Multiple Intravenous Administration Research Articles

Safety, tolerability, and pharmacokinetics of single- and multiple-ascending doses of olamkicept: Results from randomized, placebo-controlled, first-in-human phase I trials.

Olamkicept selectively inhibits the cytokine interleukin-6 (IL-6) trans-signaling pathway without blocking the classic pathway and is a promising immunoregulatory therapy for inflammatory bowel disease (IBD). These first-in-human, randomized, placebo-controlled, single- (SAD) and multiple-ascending dose (MAD) trials evaluated olamkicept safety, tolerability, pharmacokinetic, and pharmacodynamic characteristics. Doses tested in the SAD trial included seven single intravenous doses (0.75, 7.5, 75, 150, 300, 600, and 750 mg) and one subcutaneous (SC) dose (60 mg) given to healthy subjects (N = 64), and three intravenous doses (75 mg, 300 mg, and 750 mg) given to patients with Crohn's disease (CD; N = 24). Doses tested in the MAD trial included multiple intravenous doses (75, 300, and 600 mg once weekly for 4 weeks) given to healthy subjects (N = 24). No severe or serious treatment-emergent adverse events (TEAEs) were recorded. The most common TEAEs were headache, nasopharyngitis, and myalgia in the SAD trial, and diarrhea, headache, and cough in the MAD trial. Infusion-related reactions occurred in one and two subjects in the SAD and MAD trial, respectively, leading to treatment discontinuation in the MAD trial. Olamkicept showed dose-independent pharmacokinetics after single and multiple administrations, and there was no major difference in systemic exposure between healthy subjects and patients with CD. Complete target engagement (inhibition of phosphorylation of signal transducer and activator of transcription-3) was achieved in blood around or above olamkicept serum concentrations of 1-5 μg/mL. Overall, these results suggest that olamkicept is safe and well-tolerated in healthy subjects and patients with CD after single intravenous/SC and multiple intravenous administrations.

Neutralizing Antibodies Impair the Oncolytic Efficacy of Reovirus but Permit Effective Combination with T cell-Based Immunotherapies.

Reovirus type 3 Dearing (Reo), manufactured for clinical application as pelareorep, is an attractive anticancer agent under evaluation in multiple phase 2 clinical trials for the treatment of solid tumors. It elicits its anticancer efficacy by inducing both oncolysis and intratumoral T-cell influx. Because most people have been preexposed to Reo, neutralizing antibodies (NAb) are prevalent in patients with cancer and might present a barrier to effective Reo therapy. Here, we tested serum of patients with cancer and healthy controls (n = 100) and confirmed that Reo NAbs are present in >80% of individuals. To investigate the effect of NAbs on both the oncolytic and the immunostimulatory efficacy of Reo, we established an experimental mouse model with Reo preexposure. The presence of preexposure-induced NAbs reduced Reo tumor infection and prevented Reo-mediated control of tumor growth after intratumoral Reo administration. In B cell-deficient mice, the lack of NAbs provided enhanced tumor growth control after Reo monotherapy, indicating that NAbs limit the oncolytic capacity of Reo. In immunocompetent mice, intratumoral T-cell influx was not affected by the presence of preexposure-induced NAbs and consequently, combinatorial immunotherapy strategies comprising Reo and T-cell engagers or checkpoint inhibitors remained effective in these settings, also after a clinically applied regimen of multiple intravenous pelareorep administrations. Altogether, our data indicate that NAbs hamper the oncolytic efficacy of Reo, but not its immunotherapeutic capacity. Given the high prevalence of seropositivity for Reo in patients with cancer, our data strongly advocate for the application of Reo as part of T cell-based immunotherapeutic strategies.

