Influence of Renal and Hepatic Impairment on the Pharmacokinetic and Pharmacodynamic Properties and Tolerability of Fluticasone Furoate and Vilanterol in Combination

BackgroundRenal and hepatic disease may lead to alterations in drug absorption, distribution, and elimination, and, therefore, the potential effect of renal and hepatic impairment should be investigated in drugs under development.ObjectiveTo assess the effects of renal and hepatic impairment on the pharmacokinetic and pharmacodynamic properties and tolerability of fluticasone furoate/vilanterol (FF/VI) administered in combination.MethodsTwo open-label, parallel-group studies were conducted. Eligible study participants included adults with severe renal impairment (CrCl <30 mL/min) and those with mild, moderate, or severe hepatic impairment (by Child-Pugh classification). Patients were matched with healthy subjects. Participants received 7 days of inhaled FF/VI 200/25 or 100/12.5 μg (severe hepatic impairment only) once daily in the morning. Lack of effect was defined as an upper 90% confidence limit of the C_max and AUC geometric mean impaired:healthy ratios (GMRs) of <2.ResultsStudy participants included patients with severe renal impairment (n = 9) or with mild (n = 9), moderate (n = 9), or severe (n = 8) hepatic impairment, together with matched healthy subjects (n = 9 per study). Lack of effect of severe renal impairment was demonstrated with FF (GMRs [90% CI]: C_max, 0.96 [0.57–1.61]; AUC_0–24, 0.91 [0.60–1.38]) and VI (C_max, 0.70 [0.49–1.00]; AUC_0–24, 1.56 [1.27–1.92]). Day-7 dose-normalized FF AUC_0–24 was greater in the groups with mild, moderate, and severe hepatic impairment than in healthy subjects (GMRs [90% CI]: 1.34 [0.82–2.20], 1.83 [1.11–2.99], and 1.75 [1.05–2.91], respectively); lack of effect was not demonstrated. There was no effect of hepatic impairment on dose-normalized VI C_max or AUC_0–24. Apart from reduced serum cortisol weighted mean (0–24 hour) in patients with moderate hepatic impairment (34% reduction [90% CI, 11%–51%] compared with healthy subjects), there was no evidence of a difference in heart rate, serum potassium, or 24-hour serum cortisol between patients with severe renal impairment of any hepatic impairment and healthy subjects. No safety concerns were identified in any of the groups with impairment or their matched healthy controls.ConclusionsSevere renal impairment had no apparent clinically relevant effects on the pharmacokinetic or pharmacodynamic properties or tolerability of FF/VI. Hepatic impairment had no apparent effect on VI systemic exposure but increased FF exposure. Fluticasone furoate was associated with reduced serum cortisol in patients with moderate hepatic impairment. These data suggest that caution should be exercised when prescribing FF/VI in patients with moderate or severe hepatic impairment due to a risk for unwanted systemic corticosteroid effects associated with increased FF systemic exposure. Clinicaltrials.gov identifiers: NCT01266941 and NCT01266980.     

Silver-Coated Megaprosthesis of the Proximal Tibia in Patients With Sarcoma

Background

Proximal tibia arthroplasty is associated with high rates of infection. This study is the largest one that has compared the infection rates with titanium vs silver-coated megaprostheses in patients treated for sarcomas.

Percutaneous CT-guided radio-frequency ablation of osteoid osteoma of the foot and ankle

Introduction

Percutaneous radiofrequency ablation (RFA) has been considered, in recent years, the standard treatment for osteoid osteoma (OO) of the appendicular skeleton. The variable clinical presentations in the foot and ankle pose problems in diagnosis, localization and thus treatment. The aim of this study was to assess the efficacy of RFA for patients with osteoid osteoma of the foot and ankle.

Materials and methods

A total of 29 patients (22 males, 7 females; mean age 16.7?years; range 8?C44?years) with OO of the foot and ankle (distal tibia, n?=?17; distal fibula, n?=?6; talus, n?=?3; calcaneus, n?=?3) were enrolled in the study. A CT-guided RFA was performed, using a cool-tip electrode without the cooling system, heating the lesion up to 90?°C for 4?C5?min. Clinical success, assessed at a minimum follow-up of 1?year, was defined as complete or partial pain relief after RFA. Pain and clinical outcomes were scored pre-operatively and at the follow-up with a visual analogue scale (VAS) and with the American Orthopaedic Foot and Ankle Society (AOFAS) score. Complications and local recurrences were also recorded.

Results

Clinical success was achieved in 26 patients (89.6?%). After RFA, mean VAS and AOFAS score significantly improved from 8?±?1 to 2?±?1 (p?<?0.05) and from 60.7?±?12.7 to 89.6?±?7.1 (p?<?0.05), respectively. Two patients experienced partial relief of pain and underwent a second successful ablation. Local recurrences were found in three patients, always associated with pain. These underwent conventional excision through open surgery. No early or late complications were detected after RFA.

Conclusion

CT-guided RFA of foot and ankle osteoid osteoma is a safe and effective procedure, showing similar results for the rest of the appendicular skeleton.     

