A Topical Treatment Optimization Programme (TTOP) improves clinical outcome for calcipotriol/betamethasone gel in psoriasis: results of a 64-week multinational randomized phase IV study in 1790 patients (PSO-TOP).

BACKGROUND: Around two-thirds of patients with psoriasis do not adhere to topical treatment. The Topical Treatment Optimization Programme (TTOP), a five-element tool, includes guidance for the conversation between dermatologists/nurses and patients, patient information material, telephone/e-mail helpdesks and treatment reminders. It has been developed by patients and dermatologists to help increase adherence to treatment in psoriasis. OBJECTIVES: To compare TTOP with standard of care ('non-TTOP') within a large European investigator-initiated study, PSO-TOP (clinicaltrials.gov NCT01587755). METHODS: Patients with mild-to-moderate psoriasis received calcipotriol/betamethasone dipropionate gel as standardized study medication and were randomized 1 : 1 to either TTOP or non-TTOP management. Study medication was applied once daily for 8 weeks followed by 'as needed' application for an additional 56 weeks. Response was defined as a Physician's Global Assessment (PGA) of 'clear' or 'almost clear'. RESULTS: In 1790 patients (full analysis set), response rates after 8 weeks (primary objective) were significantly higher for TTOP (36·3%) than for non-TTOP (31·3%, P = 0·0267). Better clinical outcome was accompanied by higher rates of patients feeling well informed about their skin condition, treatment and other factors related to adherence, but the Dermatology Life Quality Index was not statistically different. TTOP patients regarded the structured one-to-one conversations with their dermatologist/nurse as the most important element of TTOP. CONCLUSIONS: Patients randomized to the TTOP intervention had a better clinical response than patients receiving standard of care. Improved communication between the healthcare provider and patient might be an important element in increasing adherence to topical therapy in psoriasis.

Evaluation of adherence predictors for the treatment of moderate to severe psoriasis with biologics: the importance of physician-patient interaction and communication.

BACKGROUND: Treatment efficacy of biologic agents in moderate to severe psoriasis is regarded as high with patient adherence being higher than for traditional therapies. However, use of biologics is connected to high discontinuation rates. The current investigator-initiated study was conducted to improve the understanding of adherence. MATERIALS AND METHODS: The study was designed as non-interventional retrospective multicentre trial in Germany. Questionnaires were developed based on the adherence dimensions identified by the World Health Organization, WHO. Thirteen dermatologists and 246 patients participated in the study and replied to the questionnaires. Study data were analysed for potential predictors of adherence in an explorative manner. RESULTS: Based on the physician's assessment of the patients' individual adherence, subsets of adherent and non-adherent patients were discriminated. Two main drivers were identified on the patients' side that were positively connected to adherence: a lack of efficacy of the previous treatments and the knowledge of comorbidities associated with severe psoriasis. Furthermore, physician-patient communication seems to play a central role, as on the dermatologists' side, there was a strong association of adherence and positive personal interrelation between dermatologist and patient. CONCLUSION: The data reported here underline the importance of patient education and information delivery to optimize patient adherence and thereby treatment outcomes. Treating physicians should be aware that soft aspects of their interaction with the patient might influence treatment adherence.

Long-term follow-up of photodynamic therapy with a self-adhesive 5-aminolaevulinic acid patch: 12 months data.

BACKGROUND: Photodynamic therapy with a self-adhesive 5-aminolaevulinic acid (5-ALA) patch shows high efficacy rates in the treatment of mild to moderate actinic keratosis (AK) in short term trials. OBJECTIVES: The purpose of the trial was to follow up patients after successful 5-ALA patch-PDT at 3 month intervals over a total period of 12 months. Patients who had received placebo-PDT or cryosurgery served for comparison. PATIENTS/METHODS: Three months after therapy, 360 patients from two separate randomized parallel group phase III studies (one superiority trial vs. placebo-PDT, one noninferiority trial vs. cryosurgery) were suitable for the follow-up study. Patients had to show at least one successfully treated AK lesion after initial therapy. A total of 316 patients completed the follow-up. RESULTS: Twelve months after a single treatment, 5-ALA patch-PDT still proved superior to placebo-PDT and cryosurgery (P < 0.001 for all tests). On a lesion basis, efficacy rates were 63% and 79% for PDT, 63% for cryosurgery and 9% and 25% for placebo-PDT. Recurrence rates of patch-PDT proved superior to those of cryosurgery (per protocol set: P = 0.011, full analysis set: P = 0.049). While 31% of cryosurgery lesions were still hypopigmented after 1 year, the 5-ALA patch-PDT groups showed hypopigmentation in 0% (superiority trial) and 3% (noninferiority trial) of the treated lesions. CONCLUSION: Twelve months after a single 5-ALA patch-PDT the majority of lesions were still cleared with an excellent cosmetic outcome. 5-ALA patch-PDT proved to be superior to cryosurgery in the noninferiority study setting.

