Comparative study on the predictability of statistical models (RSM and ANN) on the behavior of optimized buccoadhesive wafers containing Loratadine and their in vivo assessment

Objective: Buccoadhesive wafer dosage form containing Loratadine is formulated utilizing Formulation by Design (FbD) approach incorporating sodium alginate and lactose monohydrate as independent variable employing solvent casting method.

Methods: The wafers were statistically optimized using Response Surface Methodology (RSM) and Artificial Neural Network algorithm (ANN) for predicting physicochemical and physico-mechanical properties of the wafers as responses. Morphologically wafers were tested using SEM. Quick disintegration of the samples was examined employing Optical Contact Angle (OCA).

Results: The comparison of the predictability of RSM and ANN showed a high prognostic capacity of RSM model over ANN model in forecasting mechanical and physicochemical properties of the wafers. The in vivo assessment of the optimized buccoadhesive wafer exhibits marked increase in bioavailability justifying the administration of Loratadine through buccal route, bypassing hepatic first pass metabolism.     

Localized BCNU chemotherapy and the multimodal management of malignant glioma

ABSTRACT

Background: Gliomas account for 42% of all primary CNS neoplasms and 77% of all malignant primary CNS neoplasms. Unfortunately the high-grade variant of gliomas, glioblastoma multiforme (GBM), is difficult to treat and generally considered incurable. Survival rates are generally poor, and neurological morbidity in the setting of disease progression is high. Fortunately, significant progress has been achieved in the past decade in our understanding of the molecular biology of this aggressive tumour histology and, as a consequence, there is renewed clinical trial activity in this area focused on improving quality of life, treatment-related morbidity and outcomes.

Methods: A review of literature from June 2005 to June 2008 was conducted on multimodal treatment of malignant glioma (MG) patients, using specific search criteria in Medline, EMBASE, and BIOSIS. Abstracts from relevant US and European medical (cancer) meetings were also evaluated.

Results: The established therapies for MG include surgery, radiotherapy (RT), and local or systemic chemotherapy. However, over the last 10 years only two chemotherapeutic agents have received regulatory approval for treatment of MG: polifeprosan 20 with carmustine (BCNU implant) and temozolomide (TMZ), an imidazotetrazine derivative of dacarbazine. More recent advances in the treatment of brain tumours have been in the development of multimodal approaches. Specific interest in the combination of BCNU implant and TMZ has arisen due to the demonstrable depletion by TMZ of the DNA repair enzyme responsible for resistance to a nitrosourea such as BCNU. Further interest in this combination stems from the observation that there is a difference in the time to peak effect for each agent. Additional emerging data suggest that multimodal therapy with maximal resection and BCNU implants, followed by adjuvant therapy with radiation and TMZ, is effective and well-tolerated in patients with initial high-grade, resectable MG.

Conclusions: The increasing body of efficacy data suggests that this combination of BCNU implants and TMZ within a multimodal treatment strategy including surgery and RT may provide an enhanced benefit compared with the use of either of these agents alone in select patients with high-grade glioma.     

Oral BG-12 (dimethyl fumarate) for relapsing–remitting multiple sclerosis: a review of DEFINE and CONFIRM

Introduction: Multiple sclerosis (MS) is an autoimmune neurodegenerative disease of the central nervous system involving inflammation, chronic demyelination and axonal loss. MS affects more than 2 million people worldwide.

Areas covered: This article aims to summarize the findings from two pivotal 2-year, randomized, double-blind, placebo-controlled, Phase III studies of BG-12 (dimethyl fumarate) for relapsing–remitting MS (RRMS): DEFINE (Determination of the Efficacy and Safety of Oral Fumarate in RRMS) and CONFIRM (Comparator and an Oral Fumarate in RRMS). Results from both studies demonstrated that BG-12 provides clinical and radiological efficacy over 2 years across a range of outcomes. These results were apparent as early as 12 weeks and sustained over the course of both studies. BG-12 was found to have an acceptable safety profile, with a similar overall incidence of adverse events across all treatment groups.

Expert opinion: The combination of robust efficacy, ease of administration and established safety profile is unique to a new therapy in MS. Findings from the pivotal Phase III studies support BG-12 as a potential initial oral treatment for patients with RRMS or as an alternative to other currently available therapies.     

