Quality of life in patients with leg ulcers: results from CHALLENGE, a double-blind randomised controlled trial.

OBJECTIVE: We recently showed the superiority of a matrix metalloproteinase (MMP) modulating dressing (foam impregnated with NOSF, nano-oligosaccharide factor) compared with a lipidocolloid matrix (TLC) control dressing in median wound area reduction (WAR). Here we report the results from the same study assessing the performance and safety of TLC-NOSF in the local management of venous leg ulcers (VLUs) or mixed leg ulcers and determining its impact on the patient's health-related quality of life (HRQoL). METHOD: A superiority randomised double-blind controlled trial was conducted on patients presenting with a non-infected leg ulcer (VLUs or mixed leg ulcers) of predominantly venous origin (ABPI >0.8), with a surface area ranging from 5 to 50cm2 and a duration of 6 to 36 months. Patients were randomly allocated to either the TLC-NOSF matrix foam (UrgoStart) dressing group or to the neutral TLC foam dressing group (UrgoTul Absorb). All received appropriate compression therapy and the wounds were assessed blindly (clinical examination, wound area tracing and photographic record) every 2 weeks for a period of 8 weeks, or until complete closure. A secondary endpoint, described here, was the patient's HRQoL, documented by the patient, through the EuroQol 5D tool (EQ-5D) questionnaire and visual analogue scale (VAS). RESULTS: In total, 187 patients were randomised to either the TLC-NOSF group (n=94) or the control dressing group (n=93). The two groups were well balanced at baseline with regard to wound and patient characteristics. In the HRQoL questionnaire (EQ-5D), the pain/discomfort and anxiety/depression dimensions were significantly improved in the TLC-NOSF group versus the control one (pain/discomfort: 1.53±0.53 versus 1.74±0.65; p=0.022, and anxiety/depression: 1.35±0.53 versus 1.54±0.60, p=0.037). The VAS score was better in the test group compared with the control group (72.1±17.5 versus 67.3±18.7, respectively), without reaching significance (p=0.072). Acceptability and tolerance of the two products were similar in both groups. CONCLUSION: The double-blind clinical trial has demonstrated that the TLC-NOSF matrix dressing promotes faster healing of VLUs and mixed leg ulcers and significantly reduces the pain/discomfort and anxiety/depression experienced by the patients. These results suggest that acceleration of VLU healing could improve the HRQoL of the patients and reduced the emotional and social burden of these chronic wounds.

Management of diabetic foot ulcers with a TLC-NOSF wound dressing.

OBJECTIVE: To evaluate the efficacy, tolerance and acceptability of UrgoStart Contact (Laboratoires Urgo), a new wound dressing impregnated with NOSF, as an MMP regulator in the management of neuropathic diabetic foot ulcers. METHOD: A multicentre, pilot, prospective, non-controlled open-label clinical trial. Adult patients with type 1 or 2 diabetes mellitus, who had a grade 1A (Texas classification), uninfected, neuropathic foot ulcer, 1-15cm2 in size and of 1-20 months' duration (mean 6.7 ± 5.2 months) were included in the study. The primary endpoint was the relative reduction of the wound surface area (%) at the end of the study. Secondary endpoints included rate of complete healing, and tolerability and acceptability of the dressing. The wound dressing was changed regularly at the investigator's discretion, in accordance with the wound status and exudate level. Patients were followed up every 2 weeks for a 12-week period. At each visit, patients underwent clinical assessments, and ulcer surface area was measured by planimetry and photographs. RESULTS: Thirty-four diabetic patients with a neuropathic foot ulcer were included but only 33 cases were analysed, as data were completely lost for one patient. At baseline, mean surface area was 2.7±2.4cm2. At the 12-week follow-up, the median surface area reduction was 82.7% (mean reduction 62.7 ± 49.9%) and in 10 of the 33 analysed patients (30%) the wound was healed. Only two of the seven documented local adverse events were deemed to be dressing related. According to the nursing staff, acceptability was considered very satisfactory, particularly in term of conformability and ease of use. CONCLUSION: This pilot study indicates that use of the new UrgoStart Contact dressing, combined with offloading and debridement,may help promote the healing process of the neuropathic diabetic foot ulcers, and was well tolerated and accepted.

