High-dose Intravenous Infusion Research Articles

New uses for vitamin C, and its versatile, pleiotropic antioxidant action. - Treatment of neoplasms, skin diseases, bone diseases and stimulation of the immune system

Introduction: Vitamin C (Vit C) is an organic chemical compound from the group of unsaturated polyhydroxy alcohols. It influences physiological processes such as the facilitation of iron absorption, hormone and carnitine synthesis, and is also involved in epigenetic processes. It is a vitamin, which means that it must be provided in food. It is also an antioxidant used as a food additive. In recent times, its pleiotropic use has been proven in the treatment of immune deficiencies, the treatment of skin diseases, bone diseases and may also be used in new cancer treatment regimens. Aim of the study: To review the current literature on the use of vitamin C in various fields of health and science. Materials and Methods: We reviewed the literature available in PubMed, using the key words: "vitamin C"; "ascorbid acid"; "cancer treatment"; "vitamin C immune function". Results: Vitamin C has pleiotropic effects on the human body, both through its effects on cells and tissues and through its antioxidant mechanisms and regulation of gene expression. It has been shown to be a key antioxidant with anti-inflammatory and immune system supportive effects. Its effect of slowing down skin photo-ageing by reducing the amount of metalloproteinases induced by reactive oxygen species has been noted in the literature. Vitamin C has been shown in studies to reduce the risk of osteoporosis due to its osteoclast inhibitory properties. Beneficial effects of high-dose intravenous infusions have also been demonstrated in the treatment of cancer, as well as about reducing organ failure and vascular damage in patients with ARDS and sepsis. Summary: The versatile action of vitamin C has made it the subject of intense research. However, the reports in the literature to date on its use require further studies on larger groups of people to confirm its effects.

Dexmedetomidine-induced polyuria in the intensive care unit: a case report

Abstract Dexmedetomidine is an α2 agonist that is frequently used for sedation in intensive care units (ICUs). Hypotension and bradycardia are common adverse effects observed in clinical practice. In perioperative conditions, polyuria is a rare adverse effect with limited case reports after dexmedetomidine infusion. Similar to this situation, in ICU, there are rare cases. We present the case of a 59-year-old man who developed polyuria secondary to high-dose intravenous dexmedetomidine infusion in the medical ICU.

An Autoimmune Encephalitis Case Associated with Pembrolizumab Use

Immune checkpoint inhibitors may be associated with various adverse events, including encephalitis. Here, we report a case of encephalopathy associated with pembrolizumab therapy. A 60-year-old male diagnosed with cholangiocarcinoma with peritoneal seeding presented altered mentality and cognitive function after using pembrolizumab. Electroencephalogram showed mild diffuse cerebral dysfunction. Cerebrospinal fluid (CSF) study showed no evidence of infection or autoimmune disease and no paraneoplastic antibody was detected from CSF and serum. After high-dose methylprednisolone intravenous infusion, patient’s mentality was fully recovered.

Use of oxytocin as a low-dose intravenous push at time of cesarean delivery

Historically, oxytocin has been given as a high-dose intravenous (IV) infusion at delivery to reduce blood loss, but low-dose oxytocin given as an IV push may be equally effective. We hypothesize that a low-dose IV push of oxytocin is non-inferior to a high-dose infusion of oxytocin for prevention of blood loss at cesarean delivery.