Treatment of Radiation Lesions with Mesenchymal Stem Cells

Acute radiation syndrome (ARS) is an acute illness caused by exposure to a high dose of ionizing radiation. ARS is the deterministic effect of radiation exposure of the whole body or a significant body volume (partial body irradiation) above a threshold dose of about 1 Gy (gray). Radiation accidents, such as those in Chernobyl (1986) and Fukushima (2011), or the possible use of nuclear weapons during the hostilities or terrorist attacks, can lead to the massive development of ARS in humans. The aim of the work is to introduce a new method of post-radiation treatment – the use of allogeneic mesenchymal stem cells (MSCs). Materials and methods. The information contained in specialized scientific journals that are freely available and accessible through the global Internet was studied. Discussion of the results. In the scenario of mass exposure of the population, when from several tens (hundreds) to millions of people can be irradiated, the transfusion of hematopoietic stem cells traditionally used in such cases would be impossible. MSCs can possibly differentiate into specialized cells, that is, turn into cells of various organs and tissues or induce such kind of regeneration. For practical use, there are two main sources of their isolation and reproduction ex vivo – bone marrow and adipose tissue. To date, it has been shown that MSCs derived from adipose tissue can be effective in mitigating the effects of acute radiation illness. Intravenously applied MSCs are migrating mainly to the bone marrow and are partially restoring its function. Deep anatomical structures are also involved in local radiation injuries: bone, muscles, nerves, blood and lymphatic vessels and skin. There is a strong body of evidence suggesting the «repair effect» of MSCs when used to treat such lesions. This is because MSCs can induce the repair and regeneration of the anatomical structures which they are locally applied, possibly by the paracrine effect. The main advantage of allogeneic MSCs over autologous ones is their logistical accessibility. They can be produced in advance in quantities and stored frozen. After thawing, the cells must be cultured for at least 48 hours in humidified incubators with the addition of 5 % CO2. Findings. Treatment of MSCs should be started as soon as possible after radiation exposure. Rescue of damaged hematopoiesis in the bone marrow can be achieved by multiple intravenous administration of up to 1 million (106) freshly prepared allogeneic MSCs/kg body weight. Locally (around and in the irradiation area), the dose of MSCs may be lower – 20 million cells. Repeated topical application should be carried out at intervals of two to four weeks. Subsequent surgical reconstruction should be performed by an experienced surgeon and in a specialized center with concomitant topicalapplication of MSCs.

Pharmacokinetic properties of the compound RU-891 with repeated administration

In experiments on rats, the pharmacokinetics of compound RU-891 was studied with single and multiple intravenous administration. Data on the linear dependence of pharmacokinetic parameters are obtained. The approximation coefficient is set equal to 0.9779. Changes in pharmacokinetic parameters with a three-time administration were not detected.

An Orthogonal Protection Strategy for Synthesizing Scaffold-Modifiable Dendrons and Their Application in Drug Delivery.

Dendrons have well-defined dendritic structures. However, it is a great challenge to preserve their high structural definition after multiple functionalization because the site-selective conjugation of different functional molecules is quite difficult. Scaffold-modifiable dendrons that have orthogonal reactive groups at the scaffold and periphery are ideal for achieving the site-specific bifunctionalization. In this paper, we present a new strategy for synthesizing scaffold-modifiable dendrons via orthogonal amino protection and a solid-phase synthesis method. This strategy renders the reactive sites at the scaffold and periphery of the dendrons a super selectivity, high reactivity, and wide applicability to various reaction types. The fourth-generation dendrons can be facilely synthesized within 2 days without structural defects as demonstrated by mass spectrometry. We conjugated doxorubicin (DOX) and phenylboronic acid (PBA) groups to the scaffold and periphery, respectively. Thanks to the PBA-enhanced lysosome escape, tumor targeting ability, and tumor permeability as well as the high drug loading content larger than 30%, the dendron-based prodrug exhibited extraordinary antitumor efficacy and could eradicate the tumors established in mice by multiple intravenous administration. This work provides a practical strategy for synthesizing scaffold-modifiable dendrons that can be a promising nanoplatform to achieve function integration in a precisely controlled manner.

Accelerated blood clearance and hypersensitivity by PEGylated liposomes containing TLR agonists

Systemic administration of toll-like receptor (TLR) agonists have demonstrated impressive preclinical results as an anti-cancer therapy due to their potent innate immune-stimulatory properties. The clinical advancement has, however, been hindered by severe adverse effects due to systemic activation of the immune system. Liposomal drug delivery systems may modify biodistribution, cellular uptake, and extend blood circulation, and thus, potentially enable systemic administration of TLR agonists at therapeutic doses.In this study, we investigated potential barriers for the administration of TLR agonists formulated in polyethylene glycosylated (PEGylated) liposomes with regards to liposome formulation, TLR agonist, administration route, administration schedule, biodistribution, blood clearance, and anti-PEG antibodies. We found that administration of TLR agonists formulated in PEGylated liposomes led to high anti-PEG antibody titers, which upon multiple intravenous administrations, resulted in accelerated blood clearance and acute hypersensitivity reactions. The latter was found to be associated with anti-PEG IgG antibody and not anti-PEG IgM antibody opsonization. This study highlights the need to carefully design and evaluate nanoparticle delivery systems for immunotherapy as anti-nanoparticle immune responses may challenge the therapeutic application.