Efficacy of two compression systems in the management of VLUs: results of a European RCT.

OBJECTIVE: To evaluate the efficacy, tolerance and acceptability an innovative two-layer system (KTwo; Laboratoires URGO) versus an established four-layer bandage system (Profore; Smith & Nephew) in the local management of venous leg ulcers. METHOD: A non-inferiority European randomised controlled trial, conducted in 37 centres, in three countries (France, U.K. and Germany), on patients presenting with venous leg ulcers (VLUs). Participants were adult, non-immunosuppressed patients who presented with non-infected, non-malignant leg ulcers, predominantly of venous origin (ABPI > 0.8), with a surface area of 2-50 cm2 and duration 1-24 months. Patients were followed-up every 2 weeks for a period of 12 weeks, or until full closure. Visits included a clinical examination, wound area tracings and photographic evidence. The primary endpoint was the percentage of leg ulcers healed after the 12 weeks, with secondary endpoints of relative wound area reduction (RWAR), absolute wound area reduction (AWAR) and the percentage of wounds with RWAR > or = 40%. RESULTS: In total, 187 patients were randomised to either the two-layer bandage (2LB, n=94) or four-layer bandage (4LB; n=93) system. The two groups were comparable,with regard to wound and patient characteristics, at baseline. By week 12, 44% of VLUs in the 2LB group and 39% in the 4LB group had healed (intention-to-treat [ITT] analysis). The per-protocol (PP) analysis showed that complete wound closure was obtained in 48% and 38% of the 2LB and 4LB groups, respectively. A non-inferiority margin within -10% is considered as demonstrating a 95% and 97.5% confidence interval (p = 0.001). The AWAR was 6.6 cm2 in the test and 4.9 cm2 in the control group. The percentage of wounds with a RWAR > OR =40% was 47% and 44% for the 2LB and 4LB systems, respectively. Pain between dressing changes was reported in 27% of the test and 40% of the control group, and the incidence of adverse events was 17% and 25%, respectively. The 2LB compression system was considered to be significantly easier to apply than the 4LB (p = 0.038). CONCLUSION: The 2LB system (KTwo) was not seen to be any less effective than a well-known 4LB system (Profore) in the management of VLUs. Furthermore, the 2LB system was considered to be easier to apply, representing an alternative to the conventional treatment with 4LB currently available. DECLARATION OF INTEREST: This study was sponsored by a grant from Laboratoires URGO, manufacturers of KTwo. S. Bohbot and A. Sauvadet are employees of Laboratoires Urgo. S. Meaume has received monetary compensation as a speaker for Laboratoires Urgo. Data management and statistical analyses were conducted by Vertical (J. C. Kerihuel; Paris, France).

Evaluation of a new silver foam dressing in patients with critically colonised venous leg ulcers.

OBJECTIVE: To evaluate the performance (efficacy and safety) of an absorbent dressing impregnated with silver salts (UrgoCell Silver) in the management of leg ulcers with clinical signs of critical colonisation. METHOD: This was a prospective multicentre non-comparative phase III clinical trial. Patients were assessed weekly for up to four weeks. Assessment included clinical assessment of critical colonisation (severe spontaneous pain between dressing changes, erythema, oedema, malodour and heavy exudate), wound area tracing and photography. Acceptability was documented by the nursing staff when dressings were changed between two weekly evaluations. RESULTS: Forty-five leg ulcers were included. At baseline the mean number of clinical signs of critical colonisation per ulcer was 3.6 +/- 0.7, which decreased to 1.2 +/- 1.2 at the end of the fourth week of follow-up (an average reduction of 2.3 +/- 1.3, p < 0.001). Oedema, malodour, erythema and spontaneous pain disappeared at the fourth week in 80%, 70%, 69% and 65% of the treated ulcers respectively. Compared with baseline, the mean reduction in ulcer area was 35.0 +/- 58.0% (median 33%, p < 0.001) after the four weeks treatment. Granulation tissue covered a mean 77% of the ulcer surface area at four weeks, compared with 41% at baseline. Only three local events were documented: contact dermatitis, a burning sensation and erythema. CONCLUSION: The results suggest that the test dressing had a favourable influence on the wound prognosis, and was well tolerated and accepted in the treatment of venous leg ulcers with clinical signs of critical colonisation.

