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Clinical Benefit (clinical + benefit)
Kinds of Clinical Benefit Selected AbstractsClinical Benefits of Early Triptan Therapy for MigraineHEADACHE, Issue 2002Julio Pascual MD Although triptans have been proven effective for acute treatment of migraine, reserving them for moderate or severe pain may produce suboptimal pain relief and higher rates of recurrence. Recent evidence indicates that early intervention at the onset of pain improves outcomes. Post hoc analysis of a long-term, open-label European study of almotriptan 12.5 mg found that the percentage of attacks rendered pain-free at 2 hours was significantly greater when patients treated mild pain (84%) than when the intervention occurred during moderate or severe pain (53%). A similar pattern emerged with respect to the consistency of pain relief, with a significant advantage for early intervention (88% versus 56%, respectively). A difference in favor of early intervention was also seen with respect to recurrence, need for rescue medication, and adverse events. The recurrence rate was significantly lower in patients treating mild pain (28%) than in those delaying treatment until the pain became moderate or severe (33%), which suggests that achieving pain freedom results in less recurrence. These results were generally replicated in post hoc analysis of a subgroup of patients from a randomized, placebo-controlled trial (the Spectrum Study) of oral sumatriptan 50 mg in migraineurs. This analysis demonstrated that with early intervention, pain was less likely to intensify, fewer attacks required redosing, more attacks remained pain-free 24 hours postdose, and normal function returned more quickly. In sum, early intervention with triptans can improve outcomes, avoiding much of the pain and disability associated with treating moderate or severe attacks. [source] Clinical benefit of interventions driven by therapeutic drug monitoringHIV MEDICINE, Issue 5 2005AL Rendón Background Adequate plasma concentrations of antiretroviral drugs are key to achieving and maintaining long-term suppression of HIV replication. Multiple factors may influence drug levels, causing increases or reductions that may, respectively, result in toxicity or virological failure. Therapeutic drug monitoring (TDM) might help to detect and correct such abnormalities. Objective To evaluate the usefulness of TDM in the care of HIV-infected patients in an out-patient clinical setting. Methods All the requests for TDM of protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) for patients attending our HIV out-patient clinic from October 2000 to August 2003 were analysed. Blood samples were collected before the morning dose. Drug concentrations were measured by high performance liquid chromatography by ultraviolet waves (HPLC-UV). Results A total of 151 requests from 137 patients were assessed. The reasons for requesting TDM were drug toxicity (59%), virological failure (39%) and possible drug interactions (2%). NNRTI levels were more often requested because of toxicity, while PI levels were more often requested because of virological failure. Elevated drug levels were confirmed in 36% of patients with suspected drug toxicity, while subtherapeutic levels were found in 37% of patients failing virologically. Based on the results of TDM, dose modifications were made in 37% of patients, allowing correction of such abnormalities in 80% of cases. Moreover, adequate plasma concentrations were confirmed in 79% of patients whose levels were assessed again. Conclusions Therapeutic drug monitoring may be a useful tool to identify toxic levels of NNRTI and subtherapeutic concentrations of PI. Dose adjustments following TDM may ameliorate drug-related toxicities or improve virological response rates. [source] B-cell activation influences T-cell polarization and outcome of anti-CD20 B-cell depletion in central nervous system autoimmunity,ANNALS OF NEUROLOGY, Issue 3 2010Martin S. Weber MD Objective Clinical studies indicate that anti-CD20 B-cell depletion may be an effective multiple sclerosis (MS) therapy. We investigated mechanisms of anti-CD20-mediated immune modulation using 2 paradigms of experimental autoimmune encephalomyelitis (EAE). Methods Murine EAE was induced by recombinant myelin oligodendrocyte glycoprotein (rMOG), a model in which B cells are considered to contribute pathogenically, or MOG peptide (p)35-55, which does not require B cells. Results In EAE induced by rMOG, B cells became activated and, when serving as antigen-presenting cells (APCs), promoted differentiation of proinflammatory MOG-specific Th1 and Th17 cells. B-cell depletion prevented or reversed established rMOG-induced EAE, which was associated with less central nervous system (CNS) inflammation, elimination of meningeal B cells, and reduction of MOG-specific Th1 and Th17 cells. In contrast, in MOG p35-55-induced EAE, B cells did not become activated or efficiently polarize proinflammatory MOG-specific T cells, similar to naive B cells. In this setting, anti-CD20 treatment exacerbated EAE, and did not impede development of Th1 or Th17 cells. Irrespective of the EAE model used, B-cell depletion reduced the frequency of CD4+CD25+Foxp3+ regulatory T cells (Treg), and increased the proinflammatory polarizing capacity of remaining myeloid APCs. Interpretation Our study highlights distinct roles for B cells in CNS autoimmunity. Clinical benefit from anti-CD20 treatment may relate to inhibition of proinflammatory B cell APC function. In certain clinical settings, however, elimination of unactivated B cells, which participate in regulation of T cells and other APC, may be undesirable. Differences in immune responses to MOG protein and peptide may be important considerations when choosing an EAE model for testing novel B cell-targeting agents for MS. ANN NEUROL 2010 [source] Clinical benefit of joint distraction in the treatment of severe osteoarthritis of the ankle: Proof of concept in an open prospective study and in a randomized controlled studyARTHRITIS & RHEUMATISM, Issue 11 2002Anne C. A. Marijnissen Objective Osteoarthritis (OA) is a degenerative, disabling joint disease that affects >10% of the adult population. No effective disease-modifying treatment is available. In the present study, we used joint distraction, a relatively new treatment in which mechanical contact between the articular surfaces is avoided while intraarticular intermittent fluid pressure is maintained, to treat patients with severe OA of the ankle. Methods Patients with severe ankle OA (n = 57) who were being considered for joint fusion (arthrodesis) were treated with joint distraction in an open prospective study. In addition, a randomized trial was performed in 17 patients to determine whether joint