[What does pain intensity mean from the patient perspective? : A qualitative study on the patient perspective of pain intensity as an outcome parameter in treatment evaluation and on the interpretability of pain intensity measurements]. / Was bedeutet Schmerzintensität aus Sicht der Patienten? : Eine qualitative Studie zur Patientenperspektive auf Schmerzstärke als Konstrukt in der Therapieevaluation und die Interpretierbarkeit der Schmerzstärkemessung.

BACKGROUND: Pain intensity (PI) is a common outcome parameter in effectiveness studies on interdisciplinary multimodal pain therapy (IMPT), despite the fact that IMPT highlights dealing with rather than reducing chronic pain. Moreover, the measurement of pain intensity as a highly subjective experience is problematic. Patient participation is absolutely essential to examine the relevance of PI as a criterion of treatment success as well as to select/develop suitable measurement methods. METHOD: A qualitative multicenter study was conducted using focus groups with 69 patients (18-77 years; 80% female) at four different IMPT centers in Germany to discuss pain intensity as a therapy outcome parameter in IMPT, as well as the interpretability and feasibility of common measurement methods. RESULTS: The discussions emphasized that PI is a relevant, but not the primary, outcome in IMPT for patients. Patients' statements also demonstrate that there are some problems in measuring PI, for instance with regard to pain attacks. CONCLUSIONS: The focus group discussions suggested that, due to the highly subjective nature of PI, as well as (verbal) inaccuracies and a lack of standardization in common instruments, the measurement of pain intensity is a challenging task. These limitations should be taken into account in future studies.

A phase III randomized controlled study on the efficacy and improved bowel function of prolonged-release (PR) oxycodone-naloxone (up to 160/80 mg daily) vs oxycodone PR.

BACKGROUND: Oxycodone/naloxone (OXN PR) is a prolonged-release formulation containing oxycodone and naloxone in a 2:1 ratio. This study aimed to evaluate the tolerability and efficacy of doses up to OXN160/80 mg PR compared with oxycodone prolonged-release formulation (OxyPR) in a randomised controlled trial. METHODS: Two hundred and forty-three patients were randomised to treatment with OXN PR (n = 123) or OxyPR (n = 120) during the 5-week double-blind study. Measured were: opioid-induced constipation [bowel function index score (BFI)]; analgesic efficacy (NRS 0-10); daily laxative rescue medication use; rescue medication use, and the number of complete spontaneous bowel movements (CSBMs) per week. A subanalysis was conducted in cancer patients. RESULTS: Greater reductions in mean BFI scores were reported for the OXN PR group compared with OxyPR from Week 1 onwards; at Week 5 the mean change from baseline was -32.5 versus -14.2. Average 24-h pain scores were low and remained stable in the range 3-4 in both treatment groups. Analgesic rescue medication use was similar between the groups. Patients receiving OXN PR used significantly lower mean daily doses of laxative rescue medication than those receiving OxyPR (P = 0.006). The number of CSBM in the OXN PR group approximately doubled compared with a 25% decrease in the OxyPR group. Comparable results to the total study population were reported in the cancer patient subgroup. CONCLUSIONS: OXN PR in daily doses of up to 160/80 mg significantly improves bowel function compared with equivalent doses of OxyPR while still providing comparable analgesic efficacy. SIGNIFICANCE: Effective analgesia can be achieved using oxycodone/naloxone PR up to 160/80 mg daily without compromising bowel function. A similar outcome was reported in cancer and non-cancer patients.

Long-term efficacy and safety of oxycodone-naloxone prolonged-release formulation (up to 180/90 mg daily) - results of the open-label extension phase of a phase III multicenter, multiple-dose, randomized, controlled study.

