Long-term Infusion Research Articles

Maturation of midazolam clearance in critically ill children with severe bronchiolitis: A population pharmacokinetic analysis

PurposeThe aim of the present study was to develop a population pharmacokinetic model of midazolam, and to evaluate the influence of maturation process and other variability factors in critically ill children with severe acute bronchiolitis, who received a long-term intravenous infusion of midazolam. MethodsIn the study were included 49 critically ill children of both genders (from 0 to 130 weeks of age) with severe acute bronchiolitis hospitalised in intensive care units. Nonlinear mixed effects modelling approach was applied for data analyses and simulations. ResultsThe final model is a two-compartment model that includes the effects of body weight using allometric scaling with fixed exponents and maturation of clearance. For a typical subject, scaled to the adult body weight of 70 kg, population pharmacokinetic values were estimated at 8.52 L/h for clearance (when maturation function was 1), 25.5 L/h for intercompartmental clearance, and 5.71 L and 39.8 L for the volume of the central and peripheral compartment, respectively. Based on the final model, maturation reaches 50% of the adult clearance in 45.9 weeks of postmenstrual age. The influence of gender, ABCB1 genotype and biochemical parameters on midazolam clearance was not detected. Results of simulations indicate the need for reduced dosing in certain groups of patients in order to maintain plasma concentrations of midazolam within recommended values. ConclusionsThe developed population pharmacokinetic model can contribute to the dosing optimisation of midazolam, especially in critically ill children as it includes the influence of size and maturation of clearance, which are important parameters for achieving the desired plasma concentrations of midazolam.

Effect of Long-Term Intrathecal Bupivacaine Infusion on Blood Pressure

The local anesthetic bupivacaine is a common analgesic adjuvant medication used in combination with opioids in intrathecal drug delivery systems (IDDSs). While the acute effects of spinal bupivacaine injection on blood pressure (BP) have been studied, there is a dearth of data regarding long-term effects of continuous intrathecal bupivacaine infusion. A retrospective review of all noncancer pain patients receiving bupivacaine through IDDSs from January 2013 to November 2017 was performed. Blood pressure values before implantation, and after implant at the 1-week, 3-month, 6-month and 1-year time points are recorded as well as corresponding bupivacaine and opioid doses in the IDDS. Eighty-two patients were included in the study; median patient age was 64 years and intrathecal catheter tips were located predominantly in the lower thoracic spine. Significant decreases in systolic blood pressure (SBP) and mean arterial pressure (MAP) relative to baseline occurred in patients receiving chronic lower thoracic intrathecal bupivacaine delivery at 3, 6, and 12 months post-implant (-12.96 ± 18.21; p < 0.001 and - 6.38 ± 12.04; p < 0.001, respectively). The only significant decrease in DBP was observed at 1 year post-implant (-3.09 ± 11.76; p < 0.05). Similar decreases in BP values occurred in patients with or without hypertension. Long-term thoracic intrathecal infusion of bupivacaine likely exerts a lowering effect on BP, primarily because of a significant decrease in SBP. This effect is likely due to efferent sympathetic blockade by bupivacaine.

Low CD4⁺/CD25⁺/CD127⁻ regulatory T cell- and high INF-γ levels are associated with improved survival of neuroblastoma patients treated with long-term infusion of ch14.18/CHO combined with interleukin-2

ABSTRACTImmunotherapy with the anti-GD2 antibody (Ab) ch14.18/CHO in combination with interleukin 2 (IL-2) has improved survival of high-risk neuroblastoma (NB) patients. Here, we report immunotherapy-related effects on circulating NK cells, regulatory T cells (Tregs), granulocytes as well as on Ab-dependent cell-mediated cytotoxicity (ADCC) and cytokines IFN-γ, IL-6, IL-10, IL-18 and CCL2 and their association with progression-free survival (PFS).In a closed single-center program, 53 patients received five cycles of 6 × 106 IU/m2 subcutaneous IL-2 (d1-5; 8–12) combined with long-term infusion (LTI) of 100 mg/m2 ch14.18/CHO (d8-18). Immune cells and cytokines were analyzed by flow cytometry and ADCC by calcein-AM-based cytotoxicity assay.IL-2 administration increased cytotoxic NK cell-, eosinophil- and Treg counts in cycle 1 (2.9-, 3.1- and 20.7-fold, respectively) followed by further increase in subsequent cycles, whereas neutrophil levels were elevated only after the ch14.18/CHO infusion (2.4-fold change). Serum concentrations of IFN-γ, IL-6, IL-10, IL-18 and CCL2 in cycle 1 were increased during the combinatorial therapy (peak levels of 3,656 ± 655 pg/ml, 162 ± 38 pg/ml, 20.91 ± 4.74 pg/ml, 1,584 ± 196 pg/ml and 2,159 ± 252 pg/ml, respectively). Surprisingly, we did not observe any correlation between NK-, eosinophil- or neutrophil levels and PFS. In contrast, patients with low Tregs showed significantly improved PFS compared to those who had high levels. Treg counts negatively correlated with INF-γ serum concentrations and patients with high INF-γ and IL-18 had significantly improved survival compared to those with low levels.In conclusion, LTI of ch14.18/CHO in combination with IL-2 resulted in Treg induction that inversely correlated with IFN-γ levels and PFS.

