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Background Seizures after stroke can negatively affect the prognosis of ischemic stroke and cause a decrease in quality of life. The efficacy of intravenous (IV) recombinant tissue plasminogen activator (rt-PA) treatment in acute ischemic stroke has been demonstrated in many studies, and IV rt-PA treatment has been increasingly used around the world. The SeLECT score is a useful score for the prediction of late seizures after stroke and includes the severity of stroke (Se), large artery atherosclerosis (L), early seizure (E), cortical involvement (C), and the territory of the middle cerebral artery (T). However, the specificity and sensitivity of the SeLECTscore have not been studied in acute ischemic stroke patients that received IV rt-PA treatment. Objective In the present study, we aimed to validate and develop the SeLECT score in acute ischemic stroke patients receiving IV rt-PA treatment. Methods The present study included 157 patients who received IV thrombolytic treatment in our third-stage hospital. The 1-year seizure rates of the patients were detected. SeLECT scores were calculated. Results In our study, we found that the SeLECT score had low sensitivity but high specificity for predicting the likelihood of late seizure after stroke in patients administered IV rt-PA therapy. In addition to the SeLECT score, we found that the specificity and sensitivity were higher when we evaluated diabetes mellitus (DM) and leukoaraiosis. Conclusion We found that DM was an independent risk factor for late seizures after stroke in a patient group receiving thrombolytic therapy, and late seizures after stroke were less frequent in patients with leukoaraiosis. Resumo Antecedentes As convulsões após o AVC podem afetar negativamente o prognóstico do AVC isquêmico e causar uma diminuição na qualidade de vida. A eficácia do tratamento com ativador do plasminogênio tecidual recombinante (rt-PA) intravenoso (IV) no AVC isquêmico agudo foi demonstrada em muitos estudos, e o tratamento com rt-PA IV tem sido cada vez mais usado em todo o mundo. A pontuação SeLECT é uma pontuação útil para a previsão de convulsões tardias após AVC e inclui a gravidade do AVC (Se), aterosclerose de grandes artérias (L), convulsão precoce (E), envolvimento cortical (C) e o território do meio artéria cerebral (T). No entanto, a especificidade e a sensibilidade do escore SeLECT não foram estudadas em pacientes com AVC isquêmico agudo que receberam tratamento IV com rt-PA. Objetivo No presente estudo, objetivamos validar e desenvolver o escore SeLECT em pacientes com AVC isquêmico agudo recebendo tratamento IV com rt-PA. Métodos O presente estudo incluiu 157 pacientes que receberam tratamento trombolítico IV em nosso hospital de terceiro estágio. As taxas de convulsão de 1 ano dos pacientes foram detectadas. Os escores SeLECT foram calculados. Resultados Em nosso estudo, descobrimos que o escore SeLECT apresentou baixa sensibilidade, mas alta especificidade para prever a probabilidade de convulsão tardia após AVC em pacientes que receberam terapia IV com rt-PA. Além do escore SeLECT, descobrimos que a especificidade e a sensibilidade foram maiores quando avaliamos diabetes mellitus (DM) e leucoaraiose. Conclusão Descobrimos que DM foi um fator de risco independente para convulsões tardias após AVC em um grupo de pacientes recebendo terapia trombolítica, e convulsões tardias após AVC foram menos frequentes em pacientes com leucoaraiose.

Aims: To investigate medication dose calculation errors and other numeracy mishaps in hospitals and examine mechanisms and enablers which lead to such errors. Design: A retrospective study using descriptive statistics and thematic analysis of the nature and enablers of reported incidents. Methods: Medication dose calculation errors and other numeracy mishaps were identified from medication-related incidents reported to the Norwegian Incident Reporting System in 2016 and 2017. The main outcome measures were medications and medication classes involved, severity of harm, outcome, and error enablers. Results: In total, we identified 100 numeracy errors, of which most involved intravenous administration route (n = 70). Analgesics were the most commonly reported drug class and morphine was the most common individual medication. Overall, 78 incidents described patient harm. Frequent mechanisms were 10- or 100-fold errors, mixing up units, and incorrect strength/rate entered into infusion pumps. The most frequent error enablers were: double check omitted or deviated (n = 40), lack of safety barriers to intercept prescribing errors (n = 25), and emergency/stress (n = 21). Conclusion: Numeracy errors due to lack of or improper safeguards occurred during all medication management stages. Dose miscalculation after dilution of intravenous solutions, infusion pump programming, and double-checking were identified as unsafe practices. We discuss measures to prevent future calculation and numeracy errors. Impact: Our analysis of medication dose calculation errors and other numeracy mishaps demonstrates the need for improving safety steps and increase standardization for medication management procedures. We discuss organizational, technological, and educational measures to prevent harm from numeracy errors. This research was supported by the doctoral research funding for the first author of this paper by the University of Oslo.

