[111In]In-CP04 as a novel cholecystokinin-2 receptor ligand with theranostic potential in patients with progressive or metastatic medullary thyroid cancer: final results of a GRAN-T-MTC Phase I clinical trial.

INTRODUCTION: Medullary thyroid cancer (MTC) is a rare malignant tumour of the parafollicular C-cells with an unpredictable clinical course and currently suboptimal diagnostic and therapeutic options, in particular in advanced disease. Overexpression of cholecystokinin-2 receptors (CCK2R) represents a promising avenue to diagnostic imaging and targeted therapy, ideally through a theranostic approach. MATERIALS AND METHODS: A translational study (GRAN-T-MTC) conducted through a Phase I multicentre clinical trial of the indium-111 labelled CP04 ([111In]In-CP04), a CCK2R-seeking ligand was initiated with the goal of developing a theranostic compound. Patients with proven advanced/metastatic MTC or short calcitonin doubling time were enrolled. A two-step concept was developed through the use of low- and high-peptide mass (10 and 50 µg, respectively) for safety assessment, with the higher peptide mass considered appropriate for therapeutic application. Gelofusine was co-infused in a randomized fashion in the second step for the evaluation of potential reduction of the absorbed dose to the kidneys. Imaging for the purpose of biodistribution, dosimetry evaluation, and diagnostic assessment were performed as well as pre-, peri-, and postprocedural clinical and biochemical assessment. RESULTS: Sixteen patients were enrolled. No serious adverse events after application of the compound at both peptide amounts were witnessed; transient tachycardia and flushing were observed in two patients. No changes in biochemistry and clinical status were observed on follow-up. Preliminary dosimetry assessment revealed the highest dose to urinary bladder, followed by the kidneys and stomach wall. The effective dose for 200 MBq of [111In]In-CP04 was estimated at 7±3 mSv and 7±1 mSv for 10 µg and 50 µg CP04, respectively. Administration of Gelofusine reduced the dose to the kidneys by 53%, resulting in the organ absorbed dose of 0.044±0.019 mSv/MBq. Projected absorbed dose to the kidneys with the use of [177Lu]Lu-CP04 was estimated at 0.9±0.4 Gy/7.4 GBq. [111In]In-CP04 scintigraphy was positive in 13 patients (detection rate of 81%) with superior diagnostic performance over conventional imaging. CONCLUSION: In the present study, [111In]In-CP04 was shown to be a safe and effective radiopharmaceutical with promising theranostic characteristics for patients with advanced MTC.

Protective effect of Gelofusine against cRGD-siRNA-induced nephrotoxicity in mice.

Based on successful targeting to the αvß3 integrin of cyclic arginine-glycine-aspartic acid (cRGD), cRGD-conjugated small interfering RNA (siRNA) exhibits tumor targeting and has become a new treatment strategy for solid tumors. However, the nephrotoxicity caused by its renal retention limits its clinical application. Here, we evaluated the protective effect of Gelofusine against cRGD-conjugated siRNA-induced nephrotoxicity in mice. Male Kunming mice (six per group) were either co-injected with Gelofusine and cRGD-siRNA or injected with cRGD-siRNA alone. After administration of these treatments five times, creatinine and blood urea nitrogen (BUN) levels were determined. Hematoxylin-eosin staining (HE staining) and transferase dUTP nick end labeling (TUNEL) analysis were used to compare the difference in renal damage between the groups. Additionally, fluorescence imaging was used to observe the distribution of cRGD-siRNA in vivo. The group co-injected with Gelofusine and cRGD-siRNA displayed lower creatinine and BUN levels than the cRGD-siRNA-alone group and showed less renal damage upon HE staining and TUNEL analysis. Gelofusine decreased the retention time and accelerated the elimination of cRGD-siRNA from the organs, as observed in the fluorescence images. These data indicate that Gelofusine significantly increased the excretion of cRGD-conjugated siRNA and reduced the associated renal damage.