BACKGROUND: The inclusion of naloxone with oxycodone in a fixed combination prolonged-release formulation (OXN PR) improves bowel function compared with oxycodone (Oxy) alone without compromising analgesic efficacy. In a recent 5-week, randomized, double-blind comparative trial of OXN PR and OxyPR, it could be shown that the beneficial properties of OXN PR extend to doses up to 160/80 mg. METHODS: Bowel function, pain, quality of life (QoL) and safety of OXN PR up to 180/90 mg daily were evaluated in a 24-week open-label extension phase of the 5-week randomized comparative study in patients with non-malignant or malignant pain requiring opioids and suffering from opioid-induced constipation. RESULTS: During treatment with a mean (SD) daily dose OXN PR of 130.7 (26.56) mg (median, maximum: 120 and 180 mg), the Bowel Function Index (BFI) decreased from 45.3 (26.37) to 26.7 (21.37) with the largest decrease seen in the first week. The average pain over the last 24 h remained stable (median Pain Intensity Scale score 4.0) and QoL was maintained throughout the study. Adverse events were consistent with the known effects of OXN PR and no new safety concerns emerged. Equivalent efficacy and safety benefits were observed in cancer patients. CONCLUSIONS: The OXN PR in doses up to 180/90 mg provides effective analgesia with maintenance of bowel function during long-term treatment. The beneficial effects of such dose levels of OXN PR contribute to stable patient-reported QoL and health status despite serious underlying pain conditions, such as cancer. SIGNIFICANCE: In patients with pain requiring continuous opioid therapy at doses above 80 mg of oxycodone, stable and effective long-term analgesia can be achieved using OXN PR up to 180/90 mg daily without compromising bowel function and may be preferential to supplemental oxycodone.

Receptor tyrosine kinase Axl is required for resistance of leukemic cells to FLT3-targeted therapy in acute myeloid leukemia.

In acute myeloid leukemia (AML), about 25-30% of patients harbor a constitutively active receptor tyrosine kinase (RTK) FLT3 encoded by a FLT3 allele harboring internal tandem duplication (FLT3-ITD) mutation. The presence of FLT3-ITD correlates with poor prognosis in AML and it makes FLT3 an attractive therapeutic target in AML. Unfortunately, to date small-molecule inhibitors of FLT3 have resulted in only partial and transient clinical responses with residual leukemic blasts resistant to FLT3 inhibitors detected in blood or bone marrow. In this study, we investigated whether the RTK Axl is responsible for resistance of FLT3-ITD(+) AML cells to PKC412 and AC220, FLT3 inhibitors currently under clinical trials for FLT3-ITD(+) AML patients. Upon treatment with PKC412 or AC220, phosphorylation of Axl was significantly enhanced in the FLT3-ITD(+) MV4-11 AML cell line and in primary blasts from a FLT3-ITD(+) AML patient. Consistently, a PKC412-resistant AML cell line and PKC412-resistant primary blasts from FLT3-ITD(+) AML patients had significantly higher levels of constitutively phosphorylated Axl and total Axl when compared with a PKC412-sensitive AML cell line and PKC412-sensitive primary blasts from FLT3-ITD(+) AML patients. We also found that resistance of AML cells against the FLT3 inhibitor PKC412 and AC220 was substantially diminished by the inhibition of Axl via a small-molecule inhibitor TP-0903, a soluble receptor Axl fusion protein Axl-Fc or knockdown of Axl gene expression by shRNA. Collectively, our study suggests that Axl is required for resistance of FLT3-ITD(+) AML cells against the FLT3 inhibitor PKC412 and AC220, and that inhibition of Axl activation may overcome resistance to FLT3-targeted therapy in FLT3-ITD(+) AML.

Long-term evaluation of combined prolonged-release oxycodone and naloxone in patients with moderate-to-severe chronic pain: pooled analysis of extension phases of two Phase III trials.

BACKGROUND: While opioids provide effective analgesia, opioid-induced constipation (OIC) can severely impact quality of life and treatment compliance. This pooled analysis evaluated the maintenance of efficacy and safety during long-term treatment with combined oxycodone/naloxone prolonged-release tablets (OXN PR) in adults with moderate-to-severe chronic pain. METHODS: Patients (N = 474) received open-label OXN PR during 52-week extension phases of two studies, having completed 12-week, double-blind, randomized treatment with oxycodone prolonged-release tablets (Oxy PR) or OXN PR. Analgesia and bowel function were assessed at each study visit using 'Average pain over last 24 h scale and Bowel Function Index (BFI), respectively. Treatment Satisfaction Questionnaire for Medication was assessed at study end only. KEY RESULTS: Improvement in bowel function was particularly marked in patients who switched from Oxy PR in the double-blind phase to OXN PR during the extension phase, resulting in a clinically meaningful reduction (≥12 points) in BFI score: at the start of the extension phases, mean (SD) BFI score was 44.3 (28.13), and was 29.8 (26.36) for patients who had received OXN PR in the double-blind phase. One week later, BFI scores were similar for the two groups (26.5 [24.40] and 27.5 [25.60], respectively), as was observed throughout the following months. Fewer than 10% of patients received laxatives regularly. Mean 24-h pain scores were low and stable throughout the extension phases. No unexpected adverse events were observed. CONCLUSIONS & INFERENCES: Pooled data demonstrate OXN PR is an effective long-term therapy for patients with chronic non-cancer pain, and can address symptoms of OIC. No new safety issues were observed which were attributable to the long-term administration of OXN PR.