Magnetic nanoparticles (MNPs) present outstanding properties making them suitable as therapeutic agents for hyperthermia treatments. Since the main safety concerns of MNPs are represented by their inherent instability in a biological medium, strategies to both achieve long-term stability and monitor hazardous MNP degradation are needed. We combined a dynamic approach relying on flow field flow fractionation (FFF)-multidetection with conventional techniques to explore frame-by-frame changes of MNPs injected in simulated biological medium, hypothesize the interaction mechanism they are subject to when surrounded by a saline, protein-rich environment, and understand their behaviour at the most critical point of intravenous administration. In the first moments of MNPs administration in the patient, MNPs change their surrounding from a favorable to an unfavorable medium, i.e., a complex biological fluid such as blood; the particles evolve from a synthetic identity to a biological identity, a transition that needs to be carefully monitored. The dynamic approach presented herein represents an optimal alternative to conventional batch techniques that can monitor only size, shape, surface charge, and aggregation phenomena as an averaged information, given that they cannot resolve different populations present in the sample and cannot give accurate information about the evolution or temporary instability of MNPs. The designed FFF method equipped with a multidetection system enabled the separation of the particle populations providing selective information on their morphological evolution and on nanoparticle–proteins interaction in the very first steps of infusion. Results showed that in a dynamic biological setting and following interaction with serum albumin, PP-MNPs retain their colloidal properties, supporting their safety profile for intravenous administration.

Mesenchymal stem cells (MSC) are currently being investigated for their therapeutic applications in a wide range of diseases. Although many studies examined peripheral venous administration of MSC, few have investigated the detailed intravenous administration procedures of MSC from their preparation until they enter the body. The current study therefore aimed to explore the most efficient infusion procedure for MSC delivery by preparing and infusing them under various conditions. Canine adipose-derived mesenchymal stem cells (cADSC) were infused using different infusion apparatuses, suspension solutions, allogenic serum supplementation, infusion time and rates, and cell densities, respectively. Live and dead cell counts were then assessed by manual measurements and flow cytometry. Efficiency of live- and dead-cell infusion and cell viability were calculated from the measured cell counts and compared under each condition. Efficiency of live-cell infusion differed significantly according to the infusion apparatus, infusion rate, and combination of cell density and serum supplementation. Cell viability after infusion differed significantly between the infusion apparatuses. The optimal infusion procedure resulting in the highest cell delivery and viability involved suspending cADSC in normal saline supplemented with 5% allogenic serum at a density of 5 × 105 cells/mL, and infusing them using an automatic infusion device for 15 min. This procedure is therefore recommended as the standard procedure for the intravenous administration of ADSC in terms of cell-delivery efficiency.

Ketoprofen (KTF) is often used in hospital wards, especially in its intravenous form. According to the literature review, the compatibility of ketoprofen with parenteral nutrition (PN) admixtures has not yet been investigated. For this reason, we aimed to provide data contributing to physical compatibility to ensure the safe co-administration of these medications. In this study, we examined the compatibility of KTF with eight selected commercial PN admixtures intended for central (Lipoflex Special, Omegaflex Special, Kabiven, SmofKabiven) and peripheral (Lipoflex peri, Omegaflex peri, Kabiven Peripheral, Olimel Peri N4E) administration. The KTF solution for infusion was combined in three different volume ratios with studied PN admixtures reflecting the conditions in clinical practice. The evaluation of undesirable physical destabilization of oil-in-water system or precipitate formation involved the visual inspection and the determination of mean droplet diameter, zeta potential, pH, and turbidity changes. The results of compatibility of KTF with eight commercial PN admixtures showed that three of them: Kabiven, SmofKabiven, and Kabiven Peripheral, are incompatible with KTF and should not be concomitantly administered.