Optimizing wound care with a new lipido-colloid dressing (Urgotul Duo).

This non-comparative, multicentre clinical trial includes 43 patients whose acute or chronic wounds were treated with a new lipido-colloid dressing, Urgotul Duo, for at most 4 weeks, or until healing first occurred. The efficacy, tolerance and acceptability results obtained from this 'ready-for-use' dressing were similar to those reported for the Urgotul dressing in numerous previous clinical trials, and for all the different types of acute and chronic wounds. This well-tolerated new dressing greatly facilitates care operations in terms of execution (reduced use of supplementary gauzes for the secondary dressing) and duration (shorter nursing time), while improving patient comfort. This dressing is indicated for the local treatment of moderate exudative acute and chronic wounds in the granulation and epidermization phases.

Leg ulcers and the Urgocell Non-Adhesive wound dressing.

The objectives of this clinical trial were to evaluate the efficacy and tolerance of the Urgocell Non-Adhesive (NA) dressing in the local management of venous or mixed leg ulcers. The study was a non-comparative, prospective, multicentre (15 centres) phase III, clinical trial. The studied population was composed of non-immunodepressed adults presenting a venous or mixed leg ulcer, uninfected, non-cancerous, present for less than 18 months. Patients were followed up for 6 weeks with a weekly visit, including a clinical examination, area tracings and photographs. Evaluation by nursing staff and patients was performed at each dressing changed. Forty-three patients were included, presenting a leg ulcer with a mean surface area of 10.7 cm2. The surface area was reduced by a mean of 38% after 6 weeks of treatment. Four local adverse events were deemed to be related to the tested treatment and acceptability was noted very good for patients and nursing staff. The Urgocell NA dressing, combined with compression therapy, promoted the healing of the chronic wounds under study. The good tolerance and acceptability of the tested dressing were greatly appreciated.

Inhibition of the sarcolemmal Ca2+ pump in embryonic chick heart cells by mini-glucagon.

The effect of mini-glucagon, the metabolite (19-29) of glucagon was examined on the sarcolemmal (SL) Ca2+ pump activity measured in situ, in single quiescent embryonic chick heart ventricular cells loaded with Fura-2. The method consisted in triggering limited cytosolic Ca2+ concentration ([Ca2+]i) pulses by the addition of the Ca2+ ionophore 4-bromo-A23187. [Ca2+]i decays, imposed by the addition of EGTA, were monitored in conditions in which only the SL Ca2+ pump could ensure [Ca2+]i removal, i.e. in the presence of the sarcoplasmic reticular (SR) Ca2+ pump specific inhibitor, thapsigargin, substituting NaCI by LiCI in the external medium in order to quench the Na+/Ca2+ exchanger, and under null Ca2+ gradient. Mini-glucagon elicited a dose-dependent inhibition of the SL Ca2+ pump, maximal 80% inhibition being observed with 1 nM mini-glucagon. In addition to its effect on the SL Ca2+ pump, mini-glucagon evoked a delayed onset of a [Ca2+]i oscillatory response in cells incubated in normal conditions. Both effects of mini-glucagon were mimicked by vanadate tested at 2 microM, a concentration at which it acts as a specific inhibitor of the SL Ca2+ pump. These results define the contribution of the cardiac sarcolemmal Ca2+ pump to Ca2+ homeostasis in situ and its role as a target for mini-glucagon action.

[Hydrocolloids and lubricating materials in the treatment of acute and chronic wounds]. / Hidrocoloides y materias grasas en el tratamiento de heridas agudas y crónicas.

