Towards in vitro in vivo correlation for modified release subcutaneously administered insulins.

Therapeutic proteins and peptides are mainly administrated by subcutaneous injection. In vitro release testing of subcutaneous injectables performed using methods that take the structure and environment of the subcutaneous tissue into account may improve predictability of the in vivo behavior and thereby facilitate establishment of in vitro in vivo correlations. The aim of the study was to develop a biopredictive flow-through in vitro release method with a gel-type matrix for subcutaneously administered formulations and to explore the possibility of establishing a level A in vitro in vivo correlation for selected insulin products. A novel gel-based flow-through method with the incorporation of an injection step was used to assess selected commercial insulin formulations with different duration of action (Actrapid®, Mixtard® 30, Insulatard®, Lantus®). The in vitro release method provided the correct rank ordering in relation to the in vivo performance. For the modified release insulins Insulatard® and Lantus®, an in vitro in vivo correlation using non-linear time scaling was established based on the in vitro release data and in vivo subcutaneous absorption data of the 125I-labeled insulins taken from literature. Predicted absorption profiles were constructed using the in vitro in vivo correlation and subsequently converted into simulated plasma profiles. The approach taken may be of wider utility in characterizing injectables for subcutaneous administration.

Diclofenac Prodrugs for Intra-articular Depot Injectables: In Vitro Hydrolysis and Species Variation.

Intra-articular depot injectables based on in situ suspension formation of ester prodrugs of nonsteroidal anti-inflammatory drugs are promising for management of joint pain. As candidates for this delivery approach, 5 diclofenac ester prodrugs comprising different imidazole-containing promoieties were synthesized and their physicochemical properties characterized. In vitro hydrolysis rates were investigated in buffer solutions, in 40% (v/v) human, equine, canine, and rat plasma, and in 80% (v/v) human and equine synovial fluid. Bioconversion of the prodrugs to diclofenac was found to be enzyme-mediated and follow pseudo-first-order kinetics. Large variations in hydrolysis rates were observed between species and between prodrugs, with prodrug half-lives in plasma from canine, rat, horse, and human of 3.44-141 min, 2.51-14 min, 0.58-1.31 min, and 0.23-1.70 min, respectively. Half-lives in human and equine synovial fluid were 1.6- to 28-fold larger than in plasma. The results highlight the significance of species and tissue variation in prodrug design and suggest that the horse may constitute a suitable model for testing the intra-articular depot approach. Two prodrug candidates appeared promising for future in vivo studies based on their rapid in vitro enzyme-mediated bioconversion to diclofenac and physiochemical characteristics.

Health-related Quality of Life in Patients with Metastatic Spinal Cord Compression.

OBJECTIVE: Improvements in cancer treatment have resulted in an increased number of patients with metastatic spinal cord compression (MSCC). Because patients with MSCC often have a limited expected survival time, maintenance of a high functional level and quality of life are important. However, there is limited information about health-related quality of life (HRQoL) in patients with MSCC. The aim of this study was to examine the feasibility of routine assessment of HRQoL based on the Euroqol-5 dimensions (EQ-5D) questionnaire in a cohort of patients consecutively admitted for evaluation of acute symptoms of MSCC. METHODS: From 1 January to 31 December 2011, 544 patients diagnosed with acute symptoms of MSCC were consecutively enrolled in a cohort study. All patients were evaluated through a centralized referral system at one treatment facility. Data were prospectively registered, the variables age, sex, primary oncologic diagnosis, Tokuhashi Revised score, EQ-5D score and treatment modality being recorded on admission. The study patients were treated conservatively with radiotherapy alone or with surgery and subsequent radiotherapy. The EQ-5D questionnaire was administered on admission (baseline) and 6, 12, 26 and 52 weeks after admission. Response rates, completion rates and HRQoL scores were analyzed by relevant subgroups. Response rates were based on all questionnaires returned regardless of whether or not they had been completed, whereas completion rates were based on fully completed questionnaires (i.e., containing responses to all five questions. RESULTS: The mean age was 65 years (range, 20-95 years); 57% of the patients were men. The overall response rate to the Euroqol-5 dimensions (EQ-5D) questionnaires was 84% and the overall completion rate 72%. At baseline, mean EQ-5D scores were significantly lower for patients treated with surgery and subsequent radiotherapy 0.28 (95% CI, 0.19-0.36) than for those treated with radiotherapy alone 0.42 (95% CI, 0.38-0.46). At the one-year follow-up, the mean EQ-5D scores had improved to 0.71 (95% CI, 0.64-0.77) for patients treated with surgery and subsequent radiotherapy and 0.63 (95% CI, 0.56-0.70) for patients treated with radiotherapy alone. CONCLUSIONS: Measurement of HRQoL in patients consecutively admitted for evaluation of acute symptoms of MSCC is feasible and detects significant changes over time between treatment modalities and different strata of expected survival.