The relationship between COVID-19 and blood vitamin C; a systematic review study

Introduction: The rapid worldwide spread of COVID-19 has caused a global health crisis. Unfortunately, no vaccine or special antiviral drug has been developed against COVID-19 to date, symptomatic supportive care has been the most common treatment. Objectives: the purpose of this systematic review aims to provide a timely, rigorous, and continuously updated summary of the available evidence on the role of vitamin C in treating patients with COVID-19. Methods: In this review, we identified studies published in 2020 that describe on the relationship between COVID-19 and vitamin C. We searched PubMed, Google Scholar, Scopus, Magiran, SID and Web of Science for research articles published up to 23 December 2020 using the keywords of vitamin C, COVID-19, SARS-COV-2 and coronavirus 2. Results: At the initial stage of screening, 181articles were excluded after reviewing the title and removing irrelevant and duplicate titles, 52 articles were selected to review the abstract. After reviewing the abstract (or in articles without abstracts after reviewing the original text), nine articles were finally considered suitable for this purpose and were reviewed and finalized. Vitamin C is a pivotal component of the immune system, with proven antioxidant, cytokine storm suppressor and anti-inflammatory properties and has been tested in numerous studies for its role in severe sepsis and ICU care, especially when used as a continuous high-dose intravenous infusion. In addition, some studies indicated high-dose intravenous vitamin C treatment was associated with fewer days on mechanical ventilation, shorter ICU stay, and earlier recovery compared to the average length of mechanical ventilation, disease duration, and ICU stay in critical COVID-19 patients. Conclusion: Vitamin C can significantly improve clinical symptoms, inflammatory response, immune and organ function in COVID-19 patients. In patients affected with COVID-19, high-dose intravenous vitamin C is expected to improve pulmonary function and reduce mortality for patients with COVID-19 and can be beneficial in aspects of inflammatory response, immune and organ function for aggravation of COVID-19 patients, however further clinical trials are necessary.

BIMG-07. PHARMACOLOGICAL ASCORBATE ENHANCES RADIATION AND TEMOZOLOMIDE EFFECTIVENESS IN GLIOBLASTOMA BY A MECHANISM MEDIATED BY REDOX ACTIVE IRON

Pharmacological ascorbate (P-AscH-; high dose intravenous infusions of vitamin C generating milli-molar plasma concentrations) has re-emerged as an anti-cancer therapy. Phase 1 clinical trials combining P-AscH- with chemotherapy and ionizing radiation demonstrate safety and promising clinical outcomes in a variety of malignancies. In a first-in-human trial, subjects with newly diagnosed glioblastoma (GBM) and undetectable MGMT promoter methylation were treated with P-AscH-, ionizing radiation, and temozolomide. Results demonstrate median progression-free survival (PFS) of 10 months and median overall survival (OS) of 23 months, comparing favorably to historical GBM patients expressing MGMT. P-AscH-‘s anti-cancer mechanism is dependent upon the presence of redox active labile iron. In the presence of redox active iron, the formation of hydrogen peroxide, which causes oxidative stress and eventual cell death, selectively forms in cancer cells. Treatment with P-AscH- increased cancer cells’ labile iron pool, further enhancing sensitivity to P-AscH-. We investigated the capability of MR imaging (T2* relaxation time) to measure the redox active iron and predict response to P-AscH-. T2* relaxation time is influenced by in-field inhomogeneities, such as redox active paramagnetic iron. The active phase 2 trial evaluating P-AscH-, radiation, and temozolomide for GBM, obtains T2* imaging prior to (baseline) and immediately after ascorbate infusion (NCT02344355). A preliminary analysis of the baseline scan for the first 15 subjects suggests those with faster GBM T2* relaxation times (≤ 58 ms) have more redox active labile iron pools as well as an improved median PFS (11.4 months) compared to those with slower T2* relaxation times (> 58 ms; median PFS of 8.5 months). Pre-clinical studies evaluating the effectiveness of iron nano-particle supplementation in GBM animal models are on-going. (Supported by P01 CA217797, R01 CA169046, U01 CA140206, T32 CA078586, P30 CA086862, as well as the Gateway for Cancer Research grant G-17–1500.)

The Lazarus effect of very high-dose intravenous anakinra in severe non-familial CNS-HLH.

The interleukin (IL)-1 receptor antagonist, anakinra, is recognised to be effective in secondary haemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS).1 Mostly used subcutaneously, intravenous anakinra has been described for the cytokine storm characteristic of secondary HLH or MAS and variably for neurological involvement in HLH, but not specifically for refractory CNS-HLH1,2 (appendix p 5). Here, we describe a child with life-threatening secondary HLH on high-dose intravenous anakinra infusion, whose disease course was complicated by CNS-HLH that responded to a steep escalation of the anakinra dose.