Morphological Characterization of Polyanhydride Biodegradable Implant Gliadel® During in Vitro and in Vivo Erosion Using Scanning Electron Microscopy

Purpose. The objectives of the current study are to characterize the distribution of the chemotherapeutic agent carmustine (BCNU) in spray dried polyanhydride microspheres and to describe the morphological changes that occur during the in vitro and in vivo erosion of the polyanhydride implant-GLIADEL^®, which consists of BCNU distributed in the copolymer matrix of poly(carboxyphenoxy propane:sebacic acid) in a 20:80 molar ratio (p(CPP:SA, 20:80)). Methods. Scanning electron microscopy (SEM) was used to visualize the morphological changes of the polymer during the manufacturing process and in vitro and in vivo erosion. Results. This study revealed that BCNU was homogeneously distributed within spray dried polyanhydride microspheres with no phase separation. The porosity of the wafer fabricated from spray dried polyanhydride microspheres gradually increased during erosion. During the initial period following wafer implantation in the brains of rats, erosion was mainly confined to the surface layer of the wafer with the majority of the wafer remaining intact. The eroding front gradually advanced from the surface to the interior of the wafer in a layerwise fashion, creating pores and connecting channel. Eventually both the interior and exterior of the wafers were eroded and the same porous structure was seen throughout the whole wafer. Conclusions. This study provides the first visual observation of the morphological changes of the GLIADEL^® wafer during erosion of the polyanhydride matrix and release of the drug substance BCNU. The observations in this study support the conclusion that BCNU release from a polyanhydride wafer is controlled both by diffusion of the drug and erosion of the polymer matrix.     

Mucosal co-delivery of ketorolac and lidocaine using polymeric wafers for dental application

The current study aimed to investigate the effectiveness of a developed sodium alginate and polyvinylpyrrolidone K-25 (PVP K-25) polymeric wafer for the co-delivery of ketorolac and lidocaine to soft tissues for healing and pain control following gingivectomy. Nine ketorolac/lidocaine lyophilized wafers were formulated and assessed for their hydration capacity, mucoadhesion ability and in vitro release profile to select the optimum system for further clinical investigation. Wafer F6 containing 2:1 sodium alginate to PVP K-25 and 10% glycerol showed optimum properties and was selected for the clinical study. Twenty patients were included in the study and the ketorolac/lidocaine wafer was assessed versus a market product. Visual pain analog was evaluated daily for the first week and wound healing index was evaluated for one week, two weeks and one month following the procedure. The developed ketorolac/lidocaine polymeric wafer proved to be an effective method of reducing pain and discomfort together with enhancing wound healing following gingivectomy.     

Three weeks release BCNU loaded hydrophilic-PLGA microspheres for interstitial chemotherapy: Development and activity against human glioblastoma cells

The aim of this study is the development of microspheres of BCNU for intracranial administration, as an alternative to marketed novel Gliadel® Implant in the treatment of brain tumours. H poly-lactide-co-glycolide biodegradable microspheres of BCNU with a mean size of 33.5 ± 1.8 µm were obtained by an oil-in-water emulsion solvent evaporation method. Their small size would allow their intracranial administration through a needle by cerebral stereotaxia if tumour recurrence occurs, without a surgical intervention, as Gliadel® needs. BCNU was released from these microspheres during 21 days, mainly by a mechanism of diffusion from the polymer matrix (K = 2.91 mg days^?½). The cytotoxic effects of these microspheres on human glioblastoma cells were demonstrated all through 21 days and the value of percentage of viable cells was less than 40%. These microspheres should be commercialized as a freeze-dried product to keep at ?20°C. Three hundred and twenty milligrams of microspheres contain 61.6 mg of BCNU, the same amount of BCNU contained in 1600 mg or eight wafers of Gliadel usually implanted after the tumour resection.     

Evaluation of in vitro and in vivo antitumor activity of BCNU-loaded PLGA wafer against 9L gliosarcoma.

The purpose of the present study was to develop implantable BCNU-loaded poly(D,L-lactide-co-glycolide) (PLGA) wafer for the controlled release of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and to evaluate its in vitro and in vivo antitumor activity. The release rate of BCNU from PLGA wafer increased with the increase of BCNU amount loaded and the release was continued until 7 days. In vitro and in vivo antitumor activity of BCNU-loaded PLGA wafer was investigated using in vitro cytotoxicity against 9L gliosarcoma cells and a subcutaneous (s.c.) solid tumor model of 9L gliosarcoma, respectively. The wafers containing BCNU showed more effective cytotoxicity than BCNU powder due to its short half-life and inhibited the proliferation of 9L gliosarcoma cells. BCNU-loaded PLGA wafer delayed the growth of the tumors significantly and increasing the dose of BCNU in the wafer resulted in a substantial regression of the tumor. These results of antitumor activity of BCNU-loaded PLGA wafer demonstrate the feasibility of the wafers for clinical application.     