Long-Acting Diclofenac Ester Prodrugs for Joint Injection: Kinetics, Mechanism of Degradation, and In Vitro Release From Prodrug Suspension.

A prodrug approach for local and sustained diclofenac action after injection into joints based on ester prodrugs having a pH-dependent solubility is presented. Inherent ester prodrug properties influencing the duration of action include their pH-dependent solubility and charge state, as well as susceptibility to undergo esterase facilitated hydrolysis. In this study, physicochemical properties and pH rate profiles of 3 diclofenac ester prodrugs differing with respect to the spacer carbon chain length between the drug and the imidazole-based promoiety were determined and a rate equation for prodrug degradation in aqueous solution in the pH range 1-10 was derived. In the pH range 6-10, the prodrugs were subject to parallel degradation to yield diclofenac and an indolinone derivative. The prodrug degradation was found to be about 6-fold faster in 80% (vol/vol) human plasma as compared to 80% (vol/vol) human synovial fluid with 2-(1-methyl-1H-imidazol-2-yl)ethyl 2-(2-(2,6 dichlorophenyl)amino)phenylacetate being the poorest substrate toward enzymatic cleavage. The conversion and release of parent diclofenac from prodrug suspensions in vitro were studied using the rotating dialysis model. The results suggest that it is possible to alter and control dissolution and reconversion behavior of the diclofenac prodrugs, thus making the prodrug approach feasible for local and sustained diclofenac action after joint injection.

Pilot Randomized trial of Fibrinogen in Trauma Haemorrhage (PRooF-iTH): study protocol for a randomized controlled trial.

BACKGROUND: Haemorrhage remains a leading cause of morbidity and mortality in trauma patients. Fibrinogen is an essential endogenous component of haemostasis and the plasma level is associated with bleeding, transfusion and outcome. Fibrinogen concentrate is widely used to correct acquired hypofibrinogenaemia, recommended by several international guidelines for the treatment of trauma patients, but evidence is lacking regarding the treatment safety and efficacy. We aim to assess the efficacy and safety of an immediate pre-emptive first-line treatment with fibrinogen concentrate in patients with trauma haemorrhage in need of haemostatic resuscitation. METHODS/DESIGN: This is a single-centre, randomized (1:1, active:placebo), placebo-controlled, double-blinded, investigator-initiated phase II trial. The trial population consists of 40 adult patients (>18 years) with traumatic, critical bleeding admitted to the Level 1 Trauma Centre at Rigshospitalet in Copenhagen, with immediate need for blood transfusion on arrival and an expected need for haemostatic resuscitation with multiple transfusions during the initial resuscitation. Patients will receive either pre-emptive administration of a bolus dose of 60-70 mg/kg fibrinogen concentrate (Riastap®) or placebo 0.9 % saline in equal volume to active treatment, both given as intravenous infusion blinded for the person administering the infusion. The primary end point is the change in thrombelastograph (TEG®) functional fibrinogen maximum amplitude in millimetres at 15 min after the intervention. The follow-up period on safety events and mortality will be until day 30. To detect a difference in the change from baseline to the 15-minute post-randomization measurement of 6-8 mm in TEG® functional fibrinogen maximum amplitude with a power of 0.90 and alpha of 0.05, we require 19 patients in each group. We have chosen to include 40 patients, 20 evaluable patients in each randomization group in case of attrition, in the present trial. DISCUSSION: Patients considered to be included in the trial will temporarily have a compromised consciousness because of the acute, critical bleeding related to trauma, so scientific guardians will co-sign the informed consent form. Next of kin and the patients' general practitioner or the patients will co-sign as soon as possible. This trial will test whether immediate pre-emptive fibrinogen concentrate administered to adult trauma patients as first-line treatment of trauma haemorrhage will increase the clot strength as evaluated by thrombelastography, transfusion requirements and survival in patients receiving haemostatic resuscitation according to current standard of care. TRIAL REGISTRATION: EudraCT no. 2014-003978-16 (22/1 2015); ClinicalTrials.gov: NCT02344069 . Registered on 14 January 2015. Trial protocol version 4.2 (23-12-2014).