Randomized Controlled Trial of Over-the-Scope Clip as Initial Treatment of Severe Nonvariceal Upper Gastrointestinal Bleeding

No prior randomized controlled trial (RCT) has reported patient outcomes of large over-the-scope clip (OTSC) compared to standard hemostasis as initial endoscopic treatment of severe NVUGIB. This was our study aim. Patients with bleeding ulcers or Dieulafoy's lesions and major stigmata of hemorrhage - SRH (active spurting bleeding, visible vessel, or clot) - or lesser SRH (oozing bleeding or flat spots - with arterial blood flow by Doppler probe) were randomized to OTSC or standard endoscopic hemostasis (with hemoclips or multipolar electrocoagulation - MPEC). Patients and their healthcare providers were blinded to treatments and made all post-randomization management decisions. Ulcer patients received high dose intravenous infusions of proton pump inhibitors (PPI) for 3 days, then 27 days of oral PPI. 30 day outcomes were prospectively recorded; data management was with SAS; and data analysis was by a statistician. 53 patients (25 OTSC, 28 Standard) were randomized, with similar baseline risk factors. However, there were significant differences in OTSC vs. Standard groups in rates of rebleeding (4% vs. 28.6%; p= .017; relative risk 0.10, 95% confidence intervals 0.01, 0.91; number needed to treat 4); severe complications (0 % vs. 14.3%); and post-randomization units of red cell transfusions (0.04 vs. 0.68). All rebleeds occurred in patients with major SRH and none with lesser SRH. 1. OTSC significantly reduced rates of rebleeding, severe complications, and post-randomization red cell transfusions. 2. Patients with major stigmata benefited significantly from hemostasis with OTSC, but those with lesser stigmata did not. (ClinicalTrials.gov, Number: NCT03065465).

Preparation of Peptide and Recombinant Tissue Plasminogen Activator Conjugated Poly(Lactic-Co-Glycolic Acid) (PLGA) Magnetic Nanoparticles for Dual Targeted Thrombolytic Therapy.

Recombinant tissue plasminogen activator (rtPA) is the only thrombolytic agent that has been approved by the FDA for treatment of ischemic stroke. However, a high dose intravenous infusion is required to maintain effective drug concentration, owing to the short half-life of the thrombolytic drug, whereas a momentous limitation is the risk of bleeding. We envision a dual targeted strategy for rtPA delivery will be feasible to minimize the required dose of rtPA for treatment. For this purpose, rtPA and fibrin-avid peptide were co-immobilized to poly(lactic-co-glycolic acid) (PLGA) magnetic nanoparticles (PMNP) to prepare peptide/rtPA conjugated PMNPs (pPMNP-rtPA). During preparation, PMNP was first surface modified with avidin, which could interact with biotin. This is followed by binding PMNP-avidin with biotin-PEG-rtPA (or biotin-PEG-peptide), which was prepared beforehand by binding rtPA (or peptide) to biotin-PEG-maleimide while using click chemistry between maleimide and the single –SH group in rtPA (or peptide). The physicochemical property characterization indicated the successful preparation of the magnetic nanoparticles with full retention of rtPA fibrinolysis activity, while biological response studies underlined the high biocompatibility of all magnetic nanoparticles from cytotoxicity and hemolysis assays in vitro. The magnetic guidance and fibrin binding effects were also confirmed, which led to a higher thrombolysis rate in vitro using PMNP-rtPA or pPMNP-rtPA when compared to free rtPA after static or dynamic incubation with blood clots. Using pressure-dependent clot lysis model in a flow system, dual targeted pPMNP-rtPA could reduce the clot lysis time for reperfusion by 40% when compared to free rtPA at the same drug dosage. From in vivo targeted thrombolysis in a rat embolic model, pPMNP-rtPA was used at 20% of free rtPA dosage to restore the iliac blood flow in vascular thrombus that was created by injecting a blood clot to the hind limb area.

Diuretic Strategies for Loop Diuretic Resistance in Acute Heart Failure: The 3T Trial