The NEO-FFI domain of openness to experience moderates ketamine response in treatment resistant depression

BackgroundThere are many putative mechanisms by which ketamine has its effect and many unanswered questions about risks and benefits of long-term ketamine therapy. A research imperative is the identification of predictors of response to intravenous ketamine, especially a sustained response to maintenance ketamine. Temperament is an inherited aspect of personality and is a predictive factor for outcome in treatment resistant depressed (TRD) patients. MethodsWe analyzed which domains of personality impacted initial and sustained ketamine response. Utilizing the Neuroticism Extraversion Openness Five Factor Inventory (NEO-FFI) on 125 participants with TRD, we tested (1) whether the degree of neuroticism predicted initial and/or sustained response to ketamine; and (2) whether extraversion, agreeableness, openness to experience, and conscientiousness had an impact on response. ResultsOur findings confirmed previous literature that elevated neuroticism, low conscientiousness, and low extraversion was the pattern of our TRD population regardless of response. Openness was the only factor to significantly predict sustained treatment outcome. LimitationsOur findings are limited by the lack of placebo control, small sample size, non- standardized infusion intervals, polypharmacy rather than ketamine monotherapy, a select TRD population in that they had all failed ECT, and a primarily Caucasian population. ConclusionsOur registry adds to the literature that factors making up temperament may have predictive value in regard to treatment response, specifically the outcome for TRD patients receiving long-term ketamine infusion therapy. If confirmed, assessing for Openness could reduce inappropriate exposure to ketamine with its attendant unknown long-term risks.

Long-term Apomorphine Infusion Users Versus Short-term Users: An International Dual-center Analysis of the Reasons for Discontinuing Therapy

A retrospective analysis at 2 specialist centers was undertaken to determine the long-term efficacy of subcutaneous apomorphine infusion (APO), rates and reasons for discontinuation, and factors that might contribute to discontinuation. Demographics, clinical outcomes data, and reasons for discontinuation were collected for patients treated with APO at Chulalongkorn Centre of Excellence for Parkinson's Disease and Related Disorders, Bangkok, Thailand (n = 36) and Fundacion Jimemez Diaz Universidad Autonoma de Madrid, Spain (n = 16). There were 19 (52.7%) patients in the Thai cohort and 10 (62.5%) patients in the Spanish cohort who discontinued treatment within around 6 months of initiation, most commonly due to skin nodules (Thai cohort) and perceived lack of efficacy (Spanish cohort). Those who continued APO tended to stay on treatment. In both cohorts, APO resulted in significant reductions in Unified Parkinson's Disease Rating Scale 3 motor scores, daily OFF time, and levodopa-equivalent dose in patients who subsequently stopped therapy, suggesting APO is clinically effective even when "lack of efficacy" is stated as a reason for discontinuing. Daily OFF hours after APO therapy was found to be a significant predictive factor for APO discontinuation with an odds ratio of 5.952 (P = 0.040). The cutoff point that determined APO discontinuation was calculated to be 1.75 or more OFF hours (sensitivity, 84.6%; specificity, 63.2%). Apomorphine infusion is a minimally invasive therapy and therefore very easy to discontinue if difficulties arise. This fact might explain the high dropout rate of this technique. Successful long-term adherence to APO therapy requires a multidisciplinary health care team approach including regular patient follow-up and assessment and prompt resolution of queries and concerns.

Prognostic value of Bax expression in the primary colon tumor of patients with metastatic colorectal cancer receiving first-line treatment with a triple combination of irinotecan + oxaliplatin + long-term infusion of 5-fluorouracil