distraction had a better outcome than debridement. A standardized evaluation protocol (physical examination, assessment of pain, mobility, and functional ability) was used, and changes in radiographic joint space width and subchondral sclerosis were measured. Thirty-eight patients in the open study have been followed up for >1 year, with up to 5 years of followup in 7 of them (mean ± SD followup 2.8 ± 0.3 years). Patients in the randomized study have been followed up for 1 year. Results Significant clinical benefit was found in three-fourths of the 57 patients in the open prospective study. Most interestingly, the improvement increased over time. Radiographic evaluation showed increased joint space width and decreased subchondral sclerosis. Moreover, joint distraction showed significantly better results than debridement. Conclusion The clinical benefit of joint distraction in the treatment of severe OA is proof of the concept. Although the followup remains relatively short and effects over time remain unpredictable, our study creates possibilities for the treatment of severe OA in general. Considering the high prevalence of OA and the lack of a cure for it, joint distraction as a treatment of severe OA may have great medical, social, and economic impact. [source] Non-identical monozygotic twins, intermediate twin types, zygosity testing, and the non-random nature of monozygotic twinning: A review,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 2 2009Geoffrey Machin Abstract Monozygotic twins (MZ) are rarely absolutely "identical." This review discusses the types of genetic/epigenetic and prenatal environmental post-zygotic mechanisms that cause discordance within such twin pairs. Some of these mechanisms,ranging from heterokaryotypia to skewed X-chromosome inactivation,may cause extreme discordance, but these extremes are merely the more emphatic examples of discordance that, to some degree, underlies the majority of MZ twin pairs. Because of the entrenched misconception that MZ twins are necessarily identical, many MZ twin pairs are mistakenly designated as dizygotic (DZ). Clinical benefits to accurate zygosity determination include correct solid organ transplantation matching, if one twin requires donation for a non-genetically mediated disease; the opportunity of preventive management for disorders that do not manifest synchronously; and better counseling to parents regarding their individually unique, and often psychologically puzzling, twin offspring. In twin pairs with complex and confusing biological origins, more detailed zygosity testing may be required. For example, intermediate trigametic and tetragametic chimeric dizygotic twins are reviewed, some of whom are, nevertheless, monochorionic (MC). Because of inter-fetal vascular anastomoses in MC twins, genetic results from blood samples may not accurately reflect discordance in solid organs. Previously, it was thought that MZ twinning was some sort of embryological fluke. However, familial monozygotic twinning is more common than suggested by the literature. Seven new families are presented in an accompanying paper. Despite the difficulties and dangers of twin pregnancy (especially so for MC twins), human twinning persists, and continues to both challenge and fascinate parents, clinicians and geneticists. © 2009 Wiley-Liss, Inc. [source] Do the old psychostimulant drugs have a role in managing treatment-resistant depression?ACTA PSYCHIATRICA SCANDINAVICA, Issue 4 2010G. Parker Parker G, Brotchie H. Do the old psychostimulant drugs have a role in managing treatment-resistant depression? Objective:, As the authors have observed clinical benefit from the psychostimulants methylphenidate and dexamphetamine for treating resistant melancholic and bipolar depression, those drugs were evaluated in a consecutively recruited sample of 50 such patients. Method:, Patients (27 bipolar, 23 unipolar) received either methylphenidate (n = 44) or dexamphetamine (n = 6), with 30 having it prescribed as an augmenting drug and 20 as monotherapy. At the final review, ranging from 6 weeks to 62 months (mean 57 weeks), 52% were still receiving their psychostimulant. Results:, Thirty-four per cent reported the psychostimulant as distinctly improving their depression, 30% reported some level of improvement and 36% reported no improvement and/or side-effects. For improvers, the modal dose of methylphenidate was 20 mg. Significant side-effects were reported by 18% (including one manic response), switching was rare and limited to the bipolar subjects, and most side-effects were minor. Any positive response occurred rapidly and loss of efficacy was rare. Testing of tricyclic levels in some patients suggested that stimulant drugs may raise tricyclic levels in those who are rapid metabolizers. Conclusion:, Although this study was not controlled, the high success rate in a diagnostically refined sample implies that the psychostimulants may be efficacious for patients with melancholic and bipolar depression who have failed to respond to orthodox antidepressant drugs. [source] Psychotherapy for depression among children and adolescents: a systematic reviewACTA PSYCHIATRICA SCANDINAVICA, Issue 2 2007N. Watanabe Objective:, To examine the clinical benefit, the harm and the cost-effectiveness of psychotherapies in comparison with no treatment, waiting-list controls, attention-placebos, and treatment as usual in depressed youths. Method:, Meta-analyses were undertaken by using data from all relevant randomized-controlled trials identified by a comprehensive literature search. The primary outcome was relative risk (RR) of response. Results:, We identified 27 studies containing 35 comparisons and 1744 participants. At post-treatment, psychotherapy was significantly superior (RR = 1.39, 95% CI 1.18,1.65, P = 0.0001, number-needed to treat 4.3). There was an evidence of the existence of small study effects, including a publication bias (P < 0.001). The superiority of psychotherapy was no longer statistically significant (1.18 [0.94,1.47], P = 0.15) at 6-month follow-up. None of the studies reported adverse effects or cost-effectiveness outcomes. Conclusion:, Although the findings were biased by some small positive trials, psychotherapies appear to help depressed youths for the short term, but are no longer significantly favourable at 6-month follow-up. [source] A study comparing tolerability, satisfaction and acceptance of three different techniques for esophageal endoscopy: sedated conventional, unsedated peroral ultra thin, and esophageal capsuleDISEASES OF THE ESOPHAGUS, Issue 5 2009G. Nakos SUMMARY Three methods of esophagoscopy are available until now: sedated conventional endoscopy, unsedated ultrathin endoscopy, and esophageal capsule endoscopy. The three methods carry comparable