ObjectivesThis study compared combination diuretic strategies in acute heart failure (AHF) complicated by diuretic resistance (DR). BackgroundCombination diuretic regimens to overcome loop DR are commonly used but with limited evidence. MethodsThis study was a randomized, double-blinded trial in 60 patients hospitalized with AHF and intravenous (IV) loop DR. Patients were randomized to oral metolazone, IV chlorothiazide, or tolvaptan therapy. All patients received concomitant high-dose IV infusions of furosemide. The primary outcome was 48-h weight loss. ResultsThe cohort exhibited DR prior to enrollment, producing 1,188 ± 476 ml of urine in 12 h during high-dose loop diuretic therapy (IV furosemide: 612 ± 439 mg/day). All 3 interventions significantly improved diuretic efficacy (p < 0.001). Compared to metolazone (4.6 ± 2.7 kg), neither IV chlorothiazide (5.8 ± 2.7 kg; 1.2 kg [95% confidence interval (CI)]: −2.9 to 0.6; p = 0.292) nor tolvaptan (4.1 ± 3.3 kg; 0.5 kg [95% CI: −1.5 to 2.4; p = 0.456) resulted in more weight loss at 48 h. Median (interquartile range [IQR]) cumulative urine output increased significantly and did not differ among those receiving metolazone (7.78 [IQR: 6.59 to 10.10] l) and chlorothiazide (8.77 [IQR: 7.37 to 10.86] l; p = 0.245) or tolvaptan (9.70 [IQR: 6.36 to 13.81] l; p = 0.160). Serum sodium decreased less with tolvaptan than with metolazone (+4 ± 5 vs. −1 ± 3 mEq/l; p = 0.001), but 48-h spot urine sodium was lower with tolvaptan (58 ± 25 mmol/l) than with metolazone (104 ± 16 mmol/l; p = 0.002) and with chlorothiazide (117 ± 14 mmol/l; p < 0.001). ConclusionsIn this moderately sized DR trial, weight loss was excellent with the addition of metolazone, IV chlorothiazide, or tolvaptan to loop diuretics, without a detectable between-group difference. (Comparison of Oral or Intravenous Thiazides vs. tolvaptan in Diuretic Resistant Decompensated Heart Failure [3T]; NCT02606253)

Effect of Intravenous and Oral N-Acetylcysteine Treatment in a Patient with Sickle Cell Disease at Disease Baseline

Background: We previously showed that patients with sickle cell disease (SCD) have elevated levels of von Willebrand factor (VWF) with high adhesive activity and the level of total active VWF correlated with hemolysis at disease baseline. These findings suggest that VWF plays a role in the pathophysiology of SCD [Chen et al, Blood. 2011; 117:3680‐3]. We also showed that N-acetylcysteine (NAC), a mucolytic and antioxidant drug, can reduce the level of large VWF multimers and platelet adhesion in human plasma in vitro and in mice in vivo [Chen et al, JCI, 2011, 121:522]. Based on these findings, we hypothesized that administration of NAC in SCD patients might reduce VWF multimers in vivo and reduce oxidative stress by scavenging reactive oxygen species (ROS). We started a pilot study to evaluate the effects of intravenous (IV) and oral NAC administration in SCD patients at disease baseline (NCT01800526). In this report, we administered NAC to one patient by IV and orally and compared the effect on biomarkers by the two routes of NAC administration.Patient and protocol: The subject is a 51-year-old male with SS genotype, a history of leg ulcers and acute chest syndrome, and who was not taking hydroxyurea at the time of the study. NAC was infused at a low dose (150 mg/kg over 8 hours) and infusion was repeated at high dose (300 mg/kg over 8 hrs) after 4 weeks. Blood samples were collected before (0), during (4 hr) and after the NAC infusions (8, 24 and 72 hr). Five months after the high dose IV infusion, during which parameters returned to baseline levels, oral NAC was administered for 4 weeks at 2.4g/day. Weekly blood samples were collected four weeks before the start of oral NAC, during oral NAC, and one week after oral NAC administration. We measured RBC parameters and RBC fragments, dense cells and percentage of platelet-monocyte complexes (PMC) by flow cytometry. We also analyzed VWF antigen, VWF multimers, ADAMTS13 antigen and activity levels in plasma. We also measured total, oxidized and reduced forms of NAC, cysteine and glutathione levels in plasma and whole blood by mass spectrometry.Results: 1) The subject did not experience adverse side effect during and after the treatment period. 2) RBC, hemoglobin and hematocrit levels did not significantly change with either IV or oral NAC treatment. Oral and IV NAC decreased dense cell and RBC fragments. NAC reduced the number of dense cells 13% during low dose IV, 79% during high dose IV and 73% with the oral administration. Compared to baseline, RBC fragments decreased 40% during low dose IV, 28% during high dose IV, and 27% with the oral NAC treatment. 3) NAC reduced formation of PMC from 71% to 24% (low dose IV), from 72% to 35% (high dose IV), and from 62% to 27% (oral). 4) VWF multimer size significantly decreased during low and high dose NAC infusions but did not change with oral NAC administration. VWF antigen and ADAMTS13 activity levels did not change with either routes of NAC administration. 5) The concentration of NAC in whole blood increased during treatments: elevated to 0.5 mM and 1 mM at the end of low- and high-dose IV infusions, respectively. At the conclusion of oral administration, the NAC concentration was 4 µM. Total glutathione concentrations in whole blood did not change significantly during and after NAC treatment at either dose or by either route. Free Cys concentrations in plasma increased compared to respective baseline levels 10-fold for low dose infusion (from 10 µM to 101 µM), 20-fold for high dose infusion (from 9 µM to 200 µM), but the level did not change significantly for oral administration (from 5 µM to 7 µM). Protein-bound Cys levels in plasma as markers of oxidative stress were significantly decreased with low- and high-dose IV infusion. However, the level did not change significantly with oral NAC administration.Summary: Both IV and oral administration of NAC were safe and well tolerated in the patient with SCD. Both IV and oral administration reduced the number of dense cells, RBC fragmentation, and formation of PMCs. IV, but not oral NAC, reduced VWF multimer size. These finding suggest that IV administration resulted in higher concentration and had more biologic effects; however both approaches may have a role in treatment of patients with SCD. DisclosuresKonkle:Sangamo: Research Funding; Gilead: Consultancy; Shire: Research Funding; Genentech: Consultancy; CSL Behring: Consultancy; Bioverativ: Research Funding; BioMarin: Consultancy; Spark: Consultancy, Research Funding; Pfizer: Research Funding.