Ascorbic acid has attracted substantial attention for its potential antitumor effects by acting as an antioxidant in vivo and as a cofactor in diverse enzymatic reactions. However, solid proof of its clinical efficacy against cancer and the mechanism behind its effect have not been established. Moreover, cancer forms cancer-specific microenvironments and interacts with various cells, such as cancer-associated fibroblasts (CAFs), to maintain cancer growth and progression; however, the effect of ascorbic acid on the cancer microenvironment is unclear. This review discusses the effects and mechanisms of ascorbic acid on cancer, including the role of ascorbic acid concentration. In addition, we present future perspectives on the effects of ascorbic acid on cancer cells and the CAF microenvironment. Ascorbic acid has a variety of effects, which contributes to the complexity of these effects. Oral administration of ascorbic acid results in low blood concentrations (1 mM) and has oxidative-promoting actions that exert anticancer effects via reactive oxygen species. Therefore, intravenous administration at high concentrations is required to achieve the desired effects on cancer cells during treatment. Partial data on the effect of ascorbic acid on fibroblasts indicate that it may also modulate collagen secretion in CAFs and impart tumor-suppressive effects. Thus, future studies should verify the effect of ascorbic acid on CAFs. The findings of this review can be used to guide further research and clinical trials.

Introduction This randomized, double-blind, placebo-controlled study in healthy volunteers assessed the safety, tolerability, and pharmacokinetics of single ascending doses of intravenously administered NX210-a linear peptide derived from subcommissural organ-spondin-and explored the effects on blood/urine biomarkers and cerebral activity. Methods Participants in five cohorts (n = 8 each) were randomized to receive a single intravenous dose of NX210 (n = 6 each) (0.4, 1.25, 2.5, 5, and 10 mg/kg) or placebo (n = 2 each); in total, 10 and 29 participants received placebo and NX210, respectively. Blood samples were collected for pharmacokinetics within 180 min post dosing. Plasma and urine were collected from participants (cohorts: 2.5, 5, and 10 mg/kg) for biomarker analysis and electroencephalography (EEG) recordings within 48 h post dosing. Safety/tolerability and pharmacokinetic data were assessed before ascending to the next dose. Results The study included 39 participants. All dosages were safe and well tolerated. All treatment-emergent adverse events (n = 17) were of mild severity and resolved spontaneously (except one with unknown outcome). Twelve treatment-emergent adverse events (70.6%) were deemed drug related; seven of those (58.3%) concerned nervous system disorders (dizziness, headache, and somnolence). The pharmacokinetic analysis indicated a short half-life in plasma (6-20 min), high apparent volume of distribution (1870-4120 L), and rapid clearance (7440-16,400 L/h). In plasma, tryptophan and homocysteine showed dose-related increase and decrease, respectively. No drug dose effect was found for the glutamate or glutamine plasma biomarkers. Nevertheless, decreased blood glutamate and increased glutamine were observed in participants treated with NX210 versus placebo. EEG showed a statistically significant decrease in beta and gamma bands and a dose-dependent increasing trend in alpha bands. Pharmacodynamics effects were sustained for several hours (plasma) or 48 h (urine and EEG). Conclusion NX210 is safe and well tolerated and may exert beneficial effects on the central nervous system, particularly in terms of cognitive processing.

Supplemental Digital Content is available in the text., This 7-day randomized, double-blind, placebo-controlled fixed-dose study (NCT03766867) explored the potential for accelerating the onset of antidepressant efficacy of single-dose intravenous (IV) vortioxetine at oral vortioxetine treatment initiation. Patients (ages 18–65 years) hospitalized per standard-of-care with major depressive disorder, who were currently treated with a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor for a major depressive episode [Montgomery–Åsberg Depression Rating Scale (MADRS) total score ≥ 30], received one dose of single-blind IV placebo (1-day placebo lead-in period) before being randomly switched to either single-dose IV vortioxetine 25 mg plus daily oral vortioxetine 10 mg (n = 39), or IV placebo plus daily oral placebo (n = 41). In the placebo lead-in period, patients improved slightly by 0.6 MADRS-6 point; however, at day 1 after randomization, both treatment groups had improved by approximately 3 MADRS-6 points (mean difference = −0.8; P = 0.263), the study thus not meeting its primary endpoint. Similar results were seen for other outcomes except a numerically larger improvement in anxiety symptoms with vortioxetine vs placebo. Pharmacokinetic data confirmed that IV vortioxetine facilitated reaching steady-state plasma concentration within 24 h. IV plus oral vortioxetine was well tolerated, with low levels of nausea as the most common adverse event.