diagnostic accuracy and different complication rates. Although all of them have been found well accepted from patients, no comparative study comprising the three techniques has been published. The aim of this study was to compare the three methods of esophagoscopy regarding tolerability, satisfaction, and acceptance. Twenty patients with large esophageal varices and 10 with gastroesophageal reflux disease were prospectively included. All patients underwent consecutively sedated conventional endoscopy, unsedated ultrathin endoscopy, and esophageal capsule endoscopy. After each procedure, patients completed a seven-item questionnaire. The total positive attitude of patients toward all methods was high. However, statistical analysis revealed the following differences in favor of esophageal capsule endoscopy: (i) total positive attitude has been found higher (,2= 18.2, df = 2, P= 0.00), (ii) less patients felt pain (,2= 6.9, df = 2, P= 0.03) and discomfort (,2= 22.1, df = 2, P= 0.00), (iii) less patients experienced difficulty (,2= 13.7, df = 2, P= 0.01), and (iv) more patients were willing to undergo esophageal capsule endoscopy in the future (,2= 12.1, df = 2, P= 0.002). Esophageal capsule endoscopy was characterized by a more positive general attitude and caused less pain and discomfort. Sedated conventional endoscopy has been found more difficult. More patients would repeat esophageal capsule endoscopy in the future. Patients' total position for all three available techniques for esophageal endoscopy was excellent and renders the observed advantage of esophageal capsule endoscopy over both sedated conventional and unsedated ultrathin endoscopy a statistical finding without a real clinical benefit. [source] Monoclonal antibodies: a morphing landscape for therapeuticsDRUG DEVELOPMENT RESEARCH, Issue 10 2006Nicholas C. Nicolaides Abstract The concept of using antibodies as therapeutics to cure human diseases was postulated nearly 100 years ago by Paul Ehrlich and subsequently enabled by the discovery of hybridoma technology by Kohler and Milstein in 1975. While the use of monoclonal antibodies (mAbs) as drugs that can specifically target a disease-associated antigen is compelling, it has taken a quarter century for these molecules to be adopted as bona fide therapeutic agents. Despite their slow pursuit in drug development during the pioneering years, it is now estimated that there are nearly 500 mAb-based therapies in development. Major factors that have influenced the acceptance of monoclonal antibodies as therapeutics include their drug safety profiles, technological advancements for facilitating mAb discovery and development, and market success. Early on, it was demonstrated that antibodies could elicit clinical benefit by antagonizing a specific antigen without the common side effects that are prevalent with small chemical entities due to their nonspecific effects on homeostatic biochemical pathways. In addition, the significant technological advances that the biotechnology industry has established for developing and producing monoclonal antibodies at commercial scale in a more efficient and cost-effective manner has broadly enabled their use as therapeutics. However, despite the beneficial pharmacologic advantages and technological advances, it has been the sheer market success that monoclonal antibody products have achieved over the past few years that has propelled their vast pursuit by the biopharmaceutical industry in light of their value-creating potential. Here we provide an overview of the monoclonal antibody industry and discuss evolving technologies and strategies that are being pursued to overcome challenges in the changing marketplace. Drug Dev. Res. 67:781,789, 2006. © 2007 Wiley-Liss, Inc. [source] Equine laminitis: Ultrastructural lesions detected in ponies following hyperinsulinaemiaEQUINE VETERINARY JOURNAL, Issue 7 2009A. R. NOURIAN Summary Reasons for performing study: Anatomical changes in the hoof lamellar tissue induced by prolonged hyperinsulinaemia have not been described previously. Analysis of the induced lesions may promote understanding of hyperinsulinaemic laminitis pathogenesis and produce clinical benefit. Objectives: To use light and transmission electron microscopy (TEM) to document hoof lamellar lesions in ponies clinically lame after prolonged hyperinsulinaemia. Methods: Nine clinically normal, mature ponies were allocated randomly to either a treatment group (n = 5) or control group (n = 4). The treatment group received insulin via a modified, prolonged euglycaemic hyperinsulinaemic clamp technique (EHCT) and were subjected to euthanasia when clinical signs of Obel grade II laminitis occurred. The control group was sham treated with an equivalent volume of 0.9% saline and killed at 72 h. Lamellar tissues of the right front feet were harvested and processed for TEM. Results: Lamellae from insulin treated ponies were attenuated and elongated with many epidermal basal cells (EBC) in mitosis. Unlike carbohydrate induced laminitis in horses there was no global separation at the lamellar dermal/epidermal interface among ponies. Sporadic EBC basement membrane (BM) separation was associated with the proximity of infiltrating leucocytes. In 2 ponies, the lamellar BM was thickened. The number of hemidesmosomes/,m of BM was decreased in all insulin treated ponies. Conclusions: Prolonged hyperinsulinaemia causes unique lamellar lesions normally characteristic of acute and chronic laminitis. Lamellar proliferation may be an insulin effect through its mitogenic pathway. Aberrant lamellar mitosis may lengthen and weaken the lamellar, distal phalanx attachment apparatus and contribute to the clinical signs that developed. Potential relevance: The study shows that insulin alone, in higher than normal circulating concentrations, induces profound, changes in lamellar anatomy. Medical control of insulin resistance and hyperinsulinaemia may ameliorate lesions and produce clinical benefit. [source] The efficacy of dantrolene sodium in controlling exertional rhabdomyolysis in the Thoroughbred racehorseEQUINE VETERINARY JOURNAL, Issue 7 2003J. G. T. Edwards Summary Reasons for performing study: Dantrolene sodium (Dantrium) has been used extensively for the treatment of myopathies in man and anecdotal evidence suggests it is of clinical benefit in the control of exercise-induced rhabdomyolysis (ER) in racehorses, although data to support this are currently lacking. Objectives: To investigate the efficacy of oral dantrolene sodium in controlling ER in a randomised, double-blind, placebo-controlled crossover trial involving 77 Thoroughbred racehorses in Newmarket, UK. Methods: Horses were treated on 2 occasions 1 week apart, with treatment days coinciding with a return to exercise following 2 