The Bowel Function Index for evaluating constipation in pain patients: definition of a reference range for a non-constipated population of pain patients.

Opioid-induced constipation (OIC) is a severe, persisting side-effect of opioid therapy. The Bowel Function Index (BFI(a), numerical analogue scale 0 - 100), calculated as the mean of three variables (ease of defaecation, feeling of incomplete bowel evacuation, and personal judgement of constipation) was developed to evaluate bowel function in opioid-treated patients with pain. This clinician-administered tool allows easy measurement of OIC from the patient's perspective. The purpose of this investigation was to define a reference range reflecting BFI values in non-constipated chronic pain patients who were recruited into a cross-sectional survey and asked for their perceptions of constipation. The BFI scores were assessed and compared with those of patients with confirmed OIC obtained from two previously published trials. Results were analysed and a reference range of BFI values of 0 - 28.8, into which 95% of non-constipated chronic pain patients fell, was defined. This permits discrimination between chronic pain patients with, or without, constipation.

Fixed-ratio combination oxycodone/naloxone compared with oxycodone alone for the relief of opioid-induced constipation in moderate-to-severe noncancer pain.

OBJECTIVE: Opioid therapy is frequently associated with treatment-limiting constipation. Naloxone is an opioid antagonist with low oral systemic bioavailability. This Phase III clinical trial assessed the safety and efficacy of an oral fixed-ratio combination of oxycodone prolonged-release (PR) and naloxone PR compared with oxycodone PR in relieving opioid-induced constipation. STUDY DESIGN: This double-blind, multicenter trial was conducted in specialist and primary care centers in four European countries in an out-patients setting. The study included 322 adult patients with moderate-to-severe, noncancer pain requiring opioid therapy in a range of >or=20 mg/day and

[Local therapy of grade IIa burns: efficacy and tolerability of a new hydrosome wound gel for the local treatment of grade IIa burns as compared with silver sulfadiazine ointment]. / Lokale Behandlung von Grad-IIa-Verbrennungen : Wirksamkeit und Verträglichkeit eines neuartigen hydrosomalen Wundgels im Vergleich zu Silbersulfadiazin-Creme.

BACKGROUND: A new hydrosome wound gel is based on a new mechanism of action. It contains hydrosomes that penetrate to the wound bed and supply the wound with phospholipids, which are identical to membrane phospholipids of human cells. In this manner it supports the proliferative processes during wound healing. PATIENTS AND METHODS: In a randomized, controlled, intraindividual comparative study of 47 patients with grade IIa burns, the hydrosome wound gel was tested against silver sulfadiazine cream. Digital pictures of the burn wounds were taken daily, and the wounds were analyzed in terms of their reepithelization rate. RESULTS: Wounds receiving the hydrosome wound gel healed 1.5-2 days faster than wounds treated with sulfadiazine cream (9.9+/-4.5 days vs. 11.3+/-4.9 days, p=0.015). In 66% of the patients, faster epithelization was observed with the hydrosome wound gel treatment. The hydrosome gel guaranteed secure prophylaxis against infection, and it was well tolerated and easy to apply. CONCLUSION: In this study, the treatment of grade IIa burn wounds with hydrosome wound gel led to faster wound closure compared with treatment with sulfadiazine cream. Therefore, hydrosome gel represents a good alternative to sulfadiazine cream.

A clinical study on the tolerability of a liposomal povidone-iodine nasal spray: implications for further development.