Role of Electrostatic Interactions on the Transport of Druglike Molecules in Hydrogel-Based Articular Cartilage Mimics: Implications for Drug Delivery.

In the field of drug delivery to the articular cartilage, it is advantageous to apply artificial tissue models as surrogates of cartilage for investigating drug transport and release properties. In this study, artificial cartilage models consisting of 0.5% (w/v) agarose gel containing 0.5% (w/v) chondroitin sulfate or 0.5% (w/v) hyaluronic acid were developed, and their rheological and morphological properties were characterized. UV imaging was utilized to quantify the transport properties of the following four model compounds in the agarose gel and in the developed artificial cartilage models: H-Ala-ß-naphthylamide, H-Lys-Lys-ß-naphthylamide, lysozyme, and α-lactalbumin. The obtained results showed that the incorporation of the polyelectrolytes chondroitin sulfate or hyaluronic acid into agarose gel induced a significant reduction in the apparent diffusivities of the cationic model compounds as compared to the pure agarose gel. The decrease in apparent diffusivity of the cationic compounds was not caused by a change in the gel structure since a similar reduction in apparent diffusivity was not observed for the net negatively charged protein α-lactalbumin. The apparent diffusivity of the cationic compounds in the negatively charged hydrogels was highly dependent on the ionic strength, pointing out the importance of electrostatic interactions between the diffusant and the polyelectrolytes. Solution based affinity studies between the model compounds and the two investigated polyelectrolytes further confirmed the electrostatic nature of their interactions. The results obtained from the UV imaging diffusion studies are important for understanding the effect of drug physicochemical properties on the transport in articular cartilage. The extracted information may be useful in the development of hydrogels for in vitro release testing having features resembling the articular cartilage.

Low level of procoagulant platelet microparticles is associated with impaired coagulation and transfusion requirements in trauma patients.

BACKGROUND: Following activation, platelets release small vesicles called platelet-derived microparticles (PMPs). PMPs accelerate thrombin generation and thus clot formation at sites of injury by exposing the procoagulant membrane phospholipid phosphatidylserine (PS). The role of PMPs in coagulopathy and hemorrhage following trauma remains elusive. We hypothesized that low levels of PS-positive PMPs (PS + PMPs) would be associated with impaired clot formation. METHODS: This is a prospective observational study of 210 trauma patients admitted directly to a Level 1 trauma center. Plasma levels of PS + PMPs were determined by flow cytometry. Coagulation status was assessed by rotational thrombelastometry, and impaired clot formation was defined by an α angle less than 63 degrees using the tissue factor-based EXTEM reagent. Transfusion requirement was assessed by number of units of red blood cells (RBCs) transfused within 24 hours of admission; platelet aggregation capacity was evaluated by the Multiplate assay; and injury severity was determined by the Injury Severity Score (ISS). RESULTS: The median ISS was 17, and blood samples were obtained after a median of 65 minutes following injury. Significantly lower levels of PS + PMPs were found in patients with impaired clot formation (p < 0.001). A low level of PS + PMPs was associated with a higher number of RBCs transfused during the initial 24 hours after admission (p < 0.03) when corrected for risk factors, for example, platelet count, hemoglobin level, and ISS. Platelet aggregation and PS + PMPs did not correlate significantly. CONCLUSION: Low levels of PMPs were associated with impaired clot formation in trauma patients at admission and also with the number of RBC transfusions. This suggests that PMPs may play an important and not previously investigated role in trauma-induced coagulopathy. LEVEL OF EVIDENCE: Prognostic study, level III.