Aim: We assessed various ways of tranexamic acid (TXA) administration on the fibrinolytic system. Blood loss, transfusions, drainage and haematoma were secondary outcomes. Methods: In this prospective study, we examined 100 patients undergoing primary total knee arthroplasty (TKA) between June and November 2018. Patients were randomly assigned to 4 groups according to the following TXA regimens: 1) loading dose 15 mg TXA/kg single intravenous administration applied at initiation of anesthesia (IV1); 2) loading dose 15 mg TXA/kg + additional dose 15 mg TXA/kg 6 h after the first application of TXA (IV2); 3) IV1 regime in combination with a local wash of 2 g of TXA in 50 mL of saline (COMB); 4) topical administration of 2 g of TXA in 50 mL of saline (TOP). Results: Systemic fibrinolysis interference was insignificant in all of the regimens; we did not detect significant differences between IV1, IV2 and COMB in the monitored parameters within the elapsed time after the TKA; IV regimes had the lowest total drainage blood loss; the lowest blood loss was associated with the IV1 and IV2 regimens (IV1, IV2 < COMB < TOP); the lowest incidence of haematomas was in patients treated with TXA topically (i.e., in COMB + TOP). Conclusion: The largest antifibrinolytic effect was associated with intravenous administration of TXA. In terms of blood loss, intravenously administered TXA can interfere with the processes associated with the formation of the fibrin plug more efficiently than the simple washing of wound surfaces with TXA.

Several biologic treatments are available in addition to intravenous also in subcutaneous form for treatment of chronic diseases. Benefits of the subcutaneous application of drugs include self-administration by the patient, shorter time of application process with less infusion related adverse events and consequently lower healthcare costs. With appropriate education and support patients are able to administer their treatments at home. This leads to improvement of quality of life, reduction of time needed to travel to the healthcare institution and consequently also reduces costs also for the patient.Over one million residents in the USA and 2.5 million in Europe are estimated to have inflammatory bowel disease (IBD), with substantial costs for health care. These estimates do not factor in the ‘real’ price of IBD, which can impede career aspirations, instil social stigma and impair quality of life in patients.The Virtual Community Meeting, which offered an exchange of experience and opinions from healthcare professionals who are active in treating IBD, and patients with this chronic disease, revealed in-depth arguments and answers to some essential questions: which patients prefer subcutaneous over intravenous dosing; which patients continue to favour intravenous infusions; what are the limitations regarding both applications; what is the patient’s role in therapeutical decision-making and how does IBD affect the patient’s work, finances and quality of life? The aim of this article is to discuss the differences between subcutaneous and intravenous dosing from the health-economic, scientific, and personal perspectives.The meeting offered strong confirmation that most of the patients and healthcare professionals prefer subcutaneous over intravenous drug administration but emphasise the management of risks associated with treatment compliance. Patient education provided by the IBD team in this regard is mandatory. Quality of life of patients is poorer during active disease, but the findings that it can improve over time, including as a result of home- or self-administration of biologics, may be encouraging for individuals with this chronic disease.

Individuals who use opioids have higher rates of hospitalization compared to the general population. Insufficiently treated withdrawal and pain are major factors contributing to high rates of self-initiated hospital discharges (also referred to as leaving against medical advice) in this population. While injectable opioid agonist therapy is limited or unavailable in the majority of Canadian communities, intravenous hydromorphone (IV HM) is widely available in the hospital setting and high-dose IV HM may be a useful treatment adjunct to improve comfort and engagement in inpatient care for some individuals who use opioids. However, major barriers to its use exist including lack of comfort amongst healthcare providers and hospital policies restricting administration. In this commentary, we highlight the potential usefulness of high-dose IV HM as a treatment adjunct for individuals who use opioids in the hospital setting and advocate for expanded hospital policies to facilitate its use.

Gene supplementation therapy with plasmid DNA (pDNA) represents one of the most promising strategies for the treatment of monogenic diseases such as Fabry disease (FD). In the present work, we developed a solid lipid nanoparticles (SLN)-based non-viral vector with a size below 100 nm, and decorated with galactomannan (GM) to target the liver as an α-Galactosidase A (α-Gal A) production factory. After the physicochemical characterization of the GM-SLN vector, cellular uptake, transfection efficacy and capacity to increase α-Gal A activity were evaluated in vitro in a liver cell line (Hep G2) and in vivo in an animal model of FD. The vector showed efficient internalization and it was highly efficient in promoting protein synthesis in Hep G2 cells. Additionally, the vector did not show relevant agglutination of erythrocytes and lacked hemolytic activity. After the systemic administration to Fabry mice, it achieved clinically relevant α-Gal A activity levels in plasma, liver, and other organs, importantly in heart and kidneys, two of the most damaged organs in FD. This work shows the potential application of GM-decorated lipidic nanocarries for the treatment of FD by pDNA-based gene augmentation. This research was funded by MCIU/AEI/FEDER, UE (RTI2018-098672-B-I00) and by the University of the Basque Country UPV/EHU (GIU20/048).

