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PubMed2004

Health-related quality of life in patients with sinusitis.

The goal of treatment for patients with sinusitis is the prompt and complete relief of symptoms and consequent improvement in health-related quality of life (HRQL). HRQL has been defined as the component of overall quality of life, determined primarily by the person's health, which can be influenced by clinical interventions. HRQL is especially useful for conditions like sinusitis in which there is no gold-standard diagnostic test, and "objective" tests correlate poorly with disease severity and outcomes. Patients with sinusitis have measurable, significant decrements in HRQL. Many studies evaluating treatment efficacy in patients with sinusitis have used unvalidated HRQL measures, making their findings, at best, difficult to interpret or, at worst, potentially biased. In this article, we review the definition of HRQL, the meaning and importance of validating HRQL measures, the impact of sinusitis on HRQL, and validated measures of HRQL for use in research and in clinical practice.

Endpoint Determination↗

PubMedDate not supplied

Cerebral energy metabolite levels and survival following exposure to low inspired oxygen concentration.

To determine the relationship between brain energy metabolites and neurologic status after ischemia-hypoxia, we measured cortical tissue levels of adenosine triphosphate (ATP), phosphocreatine, and lactate. Rats with permanent unilateral carotid occlusion were exposed to 5, 10, and 15 min of hypoxic atmosphere (FIO2 0.048) and, to examine metabolic restitution, 60 min after recovery in rats exposed to the same hypoxic mixture for 15 min. At 5 and 10 min of hypoxia, there were significant reductions in phosphocreatinine and elevations in tissue lactate, but only after 15 min of hypoxia, did ATP levels significantly decrease. By 60 min after recovery, phosphocreatinine values returned to the normal range, ATP values to 15% less than normal, and tissue lactate toward normal. In parallel survival studies, neurological status was examined following hypoxic exposure (PaO2 18 to 19 torr) for 5 an 10 min. Evidence for neurological injury in the form of posthypoxic seizures occurred at a point in time preceding significant changes in brain tissue ATP level. Since injury occurs prior to ATP reduction, changes in brain tissue ATP level may not be an appropirate endpoint for determining brain tissue injury in hypoxia.

Adenosine Triphosphate↗

PubMed2005

Improving the accuracy of a photographic assessment system for breast cosmesis.

AIMS: To determine how the accuracy of a photographic system for cosmetic assessment of the breast after conserving treatment can be maximised. MATERIALS AND METHODS: Photographs of 40 women undergoing breast-conserving treatment for breast cancer were taken. Upward and lateral retraction was measured using a digitiser to enter the locations of reference marks on the photographs into a computer programme. In the readings produced, reduction in three potential sources of variation was considered by determining how few repeated photographs or measures were necessary to achieve an estimate within +/-2 mm of a mean value obtained from a large series. These included variation between assessments of the same photograph, between different photographs of the same patient and between different observers. We also sought to determine whether the attachment of white nipple markers (WNM) at the time of photography would reduce variation. RESULTS: A minimum of five readings was required from each photograph in order to obtain a result that was stable (defined as within 1 mm of that achieved by 20 readings). Using similar criteria, we found that at least four photographs of each patient were required, and that each should be assessed by at least four observers. The addition of WNM reduced the standard deviations by 36-45%. CONCLUSION: The use of WNM, which is simple, quick and cheap, is effective in reducing variation and can be recommended for use in clinical trials where overhead costs need to be contained.

Adolescent↗

PubMed2002

Angiogenesis inhibitors in clinical development for lung cancer.

The use of tumor angiogenesis as a therapeutic target is based on extensive literature showing the dependence of tumors on the process of angiogenesis for growth, invasion, and metastasis. Seminal work performed by Folkman three decades ago determined that tumors beyond the size of approximately 2 mm require angiogenesis for subsequent growth and development. This basic hypothesis stimulated research in the field of angiogenesis and has resulted in the identification of factors that both enhance and inhibit this "angiogenic switch." The intent of this article is to present data on several angiogenesis inhibitors that are currently undergoing clinical evaluation in cancer patients. These agents may be particularly useful in the treatment of lung cancer, both as adjunctive therapy in early-stage or locally advanced disease, as well as in combination strategies with platinum-based therapy in metastatic disease. Although angiogenesis inhibitors have been in clinical trials for the past decade, there has been a shift in recent years towards the development of more mechanism-based and receptor-targeted agents. Interestingly, no antiangiogenic agent has been approved as such for use in cancer, perhaps because of the challenges involved in the clinical development of these novel agents. These include the potential requirement for long-term administration, difficulties in deriving biologically efficacious doses in early clinical trials, and the inability to use tumor regression as a primary endpoint in phase II trials.

