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Efficacy and safety of loxoprofen sodium topical patch for the treatment of pain in patients with minor acute traumatic limb injuries in Brazil: a randomized, double-blind, noninferiority trial.
Fujiki, EN, Netto, NA, Kraychete, DC, Daher, MT, Tardini, R, Nakamoto, A, Lopes, DG
Pain. 2019;(7):1606-1613
Abstract
Posttraumatic injury pain is commonly treated with oral nonsteroidal anti-inflammatory drugs. However, oral nonsteroidal anti-inflammatory drugs cause several adverse events, with topical formulations arising as an important alternative. Therefore, we aimed at evaluating the efficacy and safety of loxoprofen patch (LX-P) in the treatment of patients with posttraumatic pain. This phase III, randomized, double-blind, noninferiority study enrolled Brazilian patients aged 18 to 65 years diagnosed with lower and upper limb posttraumatic injury who were experiencing moderate or severe pain. Patients were assigned to active LX-P or to loxoprofen tablet (LX-T), and pain intensity was measured based on a visual analog scale score variation after 7 days of treatment. Data on clinical symptoms, rescue medication use, and adverse events were also collected. Visual analog scale score variation was compared using a 10% noninferiority margin. Two hundred forty-two patients were randomly assigned to LX-P (n = 123) or to LX-T (n = 119). The results showed a reduction in pain after 7 days of treatment: -49.96 (n = 118; SE 1.7) in the LX-P and -47.71 (n = 117; SE 1.6) in the LX-T groups (difference of -2.25; 95% CI: -5.97 to 1.47; P = 0.23). On the safety analysis, the LX-T group presented twice as many patients with treatment-emergent adverse events as the LX-P group (30.8% and 14.2%, respectively). A sensitivity analysis demonstrated that rescue medication use has not affected the primary end point. This study showed that LX-P has a comparable efficacy to LX-T, but with a better safety profile, being a therapeutic option for the treatment of posttraumatic injury pain.
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Improvement in asymmetric dimethylarginine and oxidative stress in patients with limb salvage after autologous mononuclear stem cell application for critical limb ischemia.
Madaric, J, Valachovicova, M, Paulis, L, Pribojova, J, Mateova, R, Sebekova, K, Postulkova, L, Madaricova, T, Bucova, M, Mistrik, M, et al
Stem cell research & therapy. 2017;(1):165
Abstract
BACKGROUND Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, acts as an inhibitor of angiogenesis and is associated with an increased risk of cardiovascular mortality. Administration of stem cells may affect endogenous mechanisms that regulate ADMA production and metabolism. The aim of the present study was to analyze ADMA concentration and changes in oxidative stress in patients with advanced critical limb ischemia (CLI) after bone marrow-derived mononuclear cell (BM-MNC) therapy. METHODS Fifty patients (age 64 ± 11 years, 44 males, 6 females) with advanced CLI (Rutherford category 5 or 6) not eligible for revascularization were treated by intramuscular (n = 25) or intra-arterial (n = 25) injection of 40 ml BM-MNC concentrate. Patients with limb salvage and improved wound healing after 6 months were considered responders to cell therapy. The concentrations of markers of oxidative stress and angiogenesis were analyzed before, and at 3 and 6 months after BM-MNC delivery. RESULTS At 6-month follow-up, four patients died of reasons unrelated to stem cell therapy. Among the survivors, 80% (37/46) showed limb salvage and improved wound healing. At 6 months follow-up, ADMA concentration significantly decreased in patients with limb salvage (1.74 ± 0.66 to 0.90 ± 0.49 μmol/L, p < 0.001), in parallel with decreased tumor necrosis factor (TNF)-α (2.22 ± 0.16 to 1.94 ± 0.38 pg/ml, p < 0.001), and increased reduced glutathione (6.96 ± 3.1 to 8.67 ± 4.2 μmol/L, p = 0.02), superoxide dismutase activity (168 ± 50 to 218 ± 37 U/L, p = 0.002), and coenzyme Q10 concentration (468 ± 182 to 598 ± 283 μg/L, p = 0.02). The number of delivered BM-MNCs significantly correlated with the decrease in ADMA concentration at 3 months (p = 0.004, r = -0.48) and the decrease in TNF-α concentration at 6 months (p = 0.03, r = -0.44) after cell delivery. ADMA or TNF-α improvement did not correlate with the number of applied CD34+ cells, C-reactive protein concentration, leukocyte count, or the dose of atorvastatin. CONCLUSIONS The therapeutic benefit of BM-MNC therapy is associated with reduced ADMA levels and oxidative stress. Regulation of the ADMA-nitric oxide axis and improved antioxidant status may be involved in the beneficial effects of stem cell therapy. TRIAL REGISTRATION The study was approved and retrospectively registered by ISRCTN registry, ISRCTN16096154 . Registered on 26 July 2016.