days box rest on each occasion. For the first treatment, each horse was randomly selected to receive either 800 mg dantrolene sodium or a colour- matched placebo administered orally 1 h before exercise. This was followed by crossover to the other treatment on the second occasion, with each horse thereby acting as its own control. Degree of ER was assessed using rising serum creatine kinase (CK) levels, by subtracting pre-exercise blood CK levels from those measured in 6 h post exercise blood samples. For each horse, the difference in change between pre- and post exercise CK values between placebo and dantrolene treatments was calculated, with positive values indicating a greater rise with placebo than with dantrolene sodium treatment. Results: The overall mean difference for all horses was +104.8 iu/l and the null hypothesis, that there was no true difference in non-normally distributed post exercise rises in CK values between placebo and dantrolene treatments, was rejected (P = 0.0013) using the nonparametric Wilcoxon signed rank test. Additionally, no horses given dantrolene sodium showed clinical signs of ER, whereas 3 horses given the placebo developed ER following exercise. The incidence of ER in the study was 4% (3/77). Conclusions: The results confirmed that oral administration of dantrolene sodium, 1 h before exercise, had a statistically significant effect on reducing the difference between pre - and post exercise plasma CK levels compared with a placebo in the same animals, and preventing clinical ER in susceptible individuals. Potential relevance: This study suggested that dantrolene sodium is of use in controlling ER in the Thoroughbred racehorse. Further investigation into pre- and post exercise myoplasmic calcium levels and the repeat of the study late in the season when horses receive a much higher energy ration and more strenuous exercise would appear to be warranted. [source] Mineral metabolism disturbances in patients with chronic kidney diseaseEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 8 2007B. Kestenbaum Abstract Background Kidney disease, especially chronic kidney disease (CKD), is a worldwide public health problem with serious adverse health consequences for affected individuals. Secondary hyperparathyroidism, a disorder characterized by elevated serum parathyroid hormone levels, and alteration of calcium and phosphorus homeostasis are common metabolic complications of CKD that may impact cardiovascular health. Materials and methods Here, we systematically review published reports from recent observational studies and clinical trials that examine markers of altered mineral metabolism and clinical outcomes in patients with CKD. Results Mineral metabolism disturbances begin early during the course of chronic kidney disease, and are associated with cardiovascular disease and mortality in observational studies. Vascular calcification is one plausible mechanism connecting renal-related mineral metabolism with cardiovascular risk. Individual therapies to correct mineral metabolism disturbances have been associated with clinical benefit in some observational studies; clinical trials directed at more comprehensive control of this problem are warranted. Conclusions There exists a potential to improve outcomes for patients with CKD through increased awareness of the Bone Metabolism and Disease guidelines set forth by the National Kidney Foundation,Kidney Disease Outcomes Quality Initiative. Future studies may include more aggressive therapy with a combination of agents that address vitamin D deficiency, parathyroid hormone and phosphorus excess, as well as novel agents that modulate circulating promoters and inhibitors of calcification. [source] Dual ETA/ETB vs. selective ETA endothelin receptor antagonism in patients with pulmonary hypertensionEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2006C. F. Opitz Abstract Since the identification of endothelin as a key mediator in the pathogenesis of several diseases, including pulmonary arterial hypertension (PAH), the pharmacologic control of the activated endothelin system with endothelin receptor antagonists (ETRA) has been a major therapeutic achievement for the treatment of patients with PAH. To date, dual ETA/ETB and selective ETA receptor antagonists have clinically been evaluated. To answer the question of whether selective or dual ETRA is preferable in patients with PAH, experimental and clinical data with relevance to the pulmonary circulation are reviewed in this article. Whereas experimental and clinical data provide unambiguous evidence that ETA receptors mediate the detrimental effects of ET-1, such as vasoconstriction and cell proliferation, the elucidation of the role of ETB receptors has been more complex. It has been shown that there is a subpopulation of ETB receptors on smooth muscle cells and fibroblasts mediating vasoconstriction and proliferation. On the contrary, there is clear evidence that endothelial ETB receptors continue to mediate vasodilation, vasoprotection and ET-1 clearance despite the pathology associated with pulmonary hypertension. More difficult to assess is the net effect of these mechanisms in patients to be treated with ETRA. When considering the available data from controlled clinical trials, nonselectivity does not appear to carry a relevant clinical benefit for the treatment of patients with PAH when compared with selective ETA receptor antagonism. [source] Back to the beginning , the quest for thymic epithelial stem cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2007Jeremy B. Swann Abstract Stem cell-based therapies hold much promise for the rejuvenation of aged or damaged tissues; however, before such cells can be used therapeutically, they must first be accurately identified. In this issue of the European Journal of Immunology it is reported that MTS24, a marker previously associated with progenitor cells of the thymic epithelium, fails to accurately identify epithelial cell populations with the ability to reconstitute a functional thymus. This finding demonstrates that much progress needs to be made before thymic epithelial stem cells can be harnessed for clinical benefit. See accompanying article: http://dx.doi.org/10.1002/eji.200737275 [source] Early versus delayed initiation of entacapone in levodopa-treated patients with Parkinson's disease: a long-term, retrospective analysisEUROPEAN JOURNAL OF NEUROLOGY, Issue 12 2009H. Nissinen Background:, We analysed data from three clinical trials in Parkinson's disease (PD) patients with wearing-off to determine whether early enhancement of levodopa therapy with entacapone can lead to better long-term outcomes than delayed entacapone treatment. Methods:,Post-hoc analysis of pooled data from three randomized, double-blind, placebo-controlled