The Modular Universal Tumour And Revision System (MUTARS®) in endoprosthetic revision surgery

The aim of this study was to present the clinical and functional results of revision surgery after failed hip endoprostheses using the Modular Universal Tumour And Revision System (MUTARS®). Functional results of the hip endoprostheses were recorded by applying the Harris hip score. The extent of the presurgical radiological bone defect was measured according to the classification system of the German orthopaedic association (DGOOC). Indications for revision surgery on 45 patients (21 female, 24 male) were aseptic loosening (19 patients), infection (16 patients), or periprosthetic fracture (Vancouver classification B2, B3 and C, in nine patients). Revision surgery was performed after 8.6 years on average (min. 0.6; max. 14.25 years). Large defects of the proximal femur (80% medial or lateral diaphysis; 20% meta-diaphysis according to DGOOC classification) were adequately reconstructed. The average follow-up was 38.6 months. Complications occurred in eight patients: one luxation, two aseptic loosenings, and five reinfections were diagnosed. The Harris hip score (presurgical 30; postsurgical 78) showed significant improvement after revision surgery. Regarding the extent of the patients’ bone defects, good functional results were achieved. The comparatively low number of luxations and loosenings is due to the high modularity of the prosthesis with arbitrary antetorsion in the hip joint. However, high reinfection rates in mega-implants still constitute a problem and should be the subject of further studies.     

Antimicrobial,Insecticidal and Cytotoxic Activity of Linear Venom Peptides from the Pseudoscorpion Chelifer cancroides

Linear cationic venom peptides are antimicrobial peptides (AMPs) that exert their effects by damaging cell membranes. These peptides can be highly specific, and for some, a significant therapeutic value was proposed, in particular for treatment of bacterial infections. A prolific source of novel AMPs are arthropod venoms, especially those of hitherto neglected groups such as pseudoscorpions. In this study, we describe for the first time pharmacological effects of AMPs discovered in pseudoscorpion venom. We examined the antimicrobial, cytotoxic, and insecticidal activity of full-length Checacin1, a major component of the Chelifer cancroides venom, and three truncated forms of this peptide. The antimicrobial tests revealed a potent inhibitory activity of Checacin1 against several bacteria and fungi, including methicillin resistant Staphylococcus aureus (MRSA) and even Gram-negative pathogens. All peptides reduced survival rates of aphids, with Checacin1 and the C-terminally truncated Checacin1¹⁻²¹ exhibiting effects comparable to Spinosad, a commercially used pesticide. Cytotoxic effects on mammalian cells were observed mainly for the full-length Checacin1. All tested peptides might be potential candidates for developing lead structures for aphid pest treatment. However, as these peptides were not yet tested on other insects, aphid specificity has not been proven. The N- and C-terminal fragments of Checacin1 are less potent against aphids but exhibit no cytotoxicity on mammalian cells at the tested concentration of 100 µM.     

Knieendoprothesenimplantation bei übersehenem Osteosarkom

A 72-year-old woman presented with pain, swelling, and decreased range of motion of the left knee joint after total knee arthroplasty in 2005. We performed standard x-rays, which were highly suspicious for an osteosarcoma of the distal femur; this was proven by open biopsy. Retrospectively, the x-rays taken before implantation of the prosthesis showed suspicious findings. Because the femur was tumor-contaminated, with the intramedullary adjustment far-reaching proximally, a limb salvage procedure was no longer possible. To improve function, we decided to perform a stump-lengthening procedure using a special implant. With regard to the dismal consequences, we recommend that every suspicious finding before an elective surgical procedure be examined with further diagnostics and, if necessary, histological confirmation.     

Antimikrobielle Silberbeschichtung von Tumorprothesen

Oncologic patients are especially vulnerable due to their illness and accompanying (neo)adjuvant therapy. The early and late infection of tumor mega-endoprostheses with biofilm producing bacteria is an essential problem which can lead to secondary amputation. Prophylaxis against infection is an effective strategy for decreasing morbidity. For centuries, the anti-infective properties of silver on infected wounds has been known. Nowadays, there is a revival in silver application due to its broad spectrum of activity against bacteria and even fungi with low local and systemic toxicity. Newer applications use metallic silver and not silver salts. Surrounding conditions should be prepared in a way that does not reduce the silver ion effect (hematoma, seroma, iodine containing antiseptic lavages, etc.). In future, hospitalization and antibiotic use are likely to be reduced by the use of silver coating. Long-term results are not yet available.     

Silver-coated megaprostheses in the proximal femur in patients with sarcoma

European Journal of Orthopaedic Surgery & Traumatology - Proximal femur replacements in patients with sarcoma are associated with high rates of infection. This study is the largest one...     

The effect of rotationplasty on the ankle joint: long-term results

In patients with rotationplasty the biomechanical conditions in the ankle joint are altered dramatically. By displacement and reduction of the weight-bearing area of the joint, the stress affecting its cartilage is increased. The use of an exoprothesis results in skin and soft tissue irritation. Due to these biomechanical changes, a prearthrotic deformity or skin problems could be expected. The current study examines changes in 21 patients treated with rotationplasty (mean follow-up 13.5 years) because of a malignant bone tumour or a femoral segmental defect. Local tenderness, skin and soft tissue changes, problems with exoprostheses, and pain was assessed by clinical examination and documented. Osseous changes were evaluated by plain X-ray. A MRI-scan was also obtained in five patients. Hardened skin and blisters were located at the main loading areas of the rotated foot. These changes could be reduced by optimizing the exoprosthetic fit. Radiographically, a slight asymptomatic attenuation of the articular space was observed in four patients and a slight coexistent subchondral sclerosis with small osteophytes in one patient. No degenerative changes were observed on X-ray and no cartilaginous changes were observed on MRI. The results suggest that the foot is able to adapt to the load changes after this procedure and that rotationplasty does not cause an inevitable arthrosis in the ankle joint.