The authors carry out a study on a dressing which associates hydrocolloids and a lubricating material, Vaseline, used on 28 patients who suffer from acute or chronic wounds having diverse etiologies. The authors evaluate the biological process through which each wound builds scar tissue, its tolerance, efficiency and degree of acceptance with results which are frankly positive. The data in this study for these parameters coincide with those of other research projects which have been carried out in France, Germany and the United Kingdom.

[Calcium signal and contraction]. / Signal calcium et contraction.

The calcium ion plays a unique role as a messenger and a cofactor in cardiac contraction. This role relies on the strict control by the cell of Ca homeostasis, the components of which are described in this review. During the few last years, tools for the measurement of free intracellular Ca in living cells have been developed which include: probes (aequorin, Fura 2, Indo 1, Fluo 3...), tools for the loading of the cells (microinjection and AM-probes) and systems to analyze the signal (photometers, microfluorimeters, confocal microscopy). Those tools allowed the analysis of calcium signal in cardiomyocytes. In the cardiac cell, activation of a Ca influx through L type Ca channels is usually considered as the pathway initializing Ca mobilization and leading to contraction. It has now been demonstrated that this pathway is activated by beta 1-adrenergic agonists via cyclic AMP. However, amplification of contraction may involve other targets. Thus, the positive inotropic effect of beta 2-adrenergic agonists is also associated with a rise in cytosolic Ca but is not linked to cyclic AMP increase. The alpha 1-adrenergic pathway involves a sensitization of myofilaments for Ca, and increases contraction without an increase in cytosolic Ca. Finally, the positive inotropic effect of glucagon combines the cyclic AMP pathway with a cyclic AMP independent pathway triggered by the metabolite mini-glucagon.

Xanthine affects [Ca2+]i and contractile responses of ventricular cardiocytes to electrical stimulation.

Xanthine, a major purine by-product of ATP, accumulates during myocardial ischemia. In the present study, we show that xanthine (0.5-1 mM) impaired the occurrence of cytosolic Ca2+ concentration ([Ca2+]i) transients, visualized in fura 2-loaded cells, and twitches of contraction in ventricular cardiocytes in response to electrical stimulation. This effect of xanthine was independent of superoxide anion production. That it was a result of decreased membrane excitability was supported by the following: 1) it was reversed by increasing either the amplitude of the stimulus voltage required to stimulate cardiocytes or the extracellular concentration of NaCl; and 2) xanthine reversed the depolarization following electrical stimulation in cardiocytes loaded with the voltage-sensitive dye bis-oxonol. P2 purinergic-agonists, including ATP (10 microM), but not P1 purinergic agonists reproduced the effects seen with xanthine. In addition, a lack of additivity between xanthine and ATP at maximal concentrations was observed. We conclude that xanthine, through activation of a P2 purinoceptor, may contribute to myocardial arrhythmia occurring during ischemia-reperfusion injury.

Evidence for a beta2-adrenergic/arachidonic acid pathway in ventricular cardiomyocytes. Regulation by the beta1-adrenergic/camp pathway.

The signaling pathway mediating the contractile effect of beta2-adrenergic receptors (beta2-AR) in the heart is still matter of debate. By using embryonic chick ventricular cardiomyocytes that express both functional beta1-and beta2-ARs, we show here that the specific beta2-AR agonist, zinterol, increases the amplitude of Ca2+ transients and cell contraction of electrically stimulated cells. Zinterol, up to 10 microM, did not stimulate adenylyl cyclase activity, and its effect on Ca2+ transients was unmodified by the specific cAMP antagonist, (Rp)-cAMPS. In contrast, zinterol (10-100 nM) triggered arachidonic acid (AA) release from [3H]AA-loaded cells via the activation of the cytosolic phospholipase A2 (cPLA2). Stimulation of the Ca2+ transients by zinterol was abolished by the cPLA2 inhibitor, AACOCF3, and was mimicked by AA (0.3-3 microM). Both stimulations of [3H]AA release and of [Ca2+]i cycling by zinterol were abolished after treatment of the cardiomyocytes with pertussis toxin. Although cell responses to beta2-AR stimulation were mediated by AA, they were under cAMP control as follows: (i) the beta1-AR stimulation exerted a cAMP-mediated negative constraint on the beta2-AR/cPLA2 pathway; (ii) cAMP potentiated AA action downstream beta-AR stimulation. We conclude that, in cardiomyocytes, beta2-AR is coupled to cPLA2 activation via a pertussis toxin-sensitive G protein. These results demonstrate the involvement of the cPLA2/AA pathway in mediating positive inotropic effects, which could potentially compensate for a defective cAMP pathway.