Phenylboronic Acid Modification Augments the Lysosome Escape and Antitumor Efficacy of a Cylindrical Polymer Brush-Based Prodrug.

Timely lysosome escape is of paramount importance for endocytosed nanomedicines to avoid premature degradation under the acidic and hydrolytic conditions in lysosomes. Herein, we report an exciting finding that phenylboronic acid (PBA) modification can greatly facilitate the lysosome escape of cylindrical polymer brushes (CPBs). On the basis of our experimental results, we speculate that the mechanism is associated with the specific interactions of the PBA groups with lysosomal membrane proteins and hot shock proteins. The featured advantage of the PBA modification over the known lysosome escape strategies is that it does not cause significant adverse effects on the properties of the CPBs; on the contrary, it enhances remarkably their tumor accumulation and penetration. Furthermore, doxorubicin was conjugated to the PBA-modified CPBs with a drug loading content larger than 20%. This CPBs-based prodrug could eradicate the tumors established in mice by multiple intravenous administrations. This work provides a novel strategy for facilitating the lysosome escape of nanomaterials and demonstrates that PBA modification is an effective way to improve the overall properties of nanomedicines including the tumor therapeutic efficacy.

In vitro optimization, characterization and anti-tumor evaluation against colorectal cancer of a novel 5-fluorouracil oral nanosuspension using soy protein, polysaccharides-protein complexation, and in-situ gel formation

5-fluorouracil (FU) is an anticancer treatment with disadvantages of a short half-life and the need for multiple intravenous administrations. The idea was to formulate oral sustained-release nanosuspensions of FU, which was utilizing drug-soy protein (Sp) solid dispersions, protein-polysaccharide gels, and sedimentation of insoluble gel formulations for the development of colon resident dosage form. Sp-FU and Sp-Carrageenan kappa-FU solid dispersions were prepared and characterized. Furthermore, the solid dispersions were suspended in the aqueous gel-forming vehicle of sodium alginate (NA) with Sp excess. The nanosuspensions were characterized using UV-spectroscopy, zeta-sizer, particle size analyzer, scanning electron microscopy, and antitumor evaluation against HCT-116 cancer cells. The optimum formulations with insoluble gel of good strength, coherence, and resilience in contact with simulated gastric media were two formulations. The overall pH-profile release percentages of the optimum formulations were less than FU alone by more than 48% of the drug amount. Furthermore, those optimum formulations were nano-drug formulations. The FU nanoparticles were approved to be released as coated particles with NA. After the in vitro cell-line evaluation against colorectal cancer, the sustained-release behavior, nanoparticle formation, and the association of NA and Sp, could enhance the time-dependent efficacy compared to the free drug. Furthermore, this Sp containing nanosuspension may be an effective and safe oral alternative for cancer chemotherapy due to the need for a lower FU dose using FU nanoparticles to induce a similar effect to the original free FU (macro-sized drug).

The effect of single and multiple intravenous administration of magnetic iron oxide nanoparticles to rats on the blood coagulation

Background . Magnetic nanoparticles (MNPs) are considered as a means of targeted delivery, diagnosis and treatment, the main route of administration for them is intravascular, so it is important to evaluate their interaction with blood. We previously studied the effect of two samples of MNPs (MNP1 and MNP2) on the viability of human umbilical vein endothelial cells and hemocompatibility on human heparinized whole blood. Objective . The aim of the present study is to evaluate the effect of MNP1 and MNP2 on hemostasis. Design and methods . MNP1 and MNP2 suspensions were administered intravenously in outbred Wistar rats once and repeatedly (7 days); prothrombin time (PT), thrombin time (TT), activated partial thromboplastin time (APTT), and fibrinogen concentration were evaluated before administration, on the 15th and 31st days after the last administration. Results . It was shown that MNP1 and MNP2 decreased in TT and an increased in APTT (in the MNCH1 and MNCH2 groups) as well as its increased in the fibrinogen concentration (in the MNCH2 groups) after a single dose (400 mg/kg) on day 31. Repeated administration of 60 mg/kg MNCH1 led to decrease the fibrinogen concentration (day 15) and to increase in APTT (day 31) in females. Repeated administration of 10 mg/kg MNCH2 caused an increase in APTT (males and females) and a decrease in fibrinogen concentration (females) on the 15th and 31st days. Conclusion . Thus, a single administration of 400 mg/kg MNPs caused an imbalance in the blood coagulation system, changes were independed on the sex of animals, but depended on the time after administration. Repeated administration of MNPs caused gender-dependent hypocoagulation changes (more pronounced in females).