Gelofusine Ameliorates Colistin-Induced Nephrotoxicity.

Colistin therapy is used as the last line of defense against life-threatening Gram-negative infections. Nephrotoxicity is the major dose-limiting side effect that impedes optimal dosing of patients. This study aims to examine the nephroprotective effect of the plasma volume expander gelofusine against colistin-induced nephrotoxicity. Renal protection was assessed in mice that were subcutaneously injected with colistin sulfate (14 mg/kg of body weight × 6 doses every 2 h; accumulated dose, 84 mg/kg) and simultaneously injected in the intraperitoneal region with gelofusine (75, 150, 300, or 600 mg/kg × 6). At 2 and 20 h after the last colistin dose, mice were euthanized, and the severity of renal alteration was examined histologically. Histological findings in mice revealed that colistin-induced nephrotoxicity was ameliorated by gelofusine in a dose-dependent manner, whereas significant histological abnormalities were detected in the kidneys of mice in the colistin-only group. The impact of coadministered gelofusine on colistin pharmacokinetics was investigated in rats. Rats were administered a single intravenous dose of gelofusine at 400 mg/kg 15 min prior to the intravenous administration of colistin (1 mg/kg). Gelofusine codosing did not alter the pharmacokinetics of colistin in rats; however, gelofusine did significantly lower the accumulation of colistin in the kidney tissue of mice. This is the first study demonstrating the protective effect of gelofusine against colistin-induced nephrotoxicity. These findings highlight the clinical potential of gelofusine as a safe adjunct for ameliorating the nephrotoxicity and increasing the therapeutic index of polymyxins.

Normothermic ex vivo liver perfusion using steen solution as perfusate for human liver transplantation: First North American results.

The European trial investigating normothermic ex vivo liver perfusion (NEVLP) as a preservation technique for liver transplantation (LT) uses gelofusine, a non-US Food and Drug Administration-approved, bovine-derived, gelatin-based perfusion solution. We report a safety and feasibility clinical NEVLP trial with human albumin-based Steen solution. Transplant outcomes of 10 human liver grafts that were perfused on the Metra device at 37 °C with Steen solution, plus 3 units of erythrocytes were compared with a matched historical control group of 30 grafts using cold storage (CS) as the preservation technique. Ten liver grafts were perfused for 480 minutes (340-580 minutes). All livers cleared lactate (final lactate 1.46 mmol/L; 0.56-1.74 mmol/L) and produced bile (61 mL; 14-146 mL) during perfusion. No technical problems occurred during perfusion, and all NEVLP-preserved grafts functioned well after LT. NEVLP versus CS had lower aspartate aminotransferase and alanine aminotransferase values on postoperative days 1-3 without reaching significance. No difference in postoperative graft function between NEVLP and CS grafts was detected as measured by day 7 international normalized ratio (1.1 [1-1.56] versus 1.1 [1-1.3]; P = 0.5) and bilirubin (1.5; 1-7.7 mg/dL versus 2.78; 0.4-15 mg/dL; P = 0.5). No difference was found in the duration of intensive care unit stay (median, 1 versus 2 days; range, 0-8 versus 0-23 days; P = 0.5) and posttransplant hospital stay (median, 11 versus 13 days; range, 8-17 versus 7-89 days; P = 0.23). Major complications (Dindo-Clavien ≥ 3b) occurred in 1 patient in the NEVLP group (10%) compared with 7 (23%) patients in the CS group (P = 0.5). No graft loss or patient death was observed in either group. Liver preservation with normothermic ex vivo perfusion with the Metra device using Steen solution is safe and results in comparable outcomes to CS after LT. Using US Food and Drug Administration-approved Steen solution will avoid a potential regulatory barrier in North America. Liver Transplantation 22 1501-1508 2016 AASLD.

Efficacy of different fluids preload on propofol injection pain: A randomized, controlled, double-blinded study.