A prodrug approach involving in situ depot formation to achieve localized and sustained action of diclofenac after joint injection.

Long-acting nonsteroidal anti-inflammatory drug formulations for intra-articular injection might be effective in the management of joint pain and inflammation associated sports injuries and osteoarthritis. In this study, a prodrug-based delivery system was evaluated. The synthesized diclofenac ester prodrug, a weak base (pKa 7.52), has relatively high solubility at low pH (6.5 mg mL(-1) at pH 4) and much lower solubility at physiological pH (4.5 µg mL(-1) at pH 7.4) at 37°C. In biological media including 80% (v/v) human synovial fluid (SF), the prodrug was cleaved to diclofenac mediated by esterases. In situ precipitation of the prodrug was observed upon addition of a concentrated slightly acidic prodrug solution to phosphate buffer or SF at pH 7.4. The degree of supersaturation accompanying the precipitation process was more pronounced in SF than in phosphate buffer. In the rotating dialysis cell model, a slightly acidic prodrug solution was added to the donor cell containing 80% SF resulting in a continuous appearance of diclofenac in the acceptor phase for more than 43 h after an initial lag period of 8 h. Detectable amounts of prodrug were found in the rat joint up to 8 days after knee injection of the acidic prodrug solution.

Microenvironmental pH measurement during sodium naproxenate dissolution in acidic medium by UV/vis imaging.

Variable dissolution from sodium salts of drugs containing a carboxylic acid group after passing the acidic environment of the stomach may affect oral bioavailability. The aim of the present proof of concept study was to investigate pH effects in relation to the dissolution of sodium naproxenate in 0.01M hydrochloric acid. For this purpose a UV/vis imaging-based approach capable of measuring microenvironmental pH in the vicinity of the solid drug compact as well as monitoring drug dissolution was developed. Using a pH indicating dye real-time spatially resolved measurement of pH was achieved. Sodium naproxenate, can significantly alter the local pH of the dissolution medium, is eventually neutralized and precipitates as the acidic species naproxen. The developed approach is considered useful for detailed studies of pH dependent dissolution phenomena in dissolution testing.

Moderate precision of prognostic scoring systems in a consecutive, prospective cohort of 544 patients with metastatic spinal cord compression.

PURPOSE: Improved survival among cancer patients and diverse conclusions from recent studies make it relevant to reassess the performance of the Tokuhashi Revised score and the Tomita score. The aim of this study was to validate and compare these two scoring systems in a recent and unselected cohort of patients with metastatic spinal cord compression (MSCC). METHODS: In 2011, we conducted a prospective cohort study of 544 patients who were consecutively admitted with MSCC to one treatment facility. Patients estimated survival were assessed with the Tokuhashi Revised score and the Tomita score and compared to the observed survival. We assessed how precise the scoring systems predicted survival with McNemar's test. The prognostic value was illustrated with Kaplan-Meier curves, and the individual prognostic components were analyzed with Cox regression analysis. RESULTS: The mean age was 65 years (range 20-95), and 57 % of the patients were men. The majority of tumors were lung (23 %), prostate (21 %), and breast tumors (18 %). The overall precision of predicted survival was 58.7 % for the Tokuhashi Revised score and 52.9 % for the Tomita score. The observed survival in each of the scoring groups categorized by the scoring systems was statistically significantly different (p < 0.0001). CONCLUSIONS: The Tokuhashi Revised score and the Tomita score are useful in categorizing patients into prognostic groups, and the individual components have important prognostic values. The Tokuhashi Revised score was most precise in predicting survival. However, due to the relatively low precision, we suggest that a modification of both scoring systems is necessary.

PEGylation of phytantriol-based lyotropic liquid crystalline particles--the effect of lipid composition, PEG chain length, and temperature on the internal nanostructure.