Synergistic actions of glucagon and miniglucagon on Ca2+ mobilization in cardiac cells.

It has been recently shown that the physiological processing of glucagon into its C-terminal (19-29) fragment, miniglucagon, by cardiac cells was essential for the contractile positive inotropic effect of the hormone. However, the mechanisms underlying the effects of miniglucagon remained undetermined. In the present study, we assessed the effects of miniglucagon on Ca2+ homeostasis in embryonic chick ventricular myocytes. In quiescent cells, short-term applications of 0.1 nmol/L miniglucagon markedly increased the accumulation of 45Ca into intracellular compartments resistant to digitonin lysis and sensitive to caffeine. Ca2+ accumulation into the sarcoplasmic reticular (SR) store was further attested by fura 2 imaging studies on quiescent or prestimulated cells: miniglucagon potentiated Ca2+ release from the SR compartment triggered by caffeine and evoked a rise in cytosolic Ca2+ when applied on cells pretreated with 1 mumol/L thapsigargin, a specific inhibitor of the SR Ca2+ pump. Glucagon alone produced a small cytosolic Ca2+ signal that was considerably amplified by miniglucagon. The action of glucagon was mimicked by 8-bromo-cAMP and was blocked by isradipine, suggesting that it relied on the activation of L-type Ca2+ channels, via phosphorylation. We conclude that the combined actions of miniglucagon and glucagon on Ca2+ accumulation into SR stores and Ca2+ release from the same stores are likely to support the positive inotropic effect elicited in vivo by glucagon on heart contraction.

Arachidonic acid drives mini-glucagon action in cardiac cells.

Recent studies have shown that glucagon is processed by cardiac cells into its COOH-terminal (19-29) fragment, mini-glucagon, and that this metabolite is an essential component of the contractile positive inotropic effect of glucagon (Sauvadet, A., Rohn, T., Pecker, F. and Pavoine, C. (1996) Circ. Res. 78, 102-109). We now show that mini-glucagon triggers arachidonic acid (AA) release from [3H]AA-loaded embryonic chick ventricular myocytes via the activation of a phospholipase A2 sensitive to submicromolar Ca2+ concentrations. The phospholipase A2 inhibitor, AACOCF3, prevented mini-glucagon-induced [45Ca2+] accumulation into the sarcoplasmic reticulum, but inhibitors of lipoxygenase, cyclooxygenase, or epoxygenase pathways were ineffective. AA applied exogenously, at 0. 3 microM, reproduced the effects of mini-glucagon on Ca2+ homeostasis and contraction. Thus AA: (i) caused [45Ca2+] accumulation into a sarcoplasmic reticulum compartment sensitive to caffeine; 2) potentiated caffeine-induced Ca2+ mobilization from cells loaded with Fura-2; 3) acted synergistically with glucagon or cAMP to increase both the amplitude of Ca2+ transients and contraction of electrically stimulated cells. AA action was dose-dependent and specific since it was mimicked by its non-hydrolyzable analog 5,8,11,14-eicosatetraynoic acid but not reproduced by other lipids such as, arachidic acid, linolenic acid, cis-5,8,11,14,17-eicosapentaenoic acid, cis-4,7,10,13,16, 19-docosahexaenoic acid, or arachidonyl-CoA, even in the micromolar range. We conclude that AA drives mini-glucagon action in the heart and that the positive inotropic effect of glucagon on heart contraction relies on both second messengers, cAMP and AA.