Objective: to evaluate the prognostic value of Bax expression in the primary colon tumor of patients with metastatic colorectal cancer (mCRC) receiving first-line treatment with a triple combination of irinotecan + oxaliplatin + long-term infusion of 5-fluorouracil. Materials and methods . The study included patients with mCRC (morphologically (histologically) verified diagnosis of colonic adenocarcinoma) that have never received treatment for disseminated disease. Study participants received a new first-line treatment regimen with a triple combination of irinotecan + oxaliplatin + long-term infusion of 5-fluorouracil. We evaluated both short-term and long-term treatment outcomes. We also assessed the level of Bax expression in primary tumor samples (biopsy/surgery specimens) collected prior to initiation of first-line treatment using immunohistochemical methods. We analyzed the correlation between the levels of Bax expression and short-term/long-term treatment outcomes. Results. Seventeen out of 20 mCRC patients included in the study were tested for Bax expression in the primary tumor using immunohistochemical staining. The analysis of correlation between Bax expression in tumor tissue and time-to-progression in patients with mCRC receiving first-line treatment with a triple combination of drugs demonstrated that high Bax expression was a favorable prognostic factor associated with longer time-to-progression. Median time-to-progression was significantly longer in patients with Bax overexpression than in those with low levels of Bax expression or no expression: 15.7 15,7 ± 3.38 months vs 8.6 15,7 ± 0.6 months, р = 0.012. When analyzing the impact of Bax expression on the overall survival (OS) in patients with mCRC, we found that patients with Bax overexpression demonstrated better OS (median follow-up time 17.3 15,7 ± 2.54; OS was not reached; mean value 31.26 15,7 ± 2.85 months) than patients with low Bax expression or no expression (median OS 13.60 15,7 ± 3.03 months), p = 0.021. Conclusion. Our results suggest that Bax overexpression in the primary colon tumor is a favorable prognostic factor associated with longer progression-free survival and OS in mCRC patients receiving first-line treatment with a triple combination of drugs.

Randomized use of anti-GD2 antibody dinutuximab beta (DB) long-term infusion with and without subcutaneous interleukin-2 (scIL-2) in high-risk neuroblastoma patients with relapsed and refractory disease: Results from the SIOPEN LTI-trial.

10014 Background: We determined the role of scIL-2 combined with long term infusion (LTI) of DB in patients (pts) with high-risk relapsed/refractory neuroblastoma. Methods: 160 pts were enrolled into an open label SIOPEN Phase II clinical trial (EudraCT 2009-018077-31). Pts were randomly assigned to receive up to 5 cycles of 100 mg/m2 DB-LTI (d8-17) and 160 mg/m2 oral isotretinoin (d19-32) (81 pts) with and without 6x106IU/m2 scIL-2 (d1-5; 8-12) (79 pts). Endpoints were toxicity, response rates and 2yrs-event free and -overall survival. Results: Between 07/2014 and 07/2017, 160 pts from 11 countries were randomised. Median follow-up is 2.6 years. Pts were well balanced between arms according to stage, age, MYCN amplification, patients with relapse and remission status. The 2yrs-EFS and -OS for DB (81 pts) vs. DB combined with scIL-2 (79 pts) was 59%±6% vs 65%±6% (p = 0.721) and 79%±5% vs 84%±4% (p = 0.904). In 97 pts with evaluable disease, a response rate of 49% (9% CR, 40% PR) vs 52% (26% CR, 26% PR) after treatment with DB vs DB and scIL-2 was observed. Grade 3&amp;4 fever (16% vs 46%, P = 0.000), allergic reaction (1% vs 14%, P = 0.004), hematological toxicity (46% vs 66%, P = 0.013) and neurotoxicity (0% vs 8%, p = 0.003) were significantly worse in the combination arm, but no difference was seen for capillary leak, gastrointestinal, liver enzyme elevation and pain. Paraplegia possibly related to the treatment was observed in 2 pts in the combination arm, none in the arm without scIL-2, and one resolved to baseline. A subgroup of 34 pts who had a relapse and measurable disease at treatment start, showed a 2yrs-EFS and -OS in DB (17 pts) vs DB combined with scIL-2 (17 pts) of 35%±12% vs 69%±12% (p = 0.116) and 59%±12% vs 81%±10% (p = 0.167). However, this trend was statistically not significant. Pharmacokinetic and HACA response between both arms was not different with overlapping antibody concentration-time curves and a HACA response of 15/81 (19%) (DB) vs 16/79 (20%) (DB and scIL-2). Conclusions: No significant difference in efficacy of DB combined with scIL-2 and increased toxicity in this arm suggests that this schedule of scIL-2 is of no additional benefit. Clinical trial information: 2009-018077-31.

Randomization of dose-reduced subcutaneous interleukin-2 (scIL2) in maintenance immunotherapy (IT) with anti-GD2 antibody dinutuximab beta (DB) long-term infusion (LTI) in front–line high-risk neuroblastoma patients: Early results from the HR-NBL1/SIOPEN trial.