studies and their long-term, open-label extension phases. In all three studies, patients on levodopa/dopa-decarboxylase inhibitor (DDCI) were first randomized to entacapone (,early-start' group) or placebo (,delayed-start' group) for the initial 6-month double-blind phase, after which all patients received open-label levodopa/DDCI and entacapone treatment for up to 5 years. Results:, A total of 488 PD patients with wearing-off were included in the analysis. A statistically significant benefit of early initiation of levodopa/DDCI and entacapone was found, with an improvement in Unified Parkinson's Disease Rating Scale Part III (motor) score of ,1.66 (95% confidence intervals [,3.01, ,0.31]) points compared with the delayed-start treatment group (P < 0.05). Levodopa/DDCI and entacapone therapy was well tolerated. There was no excess of dyskinesia in the early-start group. Conclusions:, These data suggest that early rather than delayed addition of entacapone to levodopa/DDCI in PD patients with wearing-off provides a modest clinical benefit over levodopa/DDCI that is maintained for up to 5 years. [source] Outcome predictors, efficacy and safety of Botox and Dysport in the long-term treatment of hemifacial spasmEUROPEAN JOURNAL OF NEUROLOGY, Issue 3 2009A. R. Bentivoglio Background and purpose:, To review the clinical characteristics and the long-term outcome of patients with hemifacial spasm (HFS) who received botulinum neurotoxin (BoNT) over the past 10 years. Results:, A total of 108 patients received 665 treatments. Mean latency of clinical effect was 5.4 ± 5.3 days for Botox and 4.9 ± 4.6 days for Dysport (P > 0.05). Mean duration of clinical improvement was higher after the injection of Dysport than Botox: 105.9 ± 54.2 and 85.4 ± 41.6 days respectively (P < 0.01). The percentage of treatment failures was 6.5% for Botox and 4.6% for Dysport (P > 0.05). The doses of Botox significantly increased over time (, = 0.35, P < 0. 001) whilst Dysport dose remained unchanged (, = 0.16, n.s.). The duration of clinical benefit slightly increased with Botox (, = 0.12; P < 0.01), but remained constant for Dysport. Side effects occurred in 17.4% of treatments: 16.7% of patients who had received Botox, and in 19.7% who had received Dysport (P > 0.05). The most common side effects were palpebral ptosis and lacrimation; ptosis and lagophtalmos was more common in Dysport treatments (P < 0.005). Conclusions:, Both brands are effective and safe in treating HFS; efficacy is long-lasting. The differences in outcome and side effects confirm that, albeit the active drug is the same, Botox and Dysport should be considered as two different drugs. [source] Prognostic factors for patients with acute myeloid leukaemia or high-risk myelodysplastic syndromes undergoing myeloablative or non-myeloablative allogeneic blood stem cell transplantationHEMATOLOGICAL ONCOLOGY, Issue 4 2007Thorsten Graef Abstract In this uni-centre retrospective study, we studied 120 adults with acute myeloid leukaemia (AML) (n,=,88) and myelodysplastic syndrome (MDS) (n,=,32) who received first allogeneic HSCT to determine prognostic factors which are correlated with the outcome after myeloablative (MA) or non-myeloablative (non-MA) allogeneic HSCT. The median age of our cohort was 44 years. Fifty-nine per cent of the patients were transplanted in complete remission (CR) and 41% were in relapse or refractory to induction or salvage therapy. A total of 97 patients received a MA regimen and 23 were treated with a non-MA regimen. The prognostic impact for several parameters was assessed by univariate and by multivariate analyses using the Cox regression model. Three-year probabilities of non-relapse mortality (34 vs. 54%; p,=,0.9) did not differ in the MA and non-MA groups, but differences were observed in the disease-free survival (DFS) (43 vs. 17%; p,=,0.1) and the relapse rate (RR) (29 vs. 62%; p,=,0.01). Independently from the regimen, in uni- and multivariate analysis, survival was best in those patients who were transplanted in CR and experienced cGvHD. Interestingly, outcome of patients with complex cytogenetic aberrations was identical to that of better prognostic subgroups. In this study, the clinical benefit of a lower toxicity regimen was offset by higher RR resulting in inferior results in the non-MA group, especially when no CR was achieved by prior induction or salvage therapy. Copyright © 2007 John Wiley & Sons, Ltd. [source] Evidence for prolonged clinical benefit from initial combination antiretroviral therapy: Delta extended follow-upHIV MEDICINE, Issue 3 2001Delta Coordinating Committee Background The findings from therapeutic trials in HIV infection with surrogate endpoints based on laboratory markers are only partially relevant for clinical decisions on treatment. Although the collection of clinical follow-up data from such a trial would be relatively straightforward, this rarely occurs. An important reason for this may be the perception that such data have little value because the number of participants remaining on their original allocated therapy has usually fallen substantially. Methods Delta was an international, multicentre trial in which 3207 HIV infected individuals were randomly allocated to treatment with zidovudine (ZDV) alone, ZDV combined with didanosine (ddI) or ZDV combined with zalcitabine (ddC). Although the trial closed in September 1995, information on vital status, AIDS events, treatment changes and CD4 counts was still collected every 12 months until at least March 1997. This has allowed analyses of the longer term clinical effect of treatment. Results The median follow-up to date of death or last known vital status was 43 months (10th percentile 18 months; 90th percentile 55 months). The proportion of participants remaining on their allocated treatment fell steadily over time; by 4 years after trial entry, 3% remained on ZDV, 20% on ZDV + ddI and 21% on ZDV + ddC. Changes mainly involved the stopping, addition or switching of a nucleoside reverse transcriptase inhibitor (NRTIs). There was little use of protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) before the third year of the trial. Between the third and fourth years, regimens included a drug from one of these classes for approximately 17% of person-time in all treatment groups. Relative to ZDV monotherapy, the beneficial effects of combination therapy on mortality and disease progression rates increased significantly with time since randomization. The maximum effects on mortality were observed between 2 and 3 years, with a 48% reduction for ZDV + ddI and a 26% reduction for ZDV + ddC. These rates were observed when the original allocated treatment was received 42% and 47% of the time in the ZDV + ddI and ZDV + ddC groups, respectively. The mean CD4 count