PURPOSE OF STUDY: This phase I study assessed tolerability and local effect of a liposome dispersion with povidone-iodine (polyvinylpyrrolidone-iodine, PVP-I) as nasal spray. PROCEDURES: Three groups received liposomal dispersion with PVP-I (2.2, 4.4 and 0% as control) in single and repeated use (3 days, three times a day). A set of functional and cytological tests as well as safety assessments were performed. RESULTS: No safety-relevant finding or serious adverse events were reported, no evidence for cyto- nor genotoxicity obtained. No clinically relevant changes in mucosa appearance, nor in olfactory sense, nor in ciliary activity (sensitive indicator of local tolerance) occurred and no complaints about nasal airflow obstruction were observed. All liposomal formulations had a positive effect on the nasal mucosa, challenged by allergy in some volunteers. CONCLUSIONS AND MESSAGE: Application of liposomal PVP-I spray to the nasal mucosa does not result in any demonstrable limitation of the nasal function nor in detectable damage to the multilayer ciliated epithelium of the nose. Improvement of various parameters of nasal function under liposomal PVP-I suggest improved mucociliary clearance. Explanation could be humidification, improved surfactant (phospholipid) level and/or sufficient mucolytic activity of iodide due to local application of the constituents.

[Efficacy of treatment with Repithel and Jelonet in comparison to treatment with Jelonet alone - a randomized clinical trial in patients receiving meshed skin grafts]. / Wirksamkeit der Behandlung mit Repithel und Jelonet im Vergleich zur alleinigen Anwendung von Jelonet - eine randomisierte klinische Studie an Meshgraft-Transplantationswunden.

UNLABELLED: Moist wound treatment is a well recognized method for the treatment of aseptic acute and chronic wounds. While the moist environment is beneficial to the woundhealing process, it also increases the risk of bacterial superinfection. We here report on the results of a clinical phase-III-study in which we tested the effect of a new PVP-iodine liposomal hydrogel (Repithel) on split-thickness skin grafts. This formulation optimizes moist wound treatment by improving the cell proliferation rate while preventing wound infection. AIM: The aim of this phase-III-study was to analyse the efficacy and tolerance of Repithel in patients receiving meshed skin grafts. METHODS: 167 patients with transplantation wounds were either treated with lipid gauze alone (control group) or with lipid gauze and Repithel. In both groups the extent of neoepithelization, the frequency and severity of graft losses and the time until complete wound closure was achieved were determined. Analysis of the re-epithelization was achieved by photoplanimetry. Impedance measurements gave additional information on the regeneration of the epidermal barrier. RESULTS: Wounds receiving Repithel showed a significantly faster neoepithelisation than wounds which were treated with lipid gauze alone. Treatment with Repithel significantly reduced both the number of graft losses and the size of area lost. The time until wounds were closed completely was significantly shorter in patients receiving Repithel than in controls. The positive effects of Repithel on wound healing were especially observed in smokers, patients with chronic wounds, burns or infected wounds. CONCLUSIONS: Repithel supports healing of meshgraft transplants and reduces the risk of graft loss. Patients who heal poorly benefit particularly from the Repithel treatment.

PVP-iodine in hydrosomes and hydrogel--a novel concept in wound therapy leads to enhanced epithelialization and reduced loss of skin grafts.

BACKGROUND: Moist wound treatment improves healing at a possibly increased risk of bacterial infection and many local antiseptics impair healing. A moist treatment modality with efficient antimicrobial activity would be desirable. METHODS: In this monocentric, randomized, observer blinded, phase III study, a new hydrosome polyvinyl-pyrrolidone (PVP)-iodine preparation in hydrogel containing iodine in a 3% concentration (Repithel) was investigated for its effect on epithelialization in patients receiving meshed skin grafts. Grafts of 167 patients (donor site defects, burn wounds, or chronic defects) were dressed either with Repithel (n=83) covered with a gauze (Jelonet), or Jelonet-gauze only (n=84) until healing. RESULTS: Grafts receiving Repithel healed significantly earlier (9.4 days versus 12.4 days; p<0.0001) and faster than controls as measured by neo-epithelialization of mesh holes between days 7 and 11 (91.2+/-22.8% versus 82.3%+/-28.6, p<0.0001). A subgroup analysis showed that the effects on grafted burn wounds (p=0.0042) and chronic defects (p<0.0001) was more significant than on donor sites. Also a higher take rate of grafts (p=0.0053) and a reduced loss of grafts was observed with Repithel treatment (8 grafts versus 20 grafts) (p=0.0063, respectively). Smokers had improved graft take (p=0.0069) and higher rate of epithelialization (p=0.0040) compared to smokers of the control group. CONCLUSIONS: The results demonstrate significant clinical advantages of Repithel. This new local wound healing drug combines antisepsis and wound moisture efficiently resulting in significantly enhanced epithelialization, decreased transplant losses, and significantly improved healing especially in smokers.