10013 Background: We tested dose-reduced scIL2 in combination with DB-LTI and oral isotretinoin and evaluated toxicity and efficacy in high-risk neuroblastoma patients (EudraCT:2006-001489-17). Methods: High-risk patients (stage 4 ≥1y; stage 4 &lt; 1y with MYCN amplification (MNA); stage 2, 3, 0-21y with MNA) received high intensity induction (rapid COJEC or N5-MSKC and TVD for insufficient response), surgery, high dose therapy with busulfan/melphalan and local radiotherapy. Patients ≤9 months between diagnosis and HDT/SCT who achieved at least a partial response prior to HDT/SCT and without progression thereafter were randomized to receive up to 5 cycles of 100mg/m2 DB-LTI (d8-17) ± 3x106 IU/m2 scIL2 (d1-5; d8, d10, d12, d14, d16) and 160mg/m2 oral isotretinoin (d19-32). Results: Between 04/2014 and 06/2018, 408 patients from 18 countries were randomized. Median follow-up is 1.8 years. Stage, age, MNA, induction treatments and remission status were well balanced between randomization arms. The 2yrs-EFS and -OS for DB-LTI (205 pts) vs. DB-LTI&amp;scIL2 (203 pts) was 64%±4%vs63%±5% (p = 0.844) and 83%±3%vs74%±4% (p = 0.337). For patients in CR the 2yrs-EFS was 69%±5% for DB and 66%±6% for DB&amp;scIL2. Patients with evaluable disease prior DB or DB&amp;scIL2, the end of treatment response rate was 57% (26% CR, 31% PR) vs 52% (27% CR, 25% PR) with 2yrs-EFS rates of 58%±7% and 64% ±8%, respectively. Grade 3&amp;4 toxicity was lower in the group with DB vs DB&amp;scIL2 for fever (14%vs31%, p &lt; 0.001) and pain (7%vs18%, p = 0.005), and no significant difference was seen for general condition (17%vs22%,ns), allergy (3%vs3%,ns), capillary leak (4%vs8%,ns), liver enzyme elevation (20%vs27%, ns) and neurological toxicities (2%vs2%,ns). Conclusions: We previously reported grade 3&amp;4 toxicity to DB short-term infusion (STI) ± 10x6x106IU/m2 scIL2 for general condition (16%vs41%, p = 0.000), fever (14%vs40%, p = 0.000), allergic reaction (10%vs20%, p = p = 0.006), capillary leak (4%vs15%, p = 0.004), liver enzyme elevation (17%vs23%, ns), central neurotoxicity (3%vs8%, p = 0.034) and pain (16%vs26%, p = 0.048). Our results indicate that DB-LTI and dose-reduced scIL2 clearly reduced the toxicity profile, but showed absence of benefits of scIL2. DB-LTI achieved 2yrs-EFS in line with DB-STI (Ladenstein, Lancet Oncology 2018; Yu, NEJM, 2010) and a response rate &gt; 50% supporting its use as standard of care IT. Clinical trial information: EudraCT:2006-001489-17.

A Novel Step-Down Infusion Therapy: Its Safety and Effectiveness in Intracranial Pressure Control Using Barbiturate Therapy

Background: Barbiturate therapy has been widely used to suppress increased intracranial pressure (ICP); however, classical barbiturate therapy has disadvantages such as cardiac function depression. This is due to lack of detailed pharmacological dynamics of barbiturate and an established safety infusion method. Methods: Two healthy male beagles intubated and anesthetized using thiamylal (4·0 mg/kg/h) and propofol (4·0 mg/kg/h) were maintained for 36 h; one dog was maintained under normothermia and the other, hypothermia. A 1·0 mL blood sample was collected at 0, 12, 24, 36, 42, 48 h and drug concentration measured using liquid chromatography-mass spectrometry. Barbiturate therapy was performed at the earliest convenience using the ‘Step-Down Infusion’ method for severe traumatic brain injury patients or sever cerebrovascular disease patients having a Glasgow coma scale 8, and ICP was measured for at least 7 days. Findings: In the animals, thiamylal concentration increased with time and was influenced by body temperature; the dog with hypothermia had a higher concentration than normothermic dog. Stable values were noted with propofol. In the clinical study, step-down infusion of thiamylal under normothermia resulted in stable concentrations with no abnormal accumulation or threatening changes in serum potassium. Blood pressure was also stable under 25·0 g/mL and no hemodynamic instability was found. ICP increase was inhibited by the increase in thiamylal concentration and cerebral perfusion pressure (CPP) was maintained over 65 mmHg during the time course. Interpretation: Fixed long-term infusion of barbiturate induced marked drug accumulation, which was enhanced by hypothermia. Our novel “Step-down infusion” method under normothermia can maintain stable, safe thiamylal concentration to achieve both ICP reduction and CPP maintenance without serious side effects such as hypotension or hypokalemia. As the safe maximum concentration of barbiturate remains unclear, further clinical investigation is warranted. Funding Statement: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Declaration of Interests: All authors declare that no support, financial or otherwise, has been received from any organization that may have an interest in the submitted work, and there are no other relationships or activities that could appear to have influenced the submitted work. Ethics Approval Statement: All procedures in this study were carried out in strict accordance with the guidelines for animal experimentation at the Animal Research Center of Kurume University. All the animal experiments were reviewed and approved by the Institutional Animal care and use committee (No. P150516). Induction was performed under anesthesia and all efforts made to minimize suffering. The clinical study was reviewed and approved by the Institutional ethical committee of Kurume University (No. 12268).