remained significantly higher (approximately 50 cells/,L) in the combination therapy groups 4 years after randomization, suggesting a projection of a clinical benefit beyond this time point. Conclusions The sustained clinical effect of the initial allocation to combination therapy, particularly ZDV + ddI, was remarkable in light of the convergence of drug regimens actually received across the three treatment groups. Interpretation of this finding is not straightforward. One of the possible explanations is that the effectiveness of ddI and ddC is diminished if first used later in infection or with greater prior exposure to ZDV, although the data do not clearly support either hypothesis. This analysis highlights the value of long-term clinical follow-up of therapeutic trials in HIV infection, which should be considered in the planning of all new studies. [source] The case against preoperative biliary drainage with pancreatic resectionHPB, Issue 6 2006Rurik C. Johnson The majority of patients with periampullary malignancies currently undergo biliary drainage before pancreaticoduodenectomy. Placement of an endoprosthesis reliably ameliorates jaundice and pruritus. However, preoperative biliary drainage leads to bile colonization and increases the risk of postoperative wound infection after pancreatic resection. Preoperative biliary drainage does not appear to lower postoperative morbidity or mortality following pancreatic resection and does not lower but probably increases costs associated with pancreatic resection. Preoperative biliary drainage is frequently used with little clinical benefit and its utilization should be limited to specific clinical indications, i.e. patients receiving neoadjuvant therapy, patients waiting several weeks or more for surgical evaluation and resection, patients with cholangitis. [source] Efficacy of methotrexate in ulcerative colitis: Failure or promiseINFLAMMATORY BOWEL DISEASES, Issue 8 2010Hans H. Herfarth MD Abstract Background: Low-dose methotrexate is a widely used and efficacious therapy in chronic inflammatory disorders such as psoriasis and rheumatoid arthritis. Prospective randomized controlled trials have demonstrated the efficacy of parenteral methotrexate in Crohn's disease (CD). We performed a systematic review of the efficacy of methotrexate in ulcerative colitis (UC) and discuss the results in the context of the known pharmacokinetics and adverse events of methotrexate therapy in inflammatory bowel diseases and other inflammatory conditions. Materials and Methods: We performed a systematic review of the literature in Medline, Embase, and Web of Science. All publications describing patients with UC treated with methotrexate were included. Results: We identified 12 studies or retrospective case series and 5 meeting abstracts that met the inclusion criteria. Only 1 study reported a prospective randomized placebo-controlled trial using methotrexate at a dose of 12.5 mg orally with no significant clinical benefit. However, the majority of uncontrolled retrospective analyses suggest a clinical response to methotrexate therapy in a range of 30%,80% when the drug is applied by parenteral route in doses between 20,25 mg. Conclusions: The only randomized controlled trial of methotrexate in UC employed oral dosing and doses lower than those shown to be effective in CD and did not demonstrate efficacy, whereas uncontrolled, retrospective studies using doses and routes of administration similar to those employed in CD suggest benefit. Well-designed, prospective, placebo-controlled trials of methotrexate in UC are needed. Inflamm Bowel Dis 2010 [source] Infliximab in the treatment of severe, steroid-refractory ulcerative colitis: A pilot studyINFLAMMATORY BOWEL DISEASES, Issue 2 2001Dr. Bruce E. Sands Abstract We report the experience of 11 patients (of 60 planned patients) enrolled in a double-blind, placebo-controlled clinical trial of infliximab in patients with severe, active steroid-refractory ulcerative colitis. The study was terminated prematurely because of slow enrollment. Patients having active disease for at least 2 weeks and receiving at least 5 days of intravenous corticosteroids were eligible to receive a single intravenous infusion of infliximab at 5, 10, or 20 mg/kg body weight. The primary endpoint used in this study was treatment failure at 2 weeks after infusion. Treatment failure was defined as 1) unachieved clinical response as defined by a modified Truelove and Witts severity score, 2) increase in corticosteroid dosage, 3) addition of immunosuppressants, 4) colectomy, or 5) death. Safety evaluations included physical examination, clinical chemistry and hematology laboratory tests, and occurrence of adverse experiences. Four of 8 patients (50%) who received infliximab were considered treatment successes at 2 weeks, compared with none of 3 patients who received placebo. Improvement in erythrocyte sedimentation rates and serum concentrations of C-reactive protein and interleukin-6 correlated with the clinical response observed in patients receiving infliximab. Infusion with infliximab produced no significant adverse events. Infliximab was well tolerated and may provide clinical benefit for some patients with steroid-refractory ulcerative colitis. [source] Increased antitumor potential of the raloxifene prodrug, raloxifene diphosphateINTERNATIONAL JOURNAL OF CANCER, Issue 9 2008Yoshinori Okamoto Abstract Raloxifene (RAL) significantly reduced the incidence of breast cancer in women at high risk of developing the disease. Unlike tamoxifen (TAM), an increased incidence of endometrial cancer was not observed in women treated with RAL. However, RAL, having two hydroxyl moieties, can be conjugated rapidly through phase II metabolism and excreted, making it difficult to achieve adequate bioavailability by oral administration in humans. As a result, higher doses must be administered to obtain an efficacy equivalent to that achieved with TAM. To improve oral bioavailability and antitumor potential, RAL diphosphate was prepared as a prodrug. RAL diphosphate showed several orders of magnitude lower binding potential to both ER, and ER, and weak antiproliferative potency on cultured human MCF-7 and ZR-75-1 breast cancer cells, as compared to RAL. However, RAL diphosphate has a much higher bioavailability than RAL, endowing it with higher antitumor potential than RAL against both 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in rats and human MCF-7 breast cancer implanted in athymic nude mice. The RAL prodrug may provide greater clinical benefit for breast cancer therapy and prevention. © 2008 Wiley-Liss, Inc. [source] Her-2/neu and EGFR tyrosine kinase activation predict the efficacy of trastuzumab-based therapy in patients with metastatic breast cancerINTERNATIONAL