Experimental trials in amyotrophic lateral sclerosis: a review of recently completed,ongoing and planned trials using existing and novel drugs

Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that affects roughly 2 subjects per 100,000 in the United States; however, given the rapid decline and mortality, there are low prevalence rates. Although ALS is considered a single disease, it, in truth, probably represents a series of disorders with different clinical patterns and different pathophysiologic mechanisms that eventually coalesce into a single entity. The challenge has been to target these different pathophysiologic abnormalities, and so far, most drug studies have focused on only one or two different pathways. Over 50 well-designed clinical trials have been conducted in ALS over the last 25 years and with the exception of the Riluzole trial, all have failed.

Areas covered: In this review, the authors highlight some of the recently concluded, ongoing or planned Phase II and Phase III studies in ALS. Furthermore, they summarize the progress in the recently initiated stem-cell therapy trials in ALS.

Expert opinion: The challenge remains for developing effective targeted therapeutic interventions for ALS. However, with improved recognition of the complex interplay of several factors that may contribute to ALS pathogenesis, in addition to improved patient selection criteria, outcome measures and biomarkers for drug development, advancements may be made in the future.     

Talaporfin sodium

Importance of the field: Despite therapeutic advances, cancer remains the cause of an estimated 23% of deaths in the USA. New treatments for malignancy are greatly needed.

Areas covered in this review: Talaporfin sodium is a light-activated drug that causes tissue death through induction of apoptosis. Systemic antitumor effects mediated by CD8⁺ T cells have been demonstrated in preclinical studies, providing a mechanism for distant response of tumors noted in clinical trials. Talaporfin sodium is approved in Japan for early-stage endobronchial cancer. Phase I and II studies in solid tumors have shown tumor regression in patients refractory to other therapies. Phase III pivotal studies against hepatocellular carcinoma as monotherapy and liver-metastatic colorectal cancer in combination with chemotherapy are ongoing. Talaporfin sodium is also in studies in men with symptomatic benign prostatic hyperplasia. Substantial safety data from clinical trials so far indicate that the drug is well tolerated.

What the reader will gain: Talaporfin sodium has a broad safety profile and a mode of action that could affect growth in treated and untreated tumors.

Take home message: Clinical and preclinical studies indicate that talaporfin sodium treatment may offer a powerful option to synergize current therapies, as well as an alternative monotherapy in treating cancer.     

Sustainable release of carmustine from biodegradable poly[(d,l)-lactide-co-glycolide] nanofibrous membranes in the cerebral cavity: in vitro and in vivo studies

Objective: Glioblastoma multiforme (GBM) is the most common and most aggressive malignant primary brain tumor in humans. The only interstitial chemotherapy pharmaceutical approved to date for GBM treatment is the Gliadel® wafer. Despite the safety and efficacy of this approach that have been demonstrated in patients undergoing resection of both newly diagnosed and recurrent malignant gliomas, the wafer provides an effective release of the anticancer 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) for only 5 days.

Methods: In this study, the authors developed biodegradable poly[(d,l)-lactide-co-glycolide] nanofibrous membranes via electrospinning that provided a sustained release of BCNU. An elution method and a HPLC assay were employed to characterize the in vitro and in vivo release behaviors of pharmaceuticals from the electrospun membranes.

Results: The experimental results show that the biodegradable, nanofibrous membranes released high concentrations of BCNU for more than 6 weeks in the cerebral cavity of rats. Furthermore, the membranes can better conform to the geometry of the brain tissue and can cover more completely the tissue after the removal of tumors, achieving better drug transport without interfering with the normal function of the brain. Histological examination showed no obvious inflammation reactions of the brain tissues.

Conclusion: Adopting the electrospinning technique will help in manufacturing biodegradable, nanofibrous membranes for the long-term deliveries of various anticancer drugs in the cerebral cavity, which will further enhance the therapeutic efficacy of GBM treatment.     