Combinatorial Nanomedicine Made of Squalenoyl-Gemcitabine and Edelfosine for the Treatment of Osteosarcoma.

Due to chemoresistance and a high propensity to form lung metastasis, survival rates in pediatric osteosarcoma (OS) are poor. With the aim to improve anticancer activity in pediatric OS, a multidrug nanomedicine was designed using the alkyl-lysophospholipid edelfosine (EF) co-assembled with squalenoyl–gemcitabine (SQ–Gem) to form nanoassemblies (NAs) of 50 nm. SQ–Gem/EF NAs modified the total Gem pool exposure in the blood stream in comparison with SQ–Gem NAs, which correlated with a better tolerability and a lower toxicity profile after multiple intravenous administrations in mice. For in vivo preclinical assessment in an orthotopic OS tumor model, P1.15 OS cells were intratibially injected in athymic nude mice. SQ–Gem/EF NAs considerably decreased the primary tumor growth kinetics and reduced the number of lung metastases. Our findings support the candidature of this anticancer nanomedicine as a potential pediatric OS therapy.

Gadolinium deposition in the brain of dogs after multiple intravenous administrations of linear gadolinium based contrast agents.

ObjectiveTo determine the effect of a linear gadolinium-based contrast agent (GBCA) on the signal intensity (SI) of the deep cerebellar nuclei (DCN) in a retrospective clinical study on dogs after multiple magnetic resonance (MR) examinations with intravenous injections of gadodiamide and LA-ICP-MS analysis of a canine cerebellum after gadodiamide administration.Animals15 client-owned dogs of different breeds and additionally 1 research beagle dog cadaver.ProceduresIn the retrospective study part, 15 dogs who underwent multiple consecutive MR imaging examinations with intravenous injection of linear GBCA gadodiamide were analyzed. SI ratio differences on unenhanced T1-weighted MR images before and after gadodiamide injections was calculated by subtracting SI ratios between DCN and pons of the first examination from the ratio of the last examination. Additionally, 1 research beagle dog cadaver was used for LA-ICP-MS (Laser ablation inductively coupled plasma mass spectrometry) analysis of gadolinium in the cerebellum as an add-on to another animal study. Descriptive and non-parametrical statistical analysis was performed and a p-value of < 0.05 was considered significant.ResultsNo statistically significant differences of SI ratios, between DCN and pons, were detectable based on unenhanced T1-weighted MR images. LA-ICP-MS analyses showed between 1.5 to 2.5 μg gadolinium/g tissue in the cerebellum of the examined dog, 35 months after the last of 3 MRI examination with gadodiamide (two examinations at a dose of 1 x 0.1mmol/kg, last examination at a dose of 3 x 0.05mmol/kg).Conclusion and clinical relevanceAlthough the retrospective MRI study did not indicate any visible effect of SI increase after multiple gadodiamide exposures, further studies based on LA-ICP-MS showed that the optical threshold was not reached for a potential visible effect. Gadolinium was detectable at a level of 1.5 to 2.5 μg gadolinium/g tissue by using LA-ICP-MS in the cerebellum 35 months after last MRI examination. The general importance of gadolinium retention of subvisible contents requires further investigation.

A review on the recent application of ketamine in management of anesthesia, pain, and health care.

Ketamine is considered as a promising drug for many clinical applications even after five decades since its discovery. Ketamine is a dissociative anesthetic agent with a variety of pharmacological effects from anesthetic induction and maintenance to analgesic and sedative depending on the consuming dose. It can be used solely or in combination with other co-adjuvant drugs, increasing their efficacy. Many therapeutic properties of ketamine have been attributed to its antagonism mechanism to N-Methyl-D-aspartate receptor. Identifying new properties of ketamine such as neuroprotective, antiinflammatory, and antitumor effects, on one hand, and taking advantage of subanesthetic regimens of ketamine, on the other hand, have resulted in a widespread use of ketamine in various clinical applications. Ketamine is solvable in aqueous and lipid solutions, providing convenient administration via multiple routes, including oral, nasal, rectal, intravenous, intramuscular, subcutaneous, transdermal, sublingual, and intraosseous administration. Application of ketamine has some advantages over other sedative and anesthetic agents. It produces bronchodilation status, allowing for most secure induction of anesthesia in patients with life-threatening asthma and intense acute bronchial constriction. Ketamine has an excellent hemodynamic profile, makes it the agent of choice for patients with unstable hemodynamics, such as shocked or hypotensive patients. Ketamine usage has been associated with a lower risk of respiratory depression and relatively more conserved airway reflexes. Although being an anesthetic agent, ketamine has been increasingly used in subanesthetic doses for acute and chronic pain as well as depression. Using ketamine in pre and postoperative pain management is well established. However, the studies on ketamine performance in pain management demonstrated contradicting results. On the other hand, various side effects along with no confirmatory data on long-term treatment demand great caution when using ketamine for treating complex chronic pains. The present study aimed to provide a general review on the recent applications of ketamine in anesthesia, pain management, and critical care.