Optimization of photodynamic therapy with a novel self-adhesive 5-aminolaevulinic acid patch: results of two randomized controlled phase III studies.

BACKGROUND: Photodynamic therapy (PDT) is increasingly used for treatment of actinic keratoses (AKs) but is a cumbersome procedure. A thin self-adhesive patch (PD P 506 A) containing 5-aminolaevulinic acid (5-ALA) was developed to facilitate PDT. OBJECTIVES: To investigate efficacy and safety of the patch in comparison with placebo-PDT (superiority design, observer-blinded; study AK 03) and standard therapy, cryosurgery (noninferiority design, open; study AK 04). METHODS: Two separate confirmatory randomized parallel-group phase III studies were set up. In total, 449 patients with up to eight mild to moderate AK study lesions located on the head were treated in 29 German study centres (study AK 03: 103 patients; study AK 04: 346 patients). RESULTS: Twelve weeks after treatment, 5-ALA patch-PDT proved to be superior to placebo-PDT (P < 0.001) and cryosurgery (P = 0.007). Efficacy rates on a lesion basis were 82% (AK 03) and 89% (AK 04) for PDT, 77% for cryosurgery and 19% (AK 03) and 29% (AK 04) for placebo-PDT. Local reactions at the treatment site occurred in almost all patients treated with 5-ALA patch-PDT or cryosurgery. Headache was the only side-effect not related to the treatment site which occurred in more than one patient. CONCLUSIONS: PD P 506 A is an innovative, easy-to-handle 5-ALA patch for PDT of mild to moderate AK lesions. Compared with current PDT procedures, pretreatment (e.g. curettage) is not needed and handling is considerably facilitated. A single PDT treatment results in efficacy rates being statistically significantly superior to placebo and cryosurgery.

Placebo-controlled evaluation of the irritant potential of tacalcitol (1a,24-dihydroxyvitamin D3) in healthy volunteers.

In the treatment of psoriasis with topical vitamin D3 analogues, lesional and perilesional irritation is the main side-effect. The aim of this study was to investigate whether local side-effects generated by tacalcitol, a vitamin D3 analogue, show concentration dependence. 3 different concentrations of tacalcitol (0.4; 4; 40 microg/g ointment) and the vehicle were applied on normal skin of the back of 25 healthy volunteers under occlusive conditions for 5 days. Assessment of erythema, infiltration and scaling as well as measurement of transepidermal water loss (TEWL) was performed on days 1 to 5. On day 5, additional skin barrier tests (DMSO test, alkali resistance test) were performed. Erythema and slight infiltration, but no scaling, were observed in a number of subjects without significant differences. TEWL also did not show significant differences for the test formulations, though there was a tendency towards lower values in the untreated areas. In the skin barrier tests, a tendency towards higher alkali resistance in the test areas treated with 40 microg tacalcitol/g ointment was detected. Thus, under occlusive conditions, the irritant potential of tacalcitol is very low. There is no convincing evidence of concentration dependence in irritation generated by tacalcitol when applied under occlusive conditions.

[Changes in specific airway resistance after powder inhalation of formoterol or salmeterol in moderate bronchial asthma]. / Anderung des spezifischen Atemwegswiderstandes (sRaw) nach Pulverinhalation von Formoterol oder Salmeterol bei mittelschwerem Asthma bronchiale.