Enhancement of the stability of BCNU using self-emulsifying drug delivery systems (SEDDS) and in vitro antitumor activity of self-emulsified BCNU-loaded PLGA wafer

The main purpose of this study was to develop self-emulsifying drug delivery systems (SEDDS) for the improvement of the stability of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) after released from poly (D,L-lactide-co-glycolide) (PLGA) wafer and to evaluate its in vitro antitumor activity against 9L gliosarcoma cells. The in vitro stability test of BCNU was characterized by the BCNU amount in phosphate buffered saline (PBS, pH 7.4) at 37 degrees C. SEDDS increased in vitro half-life of BCNU up to 130 min compared to 45 min of intact BCNU. Self-emulsified (SE) BCNU was fabricated into wafers with flat and smooth surface by compression molding. In vitro release of BCNU from SE BCNU-loaded PLGA wafer was prolonged up to 7 days followed first order release kinetics. Beside, the cytotoxicity of SE BCNU-loaded PLGA wafer against 9L gliosarcoma cells was higher than intact BCNU-loaded PLGA wafer which is more susceptible to hydrolysis. SE BCNU degraded much more slowly than the intact BCNU in PLGA matrix at 25 degrees C. These results strongly suggest that the self-emulsion system increased the stability of BCNU after released from PLGA wafer. From these results, it could be expected that the penetration depth of BCNU could be improved in brain tissue using self-emulsion system.     

Application site adverse events associated with the buprenorphine transdermal system: a pooled analysis

Objective: To characterize the profile of application site reactions (ASRs) for patients treated with the buprenorphine transdermal system (BTDS) in chronic pain studies.

Methods: The incidences of ASRs during treatment with BTDS were examined using (a) integrated data from 16 controlled and uncontrolled Phase III chronic pain studies (N = 6566), (b) a subset of integrated data that focused on the double-blind phases of five enriched, placebo-controlled studies (n = 1806) and (c) data from an international postmarketing drug safety database. These data were compared with the ASR data reported in the full prescribing information of other transdermal patches marketed in the US.

Results: Among the 6566 patients, the overall incidence of ASRs was 23.4%, of which 98.3% were mild to moderate in intensity, none were serious and 4.4% led to treatment discontinuation. Rates of severe and inflammatory ASRs were low. Among the 1806 patients, ASR rates were higher with BTDS (16.6%) than placebo transdermal system (12.7%). Among the 6566 patients, the 1806 patients, and the postmarketing data, the most common ASRs seen were pruritus, erythema and rash. Incidences of most ASRs for other selected transdermal products were 17% or lower.

Conclusion: Incidence rates of ASRs in patients treated with BTDS were low and infrequently led to discontinuation. Severe and inflammatory-type ASRs were not common. The ASR profile of BTDS was comparable with those of other transdermal patches.     

Investigational drugs targeting 5-HT6 receptors for the treatment of Alzheimer’s disease

Introduction: There are significant efforts invested into the discovery and development of novel treatments for Alzheimer’s disease. While current discovery efforts and most scientific discussions seem to focus on disease-modifying therapy, there are several symptomatic therapy approaches that are being actively pursued. The goal of this review is to summarize the recent developments in the field of 5-HT6 receptor antagonists, a principle that has been extensively characterized preclinically and is now undergoing critical phases of clinical development.

Areas covered: The article covers the current status of 5-HT6 receptor antagonists in clinical development. It also discusses the underlying mechanisms for the observed procognitive effects. The article is based on a search for investigational drugs using the key words ‘5-HT6?, ‘cognition’, ‘dementia’, ‘Alzheimer’s disease’, ‘Phase II’ and ‘Phase III’ in various databases and from conference abstracts.

Expert opinion: After some period of little or no development activities, the field of 5-HT6 receptor antagonists attracted a lot of attention with three companies (GSK, Pfizer and Lundbeck) confirming aggressive development plans and initiating pivotal Phase II and III studies. These studies will be critical to prove that 5-HT6 receptor antagonists have a symptomatic efficacy profile that can be differentiated from that of currently used agents (cholinesterase inhibitors and the NMDA-antagonist memantine). Furthermore, there are several sets of data that point at a disease-modifying potential of this class of agents and these effects are likely to receive critical exploration if the ongoing symptomatic trials bring 5-HT6 antagonists closer to clinical use.     

Endothelin as a target for drug development: Recent progress

Introduction: The prognosis of acute myeloid leukemia (AML) is improved in the last two decades, even though induction and consolidation chemotherapy has not involved new drugs. The more effective use of well-known agents as well as refinement of supportive care during the inevitable phase of severe pancytopenia following intensive chemotherapy accounts for the reduction of treatment-related death rate. In addition, mortality due to allogeneic and autologous stem cell transplantation has also been reduced, due to adoption of more effective therapies for graft versus host disease and other transplant-related complications.