Repithel: removing the barriers to wound healing.

BACKGROUND: Various standardized and/or validated models exist to test wound healing products. This article discusses their usefulness in clinical practice. OBJECTIVES: Major barriers to wound healing have been identified after intense interaction of research and practitioners. Although extensively tested, wound healing products are still associated with trial and error due to the high variability and complexity associated with the treatment of wounds. Therefore, the results of preclinical testing are compared and contrasted with clinical observations of a liposomal hydrogel containing 3% povidone-iodine (Repithel, PVP-ILH) to assess their expressiveness and to give the practitioner more guidance in application. METHODS: Testing of PVP-ILH included physicochemical testing according to ISO norms, testing in in vitro and in vivo models. The obtained results are compared to the clinical profile of the obtained product in randomized controlled trials and ultimately expressive case studies. RESULTS: PVP-ILH displays good local tolerance, the basis for use in sensitive and predamaged tissue. As observed in laboratory testing, it readily provides moisture and takes up limited amounts of moisture. This was also seen in the clinical testing, as the ability to keep wounds moist and incorporate a certain -- but not large -- amount of exudates. Clinical results also show clean, well-debrided wounds, an effect that (in the absence of an established model for wound cleansing) was traced to the hydrogel component carbomer. DISCUSSION: Recent consensus advocates the concept of wound bed preparation as a systematic approach to removing barriers to healing (TIME). Based on the results, tissue (removing non-viable tissue and debris) and moisture (balance) can now be better understood, and infection/inflammation (control) and edge (progressing, non-advancing or undermining wound edges) are reviewed together with previously published data to assess all aspects potentially impeding wound healing. CONCLUSION: PVP-ILH successfully removes barriers to wound healing, thus laying the foundation to high-quality wound closure. Results from many scientific disciplines can help the user to better understand a product, standardization of testing is the only way of making results comparable.

Effect of polyvinylpyrrolidone-iodine liposomal hydrogel on wound microcirculation in SKH1-hr hairless mice.

AIM: Polyvinylpyrrolidone-iodine liposomal hydrogel (PVP-ILH) is a hydrogel formulation based on polyvinylpyrrolidone-iodine (PVP-I) and liposomes. The beneficial effects of PVP-ILH on wound healing have been previously shown. The aim of this study was to investigate the effects of topically applied PVP-ILH on wound microcirculation. MATERIALS AND METHODS: Experiments were performed on wounds in male SKH1-hr hairless mice (n = 48). Mice were randomized into five treatment groups: mice treated with polyacrylic acid (PAA) and PAA 1:10 as well as PVP-ILH and PVP-ILH 1:10. Mice treated with sodium chloride served as control. Immediately as well as 3, 7, and 14 days after wounding, intravital fluorescent microscopy (IFM) was performed to determine wound surface area and standard microcirculatory parameters. RESULTS: Topically administered PVP-ILH reduced wound size significantly faster compared to controls. Standard microcirculatory parameters, e.g. functional capillary density (FCD) and plasma leakage, showed no differences. FCD increases in all groups after wound creation. Using PVP-ILH, a trend towards higher FCD was observed. CONCLUSION: The wound model in hairless mice in combination with IFM is suitable to qualitatively assess wound microcirculation over a period of 2 weeks even after topical application of pigmented ointments. PVP-ILH showed a positive effect on dermal wound healing and wound microcirculation.

[Oral controlled-release oxycodone for the treatment of chronic pain. Data from 4196 patients]. / Therapie chronischer Schmerzen mit oralem retardiertem Oxycodon. Behandlungsdaten von 4196 Patienten.