Poly(ethylene glycol)-grafted 1,2-distearoyl-sn-glycero-3-phosphoethanolamines (DSPE-mPEGs) are a family of amphiphilic lipopolymers attractive in formulating injectable long-circulating nanoparticulate drug formulations. In addition to long circulating liposomes, there is an interest in developing injectable long-circulating drug nanocarriers based on cubosomes and hexosomes by shielding and coating the dispersed particles enveloping well-defined internal nonlamellar liquid crystalline nanostructures with hydrophilic PEG segments. The present study attempts to shed light on the possible PEGylation of these lipidic nonlamellar liquid crystalline particles by using DSPE-mPEGs with three different block lengths of the hydrophilic PEG segment. The effects of lipid composition, PEG chain length, and temperature on the morphology and internal nanostructure of these self-assembled lipidic aqueous dispersions based on phytantriol (PHYT) were investigated by means of synchrotron small-angle X-ray scattering and Transmission Electron Cryo-Microscopy. The results suggest that the used lipopolymers are incorporated into the water-PHYT interfacial area and induce a significant effect on the internal nanostructures of the dispersed submicrometer-sized particles. The hydrophilic domains of the internal liquid crystalline nanostructures of these aqueous dispersions are functionalized, i.e., the hydrophilic nanochannels of the internal cubic Pn3m and Im3m phases are significantly enlarged in the presence of relatively small amounts of the used DSPE-mPEGs. It is evident that the partial replacement of PHYT by these PEGylated lipids could be an attractive approach for the surface modification of cubosomal and hexosomal particles. These PEGylated nanocarriers are particularly attractive in designing injectable cubosomal and hexosomal nanocarriers for loading drugs and/or imaging probes.

Platelet aggregation following trauma: a prospective study.

We aimed to elucidate platelet function in trauma patients, as it is pivotal for hemostasis yet remains scarcely investigated in this population. We conducted a prospective observational study of platelet aggregation capacity in 213 adult trauma patients on admission to an emergency department (ED). Inclusion criteria were trauma team activation and arterial cannula insertion on arrival. Blood samples were analyzed by multiple electrode aggregometry initiated by thrombin receptor agonist peptide 6 (TRAP) or collagen using a Multiplate device. Blood was sampled median 65 min after injury; median injury severity score (ISS) was 17; 14 (7%) patients received 10 or more units of red blood cells in the ED (massive transfusion); 24 (11%) patients died within 28 days of trauma: 17 due to cerebral injuries, four due to exsanguination, and three from other causes. No significant association was found between aggregation response and ISS. Higher TRAP values were associated with death due to cerebral injuries (P < 0.01, when corrected for ISS and platelet counts), whereas lower platelet counts were associated with massive transfusion (P < 0.01, when corrected for ISS and aggregation). An aggregation value of 145 IU by TRAP significantly identified death due to cerebral injury (sensitivity 71% and specificity 76%, P < 0.01) by receiver operating characteristic-curve analysis; the corresponding value of platelet counts for massive transfusion was 189 × 10/l (sensitivity 86%, specificity 75%, P < 0.01). We concluded there was no simple relationship between platelet aggregation and injury severity. Our results indicate that high platelet aggregation values are associated with fatality of cerebral injury.

Impact of the severity of trauma on early retirement.

OBJECTIVE: To assess the association between Injury Severity Score (ISS) and subsequent risk of early retirement. DESIGN: Observational cohort study with follow-up based on prospectively collected data. Hospital-based data were linked to national register data on pension reception and vital status. SETTING: Level-one urban trauma centre. PARTICIPANTS: Patients aged 18-64 years entering the trauma centre in Copenhagen during 1999-2007 who were alive after three days were followed until early retirement, death or emigration. MAIN OUTCOME MEASURES: Primary outcome was early retirement, defined as receiving disability pension (unintentional) or voluntary early retirement pension (intentional) before the regular age of retirement (65 years). Relative risk of early retirement according to ISS (low, ISS 1-15 vs. high, ISS 16-75) was assessed using Cox proportional hazards regression, adjusted for age and gender. RESULTS: Of all 6687 patients admitted to the trauma centre, a total of 1722 trauma patients were included and followed for a median of 6.2 years (interquartile range (IQR) 3.7-9.1). Of these, 1305 (75.8%) were males, median age was 35.0 years (IQR 25.4-46.5), and median ISS was 16 (IQR 9-25). Three hundred and twenty-two patients retired during follow-up. Patients with high ISS, compared to patients with low ISS, had an increased risk of early retirement, adjusted hazard ratio 2.60 (95% confidence interval (CI) 2.05-3.30; p<0.001). Relative increase in retirement risk was 1.04 (95% CI 1.03-1.05) per ISS point and 1.03 (95% CI 1.03-1.04) per year older. Gender was not found to be a significant risk factor (p=0.69). Five-year absolute risks of early retirement were 9.9% (95% CI 7.8-12.0%) for the low ISS group and 24.6% (95% CI 21.6-27.5%) for the high ISS group. CONCLUSIONS: The risk of early retirement is 2.6 times higher in severely injured patients (ISS 16-75) than the risk in low to moderately injured patients (ISS 1-15) and they have a high absolute 5-year risk as well. Early, targeted interventions to assist with return to work might be able to reduce this risk.