Areas covered: The multitude of chromosomal and molecular abnormalities makes the treatment of AML a challenging prospect. In addition, genetic aberrations are not mutually exclusive and coexist in the leukemic cells. As a consequence, the clinical development of new biologic agents proceeds slowly. Data for this review were identified from PubMed and references from relevant articles published in English from 2000 to 2011.

Expert opinion: In Phase II studies, different new agents have been found to be active in AML and are currently under investigation in Phase III trials also in combination with conventional chemotherapy. In the near future, we would have more information about the possibility of introducing new drugs into daily practice.     

Role of ribavirin in HCV treatment response: now and in the future

Importance of the field: Ribavirin is a broad spectrum antiviral agent that is used with pegylated IFN (Peg-IFN) for HCV treatment. Ribavirin does not significantly reduce HCV viral load when used alone but increases rates of sustained virologic response (SVR) when combined with Peg-IFN. HCV genotype 1 infected patients require higher doses of ribavirin administered for a longer duration of time versus HCV genotypes 2 and 3 patients who respond effectively to Peg-IFN with lower doses of ribavirin and shorter duration of therapy. Higher serum concentrations of ribavirin are associated with higher response rates but also higher rates of hemolytic anemia which is a dose limiting side effect. Alternatives to current therapy are under clinical evaluation.

Areas covered in this review: Systematic literature review of ribavirin use in HCV patients from 1995 to 2009 was conducted.

What the reader will gain: To review the efficacy and safety of ribavirin in current HCV treatment and in new therapies in Phase III clinical trials.

Take home message: Ribavirin is a drug which is essential to produce higher SVR rates both with Peg-IFN and HCV protease inhibitors currently in Phase III clinical trials. Thus, ribavirin is and will remain an important drug to achieving higher SVR rates in HCV infected persons.     

Sorafenib: a clinical and pharmacologic review

Importance of the field: Sorafenib is an oral receptor tyrosine kinase inhibitor that inhibits Raf serine/threonine kinases and receptor tyrosine kinases (vascular endothelial growth factor receptors 1, 2, 3 and platelet-derived growth factor-β, Flt-3 and c-kit) that are implicated in tumorigenesis and tumor progression. Sorafenib is approved for the treatment of advanced inoperable hepatocellular cancer and advanced renal cell cancer.

Areas covered in this review: The findings from the major Phase III studies that led to FDA approval of this drug for the above indications are reviewed. Key aspects of sorafenib pharmacology, dosing in the presence of organ dysfunction, toxicities and weaknesses of the research done so far are summarized.

What will the reader gain: The reader will have the knowledge of the major studies that form the basis of the clinical use of sorafenib, information on the upcoming Phase III trials that could lead to changes in clinical practice and some insights on aspects of the drugs' mechanism of action and toxicity that still remain unclear.

Take home message: Sorafenib is a well-tolerated oral antiangiogenic agent approved for treatment of two angiogenesis-driven cancers. Studies to broaden the clinical indications and increase understanding of the clinical and laboratory biomarkers of response are needed.     

Emerging neuroprotective drugs for the treatment of acute ischaemic stroke

Introduction: Neuroprotection aims to restrict the ischaemic damage following stroke by preventing salvageable neurons from dying. Despite successes in experimental stroke studies, neuroprotective strategies have failed in clinical trials so far. Nevertheless, promising neuroprotective drugs are currently being investigated in clinical trials.

Areas covered: This review provides an overview of the existing treatment of acute ischaemic stroke, discusses current research goals and puts special emphasis on emerging neuroprotective drugs. The authors systematically searched the database Clinicaltrials.gov for ongoing Phase II and Phase III clinical trials of neuroprotective drugs for acute ischaemic stroke. Mechanisms of action of these candidate neuroprotectants and the results of preceding preclinical studies and clinical pilot trials are described.

Expert opinion: In order to facilitate a successful translation from bench to bedside, future experimental studies should follow rigorous quality standards. Recent concepts to overcome the translation roadblock include the implementation of multicentre preclinical Phase III studies, the use of stroke models in non-human primates and the introduction of a preclinical trial registration.     

In vitro and ex vivo anticholinesterase activities of Erythrina velutina leaf extracts

Context: Erythrina velutina (EV) Willd (Fabaceae–Faboideae) is a medicinal tree that is commonly used in Brazil for the treatment of several central nervous system disorders.