Comparison of the gastric acid inhibition function among lansoprazole, pantoprazole, and their respective stereoisomers in healthy Chinese subjects .

This study was conducted to evaluate the difference in acid inhibition function among lansoprazole (LPZ), pantoprazole (PPZ), and their respective stereoisomers following single and multiple intravenous doses in healthy Chinese subjects. The dosage groups were set as follows: 30mg single and multiple intravenous administrations of LPZ or R-LPZ, 40mg single and multiple intravenous administrations of PPZ or S-PPZ. Subjects received an intravenous infusion of LPZ, R-LPZ, PPZ, or S-PPZ injection in sterile saline solution (100mL/h, 60minutes), respectively. The intragastric pH was sampled every second for 24 hours at baseline and for 24 hours after drug administration. The baseline-adjusted pharmacodynamic (PD) parameters include ΔMean (pH), ΔMedian (pH), ΔTpH≥3 (%), ΔTpH≥4 (%), ΔTpH≥6 (%), and ΔAUECph-tτ1-τ2. The PD parameters were evaluated in different time intervals (0-24 hours, 0-4 hours and 14-24 hours). After a single dose, the ΔTpH≥4 (%) of R-LPZ, LPZ, S-PPZ and PPZ was 56.6 ± 19.6, 53.1 ± 23.3, 35.6 ± 24.9 and 26.8 ± 30.2, respectively. The ΔTpH≥6 (%) was 50.7 ± 26.1, 41.4 ± 26.2, 25.4 ± 24.9 and 22.1 ± 27.6, respectively. The ΔAUECph-τ1-τ was 45,564 ± 16,107, 41,798 ± 16,153, 31,914 ± 17,304 and 20,744 ± 21,500, respectively. Statistically significant differences were found with R-LPZ vs. S-PPZ, R-LPZ vs. PPZ, LPZ vs. S-PPZ and LPZ vs. PPZ. The average TpH≥4 of R-LPZ, LPZ, S-PPZ, and PPZ was (47.2 ± 26.1) minutes, (49.6 ± 19.3) minutes, (56.1 ± 23.7) minutes, and (72.1 ± 27.3) minutes, respectively. Statistically significant differences were found with R-LPZ vs. PPZ (p=0.009) and LPZ vs. PPZ (p=0.019). After multiple doses, the ΔTpH≥4 (%) of R-LPZ, LPZ, S-PPZ, and PPZ was 71.7 ± 20.2, 63.5 ± 19.4, 59.5 ± 17.8 and 64.0 ± 22.4, respectively. The ΔTpH≥6 (%) was 64.0 ± 22.2, 52.0 ± 19.2, 49.6 ± 20.4 and 50.9 ± 23.8, respectively. The ΔAUECph-τ1-τ was 326,149 ± 94,839, 288,565 ± 93,279, 296,189 ± 83,412 and 300,960 ± 108,057, respectively. No statistically significant differences were found in baseline-adjusted PD parameters during all time periods after multiple doses. After a single dose, the mean gastric pH inhibition value of R-LPZ was the highest, followed by LPZ, then S-PPZ and PPZ. R-LPZ and LPZ provided significantly better pH control compared with PPZ and S-PPZ in healthy subjects. The onset time of R-LPZ was the fastest and R-LPZ can provide better acid inhibition during sleeping time. After multiple doses, the mean values in all PD parameters of R-LPZ were the highest, the values of LPZ, S-PPZ, and PPZ were similar. However, no significant difference was found in acid inhibition among these four drugs after multiple doses.

Analytical Solution and Exposure Analysis of a Pharmacokinetic Model with Simultaneous Elimination Pathways and Endogenous Production: The Case of Multiple Dosing Administration.