For the Success of Oncolytic Viruses: Single Cycle Cures or Repeat Treatments? (One Cycle Should Be Enough).

For the Success of Oncolytic Viruses: Single Cycle Cures or Repeat Treatments? (One Cycle Should Be Enough).

A Case of Acute Budd-Chiari Syndrome Complicating Primary Antiphospholipid Syndrome Presenting as Acute Abdomen and Responding to Tight Anticoagulant Therapy.

A 34-year-old woman with primary antiphospholipid syndrome was admitted to the Gastroenterology Department of our hospital with fever, acute abdomen, watery diarrhea, and extremely high levels of inflammatory parameters. She had a history of left lower limb deep vein thrombosis and pulmonary embolism and was taking warfarin potassium. Acute gastroenteritis was suspected and an antibiotic was administered, but symptoms progressed. Abdominal ultrasonography showed occlusion of the left hepatic vein and the middle hepatic vein and her D-dimer level was high. Accordingly, Budd-Chiari syndrome was diagnosed and high-dose intravenous infusion of heparin was initiated. Her abdominal symptoms improved and the levels of inflammatory parameters and D-dimer decreased rapidly. It is known that antiphospholipid syndrome can be complicated by Budd-Chiari syndrome that usually occurs as subacute or chronic onset, but acute onset is rare. It is difficult to diagnose acute Budd-Chiari syndrome complicating antiphospholipid syndrome and this complication generally has a poor outcome. However, the present case can get early diagnosis and successful treatment with tight anticoagulant therapy.

Evaluation of the safety and tolerability of a high-dose intravenous infusion of allogeneic mesenchymal precursor cells

Background aimsOver the past decade, mounting evidence has shown that mesenchymal stromal cells have the potential to exert protective and reparative effects in a variety of disease settings. Clinical trials are being increasingly established to investigate the therapeutic potential of these cells; however, several safety concerns remain to be addressed, of which dosage safety for intravenous administration is paramount. Published safety studies thus far have predominantly been carried out in small-animal models, whereas data for high-dose allogeneic intravenous administration in large-animal models are limited. This study investigates the safety and tolerability of a single high-dose intravenous infusion of 450 million allogeneic ovine mesenchymal precursor cells (oMPCs) in adult sheep. MethodsAllogeneic oMPCs (n = 450 million) were intravenously administered to 2-year-old castrated male sheep through the use of three different infusion rates. Sheep were intensively monitored for 7 days by means of vital physiological observations (temperature, blood pressure, heart rate, respiratory rate and oxygen saturation) as well as venous and arterial blood analysis. In addition, full post mortem examination was performed in all animals. ResultsA single high dose of intravenously administered cells was well tolerated, with no serious adverse effects reported. No physiologically significant changes in vital signs, oxygen saturation, blood gas analysis or clinical pathology were observed over the duration of the study. ConclusionsIntravenous delivery of a single high-dose infusion of oMPCs is well tolerated in a large animal model. This study provides additional safety evidence for their intravenous use in future human clinical trials.