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Phase I trial of neoadjuvant conformal radiotherapy plus sorafenib for patients with locally advanced soft tissue sarcoma of the extremity.
Canter, RJ, Borys, D, Olusanya, A, Li, CS, Lee, LY, Boutin, RD, Christensen, SD, Tamurian, RM, Monjazeb, AM
Annals of surgical oncology. 2014;(5):1616-23
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Abstract
BACKGROUND Despite effective local therapy with surgery and radiotherapy (RT), ~50 % of patients with high-grade soft tissue sarcoma (STS) will relapse and die of disease. Since experimental data suggest a significant synergistic effect when antiangiogenic targeted therapies such as sorafenib are combined with RT, we chose to evaluate preoperative combined modality sorafenib and conformal RT in a phase I/II trial among patients with extremity STS amenable to treatment with curative intent. METHODS For the phase I trial, eight patients with intermediate- or high-grade STS >5 cm in maximal dimension or low-grade STS >8 cm in maximal dimension received concomitant sorafenib (dose escalation cohort 1:200 twice daily, cohort 2:200/400 daily) and preoperative RT (50 Gy in 25 fractions). Sorafenib was continued during the entire period of RT as tolerated. Surgical resection was completed 4-6 weeks following completion of neoadjuvant sorafenib/RT. Three sorafenib dose levels were planned. Primary endpoints of the phase I trial were maximal tolerated dose and dose-limiting toxicity (DLT). RESULTS Eight patients were enrolled in the phase I (five females, median age 44 years, two high-grade pleomorphic, two myxoid/round cell liposarcoma, four other). Median tumor size was 16 cm (range 8-29), and all tumors were located in the lower extremity. Two of five patients treated at dose level 2 developed DLT consisting of grade 3 rash not tolerating drug reintroduction. Other grade 3 side effects included anemia, perirectal abscess, and supraventricular tachycardia. Radiation toxicity (grade 1 or 2 dermatitis; N = 8) and post-surgical complications (three grade 3 wound complications) were comparable to historical controls and other series of preoperative RT monotherapy. Complete pathologic reponse (≥95 % tumor necrosis) was observed in three patients (38 %). CONCLUSION Neoadjuvant sorafenib in combination with RT is tolerable and appears to demonstrate activity in locally advanced extremity STS. Further study to determine efficacy at dose level 1 is warranted. (ClinicalTrials.gov identifier NCT00805727).
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Fluid intake and changes in limb volumes in male ultra-marathoners: does fluid overload lead to peripheral oedema?
Bracher, A, Knechtle, B, Gnädinger, M, Bürge, J, Rüst, CA, Knechtle, P, Rosemann, T
European journal of applied physiology. 2012;(3):991-1003
Abstract
An increase in body mass due to oedema has been previously described. The aim of this study was to investigate a potential association between both fluid and electrolyte intake and the formation of peripheral oedemas. Fluid and electrolyte intakes and the changes in limb volumes in 50 male 100-km ultra-marathoners were measured. Pre- and post-race serum sodium concentration ([Na(+)]), serum aldosterone concentration, serum copeptin concentration, serum and urine osmolality and body mass were determined. Fluid intake, renal function parameters and urinary output, as well as the changes of volume in the extremities, were measured. The changes of volume in the limbs were measured using plethysmography. Serum [Na(+)] increased by 1.6%; body mass decreased by 1.9 kg. Serum copeptin and aldosterone concentrations were increased. The change in serum copeptin concentration and the change in serum [Na(+)] correlated positively; the change in serum [Na(+)] and body mass correlated negatively. A mean fluid intake of 0.58 L/h was positively related to running speed and negatively to post-race serum [Na(+)]. Total fluid intake was positively related to the changes in both arm and lower leg volumes. Running speed was positively associated with the changes in arm and lower leg volumes; race time was related to the changes in serum copeptin or aldosterone concentrations. To conclude, fluid intake was related to the changes in limb volumes, where athletes with an increased fluid intake developed an increase in limb volumes.
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A phase I multi-institutional study of systemic sorafenib in conjunction with regional melphalan for in-transit melanoma of the extremity.
