Collagen fleece-bound fibrin sealant is not associated with an increased risk of thromboembolic events or major bleeding after its use for haemostasis in surgery: a prospective multicentre surveillance study.

BACKGROUND: Topical haemostatic agents are used to help achieve haemostasis during surgery when standard surgical techniques are insufficient. The objective of this study was to confirm the safety profile of an equine collagen patch coated with human fibrinogen and human thrombin with particular focus on the occurrence of thromboembolic events (TEEs), major bleeding and immunological events. METHODS: This was a non-interventional, multicentre, prospective, surveillance study in which a collagen fleece-bound fibrin sealant was prescribed in accordance with its marketing authorisation. The decision to use the sealant was based solely on current surgical practice. All patients that received the sealant and provided informed consent were included. TEEs (any coagula-based occlusion in a vessel or the heart identified by symptomatic clinical signs and/or verified by paraclinical examination), major bleeding (any bleeding that required intervention), and immunological events (hypersensitivity including anaphylaxis) that occurred during surgery, post-operative hospital stay or 6 months of follow-up were reported as adverse events. The primary endpoint was the proportion of patients experiencing a confirmed TEE. RESULTS: A total of 3098 patients were recruited at 227 centres in 12 European countries. The most frequent types of surgery were hepatic (33%), gastrointestinal (16%) and urological (14%) and the main indication for surgery was for primary (35%) or secondary (20%) malignancy. Forty-six patients (1.5%, 95% CI 1.1-2.0%) had at least one TEE during the study. The most commonly reported TEEs were pulmonary embolism or post-procedural pulmonary embolism (n = 18) and deep vein thrombosis (n = 9). There were 64 major bleedings in 62 patients and 9 immunological events in 8 patients. CONCLUSION: Collagen fleece-bound fibrin sealant does not appear to be associated with an increased risk of TEEs, major bleeding or immunological events in patients undergoing surgery. TRIAL REGISTRATION: Clinicaltrials.gov number: NCT00285623.

Pharmacokinetics, efficacy, and tolerability of fentanyl following intranasal versus intravenous administration in adults undergoing third-molar extraction: a randomized, double-blind, double-dummy, two-way, crossover study.

OBJECTIVE: The aim of this study was to compare the pharmacokinetic profile, as well as the efficacy and tolerability, of i.n. and i.v. administration of fentanyl in acute, episodic pain in patients undergoing third-molar extraction. METHODS: In this randomized, double-blind, double-dummy, 2-way, crossover study, patients were randomized to receive 1 of 4 doses (75, 100, 150, or 200 microg) by both the i.n. and i.v. routes in random order, after each of 2 separate molar extractions (interval, >or=1 week). Venous blood samples were obtained for quantification of plasma fentanyl concentrations before and at 1, 3, 5, 7, 9, 12, 15, 25, 40, 60, 90, 120, and 180 minutes after administration. Pain scores (on an 11-point numeric rating scale) were recorded before and at 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 210, and 240 minutes. Patients indicated the times at which they perceived meaningful pain relief (onset of action) and at which analgesia ended (duration of effect), after which they were able to use rescue medication (time to rescue medication use). RESULTS: A total of 24 patients were enrolled (in all, 47 extractions) (46% male; mean age, 24.1 years; 94% white, 6% Asian). Mean T(max) values were 12.8 and 6.0 minutes (P<0.001), times to onset of analgesia were 7 and 2 minutes (P<0.001), and durations of effect were 56 and 59 minutes after i.n. and i.v. administration (P=NS), respectively. Differences in the onsets and durations of analgesia after i.n. and i.v. administration of single doses were not significantly different, and neither was the difference in overall analgesia, with pain scores returning to near-predose values at statistically similar times after dosing. Duration of effect was directly related to i.n. fentanyl dose, with significantly less use of rescue medication after i.n. than after i.v. administration (P<0.005). The i.n. and i.v. formulations were both well tolerated, with similar numbers of nasally related adverse events recorded for both routes of administration. CONCLUSIONS: Onsets and durations of analgesia were not significantly different between single doses of i.n. and i.v. fentanyl in these adults undergoing third-molar extraction. Both i.n. and i.v. administration were generally well tolerated.

Matrix metalloproteinase-12 (MMP-12) in osteoclasts: new lesson on the involvement of MMPs in bone resorption.

Osteoclasts require matrix metalloproteinase (MMP) activity and cathepsin K to resorb bone, but the critical MMP has not been identified. Osteoclasts express MMP-9 and MMP-14, which do not appear limiting for resorption, and the expression of additional MMPs is not clear. MMP-12, also called metalloelastase, is reported only in a few cells, including tissue macrophages and hypertrophic chondrocytes. MMP-12 is critical for invasion and destruction in pathologies such as aneurysm and emphysema. In the present study, we demonstrate that osteoclasts express MMP-12, although only in some situations. Northern blots show that highly purified rabbit osteoclasts in culture express MMP-12 at the same level as macrophages, whereas in situ hybridizations performed on rabbit bone do not show any MMP-12 expression in osteoclasts whatever the bone type. In contrast, in situ hybridizations performed on mouse bone show MMP-12 expression in osteoclasts in calvariae and long bones. We also demonstrate that recombinant MMP-12 cleaves the putative functional domains of osteopontin and bone sialoprotein, two bone matrix proteins that strongly influence osteoclast activities, such as attachment, spreading and resorption. Furthermore, we investigated the role of MMP-12 in bone resorption and osteoclast recruitment by comparing MMP-12 knockout and wild-type mice in specialized culture models known to depend on MMP activity, as well as in the ovariectomy model, and we did not find any indication for a limiting role of MMP-12 in these processes. In conclusion, we found that osteoclasts are able to express MMP-12, but MMP-12 did not appear critical for osteoclast recruitment or resorption. The fact that none of the MMPs identified so far in osteoclasts appears limiting for resorption, gives strength to the hypothesis that the critical MMP for bone solubilization is produced by non-osteoclastic cells.

Matrix metalloproteinases (MMP) and cathepsin K contribute differently to osteoclastic activities.

The best established proteolytic event of osteoclasts is bone matrix solubilization by the cysteine proteinase cathepsin K. Here, however, we draw the attention on osteoclastic activities depending on matrix metalloproteinases (MMPs). We discuss the observations supporting that MMPs contribute significantly to bone matrix solubilization in specific areas of the skeleton and in some developmental and pathological situations. Our discussion takes into account (1) the characteristics of the bone remodeling persisting in the absence of cathepsin K, (2) the ultrastructure of the resorption zone in response to inactivation of MMPs and of cathepsin K in different bone types, (3) bone resorption levels in MMP knockout mice compared to wild-type mice, (4) the identification of MMPs in osteoclasts and surrounding cells, and (5) the effect of different bone pathologies on the serum concentrations of specific collagen fragments believed to discriminate between cathepsin K and MMP cleavage. Next, we provide evidence that MMPs are very critical for osteoclast migration, thereby controlling also the cell-matrix interactions required for cell attachment/detachment. The evidence supporting this role is based on a model of osteoclast recruitment in primitive long bones, an assay of osteoclast invasion through collagen gel, and the effect of proteinase inhibitors/knockouts in these models. Furthermore, we mention observations indicating a role of MMPs in initiation of bone resorption. Finally, we emphasize the many distinct ways MMPs may alter focally the extracellular environment thereby regulating the osteoclast behavior. Although the understanding of MMPs in osteoclast biology is rapidly expanding, it is suspected that important roles remain to be discovered.