Targeting tumor vasculature with aptamer-functionalized doxorubicin-polylactide nanoconjugates for enhanced cancer therapy.

An A10 aptamer (Apt)-functionalized, sub-100 nm doxorubicin-polylactide (Doxo-PLA) nanoconjugate (NC) with controlled release profile was developed as an intravenous therapeutic strategy to effectively target and cytoreduce canine hemangiosarcoma (cHSA), a naturally occurring solid tumor malignancy composed solely of tumor-associated endothelium. cHSA consists of a pure population of malignant endothelial cells expressing prostate-specific membrane antigen (PSMA) and is an ideal comparative tumor model system for evaluating the specificity and feasibility of tumor-associated endothelial cell targeting by A10 Apt-functionalized NC (A10 NC). In vitro, A10 NCs were selectively internalized across a panel of PSMA-expressing cancer cell lines, and when incorporating Doxo, A10 Doxo-PLA NCs exerted greater cytotoxic effects compared to nonfunctionalized Doxo-PLA NCs and free Doxo. Importantly, intravenously delivered A10 NCs selectively targeted PSMA-expressing tumor-associated endothelial cells at a cellular level in tumor-bearing mice and dramatically increased the uptake of NCs by endothelial cells within the local tumor microenvironment. By virtue of controlled drug release kinetics and selective tumor-associated endothelial cell targeting, A10 Doxo-PLA NCs possess a desirable safety profile in vivo, being well-tolerated following high-dose intravenous infusion in mice, as supported by the absence of any histologic organ toxicity. In cHSA-implanted mice, two consecutive intravenous infusions of A10 Doxo-PLA NCs exerted rapid and substantial cytoreductive activities within a period of 7 days, resulting in greater than 70% reduction in macroscopic tumor-associated endothelial cell burden as a consequence of enhanced cell death and necrosis.

A Convenient Method for Measuring Blood Ascorbate Concentrations in Patients Receiving High-Dose Intravenous Ascorbate

Objective: A simple method of using fingerstick blood glucose (FSBG) monitors to estimate blood ascorbate values after high-dose intravenous (IV) ascorbate infusion is evaluated as a substitution for high-performance liquid chromatography (HPLC) measurement. Methods: In 33 participants, readings from FSBG monitors were taken before and after IV ascorbate infusions at various time points, with the postinfusion FSBG readings subtracted from the baseline glucose readings. The results of the subtractions (AAFSBG) were correlated with ascorbate concentrations detected by HPLC (AAHPLC). Results: A linear regression was found between ascorbate concentrations detected by the fingerstick method (AAFSBG) and by HPLC (AAHPLC). The linear correlations were identical in healthy subjects, diabetic subjects, and cancer patients. Analysis of variance obtained an AAFSBG/AAHPLC ratio of 0.90, with a 90% confidence interval of (0.69, 1.20). The corrections of AAFSBG improved similarity to AAHPLC but did not significantly differ from the uncorrected values. Conclusion: The FSBG method can be used as an approximate estimation of high blood ascorbate concentration after IV ascorbate (>50 mg/dL, or 2.8 mM) without correction. However, this measurement is not accurate in detecting lower or baseline blood ascorbate. It is also important to highlight that in regard to glucose monitoring, FSBG readings will be erroneously elevated following IV ascorbate use and insulin should not be administered to patients based on these readings.