In this paper, a typical pharmacokinetic (PK) model is studied for the case of multiple intravenous bolus-dose administration. This model, of one-compartment structure, not only exhibits simultaneous first-order and Michaelis-Menten elimination, but also involves a constant endogenous production. For the PK characterization of the model, we have established the closed-form solution of concentrations over time, the existence and local stability of the steady state. Using analytical approaches and the concept of corrected concentration, we have shown that the area under the curve ([Formula: see text]) at steady state is higher compared to that at the single dose ([Formula: see text]). Moreover, by splitting the dose and dosing interval into halves, we have revealed that it can result in a significant decrease in the steady-state average concentration. These model-based findings, which contrast with the current knowledge for linear PK, confirm the necessity to revisit drugs exhibiting nonlinear PK and to suggest a rational way of using mathematical analysis for the dosing regimen design.

Gadoterate Meglumine Administration in Multiple Sclerosis has no Effect on the Dentate Nucleus and the Globus Pallidus Signal Intensities

Previous studies on possible accumulation of gadolinium-based contrast agents (GBCA) in the brain suggest that macrocyclic GBCA are less likely to accumulate than linear GBCA. However, conflicting results have been reported, especially in MS. The aim of this study is to investigate retrospectively the correlation between gadoterate-meglumine (macrocyclic GBCA) use and T1 signal intensity changes (SI) in the dentate nucleus and the GP on unenhanced T1-weighted images in a large cohort of MS patients. Unenhanced T1-weighted images of 232 MS patients who previously received multiple intravenous administrations of 0.1 mmol/kg of gadoterate-meglumine were reviewed. The change in T1 SI ratios of dentate nucleus/central pons (DN/CP) and globus pallidus/centrum semiovale (GP/CSO) was calculated between the first and last MRIs and correlated with age, number of injections, time interval between MRIs, disease duration, activity, and therapy. DN/CP ratio showed no significant changes whereas the GP/CSO ratio showed a significant decrease (p < 0.0001) between the first and last MRIs. Multivariable analyses of both ratios, controlling for age, disease duration, and time interval between MRIs, showed no significant correlation between the number of gadolinium injections and the differences in DN/CP (standardized beta = -0.018, p = 0.811) or GP/CSO SI ratios (standardized beta = -0.049, p = 0.499). Repeated administration of gadoterate-meglumine in MS patients did not result in increased T1 SI in the DN or the GP. The significant decrease of GP/CSO ratio between the first and last MRIs is not due to gadolinium accumulation but rather to varying MR parameters.

Plasmonic photothermal therapy: Approaches to advanced strategy.

The analysis of recent studies on plasmonic photothermal therapy (PPT) after intravenous administration of gold nanorods (GNRs) has demonstrated that the effectiveness of nanoparticle-assisted laser hyperthermia depends on a correct dosage strategy of nanoparticle administration. Accumulation of GNRs in tumor tissue dramatically increases the local heating of the tumor without damage to healthy tissues. However, the optimal doses of GNR intravenous injections (IVIs) for effective accumulation in tumors, and optimal protocols of PPT are not designed yet. The current study aims to improve the efficacy of PPT in tumor-bearing rats using multiple fractional intravenous administration of GNRs. For PPT experiments, the GNRs with aspect ratio of 4.1 were functionalized with thiolated polyethylene glycol (PEG) and their suspensions were used for multiple fractional intravenous administration in outbred albino male rats with experimental model of rat liver cancer (cholangiocarcinoma line PC-1). Doppler ultrasonography was performed to characterize the vascularity of transplanted rat tumors before any treatment. After a final injection of GNRs, tumor was irradiated during 15 minutes by 808-nm NIR diode laser at a power density 2.3 W/cm2 . The animals were withdrawn from the experiment and sampling of tissues for morphological study and gold accumulation was performed 24 hours and 3 weeks after PPT. The multiple IVIs of gold nanorods and further PPT of transplanted cholangiocarcinoma provided significant damage to tumor tissue resulting in pronounced necrotic mass and retardation of the tumor growth. More importantly, the proposed PPT protocol had low toxicity as evidenced by histological examination of internal organs. The efficiency of PPT depends on the presence of newly formed vasculature as revealed by the Doppler ultrasound investigation. The repeatable IVIs promote greater of GNR accumulation within the tumor thus resulting in higher PPT efficacy. Accompanying ultrasonography can be useful for prognosis and monitoring of treatment. Lasers Surg. Med. 50:1025-1033, 2018. © 2018 Wiley Periodicals, Inc.