&lt;p&gt;Metabolism of remimazolam in primary human hepatocytes during continuous long-term infusion in a 3-D bioreactor system&lt;/p&gt;

BackgroundRemimazolam is an ultra-short acting benzodiazepine under development for procedural sedation and general anesthesia. It is hydrolyzed by CES1 to an inactive metabolite (CNS7054).PurposeIn this study, the effect of continuous remimazolam exposure on its metabolism and on CES1 expression was investigated in a dynamic 3-D bioreactor culture model inoculated with primary human hepatocytes.MethodsRemimazolam was continuously infused into bioreactors for 5 days at a final concentration of 3,000 ng/ml (6.8 µM). In parallel, 2-D cultures were run with cells from the same donors, but with discontinuous exposure to remimazolam.ResultsDaily measurement of clinical chemistry parameters (glucose, lactate, urea, ammonia, and liver enzymes) in culture supernatants indicated no noxious effect of remimazolam on hepatocyte integrity as compared to untreated controls. Concentrations of remimazolam reached steady-state values of around 250 ng/ml within 8 hours in 3-D bioreactors whereas in 2-D cultures remimazolam concentrations declined to almost zero within the same time frame. Levels of CNS7054 showed an inverse time-course reaching average values of 1,350 ng/ml in perfused 3-D bioreactors resp. 2,800 ng/ml in static 2-D cultures. Analysis of mRNA expression levels of CES1 indicated no changes in gene expression over the culture period.ConclusionThe results indicated a stable metabolism of remimazolam during 5 days of continuous exposure to clinically relevant concentrations of the drug. Moreover, there was no evidence for a harmful effect of remimazolam exposure on the integrity and metabolic activity of in vitro cultivated primary human hepatocytes.

ANALISIS FAKTOR KEJADIAN PHLEBITIS DENGAN SIMULASI MODEL FISIS ALAT TERAPI INTRAVENA

Intravenous therapy through long-term infusion is at risk for complications such as phlebitis. The influence of medical factors with a history of hypertension and mechanical factors based on the location of the position of infusion is the main study of the causes of phlebitis.One of the causes of phlebitis is the flow of intravenous fluids which is not proportional to the volume of infusion fluid. Intravenous Therapy Devices with the aim of assessing the physical phenomena modeling experiments intravenous therapy with the theory of fluid mechanics and prove the existence of linkage patient's blood pressure and height of intravenous fluid drop rate. The research method is experimental with the physical modeling of intravenous therapeutic devices. Physical model of intravenous therapy devices using a manometer to measure the pressure tube as diastolic pressure and variation on fluid infusion used was NaCl 0.9% and Glucose 5%. The results of this research was obtained diastolic pressure below 80 mmHg produced a drop rate of fluid infusion is almost constant with a maximum height of a standard intravena pole 1meter, while at an altitude above the altitude variation of normal use by 90 mmHg diastolic pressure with height variations of 1.1 to 1.3 meters yield drop rate a linear of infusion liquid to height variations. So to prevent turbulence of intravenous fluids (the cause of phlebitis) by increasing the location standard for infusion

Ifosfamide-induced encephalopathy: Brand-name (HOLOXAN®) vs generic formulation (IFOSFAMIDE EG®).

Two forms of ifosfamide are commercially available in France: HOLOXAN® (brand-name drug) and IFOSFAMIDE EG® (generic drug). Following the marketing launch of the generic drug, there has been a significant increase in cases of ifosfamide-induced encephalopathy reported in France. Our objective is to compare the incidence of ifosfamide-induced encephalopathy in adult patients treated with HOLOXAN® or IFOSFAMIDE EG®. This is a retrospective study of adult patients treated with ifosfamide in two medical centers from 2013 to 2017, with data analysed from medical records. Comparisons of patients were made, according to the formulation used and according to the occurrence of ifosfamide-induced encephalopathy. The groups of patients were compared using a chi-square or Fisher's exact test for qualitative parameters and a Wilcoxon test for quantitative parameters. To include confounding factors in the analysis of the impact of drug formulation on the occurrence of ifosfamide-induced encephalopathy, a generalized linear model was performed with the occurrence of ifosfamide-induced encephalopathy as the dependent parameter, and the formulation and the confounding factors as explanatory parameters. A total of 191 patients were included: 103 patients received HOLOXAN® (53.9%) and 88 patients received IFOSFAMIDE EG® (46.1%). In the HOLOXAN® group, the median infusion time was higher (12hours vs 3h, P<0.001) and aprepitant was administered more frequently (78.6% vs 69.7%, P<0.001) than for the IFOSFAMIDE EG® group. Ifosfamide-induced encephalopathy occurred in 11 patients (5.8%, CI 95% [2.9%, 10.0%]). In the ifosfamide-induced encephalopathy group, median infusion time was higher (12hours [12; 24] vs 3hours [2; 12] P<0.001) and a poor performance status was more frequent (54.5% vs 13.9%, P=0.002) than in the group without ifosfamide-induced encephalopathy. The frequency of ifosfamide-induced encephalopathy in the HOLOXAN® group was 1.9% (2/103) against 10.2% (9/88) in the IFOSFAMIDE EG® group (P=0.014). Multivariate analysis revealed that treatment with IFOSFAMIDE EG® resulted in significantly more ifosfamide-induced encephalopathies compared to HOLOXAN® (OR and CI 95%:7.4 [1.4; 39.5], P=0.018). We identified two other risk factors for ifosfamide-induced encephalopathy: long-term infusion and a performance status of two or higher. The formation of chloroethylamine in solution could be the cause of more frequent ifosfamide-induced encephalopathies with IFOSFAMIDE EG® compared to HOLOXAN®. Application of these data could help in the choice of ifosfamide formulation in adult patients to decrease the risk of ifosfamide-induced encephalopathy, and more specifically for patients with risk factors.