Fabry disease (FD) is a monogenic X-linked lysosomal storage disorder caused by a deficiency in the lysosomal enzyme α-Galactosidase A (α-Gal A). It is a good candidate to be treated with gene therapy, in which moderately low levels of enzyme activity should be sufficient for clinical efficacy. In the present work we have evaluated the efficacy of a non-viral vector based on solid lipid nanoparticles (SLN) to increase α-Gal A activity in an FD mouse model after intravenous administration. The SLN-based vector incremented α-Gal A activity to about 10%, 15%, 20% and 14% of the levels of the wild-type in liver, spleen, heart and kidney, respectively. In addition, the SLN-based vector significantly increased α-Gal A activity with respect to the naked pDNA used as a control in plasma, heart and kidney. The administration of a dose per week for three weeks was more effective than a single-dose administration. Administration of the SLN-based vector did not increase liver transaminases, indicative of a lack of toxicity. Additional studies are necessary to optimize the efficacy of the system, however, these results reinforce the potential of lipid-based nanocarriers to treat FD by gene therapy.

Background Hemarthrosis after anterior cruciate ligament (ACL) reconstruction can create many adverse joint effects. Tranexamic acid (TXA) can be used to minimize hemarthrosis and associated pain after ACL reconstruction. We aimed to compare the efficacies of intravenous (IV) administration and intra-articular (IA) injection of TXA during ACL reconstruction for reducing postoperative hemarthrosis. Methods A total of 120 patients who underwent arthroscopic ACL reconstruction were included in this prospective and randomized study. All patients were randomized into three groups: IV group, IA group and placebo group. Patients in the IV group received intravenously administered TXA (15 mg/kg in 100 mL of saline solution) 10 min before tourniquet release; patients in the IA group received intra-articular TXA (15 mg/kg in 100 mL of saline solution) injected via the drainage tube; and patients in the placebo group received an equivalent volume of normal saline administered into the knee joint cavity and intravenously. Drainage tubes were removed 24 h after surgery, and all enrolled patients experienced a 4-week follow-up period. The drain output volume, visual analogue scale (VAS) score, patellar circumference, hemarthrosis grade and Lysholm score of all patients were recorded. Results Both the IV group and the IA group had significantly lower drain output volumes at day 1, lower VAS scores at weeks 1 and 2, smaller patellar circumferences at weeks 1 and 2, and lower hemarthrosis grades at weeks 1 and 2 than the placebo group (p p > 0.05). No obvious differences in Lysholm score were observed between any pair of groups at week 4 (p > 0.05)). Neither infection nor deep vein thrombosis occurred in any group. Conclusions Both intravenous administration and intra-articular injection can reduce intra-articular hemarthrosis, joint pain and swelling during ACL reconstruction. No significant difference in the efficacies of reducing hemarthrosis, joint pain and swelling was found between intravenous administration and intra-articular injection. Trial registration The study was registered by the Chinese Clinical Trial Registry (The comparative efficacies of intravenous administration and intra-articular injection of tranexamic acid during anterior cruciate ligament reconstruction; ChiCTR-INR-17012217; August 1, 2017).

Protein therapeutics have witnessed tremendous use and application in recent years in treatment of various diseases. Predicting efficacy and safety during drug discovery and translational development is a key factor for successful clinical development of these therapies. In general, drug related toxicities are predominantly driven by pharmacokinetic (PK) exposure at off-target sites. This work explores the ocular PK of intravenously administered protein therapeutics to understand impact of antibody format on off-site exposure. Species matched non-binding rabbit antibody proteins (rabFab and rabIgG) were intravenously administered to male New Zealand White rabbits at a single 1 mg bolus dose and exposure was measured up to 3 weeks. As anticipated based on absence of FcRn recycling, rabFab has relatively fast systemic PK (CL–943 mL/day and t1/2–1.93 days) compared to rabIgG (CL–18.5 mL/day and t1/2–8.93 days). Similarly, rabFab has lower absolute ocular exposure in ocular compartments (e.g., vitreous and aqueous humor) compared to rabIgG, despite higher relative exposures (measured as percent tissue partition in ocular tissues relative to serum, based on Cmax and AUC). In general, percent tissue partition based on AUC (in aqueous and vitreous humor) relative to serum exposure were 10.4 and 8.62 for rabFab respectively and 1.11 and 0.64 for rabIgG respectively. This work emphasizes size and format based ocular exposure of intravenously administered protein therapeutics. Findings from this work enable prediction of format based ocular exposure for systemically administered antibody based therapeutics and aid in selection of molecule format for clinical candidate to minimize ocular exposure.