Abstract CT134: A phase I study assessing the safety and clinical activity of multiple hepatic transarterial administrations of a NKG2D-based CAR-T therapy CYAD-01, in patients with unresectable liver metastases from colorectal cancer

Abstract We recently developed a novel chimeric antigen receptor (CAR) T-cell therapy, called CYAD-01 (a.k.a. NKR-2), incorporating the full-length human natural killer receptor NKG2D fused with the human CD3 zeta signaling domain, which associates with the adaptor molecule DAP10 to provide co-stimulatory signal upon ligand binding. CYAD-01 is currently evaluated in multiple intravenous administrations in the ongoing THINK study (NCT03018405) in both hematological and solid indications. Classical CAR-Ts has yet to demonstrate positive results in the context of solid tumors. Underlying reasons for this reduced clinical activity include the need to extravasate from the peripheral circulation, infiltrate into the tumor and overcome the hostile immune suppressive tumor microenvironment (TME) to deliver anti-tumor effector responses. To address the challenge related to the difficulty of CAR-T cells to access the site of metastasis, the LINK trial (Locoregional Immunotherapy with NKR-2) has been developed to assess the safety and clinical activity of multiple hepatic transarterial administrations of CYAD-01 treatment (every 2 weeks x 3 infusions) in colorectal cancer patients with unresectable liver metastases (NCT03370198). The hepatic transarterial administration (HTAA) cell therapy may offer the advantage of lower systemic toxicity and higher and more persistent concentration of the infused cells on the TME compared with systemic administration. The difference in blood supply between uninvolved liver parenchyma and metastases may favor CYAD-01 tumor homing. Moreover, based on the potential impact of the CYAD-01 treatment on the host immune system, combined with the tumor antigens spreading induced by its direct anti-cancer cells activity, the CYAD-01 HTAA may boost the adaptive immune response and therefore may control any distant lesion (aboscopal effect). This dose escalation study will use a 3+3 design including 3 dose levels of CYAD-01 (3x108, 1x109 and 3x109 cells per injection) to evaluate the maximum tolerated dose of the CYAD-01 hepatic transarterial administration. Peripheral blood samples, as well as tumor biopsies will be collected to determine systemic CYAD-01 kinetics and within the liver tumor tissues, NKG2D ligand expression and systemic cytokine levels in peripheral blood post-infusion. This study will enroll 12 patients in case of no DLT and is open for recruitment. Citation Format: Nathalie Braun, Alain Hendlisz, Leila Shaza, Michaël Vouche, Vincent Donckier, Philippe Aftimos, Ahmad Awada, Caroline Lonez, Bikash Verma, David E. Gilham, Frédéric F. Lehmann. A phase I study assessing the safety and clinical activity of multiple hepatic transarterial administrations of a NKG2D-based CAR-T therapy CYAD-01, in patients with unresectable liver metastases from colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT134.

Chapter 22 - Toxic-induced cerebellar syndrome: from the fetal period to the elderly

The cerebellum is a brain region which is particularly susceptible to intoxication. Clinical presentation is heterogeneous. It is often considered that elderly patients and patients presenting pre-existing structural lesions of the posterior fossa are particularly at risk of developing a toxic-induced cerebellar syndrome (TOICS). However, TOICS may occur at any age, including in utero. Indeed, the cerebellum is highly vulnerable during neurodevelopment. Amongst cerebellotoxic agents, ethanol is the most commonly implicated. The vermis is a privileged target. Ethanol exerts toxic effects upon neurons, glia (especially astrocytes and oligodendrocytes), and myelin sheaths. Prenatal alcohol exposure causes teratogenic effects on the developing cerebellum, impeding neuronal migration and differentiation. In adults, cerebellar ataxia is a major feature of both acute and chronic ethanol intoxication. Wernicke encephalopathy is a medical emergency characterized by a triad of ophthalmoplegia, ataxia, and impaired mental status. It requires the immediate administration of high doses of thiamine by the intravenous route. The following drugs may induce a permanent cerebellar syndrome: phenytoin, lithium salts, antineoplastics, and heroin. In addition to ethanol and drugs, environmental agents are also a source of TOICS. In particular, the cerebellum is susceptible to metal intoxication. The recently described deposits of gadolinium in cerebellar nuclei in patients who had received multiple intravenous administrations are a matter of concern on a worldwide scale but we still lack the demonstration of clinically relevant effects upon motor, oculomotor, or cognitive function. Because cerebellar symptoms may be subtle or immersed in a complex encephalopathy with combined involvement of the peripheral nervous system, the diagnosis of TOICS is often overlooked. The life-threatening risk of edema of the posterior fossa with compression of the brainstem should be kept in mind, including in cases of posterior reversible encephalopathy syndrome, and requires posterior fossa decompression when acute hydrocephalus occurs.