Angiogenesis Inhibitors↗

PubMed2004

Early assessment of the efficacy of a human papillomavirus type 16 L1 virus-like particle vaccine.

A post hoc analysis was performed using combined data from two Phase I tolerability/immunogenicity studies of monovalent human papillomavirus type 11 (HPV11) or HPV16 L1 virus-like particle (VLP) vaccines. The goal was to determine if the HPV16 L1 VLP vaccine protected against HPV16 infection. Vaccine or placebo was given at 0, 2 and 6 months. HPV16 infection was defined by positive polymerase chain reaction (PCR) results following vaccination. The incidence of HPV infection was observed to be 0 cases per 100 person-years at risk in the vaccine group, and 5 cases per 100 person-years at risk in the control group. These results support the institution of larger efficacy trials for HPV L1 VLP vaccines.

Adolescent↗

PubMed2003

Comparison between aromatase inhibitors and sequential use.

The biochemical efficacy of aromatase inhibitors and inactivators in vivo may be determined by two types of methods; by measuring plasma or tissue estrogen levels, or assessment of the conversion of the androgen substrate (in practice, androstenedione) into estrogens (estrone) by the use of tracer methods. While methods to determine plasma and tissue estrogens are limited through lack of sensitivity required to measure the very low concentrations recorded in postmenopausal women on treatment with these compounds, measurement of in vivo aromatization is an extensive procedure, applicable to a limited number of patients only. While we may correlate the mean level of aromatase inhibition achieved with different compounds to clinical efficacy, data correlating individual estrogen suppression to clinical outcome among patients treated with a specific compound is limited. The now well-characterized phenomenon of lack of cross-resistance between non-steroidal aromatase inhibitors and steroidal aromatase inactivators are likely due to biochemical effects not related to differences in total body aromatase inhibition.

Aromatase Inhibitors↗

PubMed2003

ACE inhibitors and AT-1-receptor antagonists COOPERATE in non-diabetic renal disease.

The renin-angiotensin-aldosterone system has an important role in the progression of both diabetic and non-diabetic nephropathy. COOPERATE was set up to determine whether dual blockade of angiotensin-converting-enzyme (ACE) and the AT-1 receptor was more efficacious than either ACE inhibition or AT-1 antagonism alone in non-diabetic renal disease. The combined primary end point was of time to doubling of serum creatinine concentration or end stage renal disease. By year 3, 10 of 85 (11%) of the combination patients had reached the primary end point. This was significantly less than the 20 of 86 (23%) and 20 of 85 (23%) in the losartan and trandolapril groups, respectively. Combination treatment should be considered in non-diabetic renal disease especially if the disease is progressing with ACE treatment alone.

Angiotensin Receptor Antagonists↗

PubMed2002

Defining clinically meaningful outcomes in the evaluation of new treatments for oral mucositis: oral mucositis patient provider advisory board.

Oral mucositis (OM)-related outcomes constituting a meaningful clinical advance in bone marrow transplant patients were considered by an interdisciplinary panel. Meaningful outcomes are essential in product development for OM, a condition without effective prevention or treatment. The most important outcomes to measure, the feasibility of measuring these in a clinical trial, and clinically meaningful differences in these outcomes were determined by the panel. Most important are reduction in oral pain and use of opioid analgesics, improvement in oral intake and quality of life, and reduction of hospitalization duration. Reduction in the severity of OM measured by an objective evaluation of oral mucosa could provide insight regarding the biologic activity of an intervention. Further data are required to define the precise relationship between reduction in visible OM and improvement in outcome. Minimally, clinical trials for OM should assess oral pain, opioid use, oral intake, and include objective assessment of OM.

Analgesics, Opioid↗

PubMed2000

Effectiveness and economic impact associated with a program for outpatient management of acute deep vein thrombosis in a group model health maintenance organization.

BACKGROUND: Controlled clinical trials have demonstrated that outpatient administration of low-molecular-weight heparin to patients with acute deep vein thrombosis (DVT) provides safety and efficacy equivalent to that of traditional inpatient therapy with unfractionated heparin. Whether favorable results reported in controlled clinical trials are achievable in clinical practice is an important consideration. METHODS: Appropriate patients with objectively diagnosed DVT were treated as outpatients with low-molecular-weight heparin and warfarin sodium according to an approved guideline. The primary end point for analysis consisted of objectively diagnosed symptomatic recurrent thromboembolism or major bleeding within a 90-day evaluation period. The incremental cost incurred by the organization while using the outpatient DVT treatment guideline was determined. Incremental cost savings of the outpatient DVT treatment program were determined based on the cost that would have accrued had the patient been admitted to the hospital for treatment with unfractionated heparin. RESULTS: We enrolled 391 patients (91.4%) in the outpatient DVT treatment program. Of these, 373 (95.4%) completed 90 days of therapy without reaching the primary end point. The percentage of patients reaching the primary outcome measure (4.6%) fell within the range of patients enrolled in controlled clinical trials (3.5%-9.4%). During the 2-year program evaluation, total cost savings of $1,108,587 were realized. CONCLUSIONS: Outpatient treatment of acute DVT can be managed safely and effectively in clinical practice. The potential savings associated with outpatient DVT treatment are substantial. Arch Intern Med. 2000;160:2926-2932