In Vitro and In Vivo Evaluation of a Humanized Anti-APRIL Antibody

A proliferation-inducing ligand (APRIL) is overexpressed in many cancers such as colorectal, gastric and liver. Silence APRIL gene or neutralize its expression may serve as therapeutic strategies to manage those cancers. Current phase I clinical trial shows that heavily pretreated patients were well tolerated high dose intravenous infusion. Herein, we report a humanized antibody (Ab) that neutralizes APRIL protein and inhibits cancer cell proliferation both in vitro and in vivo. The Ab was generated through conjugating foreign immunodominant T-helper cell (Th) epitopes to the N- or C-terminal of four soluble APRIL mutants. In vitro anti-proliferation effects were evaluated in both Raji and Jurkat cell lines. In vivo inhibition of tumor growth was determined in a tumor xenograft animal model with green fluorescent protein (GFP) positive Raji cell line. In vitro data demonstrated that this Ab significantly inhibited both Raji and Jurkat cell proliferation in a dose-dependent manner. The molecular imaging data demonstrated in vivo tumor growth delay when animals were treated with Ab. In conclusion, we have developed a humanized anti-APRIL Ab, which is effective in inhibiting tumor cell proliferations both in vitro and vivo. The humanized Ab has potential to reduce the immunoresponse in the clinical situation. This Ab also can be used in other APRIL mediated diseases such as Sjogren syndrome, multiple sclerosis and systemic lupus erythematosus.

A Case of Successful Recovery from High Dose Intravenous Nicorandil Infusion in Refractory Coronary Vasospasm with Hemodynamic Collapse

A 70-year-old male came to the emergency room of the authors’ hospital because of sudden cardiac arrest due to inferior wall ST elevation myocardial infarction. His coronary angiography revealed multiple severe coronary spasms in his very long left anterior descending artery. After an injection of intracoronary nitroglycerine, his stenosis improved. The cardiac arrest relapsed, however, accompanied by ST elevation of the inferior leads, while the patient was on diltiazem and nitrate medication to prevent coronary spasm. Recovery was not achieved even with cardiac massage, intravenous injection of epinephrine and atropine, and intravenous infusion of nitroglycerine. The patient eventually recovered through high-dose nicorandil intravenous infusion without ST elevation of his inferior leads. Therefore, intravenous infusion of a high dose of nicorandil must be considered a treatment option for cardiac arrest caused by refractory coronary vasospasm.

High‐dose silibinin rescue treatment for HCV‐infected patients showing suboptimal virologic response to standard combination therapy

Incomplete suppression of hepatitis C virus (HCV) replication with persistence of minimal viremia (partial virologic response) leading to treatment failure can be observed in a significant proportion of HCV type 1-infected patients during antiviral therapy. Recently, high-dose intravenous silibinin has demonstrated strong antiviral activity against HCV. We were therefore interested in whether patients with partial virologic response can be rescued by the on-treatment addition of a short-term course of high-dose intravenous silibinin infusions. Twenty patients who failed to achieve a complete virologic response to different interferon-based regimens qualified for the rescue strategy and received 1400 mg/day silibinin infusions on two consecutive days. Complete viral suppression (below the limit of detection <6 IU/mL, TMA assay) could be induced in 13 of 20 patients within the first week after the short-term silibinin infusion, and all but one of them also remained HCV RNA negative during the subsequent follow-up period on continued peginterferon plus ribavirin treatment. In the remaining seven patients, no complete suppression could be achieved although four showed a significant HCV RNA reduction in response to silibinin. Silibinin infusions were generally well tolerated, and activation of abdominal peristalsis with nausea, diarrhoea and vomiting were the most prominent side effects. Of the twelve patients who exhibited a durable response to peginterferon and ribavirin treatment, three achieved an SVR, two achieved a week 12 SVR and four suffered a viral relapse. Three patients could not complete the assigned antiviral treatment with peginterferon alpha and ribavirin for nonvirological reasons. Short-term administration of high-dose intravenous silibinin might be an interesting approach to rescue patients with ongoing minimal residual viremia while on interferon-based therapy. These preliminary findings may stimulate further studies to evaluate more refined therapeutic strategies.

Sinus node dysfunction as an initial presentation of adult systemic lupus erythematosus

Cardiac involvement in systemic lupus erythematosus (SLE) has been well described. However, sinus node involvement with profound sinus bradycardia as an early manifestation of adult SLE has not been reported. A 27-year-old previously healthy female was admitted due to intermittent fever for 4 days. SLE was diagnosed based on clinical manifestations and laboratory data. Profound sinus bradycardia (heart rate = 41/min) with weakness was noted during hospitalization. ECG abnormalities completely resolved after a high-dose intravenous steroid infusion. Sinus node involvement with significant bradycardia is one of the possible complications in the early stage of adult SLE. Close cardiovascular monitoring and serial ECGs are suggested for early detection of this serious complication of adult SLE.