Injection pain of propofol remains a common clinical problem. Previous studies demonstrated that propofol injection pain was alleviated by applying nitroglycerin ointment to the skin of injection site, which inspires us to test whether venous vasodilation induced by fluid preload could alleviate the pain. Different types or volumes of fluid preload were compared. 200 ASA I-II adult patients were randomly assigned to five groups of 40 each. A 20 G cannula was established on the dorsum or wrist of the hand. When fluid preload given with Plasma-Lyte A 100 mL (P100 group), 250 mL (P250 group), 500 mL (P500 group), 0.9% saline 500 mL (N500 group) or Gelofusine 500 mL (G500 group) was completed within 30 min, respectively, Propofol (0.5 mg/kg, 1%) was injected at a rate of 0.5 mL/s. A blind investigator assessed the pain using a four-point scale. Incidence of pain in P100, P250, and P500 groups was 87.5%, 57.5% and 35%, respectively (P<0.05). The median pain intensity score was significantly lower in P500 group than that in P250 and P100 groups (P<0.05 and P<0.01, respectively). Comparison of the effect of different types of solution preload indicated that the highest incidence of pain was in N500 group (62.5%) (N500 vs. P500, P=0.014; N500 vs. G500, P=0.007). The median pain intensity score in N500 group was higher than that in P500 group (P<0.05) and G500 group (P<0.05). There was no significant difference between P500 and G500 groups. It is suggested that Plasma-Lyte A or Gelofusine preload with 500 mL before propofol injection is effective in alleviating propofol-induced pain.

Effect of 4% gelofusine plus antibiotics on renal impairment and mortality in high-risk cirrhotic patients with spontaneous bacterial peritonitis.

BACKGROUND: Spontaneous bacterial peritonitis (SBP) increases the rates of renal impairment and mortality in cirrhotic patients. A previous study showed that cefotaxime plus albumin treatment decreased renal impairment more than antibiotic treatment alone in patients with serum bilirubin > 4 mg/dL or creatinine > 1 mg/dL. 4% Gelofusine is a colloidal volume replacement fluid used for fluid resuscitation and hemodynamic stabilization. Only one study showed that intravenous 4% gelofusine plus antibiotic could decrease the rates of renal impairment and mortality in comparison with the treatment with albumin plus antibiotic in high-risk cirrhotic patients with SBP OBJECTIVE: To evaluate the effects of 4% gelofusine plus antibiotics on renal impairment and mortality rates in high-risk cirrhotic patients with spontaneous bacterial peritonitis. MATERIAL AND METHOD: Eighteen cirrhotic patients with SBP and serum bilirubin > 4 mg/dL or creatinine > 1 mg/dL were enrolled. Ceftriaxone was given intravenously in doses of 2 g/day. Gelofusine 4% was given intravenously at 1.5 g/kg of body weight at the time of the diagnosis, followed by 1 g/kg on the 3 day. Renal impairment and mortality rates were evaluated during and after treatment. RESULTS: Five patients (27.8%) had pre-existing renal failure. Infection resolved in 15 patients (83.3%). Renal impairment developed in three patients (16.7%), and six patients (33.3%) died during hospitalization. After one month, the mortality rate was 33.3% (a total of 6 deaths). Patients with renal impairment had higher levels of plasma renin activity than those without renal impairment but the values were not statistically significant. CONCLUSION: In high-risk cirrhotic patients with spontaneous bacterial peritonitis, treatment with 4% gelofusine intravenously plus antibiotic reduced the incidence of renal impairment but did not reduce mortality in comparison with previous studies. Studies with larger sample sizes may be useful to evaluate these effects.

Effects of polygeline and hydroxyethyl starch solutions on liver functions assessed with LIMON in hypovolemic patients.

