Psoriasis relapse evaluation with week-end cyclosporine A treatment: results of a randomized, double-blind, multicenter study

Cyclosporine A (CsA) effectively controls psoriasis, however, its long-term continuous use is not recommended. This study aims to evaluate the efficacy and tolerability of week-end CsA microemulsion for the reduction of relapse rate in patients with chronic plaque psoriasis who had achieved clinical remission following continuous CsA therapy. The PREWENT (Psoriasis Relapse Evaluation with Week-End Neoral Treatment) study was a 24 week, randomized, double-blind, multicenter study, carried out in 22 Italian hospital or University Dermatology units. CsA was discontinued for 8 days previous to the patients being randomized to oral CsA 5 mg/kg/day or placebo for two consecutive days/week, for a total period of 24 weeks. The primary endpoint was clinical success rate at week 24, defined as the proportion of patients with no clinical worsening (no relapse or a Psoriasis Area and Severity Index (PASI) < 75 percent of pre-treatment PASI). A total of 162 patients were randomized to CsA and 81 to placebo. Clinical success rates at 24 weeks were 66.9 and 53.2 percent with CsA and placebo, respectively (p = 0.072). Time to first relapse was significantly prolonged with CsA versus placebo (p = 0.023), and PASI was significantly lower from weeks 4 to 16 in CsA recipients. In patients with moderate-severe psoriasis, the clinical success rate was significantly increased with CsA compared to placebo (69.9% vs 46.3%; p = 0.011), and significantly lower increases in PASI were observed from week 4 to week 24 (p < 0.05 vs placebo). CsA was well tolerated, with no differences in mean blood creatinine or blood pressure between CsA and placebo recipients. However, the high withdrawal rate (22.2% of randomized patients), which was not related to side effects, may have led to an overestimation of efficacy, but the study had a good statistical power (88% greater than that observed in similar studies, i.e. 80%). Week-end CsA administration was shown to prolong safely and effectively the time to first relapse in psoriasis patients.     

Sauna-induced myocardial ischemia in patients with coronary artery disease.

PURPOSE: Sauna bathing is a popular recreational activity that is generally considered to be safe. However, there have been case reports of adverse cardiac events. We sought to determine whether sauna use caused myocardial ischemia in patients with coronary artery disease. METHODS: Sixteen patients with proven coronary artery disease were submitted to three conditions (rest, exercise, and sauna bathing) with continuous electrocardiographic (ECG) monitoring and regular blood pressure measurements. During each condition, patients were injected with Tc-99 sestamibi followed by nuclear scintigraphic imaging. Perfusion defect scores were calculated in 15 patients. RESULTS: Sauna bathing was well tolerated. There was a mean (+/- SD) increase in heart rate of 32% +/- 20% in the sauna (resting mean heart rate = 60 +/- 9 beats per minute vs sauna mean heart rate = 79 +/- 11 beats per minute, P <0.001) and a 13% +/- 6% drop in systolic blood pressure (resting mean systolic blood pressure = 142 +/- 14 mm Hg vs sauna mean systolic blood pressure = 123 +/- 15 mm Hg, P <0.001). There were no arrhythmias or ECG changes in the sauna. Compared with rest, there was significant ischemia during sauna bathing (average perfusion defect score at rest = -0.44 vs average sauna score = -0.93, P <0.001). The perfusion defect score in the sauna was worse than the resting score in 14 of the 15 patients. Sauna-associated perfusion defect scores were highly correlated with exercise-induced scores (R2 = 0.65, P <0.001). CONCLUSION: In patients with stable coronary artery disease, sauna use is clinically well tolerated but is associated with scintigraphically demonstrated myocardial ischemia.     

Efficacy and safety assessment of acute sports-related traumatic soft tissue injuries using a new ibuprofen medicated plaster: results from a randomized controlled clinical trial

Objective: To investigate the efficacy and safety of a recently developed ibuprofen medicated plaster in the treatment of acute sports impact injuries/contusions.

Methods: In this double-blind, multi-center, placebo-controlled, parallel group, phase 3 study (EudraCT Number: 2012–003257-2) patients (n = 132; ages 18 to 60 years) diagnosed with acute sports-related traumatic blunt soft tissue injury/contusion to the upper or lower limbs were randomized to receive either ibuprofen 200 mg plaster (n = 64) or placebo plaster (n = 68). Plasters were administered once daily for five consecutive days. The primary assessment was the area under the curve (AUC) of the visual analogue scale (VAS) of pain on movement (POM) over 0 to 72 h (VAS_0-72).