Beasley, GM, Coleman, AP, Raymond, A, Sanders, G, Selim, MA, Peterson, BL, Brady, MS, Davies, MA, Augustine, C, Tyler, DS
Annals of surgical oncology. 2012;(12):3896-3905
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BACKGROUND Isolated limb infusion with melphalan (ILI-M) corrected for ideal body weight (IBW) is a well-tolerated treatment for patients with in-transit extremity melanoma with an approximate 29 % complete response (CR) rate. Sorafenib, a multi-kinase inhibitor, has been shown to augment tumor response to chemotherapy in preclinical studies. METHODS A multi-institutional, dose-escalation, phase I study was performed to evaluate the safety and antitumor activity of sorafenib in combination with ILI-M. Patients with AJCC stage IIIB/IIIC/IV melanoma were treated with sorafenib starting at 400 mg daily for 7 days before and 7 days after ILI-M corrected for IBW. Toxicity, drug pharmacokinetics, and tumor protein expression changes were measured and correlated with clinical response at 3 months. RESULTS A total of 20 patients were enrolled at two institutions. The maximum tolerated dose (MTD) of sorafenib in combination with ILI-M was 400 mg. Four dose-limiting toxicities occurred, including soft tissue ulcerations and compartment syndrome. There were three CRs (15 %) and four partial responses (20 %). Of patients with the Braf mutation, 83 % (n = 6) progressed compared with only 33 % without (n = 12). Short-term sorafenib treatment did alter protein expression as measured with reverse phase protein array (RPPA) analysis, but did not inhibit protein expression in the MAP kinase pathway. Sorafenib did not alter melphalan pharmacokinetics. CONCLUSION This trial defined the MTD of systemically administered sorafenib in combination with ILI-M. Although some responses were seen, the addition of sorafenib to ILI-M did not appear to augment the effects of melphalan but did increase regional toxicity.
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[Treatment for crush syndrome of extremities with antioxidants].
Fu, CG
Zhongguo gu shang = China journal of orthopaedics and traumatology. 2008;(2):109-10
Abstract
OBJECTIVE To study the clinical therapeutic effect of antioxidants assistant treatment of extremities crush syndrome (CS)in order to find new therapy. METHODS Twenty-one male patients (aged from 24 to 48 years, mean 36 years) were treated with the next antioxidants in early stage: (1) 20% Mannitol 250 ml intravenous drip in 30 minutes (one time per 6 to 8 h). (2) Sodium aescinate 20 mg, Salvia Miltiorrhiza 20 ml were dissolved respectively in isotonic saline or 5% glucose 200 ml and dripped by intravenous drip (50 to 60 drips per minute). The drugs were used for 5 to 7 days (one time per day). Basifying urine, keeping the nagative liquid banlance and electrolyte banlance, preventing infection and hold out treatment were done. When the pressure of muscular osteofascial compartment was more than 30 mmHg, deep fasia was cut to decompress timely and the above-mentioned drugs were continuously applied for patients. RESULTS Myoglobin urine of 21 cases died out after 2 to 3 days, of them, 13 cases were performed to decompress. After open decompression, 2 cases suffered from amputation because of long time of ischemia, 2 cases took place slight dysfunction of lower limbs, one hand had ischemia muscular contracture in 1 case and one foot down-vertical in 1 case. After followed-up of 8 months to 1 year, according to the function standard, the result were excellent in 8 cases, good in 7 cases, fair in 2 cases, poor in 4 cases. The excellent and good rate was about 71.4% (15/21). CONCLUSION After extremities crushed for long time, application of antioxidents as early as possible can decrease significantly the incidence and invalidity rate of CS.
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Microdialysis and response during regional chemotherapy by isolated limb infusion of melphalan for limb malignancies.
Thompson, JF, Siebert, GA, Anissimov, YG, Smithers, BM, Doubrovsky, A, Anderson, CD, Roberts, MS
British journal of cancer. 2001;(2):157-65
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This study sought to use a microdialysis technique to relate clinical and biochemical responses to the time course of melphalan concentrations in the subcutaneous interstitial space and in tumour tissue (melanoma, malignant fibrous histiocytoma, Merkel cell tumour and osteosarcoma) in patients undergoing regional chemotherapy by Isolated Limb Infusion (ILI). 19 patients undergoing ILI for treatment of various limb malignancies were monitored for intra-operative melphalan concentrations in plasma and, using microdialysis, in subcutaneous and tumour tissues. Peak and mean concentrations of melphalan were significantly higher in plasma than in subcutaneous or tumour microdialysate. There was no significant difference between drug peak and mean concentrations in interstitial and tumour tissue, indicating that there was no preferential uptake of melphalan into the tumours. The time course of melphalan in the microdialysate could be described by a pharmacokinetic model which assumed melphalan distributed from the plasma into the interstitial space. The model also accounted for the vascular dispersion of melphalan in the limb. Tumour response in the whole group to treatment was partial response: 53.8% (n = 7); complete response: 33.3% (n = 5); no response: 6.7% (n = 1). There was a significant association between tumour response and melphalan concentrations measured over time in subcutaneous microdialysate (P< 0.01). No significant relationship existed between the severity of toxic reactions in the limb or peak plasma creatine phosphokinase levels and peak melphalan microdialysate or plasma concentrations. It is concluded that microdialysis is a technique well suited for measuring concentrations of cytotoxic drug during ILI. The possibility of predicting actual concentrations of cytotoxic drug in the limb during ILI using our model opens an opportunity for improved drug dose calculation. The combination of predicting tissue concentrations and monitoring in microdialysate of subcutaneous tissue could help optimise ILI with regard to post-operative limb morbidity and tumour response.