Oral controlled-release oxycodone has been available for the treatment of chronic pain in Germany since 1998. Controlled trials have shown good clinical efficacy and tolerability. This survey reports results from six open prospective multicenter trials. In these trials 4196 patients suffering from cancer pain and non-cancer-related pain with inadequate pain relief were treated with oral controlled-release oxycodone for 3-4 weeks. Only a few participating physicians were pain specialists. A total of 356 patients suffering from pain of the musculoskeletal system and receiving oxycodone therapy were monitored for 6 months. Exclusion from the studies was due mainly to inadequate analgesia, side effects, and noncompliance. The efficacy of oxycodone was rated to be better than moderate by most of the patients, quality of life parameters increased significantly, and patient satisfaction was high. The treatment with oral controlled-release oxycodone was a safe and effective option even when used by nonspecialized physicians.

In vitro antiviral activity of thirty-six plants from La Réunion Island.

Methanol extracts of 36 medicinal plants from La Réunion Island were evaluated against two viruses: Herpes simplex type 1 (HSV-1) and poliovirus type 2 (PV). Five of them showed an effect against HSV-1 and five against PV, Senecio ambavilla being inhibitor for both viruses.

[Preparation for colonoscopy: A comparison between 3 commercially available Golytely solutions]. / Koloskopievorbereitung: ein Vergleich von 3 Fertig-Golytely-Lösungen.

The preparation for colonoscopy is essential for the results of the examination. The effectiveness of 3 commercially available Golytely solutions for colonoscopy (Original-Golytely-salt, Oralav and Delcoprep) were compared in a randomized prospective study. 310 outpatients were randomized into 3 groups. One of the above-mentioned solutions were used in these patients. Before the examination the patients were asked to drink 3 l of the given solution within 2 h. The colonoscopy was realized within 3-5 h after the end of preparation. Outcome criteria were the subjective acceptability of the solution for the patient, cleanness of the bowel and the formation of foam. In all 3 groups sufficient up to very good results could be achieved. There were no significant differences in the 3 groups. We conclude that the used procedure is absolutely sufficient to prepare for colonoscopy and that administration of liquids of more than 3 l or the use of enema or laxans on the previous day, are unnecessary. The suggested procedure can be used for children, too.

Polyvinyl pyrrolidone-iodine liposome hydrogel improves epithelialization by combining moisture and antisepis. A new concept in wound therapy.

Moist treatment of wounds has been shown to improve epithelialization, however at an increased risk of bacterial infection. In this monocentric, randomized, open, phase II pilot study of polyvinyl pyrrolidone-iodine, a well-established topical antiseptic was tested in a new liposomal complexed form in patients receiving meshed skin grafts after burns or reconstructive procedures. Mesh skin graft sites of 36 patients were dressed either with the new polyvinyl-pyrrolidone-iodine liposome hydrogel formulation (Betasom hydrogel) (n = 21), or chlorhexidine-gauze (n = 15). After the first dressing change, wounds were assessed daily and documented every other day until they were healed. Methods of analysis included clinical assessment, photoplanimetry (rate of epithelialization), impedance measurement (moisture of surface and wound healing quality), patient's assessment of pain and other sensations, and thyroid hormones (T3, T4, and TSH). The rate of epithelialization was improved with Betasom hydrogel compared to chlorhexidine-gauze on day 11 (96.3% vs. 75.9% p = 0.056) and significantly on day 13 (100% vs. 82.3% p = 0.005), respectively. Impedance measurements showed an earlier return to normal values (day 9) in Betasom-hydrogel-treated wounds as opposed to chlorhexidine treatment (day 11). Clinical assessment indicated significantly better antiseptic efficacy (p = 0.002) and wound healing quality (p = 0.004) of Betasom hydrogel. Graft loss occurred at a significantly lower rate in Betasom treatment (n = 1; 5%), than in chlorhexidine treatment (n = 5; 35.7%) (p = 0.001). No relevant adverse events or clinically relevant changes of thyroid hormones were observed with Betasom hydrogel. The rationale of this new polyvinyl pyrrolidone-iodine liposomal formulation was based on the properties of liposomes that provide higher moisture to the wound surface, release PVP-iodine at a low rate, and target the substance more exactly by interaction with the cell surface. These initial clinical results show earlier epithelialization and better healing in wounds treated with polyvinyl pyrrolidone-iodine liposome hydrogel, which combines moisture and antisepsis, compared to wounds treated with a conventional antiseptic chlorhexidine-gauze.