BACKGROUND: Hypovolemia is a common clinical entity in critical patients, and adequate volume replacement therapy seems to be essential for maintaining tissue perfusion. However, it is still uncertain which solution is most appropriate for fluid resuscitation. OBJECTIVE: The aim of this study was to investigate the effects of fluid resuscitation with 3.5% polygeline versus 6% hydroxyethyl starch solutions on hemodynamic functions and liver functions assessed with a noninvasive liver function monitoring system (LIMON) in hypovolemic patients. DESIGN: This study is a prospective randomized clinical trial. MEASUREMENTS AND RESULTS: Thirty hypovolemic patients (intrathoracic blood volume index, <850 mL/m(2)) were randomized into hydroxyethyl starch (mean molecular weight, 130,000 Da) and polygeline (mean molecular weight, 30,000 Da) groups (15 patients each). Indocyanine green plasma disappearance elimination (ICG-PDR) were conducted concurrently using LIMON. A dose of 0.3 mg/kg ICG was given through a cubital fossa vein as a bolus. For fluid resuscitation, 500 mL of colloid was given to the patients. Repeated hemodynamic and ICG-PDR measurements were done at baseline, after infusion, and then at 30 minutes after infusion. RESULTS: Intrathoracic blood volume index and systolic, diastolic, and mean blood pressures increased significantly after infusion and remained elevated for 30 minutes after infusion, but there was no significant difference between the 2 groups. Indocyanine green plasma disappearance elimination values were similar in both groups with no significant difference between the two. CONCLUSION: Increasing intrathoracic blood volume index and hemodynamic variables by fluid loading is not associated with a significant change in ICG-PDR.

Overdose of methyldopa, indapamide and theophylline resulting in prolonged hypotension, marked diuresis and hypokalaemia in an elderly patient.

An 89-year-old man with a history of hypertension, chronic obstructive pulmonary disease, personality disorder and previous attempts of self-poisoning attempted suicide by swallowing two mouthfuls of tablets (methyldopa 250 mg, theophylline SR 200 mg, indapamide 2.5 mg and paracetamol 500 mg). He had prolonged, severe hypotension, necessitating the use of 3000 ml of Gelofusine and almost 2 days of intravenous norepinephrine infusion. He had marked diuresis for 4.5 days, requiring continuous and bolus infusions of intravenous fluids. He had marked renal potassium loss, requiring vigorous potassium replacement therapy. Multiple-dose activated charcoal was used to enhance theophylline elimination. The plasma paracetamol level was below the treatment line. Methyldopa via its metabolite stimulates postsynaptic alpha-adrenergic receptors in cardiovascular control centres in the brain, causing a reduction in peripheral sympathetic tone and a fall in arterial blood pressure and heart rate. In overdose, it causes hypotension, bradycardia and drowsiness. The natriuretic, kaliuretic and vasodilatory effects of indapamide are exaggerated in overdose, resulting in diuresis, hypokalaemia and hypotension. Theophylline markedly increases the level of circulating catecholamines, which stimulate the vascular beta(2)-adrenergic receptors with decreased peripheral vascular resistance. Peripheral vasodilation and hypotension occur in significant theophylline poisoning. Intracellular shift of potassium results in hypokalaemia. The prescribing physicians should recognise elderly patients at a high risk of self-poisoning and avoid using drugs with a high toxicity in overdose (e.g. theophylline and methyldopa). Restricting access to hazardous drugs (in overdose) would be of paramount importance to reduce the number of severe acute poisoning cases and case-fatalities.

An open pilot study of the efficacy and safety of Polygeline in adult subjects with dengue haemorrhagic fever.