Objective: The anticholinesterase activity of EV is described in this work.

Methods: Concentration-response curves (0–1.6?mg/mL) for EV leaf aqueous extract (AE) and alkaloid-rich extracts (AKEs) were performed in vitro. Cholinesterase inhibition was examined in mouse brains, as the cholinesterase source, and in pure acetylcholinesterase (AChE) or butyrylcholinesterase (BuChE). Mice were treated with AE or AKE (100, 200, and 400?mg/kg, p.o.) and their brains were used for the measurement of cholinesterase activity (CA) ex vivo.

Results: CA was inhibited by AE (IC₅₀?=?0.57 [0.43–0.75] mg/mL) and AKE (IC₅₀?=?0.52 [0.39–0.70] mg/mL) in brain homogenates in a concentration-dependent manner. The ex vivo experiments indicated that AE (400?mg/kg, p?<?0.05, 32.2?±?3.9% of inhibition) and AKE (all doses: p?<?0.05–p?<?0.001, 29.6?±?3.2% as the maximum inhibition) significantly inhibited CA in the central nervous system after oral administration. AE and AKE inhibited AChE and BuChE activities in a concentration-dependent manner (AE: IC_50AChE?=?0.56 [0.38–0.81] mg/mL, IC_50BuChE?=?2.95 [1.51–5.76] mg/mL, AKE: IC_50AChE?=?0.87 [0.60–12.5] mg/mL, IC_50BuChE?=?2.67 [0.87–8.11] mg/mL).

Discussion and conclusions: These data indicated that AE and AKE crossed the blood-brain barrier to inhibit CA in the brain. AE and AKE also exhibited a dual inhibitory action on acetyl- and BuChE.     

New treatment for acute myelogenous leukemia

Introduction: Acute myelogenous leukemia (AML) is a genetically heterogeneous disease. Yet current therapy has changed little over the decades and includes the nucleoside analog cytarabine in combination with an anthracycline as primary therapy. With this approach, durable cures occur in the minority of patients. With the recent improved scientific understanding of the underlying genetic and epigenetic aberrations in AML, there is now the potential of individualized and targeted therapeutic approaches for the curative treatment of AML.

Areas covered: The focus of this article is to review the therapeutic potential of many of the novel agents currently under investigation in the treatment of acute myeloid leukemia. The results of pivotal Phase III studies, as well as ongoing Phase II and III studies and selected Phase I studies with impact on the field of AML therapy will be discussed.

Expert opinion: Advances in the scientific knowledge of the various genetic and epigenetic alterations in AML, in conjunction with more effective, rationally designed and/or novel targeted therapeutics, offers a real hope and expectation of improved AML outcomes in the future.     

Efficacy and tolerability of an ulcer compression stocking for therapy of chronic venous ulcer compared with a below-knee compression bandage: results from a prospective,randomized, multicentre trial

SUMMARY

Objective: To investigate the possibility of improving healing rates in ulcus cruris venosum by using an ulcer compression stocking (U-Stocking) (Venotrain* ulcertec) as compared to compression bandages.

Research design and setting: Prospective, multicentre, open-labelled, randomized, active-controlled study with blinded assessment of the primary endpoint. Sixteen phlebology outpatient clinics in Germany or the Netherlands or German medical practices specialized in phlebology.

Patients and methods: 134 patients with venous leg ulcers entered the study. Among others, patients with infected ulcer or obesity were excluded. 121 patients were eligible for primary efficacy analyses. U-Stocking or bandages applied for at least eight hours per day and for up to 12 weeks. The primary endpoint was the healing rate after 12 weeks as assessed by planimetric measures. The secondary outcome variables were time to healing, changes in ulcer size (planimetry), experience of use and patient compliance.

Main outcome measures: Therapy with the U-Stocking produced a significantly higher rate of complete healing of 47.5% (29/61) versus 31.7% (19/60) with bandages, 1-sided p = 0.0129 [CI: 95% for differences: 4.3% to 28.5%]. Mean time to healing was 46 days in both groups. Time required for application of the U-Stocking was a mean of 5.4?min (SD 5.4) versus 8.5?min (SD 6.5) for bandages, p = 0.0001. Around three patients in each treatment group were affected by serious adverse events. All treatment-related adverse events are known for compression therapy.

Conclusions: The U-Stocking was superior to bandages in compression therapy for venous ulcer. This is of significance to new treatment standards as well as to future studies of longer term therapy (> 12 weeks) for unhealed ulcers or prevention of recurrence.