Background IgA nephropathy (IgAN) is one of the most frequently occurring types of chronic glomerulonephritis. Previous analyses have revealed that a major pathogen of dental caries, Streptococcus mutans [which expresses collagen-binding protein (Cnm) on its surface], is involved in the pathogenesis of IgAN. Methods Cnm-positive S. mutans isolated from a patient with IgAN was intravenously administered to specific pathogen-free Sprague–Dawley rats to evaluate their kidney conditions. Results The urinary protein level of the S. mutans group reached a plateau at 30 days, with increased numbers of mesangial cells and an increased mesangial matrix. The numbers of rats with IgA-positive and/or C3-positive glomeruli were significantly greater in the S. mutans group than in the control group at 45 days (P S. mutans group. There were significantly more CD68-positive cells (macrophages) in the glomeruli of the S. mutans group than in the glomeruli of the control group during the late phase (P Conclusion Our results suggested that intravenous administration of Cnm-positive S. mutans caused transient induction of IgAN-like lesions in rats.

Background/aim Preoperative intravenous oxycodone may help to prevent or attenuate intubation-related hemodynamic responses (IRHRs), but its pharmacokinetics differs according to age and sex. Therefore, we investigated the 95% effective dose (ED95) of intravenous oxycodone for attenuating all IRHRs, depending on the age and sex of the study population. Materials and methods All patients were allocated to one of 6 groups: 1) 20–40 year old males, 2) 41–65yearold males, 3) 66–80 year old males, 4) 20–40 year old females, 5) 41–65yearold females, and 6) 66–80 year old females (groups YM, OM, EM, YF, OF, and EF, respectively). Using Dixon’s up-and-down method, the first patient in each group was slowly injected with intravenous oxycodone (0.1 mg kg–1) 20 min before intubation. The subsequent patient received the next oxycodone dose, which was decreased or increased by 0.01 mg kg–1, depending on the “success” or “failure” of attenuation of all IRHRs to within 20% of the baseline values at 1 min after intubation in the previous patient. After obtaining 8 crossover points, predictive ED95 was estimated with probit regression analysis. Results ED95 varied greatly according to age and sex. ED95was 0.133 mg kg–1, 0.181 mg kg–1, 0.332 mg kg–1, 0.183 mg kg–1, 0.108 mg kg–1, and 0.147 mg kg–1in groups YM, OM, EM, YF, OF, and EF, respectively. Conclusion ED95 is higher in males with increasing age but is ambiguous for females. ED95 is higher in males than in females over 40 years of age but is higher in females than in males under 41 years of age. However, after considering the age and sex of the study population, these results can be used as reference doses for further studies to verify the clinical effects of oxycodone for attenuating all IRHRs.

Background Patient-controlled epidural analgesia (PCEA) is known to provide good postoperative analgesia in many types of surgery including laparoscopic surgery. However, no study has compared PCEA with patient-controlled intravascular analgesia (PCIA) in laparoscopic radical prostatectomy (LARP). In this study, the efficacy and side effects of PCEA and PCIA after LARP were compared. Methods Forty patients undergoing LARP were randomly divided into two groups: 1) a PCEA group, treated with 0.2% ropivacaine 3 ml and 0.1 mg morphine in the bolus; and 2) a PCIA group, treated with oxycodone 1 mg and nefopam 1 mg in the bolus. After the operation, a blinded observer assessed estimated blood loss (EBL), added a dose of rocuronium, performed transfusion, and added analgesics. The numeric rating scale (NRS), infused PCA dose, and side effects were assessed at 1, 6, 24, and 48 h. Results EBL, added rocuronium, and added analgesics in the PCEA group were less than those in the PCIA group. There were no significant differences in side-effects after the operation between the two groups. Patients were more satisfied with PCEA than with PCIA. The NRS and accumulated PCA count were lower in PCEA group. Conclusions Combined thoracic epidural anesthesia could induce less blood loss during operations. PCEA showed better postoperative analgesia and greater patient satisfaction than PCIA. Thus, PCEA may be a more useful analgesic method than PICA after LARP.