JOURNAL OF CANCER, Issue 5 2006Gernot Hudelist Abstract Her-2/neu overexpression in human breast cancer leads to an aggressive biological behavior and poor prognosis. Although the anti-Her-2/neu antibody trastuzumab (Herceptin®) has become a valuable therapeutic option for patients with Her-2/neu -overexpressing breast cancer, many patients do not benefit from this therapy. To evaluate the effect of receptor activation on tumor response, we have investigated the phosphorylation status of Her-2/neu and EGFR in 46 Her-2/neu -overexpressing tumor samples from trastuzumab-treated metastatic breast cancer patients by immunohistochemistry. Activated (p)tyr-1248 Her-2/neu was detected in 9 of 46 breast cancers (20%), and activated (p)tyr-845 and (p)tyr-1173 EGFR were both present in 6 tumors (13%) while EGFR was present in 16 cases (35%). ptyr-1248 Her-2/neu showed a trend to correlate with increased response to trastuzumab (p = 0.063), while ptyr-845, ptyr-1173 EGFR and EGFR did not. The presence of ptyr-1248 Her-2/neu and ptyr-845 or ptyr-1173 EGFR, however, was a strong predictor of both response to trastuzumab-based treatment (OR = 8.0, p = 0.021 and OR = 8.0, p = 0.021) and clinical benefit (OR = 5.47, p = 0.041 and OR = 6.22, p = 0.028 multivariate logistic regression analysis). Furthermore, ptyr-845 EGFR and ptyr-1248 Her-2/neu were both independent predictors of progression-free survival (RR = 0.21, p = 0.01 and RR = 0.45, p = 0.026, multivariate analysis). Patients with ptyr-845 EGFR positive tumors also tended toward increased overall survival (RR = 0.17, p = 0.082). Taken together, we have demonstrated that the determination of activated EGFR improves the utility of ptyr-1248 Her-2/neu staining in predicting the clinical outcome of patients undergoing trastuzumab treatment. We hypothesize that the activation state of both Her-2/neu and EGFR are key determinants for trastuzumab efficacy. © 2005 Wiley-Liss, Inc. [source] On the ropivacaine-reducing effect of low-dose sufentanil in intrathecal labor analgesiaACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 8 2010C. M. ORTNER Background: Combining ropivacaine with sufentanil for intrathecal (i.t.) analgesia in labor is well recognized, but information on dosing is limited. This study aimed to determine the ED 50 of i.t. ropivacaine and to assess the effect of adding defined low doses of sufentanil. Methods: This was a two-phase, double-blind, randomized and prospective study. One hundred and fifteen parturients receiving combined spinal epidural analgesia were allocated to one of four groups to receive ropivacaine or sufentanil alone or in combination. In phase one, sufentanil dose,response was calculated using logistic regression. In phase two, ED 50 of ropivacaine and of the combination with a fixed dosage of sufentanil at ED 20 and ED 40 was evaluated using the technique of up,down sequential allocation. Analgesic effectiveness was assessed 15 min after injection using a 100 mm visual analog scale, with <10 mm lasting for 45 min defined as effective. Furthermore, side effects and duration were recorded. Results: The ED 50 of i.t. ropivacaine was 4.6 mg [95% confidence intervals (95% CI) 4.28, 5.31]. Adding sufentanil at ED 20 significantly decreased the ED 50 of i.t. ropivacaine to 2.1 mg (95%CI 1.75, 2.5) (P<0.005); at ED 40, the reduction was similar (P<0.005). Combining sufentanil with ropivacaine resulted in a dose-independent prolongation of analgesia. Besides pruritus, which was well tolerated, there were no differences in side effects. Conclusion: Adding sufentanil at ED 20 results in a more than 50% dose-sparing effect of ropivacaine and considerably prolongs analgesia. Increasing dosage implicates no clinical benefit. [source] Bleeding risk with AZD6140, a reversible P2Y12 receptor antagonist, vs. clopidogrel in patients undergoing coronary artery bypass grafting in the DISPERSE2 trialINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 4 2009S. Husted Summary AZD6140, the first reversible oral P2Y12 receptor antagonist, exhibits greater and more consistent inhibition of platelet aggregation than the irreversible thienopyridine clopidogrel. As a result of its reversible effect, AZD6140 may pose less risk for bleeding when antiplatelet treatment cannot be stopped at least 5 days before coronary artery bypass graft (CABG) surgery or other invasive procedures. The Dose conflrmation Study assessing anti-Platelet Effects of AZD6140 vs. clopidogRel in NSTEMI (DISPERSE2) trial showed overall comparable bleeding rates with antiplatelet treatment with AZD6140 90 mg twice daily or 180 mg twice daily vs. clopidogrel 75 mg once daily in 984 patients with non-ST-elevation acute coronary syndromes. A post hoc exploratory analysis of bleeding outcomes in the subset of 84 patients undergoing CABG in DISPERSE2 suggests reduced risk for total bleeding (41% and 58% vs. 62%), all major bleeding (38% and 50% vs. 62%), and life-threatening bleeding (22% and 38% vs. 54%) with AZD6140 90 mg (n = 32) and 180 mg (n = 26) vs. clopidogrel (n = 26) respectively. Trends suggested that major bleeding rates were reduced with AZD6140 (combined groups) vs. clopidogrel when treatment was stopped , 5 days prior to surgery (39% vs. 63%, p = 0.15) but not when treatment was stopped > 5 days before surgery (50% vs. 60%). This observation is consistent with the reversible binding of AZD6140 to the P2Y12 receptor. Further prospective studies are planned to assess the relationship between this potential clinical benefit of AZD6140 and the reversibility of its antiplatelet effects. [source] Safety and efficacy of the combination of trastuzumab with docetaxel for HER2-positive women with advanced breast cancer.INTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 6 2004A review of the existing clinical trials, results of the expanded access programme in the UK Summary Trastuzumab is a humanised monoclonal antibody against the extracellular domain of HER2 (human epidermal growth factor receptor-2) that is overexpressed in about 25% of human breast cancers. It has shown clinical benefit in HER2-positive breast cancer cases when used alone or in combination with chemotherapy. Trastuzumab increases the response rate to chemotherapy and prolongs survival when used in combination with taxanes. In this article, we review the clinical trials where trastuzumab has been administered together with docetaxel, and we present the results of the trastuzumab expanded access programme (EAP) in the UK. Combination of trastuzumab with docetaxel results in similar response rates and time-to-progression with the trastuzumab/paclitaxel combinations. The toxicity of the combination and the risk of heart failure are low. The clinical data for the docetaxel/trastuzumab combination indicate a favourable