SPECT/CT imaging of radiolabeled cubosomes and hexosomes for potential theranostic applications.

We have developed a highly efficient method for the radiolabeling of phytantriol (PHYT)/oleic acid (OA)-based hexosomes based on the surface chelation of technetium-99m ((99m)Tc) to preformed hexosomes using the polyamine 1, 12-diamino-3, 6, 9-triazododecane (SpmTrien) as chelating agent. We also report on the unsuccessful labeling of cubosomes using the well-known chelating agent hexamethylpropyleneamine oxime (HMPAO). The (99m)Tc-labeled SpmTrien-hexosomes ((99m)Tc-SpmTrien-hexosomes) were synthesized with good radiolabeling (84%) and high radiochemical purity (>90%). The effect of radiolabeling on the internal nanostructure and the overall size of these aqueous dispersions was investigated by using synchrotron small angle X-ray scattering (SAXS), dynamic light scattering (DLS), and transmission electron cryo microscopy (cryo-TEM). Further, we show the utility of (99m)Tc-SpmTrien-hexosomes for the in vivo imaging of healthy mice using single photon emission computed tomography (SPECT) in combination with computed tomography (CT), i.e. SPECT/CT. SPECT/CT experiments of subcutaneously administered (99m)Tc-SpmTrien-hexosomes to the flank of mice showed a high stability in vivo allowing imaging of the distribution of the radiolabeled hexosomes for up to 24 h. These injected (99m)Tc-SpmTrien-hexosomes formed a deposit within the subcutaneous adipose tissue, displaying a high biodistribution of ≈ 343% injected dose/g tissue (%ID/g), with negligible uptake in other organs and tissues. The developed (99m)Tc labeling method for PHYT/OA-based hexosomes could further serve as a useful tool for investigating and imaging the in vivo performance of cubosomal and hexosomal drug nanocarriers.

Prolonged naproxen joint residence time after intra-articular injection of lipophilic solutions comprising a naproxen glycolamide ester prodrug in the rat.

Intra-articular injection of oil solutions of lipophilic prodrugs that rapidly degrade to their parent compound in synovial fluid may constitute a feasible approach to increase the joint residence time of non-steroidal anti-inflammatory drugs. In this in vivo study, oil solutions of the N,N-diethyl glycolamide ester prodrug of naproxen (16 mg/ml) were injected into the rat knee joint by dosing 6 µl formulation per 100g body weight. The sustained release properties were compared to those of intra-articularly injected aqueous and oil solutions of naproxen by monitoring the naproxen serum concentrations over time. Two oils, medium-chain triglycerides and castor oil, differing with respect to viscosity were tested. After intra-articular administration of oil prodrug solutions, a significant increase in the time to maximum naproxen serum concentration from around 40 to 245 min, an increase in the MRT(j) from around 0.11 to 3.3h and a 30% reduction in the maximum serum concentration were observed compared to that of the parent naproxen. The similar serum profiles obtained using the two oils indicate that the release was not affected by the oil viscosity. A prolonged naproxen joint residence time in rats was shown by intra-articular injection of an oil prodrug solution.

Prognosis in patients with symptomatic metastatic spinal cord compression: survival in different cancer diagnosis in a cohort of 2321 patients.