A randomized phase II study comparing oral S-1 plus 24-hour infusion of irinotecan (Iri) and bevacizumab (Bev) with FOLFIRI plus bevacizumab in patients with metastatic colorectal cancer (MCRC).

613 Background: FOLFOX or FOLFIRI plus Bev is a first-line treatment for MCRC. Recent studies have confirmed that oral S-1 combined with Iri and Bev is equivalent to FOLFIRI plus Bev. Iri is usually administered as a short-term 90-min. infusion. However, the cytocidal activity is S-phase specific, and carboxylesterases, that convert Iri into SN-38, are less likely to become saturated when Iri is given as a long-term infusion. Therefore, a low dose of Iri given as a long-term infusion is expected to enhance antitumor activity. We conducted a randomized phase II study to compare this regimen with FOLFIRI plus Bev. Methods: The subjects comprised 120 chemotherapy-naïve patients with MCRC. The study group received 24-hr infusion of Iri at a dose of 125 mg/m2 on days 1 and 15, combined with oral S-1 80 mg/m2 on days 1 to 14. The FOLFIRI group received Iri at a dose of 150 mg/m2, 5-FU given at a dose of 400 mg/m2 as a bolus injection and at a dose of 2400 mg/m2 as a 46 hr-infusion, 200 mg/m2 of leucovorin on days 1 and 15. Bev was given at a dose of 5.0 mg/kg on days 1 and 15 in both groups. Treatment was repeated every 4 weeks. The primary endpoint was the 1 y progression-free survival (PFS). Secondary endpoints were PFS, response rates (RR), overall survival (OS), and adverse events (AEs). Results: From October 2013 through December 2017, a total of 61 patients assigned to receive IRIS plus Bev (the A group) and 59 patients assigned to receive FOLFIRI plus Bev (the B group) were included in the analysis. The 1y RFS was 37.3% in the A group and 17.0% in the B group (p = 0.0281). The PFS was 10.2 mon in the A group and 10.0 mon in the B group, and the median OS was 27.0 mon and 28.6 mon, respectively (p = 0.26, p = 0.68). RR was significantly higher in the A group (87.0%) than in the B group (61.7%) (p = 0.005). The main grade 3 or 4 AEs were neutropenia (27.8%) and diarrhea (11.1%) in the A group and neutropenia (23.4%) and leukopenia (6.4%) in the B group. Conclusions: Our results showed that Iri, given biweekly as a 24-hour infusion in combination with oral S-1 and Bev, is a highly effective and well-tolerated regimen for the first-line treatment of MCRC. Clinical trial information: UMIN000014664.

Albumin administration for refractory ascites in cirrhotic patients

A recent article published in Liver International reported that long-term administration of albumin to cirrhotic patients with refractory ascites improved survival and reduced inpatient hospitalization (1). In addition to reducing complications associated with liver cirrhosis, such as ascites and spontaneous bacterial peritonitis (SBP), long-term albumin administration also reduced complications such as hepatic encephalopathy and non-SBP infection. These findings indicated that long-term albumin infusion therapy may benefit cirrhotic patients, not only by improving hemodynamics but also by enhancing the scavenging of toxic substances, thereby improving patient prognosis.

Safety and efficiency of the port-catheter for intensive intravenous chemotherapy in patients with multi-drug resistant tuberculosis and extensively drug-resistant tuberculosis