AIM: To observe the efficacy and safety of Polygeline colloid (Haemaccel) in adults with stage I - II of dengue haemorrhagic fever (DHF). METHODS: An open, non-comparative clinical trial. The subjects were male or female between 17 - 55 years old, who fulfilled the criteria of stage I or II of DHF according to WHO and selected with consecutive sampling. Fluid treatments were given following this protocol: polygeline i.v. infusion: 500 ml over first 6 hours and continued with 500 ml for the next 18 hours, and maintained to 1000 mL/24 hours from day-2 until maximum day-5. Ringer's lactate infusion: 1000 mL/18 hours from the first day to maximum day-5, as maintenance. Efficacy and safety of polygeline colloid were evaluated using initial stabilization of haematocrite level, measured as percentage of clinical trial subject who has stabilization of haemodynamic status based on serial haematocrite levels examinations, total parenteral fluid required and length of hospitalization. Statisticial analysis was done using ANOVA test and post hoc analysis using Turkey test. RESULTS: There were 43 subjects who completely participated in this study and included in analysis. From baseline levels, haematocrite decreased in first 6 hours during fluid treatment. This decrement persisted in 48 hours of observation. Statistical analysis with ANOVA test showed the significant differences of haematocrite level during observation (Sum of square between groups 495 and within group 4845, p= 0.000). Post hoc analysis with Turkey test showed significant differences of haematocrite level from baseline level to 48, 72 and 96 hours during observation periods. CONCLUSION: This pilot study showed that polygeline colloid was a safe initial fluid treatment and can be used for maintaining fluid adequacy in adults with stage I-II of DHF.

[Efficiency of using gelofusine and voluven in acute normovolemic hemodilution during cardiosurgical interventions].

The aim of the study was to assess the use of gelofusine and voluven for acute normovolemic hemodilution at cardiac surgery under extracorporeal circulation (EC). Sixty-seven patients with coronary heart disease were examined. Heart rate, total peripheral vascular resistance, pulmonary pressure, pulmonary artery wedge pressure, oxygen delivery and consumption, central venous pressure, arteriovenous oxygen difference, oncotic pressure, and postoperative clinical course were studied. No significant group differences were found in indices, other than arteriovenous oxygen difference, after acute normovolemic hemodilution and in central venous pressure following 6 hours of EC termination. The administration of gelofusine caused a more steady-state oxygen-transport function of the circulatory system. The use of the agent for acute normovolemic hemodilution at cardiac surgery under EC is more economically justified than that of volumen.

Effects of gelatine and medium molecular weight starch as priming fluid in cardiopulmonary bypass--a randomised controlled trial.

Perioperative volume replacement after cardiopulmonary bypass is complicated by post-bypass systemic inflammatory process. The aim of this study was to assess the effects of using two different colloid solutions as priming fluids in cardiopulmonary bypass. The study's primary end point was to measure the amount of fluid replacement needed during and post-cardiopulmonary bypass; blood loss, change in blood profile and intraocular pressure were secondary end points, used as measures of plasma oncotic pressures. Patients undergoing coronary artery bypass grafting were recruited. Both patients and surgeons were blinded to receive either Gelofusine or Voluven as priming fluids. At fixed intervals during cardiopulmonary bypass, the patients had their intraocular pressures measured. Intra and postoperative fluid replacement was in the form of 4.5% human albumin and the amount was recorded for each subject. The result did not show any significant differences in the amount of fluid needed to be replaced, in blood loss or in blood profile between the two groups. However, it showed an increase in intraocular pressure in both groups once cardiopulmonary bypass commenced. The average intraocular pressure was higher in the Gelofusine group compared to the Voluven group. The significant increase in intraocular pressure measurements in the Gelofusine group compared to the Voluven group support the hypothesis that Voluven maintains the plasma oncotic pressure better and reduces fluid shift.

Hearing loss after spinal anesthesia: the effect of different infusion solutions.

OBJECTIVE: We speculate that the preoperative volume replacement with a convenient solution may protect the inner ear function after spinal anesthesia. METHODS: The patients were randomized in a single-blind fashion into two groups: group LR (n = 40) received lactated Ringer's and group GF (n = 40) received gelatin polysuccinate 4% (Gelofusine). Spinal anesthesia was performed with a 25 G Quincke needle and was given bupivacaine 0.5% 10 mg and fentanyl 25 microg. Audiograms were performed preoperatively and 2 days postoperatively. RESULTS: The overall incidence of hearing loss was 7.5%. The hearing loss was unilateral in two and bilateral in four patients. Hearing loss occurred within the low-frequency range and the hearing thresholds returned to normal by the fifth postoperative day. CONCLUSIONS: Although the incidence of hearing loss for the lactated Ringer's group was higher than the Gelofusine group, there was no statistically significant difference between the groups. For medicolegal and ethical reasons, patients should be informed about the possibility of hearing loss after spinal anesthesia.