STUDY DESIGN: A retrospective cohort study of 2321 patients consecutively admitted to one center and diagnosed with acute symptoms of metastatic spinal cord compression (MSCC). OBJECTIVE: To assess the possible change in 1-year survival for patients with MSCC from year 2005 through 2010 with respect to the primary cancer diagnosis. SUMMARY OF BACKGROUND DATA: An increasing number of patients are offered surgical treatment for MSCC. Among the reasons for this development are high evidence clinical studies, improved surgical techniques, and an increasing number of patients being treated for an oncological condition. Preoperative scoring systems are routinely used in the evaluation of these patients, and the primary oncological diagnosis is an important variable in all these systems. To our knowledge, no studies in a large group of patients have assessed the change in survival in these patients. This is of relevance because such changes in survival could have implications on the scoring systems used in the preoperative evaluation. METHODS: All patients referred to the university hospital, Rigshospitalet, suspected of acute symptoms caused by spinal metastases and diagnosed with MSCC from January 1, 2005, to December 31, 2010, were included in a retrospective cohort, n = 2321. For all patients primary tumor, treatment, and 1-year survival was registered. RESULTS: The overall 1-year survival did not change significantly from 2005 to 2010, but there was a significant increase in 1-year survival for the subgroups of patients with lung cancer hazard ratio = 0.93 (P = 0.008, 95% CI: 0.83-0.98) and renal cancer hazard ratio = 0.77 (P = 0.004, 95% CI: 0.56-0.92). CONCLUSION: Patients with MSCC from pulmonary and renal cancers experienced improved survival in the study period. No improvement was seen for patients with other oncological diagnoses. This corresponds to reports from oncological studies and could affect preoperative scoring systems.

Low hemorrhage-related mortality in trauma patients in a Level I trauma center employing transfusion packages and early thromboelastography-directed hemostatic resuscitation with plasma and platelets.

BACKGROUND: Hemorrhage accounts for most preventable trauma deaths, but still the optimal strategy for hemostatic resuscitation remains debated. STUDY DESIGN AND METHODS: This was a prospective study of adult trauma patients admitted to a Level I trauma center. Demography, Injury Severity Score (ISS), transfusion therapy, and mortality were registered. Hemostatic resuscitation was based on a massive transfusion protocol encompassing transfusion packages and thromboelastography (TEG)-guided therapy. RESULTS: A total of 182 patients were included (75% males, median age 43 years, ISS of 17, 92% with blunt trauma). Overall 28-day mortality was 12% with causes of death being exsanguinations (14%), traumatic brain injury (72%, two-thirds expiring within 24 hr), and other (14%). One-fourth, 16 and 15% of the patients, received red blood cells (RBCs), plasma, or platelets (PLTs) within 2 hours from admission and 68, 71, and 75%, respectively, of patients transfused within 24 hours received the respective blood products within the first 2 hours. In patients transfused within 24 hours, the median number of blood products at 2 hours was 5 units of RBCs, 5 units of plasma, and 2 units of PLT concentrates. Nonsurvivors had lower clot strength by kaolin-activated TEG and TEG functional fibrinogen and lower kaolin-tissue factor-activated TEG α-angle and lysis after 30 minutes compared to survivors. None of the TEG variables were independent predictors of massive transfusion or mortality. CONCLUSION: Three-fourths of the patients transfused with plasma or PLTs within 24 hours received these in the first 2 hours. Hemorrhage caused 14% of the deaths. We introduced transfusion packages and early TEG-directed hemostatic resuscitation at our hospital 10 years ago and this may have contributed to reducing hemorrhagic trauma deaths.

Trauma-induced coagulopathy: standard coagulation tests, biomarkers of coagulopathy, and endothelial damage in patients with traumatic brain injury.