Background: B cells may be involved in the pathophysiology of multiple sclerosis (MS). Inebilizumab (formerly MEDI-551) binds to and depletes CD19+ B cells. Objectives: To assess safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of inebilizumab in adults with relapsing MS. Methods: This phase 1 trial randomised 28 patients 3:1 (21, inebilizumab; 7, placebo) to inebilizumab (2 intravenous (IV) doses, days 1 and 15: 30, 100 or 600 mg; or single subcutaneous (SC) dose on day 1: 60 or 300 mg) or matching placebo, with follow-up until at least week 24 or return of CD19+ B-cell count to ⩾80 cells/µL. Results: Complete B-cell depletion was observed across all doses. Infusion/injection (grade 1/2) reactions occurred in 6/15 patients receiving inebilizumab IV, 2/5 placebo IV and 1/6 inebilizumab SC. Serious adverse events occurred in three patients receiving inebilizumab: pyrexia, mixed-drug intoxication (unrelated to inebilizumab; resulted in death) and urinary tract infection. Mean number of cumulative new gadolinium-enhancing lesions over 24 weeks was 0.1 with inebilizumab versus 1.3 with placebo; mean numbers of new/newly enlarging T2 lesions were 0.4 and 2.4, respectively. Conclusion: Inebilizumab had an acceptable safety profile in relapsing MS patients and showed a trend in reductions in new/newly enlarging and gadolinium-enhancing lesions.

Background Niemann-Pick Disease Type C (NPC) is an inherited, often fatal neurovisceral lysosomal storage disease characterized by cholesterol accumulation in every cell with few known treatments. Defects in cholesterol transport cause sequestration of unesterified cholesterol within the endolysosomal system. The discovery that systemic administration of hydroxypropyl-beta cyclodextrin (HPβPD) to NPC mice could release trapped cholesterol from lysosomes, normalize cholesterol levels in the liver, and prolong life, led to expanded access use in NPC patients. HPβCD has been administered to NPC patients with approved INDs globally since 2009. Results Here we present safety, tolerability and efficacy data from 12 patients treated intravenously (IV) for over 7 years with HPβCD in the US and Brazil. Some patients subsequently received intrathecal (IT) treatment with HPβCD following on average 13 months of IV HPβCD. Several patients transitioned to an alternate HPβCD. Moderately affected NPC patients treated with HPβCD showed slowing of disease progression. Severely affected patients demonstrated periods of stability but eventually showed progression of disease. Neurologic and neurocognitive benefits were seen in most patients with IV alone, independent of the addition of IT administration. Physicians and caregivers reported improvements in quality of life for the patients on IV therapy. There were no safety issues, and the drug was well tolerated and easy to administer. Conclusions These expanded access data support the safety and potential benefit of systemic IV administration of HPβCD and provide a platform for two clinical trials to study the effect of intravenous administration of HPβCD in NPC patients.

[Objectives]: Although new therapies against metastatic cancer have been developed in recent decades, chemotherapy is still an important treatment option. Prolonged treatment and side‐effects are often discouraging for patients, and in many cases, therapy is only palliative, not curative. This study explores patient preference for oral or intravenous (IV) chemotherapy in the treatment of metastatic breast or lung cancer. [Methods]: It is a descriptive, open label, multicentre, nation‐wide study, in which a 16‐item questionnaire consisting of single‐choice questions scored on a 5‐point Likert scale was administered to patients in a single visit, and another 11‐item questionnaire was self‐administered by the patient’s oncologist. [Results]: A total of 131 breast and lung cancer specialists at 64 hospitals enrolled 412 patients (lung cancer = 161; breast cancer = 251). To be eligible, patients must have already received IV therapy and at least 2 cycles of oral chemotherapy. Most (77%) patients expressed preference for oral therapy. Most considered their daily life was less disrupted with tablets (70.4%), had no trouble swallowing them (86.9%), and were not concerned about forgetting to take them (56.8%). Half (56.3%) were worried about problems related to drug infusion with IV therapy, 61.7% were concerned about nurses failing to find a suitable vein, and 63.1% were dissatisfied with hospital waiting times. A uniform response was obtained from both samples of patients. [Conclusion]: Convenience, ease of administration, fewer side effects and better quality of life tilt the balance towards oral drug administration.