PURPOSE. To study the efficacy and tolerability of the port catheter for continuous intravenous infusion in patients with MDR-TB and XDR-TB.&#x0D; MATERIALS AND METHODS. In a controlled study examined the effectiveness of the port catheter during an intensive 7-component anti-TB treatment with intravenous application of 3 anti-TB drugs (moxifloxacin, PAS, linezolid) in 16 patients with MDR-TB and XDR-TB. In the comparison group, which is formed by a pair of matching according to the drug resistance profile of MTB, the same intensive chemotherapy regimens in which the infusion of these drugs was carried out by daily injections of veins. In each group dominated patients with retreatment cases – 14 (87.5 %) patients. The planned duration of intravenous therapy was 2–4 months.&#x0D; RESULTS. Port-catheter for continuous infusion of combination of anti-tuberculosis drugs in comparison to their administration in the usual way ensures high efficiency and safety. In any case, was not observed phlebitis, no complaints of pain at the injection site, only 12.5 % cases were hematoma after setting the port in comparison to 100.0 % of patients with daily venous injections. In the study group was not a single case of interruption of intravenous infusion. In the control group, 56.2 % of patients discontinued intravenous treatment due to inability to penetrate the vein, patient’s complaints pain or phlebitis. At the end of the intensive phase of chemotherapy sputum conversion and disappearance of clinical symptoms were observed in 15 (3.7 %) patients of the study group, that was 26.7 % higher, than in control group (p&gt;0,05). We found significant difference in terms of sputum conversion, which occurred in the study group through (2,2±0,1) months vs (3,7±0,3) months (&lt;0,05) in control group.&#x0D; CONCLUSIONS. Port-catheter for long-term daily infusions of combination of anti-TB drugs compared with their usual daily injections is safe and effective method of intravenous therapy. It is not accompanied by subjective complaints of patients and the development of phlebitis, which leads to early sputum conversion. With daily injections of veins 56.2 % of patients prematurely discontinued treatment through intensive local complications or phlebitis. Application of intensive treatment with the introduction of anti-TB drugs allows for faster time to achieve sputum conversion.

Impact of HACA on Immunomodulation and Treatment Toxicity Following ch14.18/CHO Long-Term Infusion with Interleukin-2: Results from a SIOPEN Phase 2 Trial.

GD2-directed immunotherapies improve survival of high-risk neuroblastoma (NB) patients (pts). Treatment with chimeric anti-GD2 antibodies (Ab), such as ch14.18, can induce development of human anti-chimeric Ab (HACA). Here, we report HACA effects on ch14.18/CHO pharmacokinetics, pharmacodynamics and pain intensity in pts treated by long-term infusion (LTI) of ch14.18/CHO combined with IL-2. 124 pts received up to 5 cycles of ch14.18/CHO 10 days (d) infusion (10 mg/m2/d; d8–18) combined with s.c. IL-2 (6 × 106 IU/m2/d; d1–5, d8–12). HACA, treatment toxicity, ch14.18/CHO levels, Ab-dependent cellular- (ADCC) and complement-dependent cytotoxicity (CDC) were assessed using respective validated assays. HACA-negative pts showed a steadily decreased pain in cycle 1 (74% pts without morphine by d5 of LTI) with further decrease in subsequent cycles. Ch14.18/CHO peak concentrations of 11.26 ± 0.50 µg/mL found in cycle 1 were further elevated in subsequent cycles and resulted in robust GD2-specific CDC and ADCC. Development of HACA (21% of pts) resulted in strong reduction of ch14.18/CHO levels, abrogated CDC and ADCC. Surprisingly, no difference in pain toxicity between HACA-positive and -negative pts was found. In conclusion, ch14.18/CHO LTI combined with IL-2 results in strong activation of Ab effector functions. Importantly, HACA response abrogated CDC but did not affect pain intensity indicating CDC-independent pain induction.

The cause analysis and nursing care of patients with venous thrombosis induced by PICC

Objective To explore the causes of venous thrombosis after peripherally inserted central catheter(PICC) in tumor patients and corresponding nursing precautions. Methods A total of 105 patients with tumors undergoing long-term infusion and chemotherapy in this hospital were selected as the research subjects.All patients were treated with PICC catheterization.Nursing measures were observed and administered at the beginning of catheterization. Results A total of 6 patients developed venous thrombosis, and the patients' condition gradually recovered after anticoagulation therapy.It was found that venous thrombosis was not only directly related to catheterization, but also related to drug use in the course of disease treatment and activity of patients. Conclusion Skilled puncture techniques and related nursing measures can effectively reduce the occurrence of venous thrombosis in patients with PICC. Key words: Venous thrombosis; PICC; Nursing measures

Safety and efficiency of the port-catheter for intensive intravenous chemotherapy in patients with multi-drug resistant tuberculosis and extensively drug-resistant tuberculosis