Formoterol and salmeterol are two long acting beta 2 agonists available for the treatment of asthma which show differences in onset of action. In a multicentre parallel group study, patients with moderate asthma were investigated by measuring the specific airway resistance (sRaw), a more sensitive parameter than FEV1. A total of 99 patients were randomised for open treatment with either 12 micrograms formoterol delivered via Turbohaler or 50 micrograms salmeterol via Diskus. The patients were between 18 and 66 years of age, had a medium FEV1 of 68.8% (+/- 17.8%) predicted and showed a medium reversibility of 28.8% (+/- 16.5%). The patients response to one inhalation of the study drug was investigated by sRaw measurements 2, 5, 10, 20 and 60 minutes after inhalation of the formulation. Additionally, FEV1 was measured. The results show a significant decrease in specific airway resistance of 29% within the first two minutes in patients who had received 12 micrograms formoterol via Turbohaler. However, patients on salmeterol showed no change (sRaw +/- 1%). This difference is statistically highly significant (p < 0.0001). Furthermore, in 49% of the patients treated with salmeterol an increase in sRaw was seen immediately after inhalation of the drug. This increase was +16.4% in an average of 2 minutes after inhalation. One hour after inhalation the differences between the groups were small and not significant neither between formoterol and salmeterol-treated patients nor within the salmeterol group. In the following week patients were treated with 12 micrograms formoterol Turbohaler b.i.d. or 50 micrograms salmeterol Diskus b.i.d., respectively. A further sRaw measurement was performed 11 +/- 1 hours after the last inhalation of the drug. The results for sRaw and FEV1 show no differences between both study drugs indicating a similar duration of action for both formoterol Turbohaler and Salmeterol Diskus in moderate asthma. No serious adverse events were reported. The adverse event profile observed in both study groups was comparable. Thus, this study shows once again that formoterol delivered via Turbohaler has a more rapid onset of bronchodilating action compared with salmeterol Diskus. Furthermore the inhalation of salmeterol via Diskus in one-half of the patients led to an increase in specific airway resistance within the first minutes after inhalation. It is worth discussing whether an unspecific reaction to the relatively large lactose particles which are components of the salmeterol Diskus formulation are responsible for this observation.

Primary structure and functional expression of a developmentally regulated skeletal muscle chloride channel.

Skeletal muscle is unusual in that 70-85% of resting membrane conductance is carried by chloride ions. This conductance is essential for membrane-potential stability, as its block by 9-anthracene-carboxylic acid and other drugs causes myotonia. Fish electric organs are developmentally derived from skeletal muscle, suggesting that mammalian muscle may express a homologue of the Torpedo mamorata electroplax chloride channel. We have now cloned the complementary DNA encoding a rat skeletal muscle chloride channel by homology screening to the Cl- channel from Torpedo. It encodes a 994-amino-acid protein which is about 54% identical to the Torpedo channel and is predominantly expressed in skeletal muscle. Messenger RNA amounts in that tissue increase steeply in the first 3-4 weeks after birth, in parallel with the increase in muscle Cl- conductance. Expression from cRNA in Xenopus oocytes leads to 9-anthracene-carboxylic acid-sensitive currents with time and voltage dependence typical for macroscopic muscle Cl- conductance. This and the functional destruction of this channel in mouse myotonia suggests that we have cloned the major skeletal muscle chloride channel.

Inactivation of muscle chloride channel by transposon insertion in myotonic mice.

MYOTONIA (stiffness and impaired relaxation of skeletal muscle) is a symptom of several diseases caused by repetitive firing of action potentials in muscle membranes. Purely myotonic human diseases are dominant myotonia congenita (Thomsen) and recessive generalized myotonia (Becker), whereas myotonic dystrophy is a systemic disease. Muscle hyperexcitability was attributed to defects in sodium channels and/or to a decrease in chloride conductance (in Becker's myotonia and in genetic animal models). Experimental blockage of Cl- conductance (normally 70-85% of resting conductance in muscle) in fact elicits myotonia. ADR mice are a realistic animal model for recessive autosomal myotonia. In addition to Cl- conductance, many other parameters are changed in muscles of homozygous animals. We have now cloned the major mammalian skeletal muscle chloride channel (ClC-1). Here we report that in ADR mice a transposon of the ETn family has inserted into the corresponding gene, destroying its coding potential for several membrane-spanning domains. Together with the lack of recombination between the Clc-1 gene and the adr locus, this strongly suggests a lack of functional chloride channels as the primary cause of mouse myotonia.