It remains to be debated whether traumatic brain injury (TBI) induces a different coagulopathy than does non-TBI. This study investigated traditional coagulation tests, biomarkers of coagulopathy, and endothelial damage in trauma patients with and without TBI. Blood from 80 adult trauma patients was sampled (median of 68 min [IQR 48-88] post-injury) upon admission to our trauma center. Plasma/serum were retrospectively analyzed for biomarkers reflecting sympathoadrenal activation (adrenaline, noradrenaline), coagulation activation/inhibition and fibrinolysis (protein C, activated protein C, tissue factor pathway inhibitor, antithrombin, prothrombin fragment 1+2, thrombin/antithrombin complex, von Willebrand factor, factor XIII, d-dimer, tissue-type plasminogen activator, plasminogen activator inhibitor-1), immunology (interleukin [IL]6), endothelial cell/glycocalyx damage (soluble thrombomodulin, syndecan-1), and vasculogenesis (angiopoietin-1, -2). Patients were stratified according to: (1) isolated severe head/neck injuries (Abbreviated injury score [AIS]-head/neck ≥ 3, AIS-other<3) (isoTBI); (2) severe head/neck and extracranial injuries (AIS-head/neck ≥ 3, AIS-other>3) (sTBI+other); and (3) injuries without significant head/neck injuries (AIS-head/neck<3, including all AIS-other scores) (non-TBI). Twenty-three patients presented with isoTBI, 15 with sTBI+other and 42 with non-TBI. Acute coagulopathy of trauma shock, defined as activated partial thromboplastin time (APTT) and/or international normalized ratio (INR)>35 sec and>1.2, was found in 13%, 47%, and 5%, respectively (p=0.000). sTBI+other had significantly higher plasma levels of adrenaline, noradrenaline, annexin V, d-dimer, IL-6, syndecan-1, soluble thrombomodulin, and reduced protein C and factor XIII levels (all p<0.05). No significant biomarker differences were found between isoTBI and non-TBI patients. Injury severity scale (ISS) rather than the presence or absence of head/neck injuries determined the hemostatic and biomarker response to the injury. The coagulopathy identified thus reflected the severity of injury rather than its localization.

Modification of concomitant drug release from oil vehicles using drug-prodrug combinations to achieve sustained balanced analgesia after joint installation.

Intra-articular injection of two drugs in a sustained drug delivery system combining the use of lipophilic solution with the prodrug approach may provide efficient and prolonged postoperative pain treatment after arthroscopic procedures. In the present study, the concomitant release of N,N-diethyl glycolamide ester of naproxen and ropivacaine from an oil vehicle consisting of medium-chain triglycerides were investigated in vitro. The release into both phosphate buffer and 80% (v/v) synovial fluid at pH 7.4 was examined in two dialysis membrane-based release models. The ester prodrug exhibited high solubility in medium-chain triglyceride, a high partition coefficient and was rapidly converted to naproxen in synovial fluid. Compared to naproxen, the release of the prodrug from the oil was sustained. In synovial fluid, the reconversion to naproxen resulted in faster release compared to that observed using buffer. In both release models, the use of ropivacaine-prodrug combination provided concomitant release from the oil into synovial fluid with ropivacaine being released faster than naproxen. The use of lipophilic prodrugs that are converted fast to the parent drug in synovial fluid seems to be a feasible approach to obtain prolonged joint residence time.

Drug release into hydrogel-based subcutaneous surrogates studied by UV imaging.

Upon subcutaneous administration, the distribution of drug between the delivery vehicle and the biological tissue critically affects the absorption of drug substances. Utilization of physical models resembling the native tissues appears promising for obtaining a detailed understanding of the performance of drug delivery systems based on in vitro experiments. The objective of this study was to evaluate a UV imaging-based method for real-time characterization of the release and transport of piroxicam in hydrogel-based subcutaneous tissue mimics/surrogates. Piroxicam partitioning from medium chain triglyceride (MCT) into 0.5% (w/v) agarose or 25% (w/v) F127-based hydrogels was investigated by monitoring the concentration profiles of the drug in the gels. The effect of pH on piroxicam distribution and diffusion coefficients was studied. For both hydrogel systems, the diffusion of piroxicam in the gels was not affected significantly by the pH change from 4.0 to 7.4 but a considerable change in the oil-gel distribution coefficients was found (24 and 34 times less at pH 7.4 as compared those observed at pH 4.0 for F127 and agarose gels, respectively). In addition, the release and transport processes of piroxicam upon the injection of aqueous or MCT solutions into an agarose-based hydrogel were investigated by UV imaging. The spatial distribution of piroxicam around the injection site in the gel matrix was monitored in real-time. The disappearance profiles of piroxicam from the injected aqueous solution were obtained. This study shows that the UV imaging methodology has considerable potential for characterizing transport properties in hydrogels, including monitoring the real-time spatial concentration distribution in vitro after administration by injection.