Aged↗

PubMed2002

Statistical issues in studies of toxicity modifiers.

The primary focus of oncology is the search for a cure. In pursuit of this goal, therapeutic regimens have increased in intensity, often causing increased normal tissue morbidity. Pharmacologic agents are being developed to ameliorate or prevent these toxicities. The stepwise investigation of these agents requires a different paradigm from standard drug development. Traditionally, phase I studies are designed to find the maximum tolerated dose of an experimental drug; however, in pharmacologic agents that aim to reduce toxicity, defining the maximum tolerated dose, may not be necessary. The focus of phase I studies in these agents is the establishment of the maximum effective dose. Phase II studies traditionally are designed to establish efficacy of an experimental regimen before advancing to a phase III study. To determine potential efficacy, predictable efficacy levels must be available in the literature for standard therapy. In this manner, the phase II study can be evaluated against the historical control to determine if a phase III study should be conducted. This generally is not possible in the context of toxicity modifiers. Because of variability in toxicity assessment, prior rates of toxicity may not be reliable when evaluated against a phase II study focusing on toxicity amelioration. Because the assessment of toxicity is subjective, retrospective comparisons may be biased and lead to the wrong conclusion. One method to correct for this bias is to conduct placebo-controlled, randomized phase II studies. Phase III studies of toxicity modifiers have toxicity amelioration or prevention as the primary objective. These studies should be designed to assess the subjective and objective components of toxicity, evaluate quality of life, and assess possible adverse effects on therapeutic outcomes. Design and analysis issues are discussed in this report.

Clinical Trials, Phase III as Topic↗

PubMed2001

Platelet reactivity characterized prospectively: a determinant of outcome 90 days after percutaneous coronary intervention.

BACKGROUND: Platelet activation is pivotal in the pathogenesis of complications after percutaneous coronary interventions (PCI). We previously reported substantial interindividual variability in activation of glycoprotein (GP) IIb/IIIa in response to a low concentration of ADP. We assessed GP IIb/IIIa activation prospectively to determine whether this could differentiate patients at low risk from those at high risk for complications early and late after PCI. Methods and Results-- A total of 112 patients undergoing PCI were studied. Platelet reactivity was determined with the use of flow cytometry. Patients were classified into high and low platelet reactivity groups on the basis of extent of activation of GP IIb/IIIa in response to 0.2 micromol/L ADP. The median value was used for differentiation. The incidence during 90-day follow-up interval of a composite end point (myocardial infarction, urgent revascularization, or repeat revascularization) was determined in each group. Follow up was completed in all 112 patients. The 2 groups were similar with respect to diverse clinical characteristics. Nevertheless, the incidence of the composite end point occurred in 26.8% of the high and 7.1% in the low platelet reactivity group (P=0.01). The difference in the composite end point was most striking during the 30- to 90-day interval after PCI (16.7% versus 1.9%; P=0.02). Repeat revascularization was more frequent in those with increased platelet reactivity (17.9% versus with 3.6%, P=0.029). CONCLUSIONS: Prospective assessment of platelet GP IIb/IIIa activation permits stratification of patients into low- and high-risk groups with respect to adverse events after PCI.

Angioplasty, Balloon, Coronary↗

PubMed2002

Vitamin intervention for stroke prevention.

Vitamin Intervention for Stroke Prevention (VISP) is designed to determine whether the utilization of folic acid, vitamins B(6) and B(12), in addition to other risk factor reducing measures, have a demonstrable effect on prevention of recurrent stroke. The entry criteria are a first-ever nondisabling stroke, the patient signs informed consent with willingness to participate and randomization to a high- or low-dose vitamin intervention regimen. Case acquisition of 3,688 individuals has been completed, half in the high-dose and the other half in the low-dose intervention arm. Follow-up is in progress and the end results are expected within the year. The Vitamins to Prevent Stroke (VITATOPS) is a parallel study based in Australia with similar goals, and, hopefully, the data from the two will be comparable and supportive.