The effects of multiple intravenous tranexamic acid administrations after total knee arthroplasty on fibrinolytic activity and inflammatory response

Objective To explore the effects of multiple intravenous tranexamic acid (IV-TXA) administrations after total knee arthroplasty (TKA) on fibrinolytic activity and inflammatory response in an enhanced recovery after surgery (ERAS) program and to assess the efficacy and safety of IV-TXA. Methods One hundred and forty-one severe knee osteoarthritis patients following primary unilateral TKA from January 2016 to April 2017 were investigated retrospectively. The patients were divided into following three groups based on the dosage of IV-TXA after surgery: 40 patients received ≤3 g IV-TXA after surgery (group T1), 50 patients received 4 g (group T2) and the other 51 patients received ≥5 g IV-TXA (group T3). The total blood loss (TBL), hidden blood loss (HBL), transfusion rate, maximum hemoglobin (Hb) drop, the incidence of intramuscular venous thrombosis, deep vein thrombosis (DVT) and pulmonary embolism (PE), fibrinolysis parameters [fibrin(-ogen) degradation products (FDP), D-dimer], and inflammation markers [C-reactive protein (CRP), interleukin-6 (IL-6)] during perioperative period were evaluated. In addition, correlation analyses between the dosage of IV-TXA and fibrinolysis parameters and inflammation markers were conducted. Results The mean TBL, HBL and maximum Hb drop in group T2 (537.16±270.43 ml, 431.36±271.99 ml, 19.68±10.68 g/L) and T3 (541.31±290.00 ml, 439.94±290.71 ml, 20.24±8.48 g/L) were lower than those in group T1 (748.22±394.34 ml, P=0.012, 0.013; 636.47±388.14 ml, P=0.011, 0.015; 25.88±11.77 g/L, P=0.005, 0.010, respectively). No patient needed transfusion in all groups. There was no statistically difference in the incidence of intramuscular venous thrombosis of lower limbs among three groups (P>0.05). No episode of DVT or PE occurred in any group in two weeks after surgery. There were negative correlation between the dosage of IV-TXA and FDP at postoperative day 1 and day 3 (r=-0.191, P=0.025; r=-0.291, P=0.001) and D-dimer on postoperative day 3 (r=-0.176, P=0.048). Moreover, the CRP (r=-0.184, P=0.036) and IL-6 (r=-0.269, P=0.002) level in serum on postoperative day 1 also showed a negative relationship with the dosage of IV-TXA after surgery. Conclusion The multiple IV-TXA (≥4 g) after surgery can further reduce the TBL, HBL and maximum Hb drop following primary TKA in ERAS program without increasing the risk of thrombotic events. Most importantly, the effect of anti-fibrinolysis will be enhanced and may have an anti-inflammatory effect with the dosage of IV-TXA increased. Key words: Tranexamic acid; Arthroplasty, replacement, knee; Fibrinolysis; Inflammation

Clinical efficacy of piperacillin/tazobactam in the treatment of complicated skin and soft tissue infections

ABSTRACTIntroduction: Complicated skin and soft tissue infections (cSSTIs) are skin and soft tissue infections (SSTIs) that involve deep soft tissue. cSSTIs often require surgical intervention and/or hospitalization. cSSTIs are associated with significant mortality and morbidity, and carry a significant burden on health care systems. Piperacillin/tazobactam has been regarded as a standard treatment for cSSTIs because of its antibiotic spectrum, safety and clinical efficacy. Several antibiotics, as compared to piperacillin/tazobactam, have been evaluated in the treatment of cSSTIs.Areas covered: This review summarizes randomized controlled trials (RCTs) evaluating the clinical efficacy of piperacillin/tazobactam for the treatment of cSSTIs.Expert opinion: Piperacillin/tazobactam, which covers most causative organisms in cSSTIs, is the drug of choice for the treatment of cSSTIs. Other options such as ertapenem and moxifloxacin may be reasonable where multiple daily dosing or intravenous administration is inappropriate. But in general, they should be avoided as an empirical treatment because of their highly association with resistant bacteria, which are becoming a global threat. Therefore, piperacilin/tazobactam is appropriate as an empirical therapy for the treatment of SSTIs and should be de-escalated as soon as causative organisms are identified, their drug-sensitivity results are available, and clinical condition becomes stable.