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Cost effectiveness analysis of intravenous ketorolac and morphine for treating pain after limb injury: double blind randomised controlled trial.
Rainer, TH, Jacobs, P, Ng, YC, Cheung, NK, Tam, M, Lam, PK, Wong, R, Cocks, RA
BMJ (Clinical research ed.). 2000;(7271):1247-51
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OBJECTIVES To investigate the cost effectiveness of intravenous ketorolac compared with intravenous morphine in relieving pain after blunt limb injury in an accident and emergency department. DESIGN Double blind, randomised, controlled study and cost consequences analysis. SETTING Emergency department of a university hospital in the New Territories of Hong Kong. PARTICIPANTS 148 adult patients with painful isolated limb injuries (limb injuries without other injuries). MAIN OUTCOME MEASURES Primary outcome measure was a cost consequences analysis comparing the use of ketorolac with morphine; secondary outcome measures were pain relief at rest and with limb movement, adverse events, patients' satisfaction, and time spent in the emergency department. RESULTS No difference was found in the median time taken to achieve pain relief at rest between the group receiving ketorolac and the group receiving morphine, but with movement the median reduction in pain score in the ketorolac group was 1.09 per hour (95% confidence interval 1.05 to 2.02) compared with 0.87 (0.84 to 1.06) in the morphine group (P=0.003). The odds of experiencing adverse events was 144.2 (41.5 to 501.6) times more likely with morphine than with ketorolac. The median time from the initial delivery of analgesia to the participant leaving the department was 20 (4.0 to 39.0) minutes shorter in the ketorolac group than in the morphine group (P=0.02). The mean cost per person was $HK44 ( pound4; $5.6) in the ketorolac group and $HK229 in the morphine group (P<0.0001). The median score for patients' satisfaction was 6.0 for ketorolac and 5.0 for morphine (P<0.0001). CONCLUSION Intravenous ketorolac is a more cost effective analgesic than intravenous morphine in the management of isolated limb injury in an emergency department in Hong Kong, and its use may be considered as the dominant strategy.
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Caffeine-potentiated radiochemotherapy and function-saving surgery for high-grade soft tissue sarcoma.
Tsuchiya, H, Yamamoto, N, Asada, N, Terasaki, T, Kanazawa, Y, Takanaka, T, Nishijima, H, Tomita, K
Anticancer research. 2000;(3B):2137-43
Abstract
Caffeine, which has a DNA-repair inhibiting effect, enhances the cytocidal effects of anticancer drugs and radiation. We present a preliminary report on the results of a new treatment, "radiochemotherapy combined with caffeine" (K3 protocol), for high-grade soft tissue sarcomas. Seventeen patients with various high-grade soft tissue sarcomas were included in this study. Preoperatively, three to five courses of intra-arterial chemotherapy using cisplatin, caffeine and doxorubicin after radiation therapy were administered. Following the preoperative therapy, function-saving surgery was performed for all cases. Complete response was observed in six patients, partial response in six and no change in five. The effectiveness rate of caffeine-potentiated radiochemotherapy was therefore 71%. The histological response for radiochemotherapy was better than that for chemotherapy alone, that is, total tumor necrosis was identified in six patients and over 90% necrosis in another six. Complications resulting from the preoperative radiation comprised of serious inflammation in three patients and skin necrosis in another three. Twelve patients have remained free of disease, two patients are alive with disease and three have died of metastatic disease with a mean follow-up period of 36 months. There was no local tumor recurrence. These preliminary findings suggest that caffeine-potentiated radiochemotherapy contributed to a satisfactory local response and the success of function-saving surgery for high-grade soft tissue sarcomas.