Aged↗

PubMed2002

Treatment options: the latest evidence with galantamine (Reminyl).

Vascular dementia (VaD) has a great deal of overlap (in terms of features and symptoms) with Alzheimer's disease (AD). Mixed dementia, or AD with concomitant cerebrovascular disease (AD with CVD), is increasingly being recognized as a distinct clinical condition that occurs with substantial frequency. The robust evidence for the effectiveness of cholinergic treatments such as galantamine (Reminyl) in AD suggests its potential use in the treatment of dementias related to CVD, and preclinical evidence supports this rationale. Galantamine, which has a unique dual cholinergic mode of action, may be of particular benefit in VaD and AD with CVD. For example, behavioral symptoms, which can be more severe in VaD than in AD and are important determinants of the impact of dementia, may be especially benefited by galantamine. This results from its potential to modulate systems involving other neurotransmitters such as 5-HT (serotonin) and dopamine, which affect mood and emotional balance. The results of a recent landmark clinical trial with galantamine in patients with VaD, or AD with CVD, indicate that galantamine produces benefits across a broad range of symptoms of dementia in both patient populations. Significant cognitive improvements over 6 months, long-term maintenance of cognition for at least 12 months, and global benefits, as well as efficacy in both behavioral and functional symptoms, indicate efficacy with galantamine that is so far unsurpassed by any other drug treatment for dementia. Galantamine therefore has potential to benefit a wide range of patients with dementia in the clinic.

Alzheimer Disease↗

PubMed2002

Cytotoxic and antiviral activities of Colombian medicinal plant extracts of the Euphorbia genus.

Forty-seven plant extracts of 10 species of the genus Euphorbia (Euphorbiaceae) used by Colombian traditional healers for the treatment of ulcers, cancers, tumors, warts, and other diseases, were tested in vitro for their potential antitumour (antiproliferative and cytotoxic) and antiherpetic activity. To evaluate the capacity of the extracts to inhibit the lytic activity of herpes simplex virus type 2 (HSV-2) and the reduction of viability of infected or uninfected cell cultures, the end-point titration technique (EPTT) and the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] colorimetric assay were used, respectively. The therapeutic index of the positive extracts for the antiviral activity was determined by calculating the ratio CC50 (50% cytotoxic concentration) over IC50 (50% inhibitory concentration of the viral effect). Five of the 47 extracts (11%) representing 3 out of 10 Euphorbia species (30%) exhibited antiherpetic action; the highest activity was found in the leaf/stem water-methanol extracts from E. cotinifolia and E. tirucalli. The therapeutic indexes of these two plant species were > 7.1; these extracts exhibited no cytotoxicity. Six extracts (13%) representing 4 plant species (40%) showed cytotoxic activity. The highest cytotoxicity was found in the dichloromethane extract obtained from E. cotinifolia leaves and the CC50 values for the most susceptible cell lines, HEp-2 and CHO, were 35.1 and 18.1 microgram/ml, respectively.

Animals↗

PubMedDate not supplied

Open label trial of tamoxifen in scleroderma.

BACKGROUND: Previous reports have suggested that treatment with the selective estrogen antagonist tamoxifen may be effective in diminishing primary and secondary Raynaud's vasospasm, including cases occurring in the setting of scleroderma. Tamoxifen treatment has also been associated with improvement of retroperitoneal fibrosis and desmoid tumors, conditions also associated with abnormal fibroblast proliferation. Tamoxifen increases production of the immunosuppressive cytokine TGF beta which modulates fibroblast activity. The potential effect of tamoxifen on vascular reactivity and fibrotic lesions raised questions about its utility as a therapeutic agent in scleroderma. OBJECTIVE: To determine the utility of tamoxifen therapy in scleroderma. METHODS: Open label preliminary, prospective, proof of concept study of tamoxifen. RESULTS: Fifteen patients (3 male, 12 female) with scleroderma were enrolled (10 diffuse disease, 5 CREST). Mean age was 55 (34-75) years. Mean duration of scleroderma was 9.3 (1-25) years. Two patients were excluded. For 13 patients, mean duration of treatment was 7 (1.5-32) months. Two of 13 patients treated with tamoxifen experienced transient improvement. They did not appear to have clinical features that identified them as a unique subset. Both patients subsequently relapsed, in one case 12 months, and in the other 24 months after treatment. CONCLUSION: Based on these results, we would not recommend tamoxifen for further large scale studies in scleroderma.

Aged↗

PubMed2002

Randomized comparison of enoxaparin with unfractionated heparin following fibrinolytic therapy for acute myocardial infarction.