profile from both the efficacy and the safety point of view and confirm the feasibility and safety of trastuzumab administration both as monotherapy and in combination with docetaxel. [source] Rapid response to infliximab in severe pustular psoriasis, von Zumbusch typeINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 7 2002Meggan R. Newland MD Tumor necrosis factor-alpha (TNF-,) is a chemokine secreted by T cells which is thought to play a critical role in the pathophysiology of psoriasis. The monoclonal antibody, infliximab, complexes with TNF-,, rendering it inactive. A recent clinical trial has reported the clinical benefit and safety of infliximab in moderate to severe plaque psoriasis. We report a case of rapid response and clinical benefit using infliximab in severe pustular psoriasis of von Zumbusch. [source] Flu: Effect of Vaccine in Elderly Care Home Residents: A Randomized TrialJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 12 2007Fiona Gaughran MD OBJECTIVES: To determine whether assessing seroprotection after influenza vaccine and administering booster vaccination where not achieved reduces hospitalization and death. To estimate the overall seroprotection rate of influenza vaccine. DESIGN: A two-arm, partially blind, randomized, multicenter, parallel-group, controlled trial. SETTING: Twenty-six care homes in three South London boroughs in fall 2004. PARTICIPANTS: Two hundred seventy-seven elderly permanent care home residents meeting eligibility criteria. INTERVENTION: Postvaccination blood samples were randomized to booster evaluation or no booster evaluation (control). If evaluation revealed inadequate seroprotection, a booster vaccine was administered. MEASUREMENTS: Primary outcome was hospitalization to end April 2005; secondary outcomes were death, antibiotic use, and seroprotection. RESULTS: Sixty percent of the controls and 41% of the booster evaluation group responded to routine vaccination. Booster vaccination where indicated increased seroprotection rates in the booster evaluation group to 66%. Treatment groups did not differ in any outcome measures in the intention-to-treat analysis (hospitalization odds ratio=1.02, 95% confidence interval=0.55,1.87). There was a tendency towards greater differences between groups in the per-protocol analysis than in the intention-to-treat analysis, particularly regarding seroprotection rates. The same effect was observed in the a priori exploratory analysis of residents not seroprotected after routine vaccination alone. CONCLUSION: In a year without circulating influenza, there is no clinical benefit of administering a booster vaccine if routine trivalent vaccination fails to result in seroprotection. Hemagglutination titers rose in two strains postbooster vaccination but fell against the novel strain, Wyoming. The benefit of such a booster strategy when influenza is prevalent thus remains unc ertain. [source] Ablation of Atypical Atrial Flutter Guided by the Use of Concealed Entrainment in Patients Without Prior Cardiac SurgeryJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 2 2000FRANK BOGUN M.D. Ablation of Atypical Atrial Flutter. Introduction: Mapping techniques have not been systematically evaluated with respect to atypical atrial flutter (AF) not involving the inferior vena cava isthmus. The purpose of this study was to assess prospectively the use of concealed entrainment (CE) in mapping of AF and to assess the clinical benefit of ablation of clinically relevant atypical AF. Methods and Results: In seven consecutive patients without prior cardiac surgery presenting with atypical AF, mapping was performed in the right and, if necessary, left atrium. At sites with CE, radiofrequency energy was delivered. In a posthoc analysis, the endocardial activation time, stimulus-flutter wave (F) interval, presence of split potentials and diastolic potentials, and postpacing Interval were assessed, and effective sites were compared to ineffective sites. A total of 22 forms of atypical AE either could be induced or were present at the time of the study. Eleven of the 13 targeted atypical AFs (85%) were successfully ablated. The positive predictive value of CE increased from 45% to 75% in the presence of matching electrogram-F and stimulus-F intervals or if flutter terminated during entrainment pacing, and to 88% in the presence of split atrial electrograms or diastolic potentials. During short-term clinical follow-up, none of the patients had recurrence of the ablated AE. However, the majority of patients required either medication for atrial fibrillation or repeated interventions for new forms of AF. Conclusion: Mapping and ablation of atypical AF is feasible if sites with CE can be identified. However, the clinical benefit of successful ablations in patients with atypical flutter appears to be limited. [source] Granulocyte transfusion therapy in abdominal organ transplant recipientsJOURNAL OF CLINICAL APHERESIS, Issue 5 2009Nikhil R. Oak Abstract Background: Patients with neutropenia are at increased risk for infections. Granulocyte transfusions (GT) have had mixed success in treatment of neutropenic infections in adult patients with hematologic malignancy. This study examined the outcomes of GT therapy in neutropenic solid organ transplant recipients, a novel population for this therapy. Methods: We performed a retrospective examination of the transfusion and medical records of all 14 solid organ-transplant recipients without hematologic malignancy who experienced neutropenia and received GT therapy from 2004 to 2006. Results: Twelve patients received GT therapy for an active infection and two patients for infection prophylaxis. The mean absolute neutrophil count (ANC) one day increment per GT in these patients was 526/,l (median 215/,l). The mean ANC one day increment per dose of 1010 granulocytes was 246/,l (median 86/,l). Of the 12 infected patients, four patients (33%) showed a clinical response to GT with improvement or resolution of the infection, 7 (58%) patients had no clinical response and one additional patient had a clinical response to a course of GT but died during a second GT course. Neither patient receiving GT for prophylaxis developed an infection. Conclusions: We observed temporal increases in ANC to levels above 1,000/,l in 15/18 (83.3%) courses of GT. We observed a clinical response to infection in 5/12 (42%) patients, the remaining infected patients had no clinical response. Our results suggest that GT therapy in neutropenic solid organ transplant recipients can boost peripheral blood neutrophil counts. Additional studies areneeded to document an independent clinical benefit for GT in this patient population. J. Clin. Apheresis, 2009. © 2009 Wiley-Liss, Inc. [source] | |||||||||||||||||||||||||||||||||||||||||||