PURPOSE. To study the efficacy and tolerability of the port catheter for continuous intravenous infusion in patients with MDR-TB and XDR-TB.&#x0D; MATERIALS AND METHODS. In a controlled study examined the effectiveness of the port catheter during an intensive 7-component anti-TB treatment with intravenous application of 3 anti-TB drugs (moxifloxacin, PAS, linezolid) in 16 patients with MDR-TB and XDR-TB. In the comparison group, which is formed by a pair of matching according to the drug resistance profile of MTB, the same intensive chemotherapy regimens in which the infusion of these drugs was carried out by daily injections of veins. In each group dominated patients with retreatment cases — 14 (87.5 %) patients. The planned duration of intravenous therapy was 2—4 months.&#x0D; RESULTS. Port-catheter for continuous infusion of combination of anti-tuberculosis drugs in comparison to their administration in the usual way ensures high efficiency and safety. In any case, was not observed phlebitis, no complaints of pain at the injection site, only 12.5 % cases were hematoma after setting the port in comparison to 100.0 % of patients with daily venous injections. In the study group was not a single case of interruption of intravenous infusion. In the control group, 56.2 % of patients discontinued intravenous treatment due to inability to penetrate the vein, patient’s complaints pain or phlebitis. At the end of the intensive phase of chemotherapy sputum conversion and disappearance of clinical symptoms were observed in 15 (3.7 %) patients of the study group, that was 26.7 % higher, than in control group (p&gt;0,05). We found significant difference in terms of sputum conversion, which occurred in the study group through (2,2±0,1) months vs (3,7±0,3) months (&lt;0,05) in control group.&#x0D; CONCLUSIONS. Port-catheter for long-term daily infusions of combination of anti-TB drugs compared with their usual daily injections is safe and effective method of intravenous therapy. It is not accompanied by subjective complaints of patients and the development of phlebitis, which leads to early sputum conversion. With daily injections of veins 56.2 % of patients prematurely discontinued treatment through intensive local complications or phlebitis. Application of intensive treatment with the introduction of anti-TB drugs allows for faster time to achieve sputum conversion.

Circadian variations in the pharmacokinetics of the oral anticancer agent tegafur-uracil (UFT) and its metabolites in rats

Uracil-tegafur (UFT) is an oral anticancer drug containing uracil and 5‑fluorouracil prodrug tegafur and is widely used for adjuvant chemotherapy of colorectal cancer. Although clinical data show circadian variations in plasma 5‑fluorouracil concentrations during its long-term infusion, and feasibility studies of chronomodulated administration have been previously reported, the circadian pattern in plasma 5‑fluorouracil concentration after UFT administrations remains unclear. The aim of this study was to identify factors causing circadian variations in UFT pharmacokinetics and estimate circadian patterns of plasma 5‑fluorouracil concentration corresponding to UFT dosing time in rats. Rats were orally administered UFT (15 mg/kg as tegafur) at three different times of the day: 07:00 (23 h after light onset, HALO), 13:00 (5 HALO), or 19:00 (11 HALO), and then plasma concentrations of tegafur, 5‑fluorouracil, and uracil were measured after UFT administration. We found that the area under the plasma concentration-time curves (AUC0−∞) of 5‑fluorouracil depended on the UFT dosing time of day with a 2.4-fold difference between the peak (at 19:00: 13.7 ± 1.4 μmol·h/L) and trough (at 13:00: 5.6 ± 1.3 μmol·h/L). The simulated population mean clearance of 5‑fluorouracil followed a 24-h cosine circadian curve, with the highest value in the early light phase being 2.2-fold higher than the lowest value in the early dark phase, which was an inverse circadian pattern compared to the plasma 5‑fluorouracil concentration. The plasma tegafur levels suggested that circadian variation in tegafur absorption and conversion to 5‑fluorouracil are factors causing variations in plasma 5‑fluorouracil levels following UFT administration. In conclusion, the circadian pattern of 5‑fluorouracil clearance and circadian variations in tegafur pharmacokinetics are important determinants of plasma 5‑fluorouracil concentrations following UFT administration. This knowledge could help in developing a chronomodulated administration strategy of UFT for improving clinical outcomes.

Prolonged dexmedetomidine infusion in critically ill adult patients: a retrospective analysis of a large clinical database Multiparameter Intelligent Monitoring in Intensive Care III.

There is no conclusive evidence for the effects of prolonged infusion of dexmedetomidine in critically ill patients. We aimed to investigate the safety of long-term dexmedetomidine infusion in a large critically ill patients cohort from the Multiparameter Intelligent Monitoring in Intensive Care III (MIMIC-III) database. We retrospectively extracted records from MIMIC-III database. Dexmedetomidine administration time was the basis for group. Variables were compared by chi-square tests, and Mann-Whitney U test as appropriate. We used logistic regression model for multivariate analysis. Contour maps were drawn to measure rebound of heart rate (HR) and blood pressure (BP). We finally got 1,946 records including 1,368 distinct individuals. Age, body mass index (BMI), length of stay in hospital, accumulated doses of dexmedetomidine and Sequential Organ Failure Assessment (SOFA) score were independent risk factors of in-hospital mortality (P<0.05). But prolonged dexmedetomidine infusion (≥24 h) and abrupt cessation did not increase in-hospital mortality. Furthermore, the rebound of HR and BP was more likely to occur in patients with prolonged infusion of dexmedetomidine. Prolonged dexmedetomidine infusion is not related to an increased in-hospital mortality, but it is associated with the rebound effect of HR and BP. Further prospective studies are needed.