[Comparative study of hospital costs associated with human albumin 20% (Vialebex 20%) or polygeline as a fluid resuscitation strategy for cirrhotic ascites]. / Etude comparative des coûts hospitaliers liés à une stratégie de remplissage vasculaire par albumine humaine à 20% (Vialebex 20%) ou par polygéline dans le traitement des ascites cirrhotiques.

OBJECTIVES: To compare the hospital costs associated with two fluid resuscitation strategies for cirrhotic ascites: one with human albumin 20% (Vialebex 20%) and one with polygeline. METHODS: Multicenter prospective randomized double-blinded comparative trial (that also compared efficacy and tolerance). The economic evaluation was based on direct medical costs throughout the follow-up period: days of hospitalization, hospital consultations, medical procedures, and fluid resuscitation products. This cost-minimization study had a 6-month follow-up period. Daily costs in euros were adjusted over a 30-day period. The study was interrupted prematurely because of an alert due to the bovine origin of the polygeline, and the inclusion objectives could therefore not be met. RESULTS: The economic analysis included all patients in the efficacy population (group receiving human albumin 20%: n=30, polygeline group: n=38). It found a standardized cost per patient for 30 days of treatment that was significantly lower (p=0.004) for human albumin 20% (median: 1915 euro; range: 1330-4105) than for polygeline (median: 4612 euro; range: 2138-12234). This difference is related mainly to a reduction in the frequency and duration of hospitalization in specialized units, but also to other aspects of management: hospitalization in other departments, specific solutions for the study products, and hospital procedures. CONCLUSION: The economic results of this trial favor a fluid resuscitation strategy that uses human albumin 20% for cirrhotic patients. They are consistent with the clinical results and help assess the cost-benefit ratio of human albumin 20% for this indication.

Influence of different strategies of volume replacement on the activity of matrix metalloproteinases: an in vitro and in vivo study.

BACKGROUND: Excessive production of matrix metalloproteinase 9 (MMP-9) is linked to tissue damage and anastomotic leakage after large bowel surgery. Hence, the aim of this study was to verify whether different strategies of fluids administration can reduce MMP-9 expression. METHODS: In the in vitro experiment, the authors tested the hypothesis of a direct inhibition of MMP-9 by the fluids used perioperatively, i.e., lactated Ringer's solution, 3.4% poligeline, and hydroxyethyl starch 130/0.4. In the in vivo experiment, 36 patients undergoing surgery for colon cancer were randomly assigned to three groups to receive lactated Ringer's solution, poligeline, or hydroxyethyl starch. MMP-9 and tissue inhibitor of metalloproteinases were measured from venous blood samples; the MMP-9/tissue inhibitor of metalloproteinases ratio was calculated as an index of equilibrium between the action of MMP-9 and its inhibition. RESULTS: In the in vitro experiment, the presence of hydroxyethyl starch 130/0.4 in the MMP-9 assay system showed a strong inhibition of the enzymatic activity compared with lactated Ringer's solution. In the in vivo experiment, MMP-9 and tissue inhibitor of metalloproteinases plasma levels did not differ among the three groups at baseline, whereas those levels increased significantly at the end of surgery. At that time, the MMP-9 plasma levels and the MMP-9/tissue inhibitor of metalloproteinases ratio were significantly higher in the lactated Ringer's solution and poligeline groups than in the hydroxyethyl starch group. These results were confirmed 72 h after surgery. CONCLUSIONS: This study demonstrates that hydroxyethyl starch 130/04 decreases the circulating levels of MMP-9 in patients undergoing abdominal surgery.