed the 5-year overall survival rates for patients who had high COX-2 expression was 27% compared with 60% for those with low/absent expression (p = .047). Pattern of failure analysis showed no significant difference between high and low COX-2 expression in locoregional failure (27% vs 25%, p = .91). However, patients with N0 to N1 disease and high COX-2 expression had a significantly higher incidence of distant metastasis compared with patients with stage N0 to N1 disease and low COX-2 expression (83% vs 15%, p = .004). This difference was not observed in patients with N2 to N3 disease. This difference contributed to worse survival of patients whose tumors had high COX-2 expression levels. The selective COX-2 inhibitor NS-398 was directly cytotoxic to NPC-BM1 cells in vitro, as judged in an MTT assay (viable cells decreased from 92% to 76%, 52%, and 22%, with increases of NS-398 from 20 to 40, 60, and 80 ,M, respectively). Radiation-induced cell death was also increased by treatment with NS-398. At a 10% survival level, 40 ,M NS-398 increased radiation cytotoxicity by a factor of 1.37, whereas 60 ,M increased it by a factor of 4.9. Conclusions. COX-2 overexpression is a predictor for poor survival for advanced stage NPC. In vitro, NS-398 radiosensitizes the NPC-BM1 cell line, providing a basis for testing the combination of COX-2 inhibitors with radiation in the treatment of patients with NPC. © 2005 Wiley Periodicals, Inc. Head Neck27: XXX,XXX, 2005 [source] Distant metastases after definitive radiotherapy for squamous cell carcinoma of the head and neckHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 8 2003Majid O. F. Al-Othman MD Abstract Purpose. To analyze parameters that influence the risk of distant metastases after definitive radiotherapy. Methods. Between 1983 and 1997, 873 patients were treated with definitive radiotherapy and had follow-up for 2 years or more. Univariate and multivariate analyses were performed to evaluate risk factors that might influence the risk of distant metastases. Results. The 5-year distant metastasis-free survival rate was 86%. Univariate analyses revealed that the risk of distant metastases was significantly influenced by gender (p = .0092), primary site (p = .0023), T stage (p < .0001), N stage (p < .0001), overall stage (p < .0001), level of nodal metastases in the neck (p < .0001), histologic differentiation (p = .0096), control above the clavicles (p < .0001), and time to locoregional recurrence (p < .0001). Multivariate analysis of freedom from distant metastases revealed that gender (p = .0390), T stage (p < .0001), N stage (p = .0060), nodal level (p < .0001), and locoregional control (p < .0001) significantly influenced this end point. Multivariate analysis revealed that gender (p = .0049), T stage (p < .0001), N stage (p < .0001), and locoregional control (p < .0001) significantly influenced cause-specific survival. Conclusions. The risk of distant metastases after definitive radiotherapy is 14% at 5 years and is significantly influenced by gender, T stage, N stage, nodal level, and locoregional control. © 2003 Wiley Periodicals, Inc. Head Neck 25: 629,633, 2003 [source] Early change in bilirubin levels is an important prognostic factor in severe alcoholic hepatitis treated with prednisoloneHEPATOLOGY, Issue 6 2003Philippe Mathurin M.D. Early identification of patients with severe (discriminant function ,32) biopsy-proven alcoholic hepatitis (AH) who are not responding to corticosteroids would be clinically relevant. Our goal was to develop simple criteria that will help physicians to promptly identify nonresponders to corticosteroids. A total of 238 patients were included. We used 6 months survival as an end point because of the rule requiring 6 months for listing alcoholic patients for transplantation. Overall survival at 1 and 6 months was 85% ± 2.3% and 64.3% ± 3.3%, respectively. An early change in bilirubin levels (ECBL) at 7 days (defined as bilirubin level at 7 days lower than bilirubin level on the first day of treatment) was observed in 73% of patients. At 7 days, in patients with ECBL, bilirubin decreased (84 ± 75 ,mol/L [4.94 ± 4.40 mg/dL]), whereas it increased in patients without ECBL (76.5 ± 77 ,mol/L [4.50 ± 4.54 mg/dL], P < .0001). Ninety-five percent of patients with ECBL continued to have improved liver function during treatment. At 6 months, survival of patients with ECBL was significantly higher than that of patients without ECBL, 82.8% ± 3.3% versus 23% ± 5.8%, P < .0001. On multivariate analysis, ECBL, discriminant function and creatinine were independent prognostic variables, and ECBL had the most important prognostic value. In conclusion, ECBL is a very simple predictive factor for identifying nonresponders. A recommendation to discontinue corticosteroids after 7 days in patients without ECBL, suggested by our results, awaits additional confirmation. [source] Varicocelectomy: semen parameters and protamine deficiencyINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 2 2009M. H. Nasr-Esfahani Summary Different methods have been used to evaluate the beneficial effect of varicocelectomy; these include semen parameters and pregnancy rate. Because of high biological variability of semen parameters, sperm functional tests have been considered as an efficient end point in assessment of fertility. Therefore, the aim of this study was to evaluate the effect of varicocelectomy on semen parameters and sperm protamine deficiency in 192 patients. The results of the present study show that all the three semen parameters and percentage of sperms with normal protamine content have improved post-surgery. The cumulative pregnancy rate was 34.6%. Comparing the results of the semen parameters and protamine content between patients whose partner became pregnant to those who did not benefit from varicocelectomy before and 6 months after surgery, show that patients may benefit from varicocelectomy that had higher initial semen density and better sperm morphology prior to surgery. Detailed analyses of sperm morphology, along with aforementioned results reveal that the factors which account for pregnancy difference are: (i) improvement in early events of spermatogenesis, possibly during spermatocytogensis and reduction division; and (ii) late spermiogenesis events. Thus, it can be suggested that patients with low initial sperm count may benefit more from assisted reproductive techniques or varicocelectomy followed by assisted reproduction. [source] Could interchangeable use of dry powder inhalers affect patients?INTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 2005D. Price Summary The aim of asthma treatment is optimal disease control. Poor asthma control results in considerable patient morbidity, as well as contributing to the considerable burden placed by the disease on healthcare budgets. There is a need for costs to be carefully scrutinised, with the switching of patients to inhaler devices with lower acquisition costs likely to be increasingly considered. However, before such practice becomes widespread, it is important to establish whether or not this could adversely impact on patients and the level of disease control. For approval to have been given, all marketed inhalers must have satisfied current regulatory requirements for devices. Full preclinical and clinical development programmes are not required when application is made for authorisation to market a new inhaler containing an existing chemical entity, although clinical equivalence testing must be used. Both beneficial and adverse effects should be tested, and the limits of equivalence must be clearly defined, based on therapeutic relevance. It should be noted that equivalence studies are invalid when the end point is not responding (i.e. at the top of the dose,response curve) and when equivalence limits approach or are equal to the magnitude of the drug effect. Approval on the basis of regulations designed to safeguard quality of dry powder inhalers does not mean that devices are interchangeable. When using an inhaler, there are many stages between the patient and the therapeutic effect, involving device design, pharmaceutical performance and patient behaviour. Regulations governing new devices cover only a few of the many factors affecting disease control. Furthermore, clinical trials to assess equivalence may not take into account factors in patient behaviour or variations in patient inhaler technique that may affect use of devices in real-life situations. When assessing the consequences of interchangeable use of dry powder inhalers on healthcare costs, it is important to ensure that the acquisition cost of the devices is not the only cost considered. Other costs that should be considered include the cost of time spent demonstrating to the patient how to use the new device, the cost of additional physician visits to address patient concerns and the management costs if disease control is adversely affected. [source] Inflammation-associated remodelling and fibrosis in the lung , a process and an end pointINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 2 2007William A.H. Wallace Summary Fibrosis by common usage in the pathological and clinical literature is the end result of a healing process and synonymous with scarring. We would argue that its use to describe a dynamic series of events which may be reversible is unhelpful and that the term ,lung remodelling' is a better description for this process as it reflects changes in tissue organization that may or may not progress to ,fibrosis' as a final fixed point. Resolution, through reversal of active lung remodelling, by therapeutic intervention is possible providing the alveolar architecture remains intact. If the lung architecture is lost then healing by permanent fibrosis with loss of organ function is inevitable. [source] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||