Results: The ibuprofen medicated plaster was associated with a reduction in pain on movement (POM) based on lower VAS AUC_0-72h (2399.4 mm*h) compared with placebo (4078.9 mm*h) (least squares mean difference: – 1679.5 mm*h; P < 0.0001). The reduction in AUC of POM was also significantly greater for the ibuprofen medicated plaster compared with placebo at 12, 48, 24, and 120 h (P < 0.0001). Algometry/tenderness measurements found that the ibuprofen medicated plaster was associated with greater reduction in tenderness/pain than placebo at each timepoint (P values <0.0001). Seven patients experienced drug-related adverse events (n = 1 [1.6%] for the ibuprofen plaster, and n = 6 [8.8%] for placebo). All drug-related AEs were administration site reactions and were mild in intensity.

Conclusions: The results of this study indicate that ibuprofen medicated plaster results in rapid and clinically relevant reduction of pain in patients suffering from blunt musculoskeletal injuries or recurrent pain. The ibuprofen medicated plaster was well tolerated.     

Identification, characterization, and implications of species-dependent plasma protein binding for the oral Hedgehog pathway inhibitor vismodegib (GDC-0449)

Vismodegib (GDC-0449) is is an orally available selective Hedgehog pathway inhibitor in development for cancer treatment. The drug is ≥95% protein bound in plasma at clinically relevant concentrations and has an approximately 200-fold longer single dose half-life in humans than rats. We have identified a strong linear relationship between plasma drug concentrations and α-1-acid glycoprotein (AAG) in a phase I study. Biophysical and cellular techniques have been used to reveal that vismodegib strongly binds to human AAG (K(D) = 13 μM) and binds albumin with lower affinity (K(D) = 120 μM). Additionally, binding to rat AAG is reduced ～20-fold relative to human, whereas the binding affinity to rat and human albumin was similar. Molecular docking studies reveal the reason for the signficiant species dependence on binding. These data highlight the utility of biophysical techniques in creating a comprehensive picture of protein binding across species.     

Delayed gastric emptying does not normalize after gluten withdrawal in adult celiac disease

Objective Delayed gastric emptying has been frequently detected in patients with untreated celiac disease. According to several studies, gluten withdrawal showed to be effective in normalizing the gastric emptying rate. The aim of this study was to evaluate the gastric emptying rate of solids in patients with celiac disease before and after a gluten-free diet. Methods Twelve adult patients with celiac disease (age range 20–57 years) and 30 healthy controls (age range 30–54 years) underwent a ¹³C-octanoic acid breath test to measure gastric emptying. Half emptying time (t_1/2) and lag phase (tlag) were calculated. After at least 12 months of a gluten-free diet, celiac patients underwent a new ¹³C-octanoic acid breath test. A symptom score was utilized to detect dyspeptic and malabsorption symptoms in all the patients. Results The gastric motility parameters, t_1/2 and t_lag, were significantly longer in patients than in controls. On a gluten-free diet, surprisingly, the gastric emptying did not normalize despite an improvement of symptom score. No significant correlation between abnormal gastric emptying and specific symptom patterns, anthropometric parameters or severity of histological damage was found. Conclusions This finding supports the hypothesis that gluten-driven mucosal inflammation might determine motor abnormalities by affecting smooth muscle contractility or impairing gut hormone function. The persistence of these abnormalities on a gluten free diet suggests the presence of a persistent low-grade mucosal inflammation with a permanent perturbation of the neuro-immunomodulatory regulation.     

Open-wedge high tibial osteotomy: comparison between manual and computer-assisted techniques

Purpose

The purpose of our study was to compare clinical and radiological results of two groups of patients treated for medial compartment osteoarthritis of the knee with either conventional or computer-assisted open-wedge high tibial osteotomy (HTO). Goals of surgical treatment were a correction of the mechanical axis between 2° and 6° of valgus and a modification of posterior tibial slope between ?2° and +2°.

Methods

Twenty-four patients (27 knees) affected by varus knee deformity and operated with HTO were prospectively followed-up. They were randomly divided in two groups, A (11 patients, conventional treatment) and B (13 patients, navigated treatment). The American Knee Society Score and the Modified Cincinnati Rating System Questionnaire were used for clinical assessment. All patients were radiologically evaluated with a comparative lower limb weight-bearing digital radiograph, a standard digital anteroposterior, a latero-lateral radiograph of the knee, and a Rosenberg view.

Results

Patients were followed-up at a mean of 39 months. Clinical evaluation showed no statistical difference (n.s.) between the two groups. Radiological results showed an 86% reproducibility in achieving a mechanical axis of 182°–186° in group B compared to a 23% in group A (p = 0.0392); furthermore, in group B, we achieved a modification of posterior tibial slope between ?2° and +2° in 100% of patients, while in group A, this goal was achieved only in 24% of cases (p = 0.0021).

Conclusion

High tibial osteotomy with navigator is more accurate and reproducible in the correction of the deformity compared to standard technique.

Level of evidence

Therapeutic study, Level II.