AIMS: To compare the efficacy and safety of low molecular weight heparin with unfractionated heparin following fibrinolytic therapy for acute myocardial infarction. METHODS AND RESULTS: Three-hundred patients receiving fibrinolytic therapy following acute myocardial infarction were randomly assigned to low molecular weight heparin as enoxaparin (40 mg intravenous bolus, then 40 mg subcutaneously every 8 h, n=149) or unfractionated heparin (5000 U intravenous bolus, then 30 000 U. 24 h(-1), adjusted to an activated partial thromboplastin time 2-2.5x normal, n=151) for 4 days in conjunction with routine therapy. Clinical and therapeutic variables were analysed, in addition to use of enoxaparin or unfractionated heparin, to determine independent predictors of the 90-day composite triple end-point (death, non-fatal reinfarction, or readmission with unstable angina). The triple end-point occurred more frequently in patients receiving unfractionated heparin rather than enoxaparin (36% vs. 26%; P=0.04). Logistic regression modelling of baseline and clinical variables identified the only independent risk factors for recurrent events as left ventricular failure, hypertension, and use of unfractionated heparin rather than enoxaparin. There was no difference in major haemorrhage between those receiving enoxaparin (3%) and unfractionated heparin (4%). CONCLUSION: Use of enoxaparin compared with unfractionated heparin in patients receiving fibrinolytic therapy for acute myocardial infarction was associated with fewer recurrent cardiac events at 90 days. This benefit was independent of other important clinical and therapeutic factors.

Aged↗

PubMed2003

Reliability of 2 functional goniometric methods for measuring forearm pronation and supination active range of motion.

STUDY DESIGN: Test-retest reliability study. OBJECTIVES: To determine intra- and intertester reliability of the hand-held pencil (HHP) and the plumbline goniometer (PLG) methods for measuring active forearm pronation and supination motions in individuals with and without injuries. BACKGROUND: The distal forearm method has been considered the gold standard for measuring forearm pronation and supination motion. The HHP and PLG, however, are 2 more functional methods for measuring forearm motions, though limited information on the psychometric properties of these tests is currently available. METHODS AND MEASURES: Intra- and intertester reliability of the HHP and PLG methods were determined in 40 subjects of convenience (20 injured and 20 noninjured). Two testers performed 3 repeated measurements for each motion and method on all subjects. Intraclass correlation coefficients (ICC3,1 for intratester reliability, ICC2,3 for intertester reliability) and standard error of measurements (SEMs) were determined. RESULTS: The ICCs for the measurements of pronation and supination using the HHP and PLG methods were high (range, 0.86-0.98) for individuals with and without injuries, with the reliability for the PLG method being equal or slightly greater than the HHP method for the majority of pronation and supination measurements. Intratester ICCs were higher (SEMs were conversely lower) than intertester ICCs for nearly all measurements. The ICC values were generally the same or higher for individuals with injuries compared to individuals without injuries. CONCLUSIONS: The HHP and PLG are highly reliable methods for measuring functional forearm pronation and supination. Because plumbline goniometers are not commercially available and the instrumentation for the HHP method is readily accessible, clinicians should consider the latter as their method of choice for measuring functional forearm pronation and supination.

Adult↗

PubMed2004

Postoperative evaluation of microsurgical resection for cavernous malformations of the brainstem.

OBJECT: The aim of this study was to propose criteria to determine whether complete resection of cavernous malformations in the brainstem had been achieved. METHODS: The authors retrospectively analyzed data in 10 patients harboring a single cavernous malformation who had presented with hemorrhagic symptoms and had been followed up for longer than 2 years postsurgery. The study population consisted of five male and five female patients ranging in age from 13 to 57 years (mean 36.8 years). When preoperative magnetic resonance (MR) images demonstrated the lesion as a homogeneous hyperintense mass, the surgery was defined as complete or incomplete based on intraoperative findings. When preoperative MR images revealed other findings, complete resection was determined according to whether postoperative MR imaging results demonstrated lesions distinct from the peripheral hemosiderin rim. Among the 13 operations in this series, nine resulted in complete resection and were associated with no postoperative clinical relapse of hemorrhage, whereas four operations resulted in incomplete resection and were correlated with postoperative recurrent hemorrhage. The seven patients in whom the outcome of the initial operation was complete demonstrated good neurological recovery in the long-term follow-up period, whereas the three patients in whom the outcome of the initial surgery was judged to be incomplete showed inadequate neurological recovery due to recurrent hemorrhage. CONCLUSIONS: The criteria proposed in this study to evaluate surgical treatment may be a reliable means of predicting the recurrence of hemorrhage postoperatively.

Adolescent↗