This 2-week randomized, double-blind, placebo-controlled fixed-dose study (NCT02919501) explored the potential of accelerating onset of antidepressant efficacy and plasma exposure with single-dose intravenous vortioxetine at oral vortioxetine treatment initiation. Outpatients (ages 18-65 years) with major depressive disorder and a current depressive episode (Montgomery Åsberg Depression Rating Scale total score ≥30) were randomized to an initial single dose of either intravenous vortioxetine 17 mg (n = 27) or intravenous placebo (n = 28), both treatments followed by 2 weeks of oral vortioxetine (10 mg/day). From baseline to day 7, both groups exhibited fast and substantial improvements by approximately 14 Montgomery Åsberg Depression Rating Scale points, with no statistically significant treatment difference for this primary endpoint. Improvements were substantial already within 24 hours, with numerical treatment differences of 1.3 and 1.6 points at days 1 and 3, respectively, in favour of intravenous vortioxetine + oral vortioxetine. Pharmacokinetic data confirmed that intravenous vortioxetine facilitated reaching steady-state plasma concentration within 24 hours. Intravenous vortioxetine + oral vortioxetine was safe and well-tolerated, with nausea as the most common adverse event. This study supported intravenous vortioxetine as a means of rapidly reaching therapeutic vortioxetine blood levels.

The growing incidence of brain-related pathologies and the problems that undermine the development of efficient and effective treatments have prompted both researchers and the pharmaceutical industry to search for novel therapeutic alternatives. Polymer therapeutics (PT) display properties well suited to the treatment of neuro-related disorders, which help to overcome the many hidden obstacles on the journey to the central nervous system (CNS). The inherent features of PT, derived from drug(s) conjugation, in parallel with the progress in synthesis and analytical methods, the increasing knowledge in molecular basis of diseases, and collected clinical data through the last four decades, have driven the translation from "bench to bedside" for various biomedical applications. However, since the approval of Gliadel (R) wafers, little progress has been made in the CNS field, even though brain targeting represents an ever-growing challenge. A thorough assessment of the steps required for successful brain delivery via different administration routes and the consideration of the disease-specific hallmarks are essential to progress in the field. Within this review, we hope to summarize the latest developments, successes, and failures and discuss considerations on designs and strategies for PT in the treatment of CNS disorders. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

Objectives Although new therapies against metastatic cancer have been developed in recent decades, chemotherapy is still an important treatment option. Prolonged treatment and side-effects are often discouraging for patients, and in many cases, therapy is only palliative, not curative. This study explores patient preference for oral or intravenous (IV) chemotherapy in the treatment of metastatic breast or lung cancer. Methods It is a descriptive, open label, multicentre, nation-wide study, in which a 16-item questionnaire consisting of single-choice questions scored on a 5-point Likert scale was administered to patients in a single visit, and another 11-item questionnaire was self-administered by the patient's oncologist. Results A total of 131 breast and lung cancer specialists at 64 hospitals enrolled 412 patients (lung cancer = 161; breast cancer = 251). To be eligible, patients must have already received IV therapy and at least 2 cycles of oral chemotherapy. Most (77%) patients expressed preference for oral therapy. Most considered their daily life was less disrupted with tablets (70.4%), had no trouble swallowing them (86.9%), and were not concerned about forgetting to take them (56.8%). Half (56.3%) were worried about problems related to drug infusion with IV therapy, 61.7% were concerned about nurses failing to find a suitable vein, and 63.1% were dissatisfied with hospital waiting times. A uniform response was obtained from both samples of patients. Conclusion Convenience, ease of administration, fewer side effects and better quality of life tilt the balance towards oral drug administration.

Lidocaine, as the only local anesthetic approved for intravenous administration in the clinic, can relieve neuropathic pain, hyperalgesia, and complex regional pain syndrome. Intravenous injection of lidocaine during surgery is considered as an effective strategy to control postoperative pain, but the mechanism of its analgesic effect has not been fully elucidated. This paper intends to review recent studies on the mechanism of the analgesic effect of lidocaine. To the end, we conducted an electronic search of the PubMed database. The search period was from 5 years before June 2019. Lidocaine was used as the search term. A total of 659 documents were obtained, we included 17 articles. These articles combined with the 34 articles found by hand searching made up the 51 articles that were ultimately included. We reviewed the analgesic mechanism of lidocaine in the central nervous system.

The growing incidence of brain-related pathologies and the problems that undermine the development of efficient and effective treatments have prompted both researchers and the pharmaceutical industry to search for novel therapeutic alternatives. Polymer therapeutics (PT) display properties well suited to the treatment of neuro-related disorders, which help to overcome the many hidden obstacles on the journey to the central nervous system (CNS). The inherent features of PT, derived from drug(s) conjugation, in parallel with the progress in synthesis and analytical methods, the increasing knowledge in molecular basis of diseases, and collected clinical data through the last four decades, have driven the translation from "bench to bedside" for various biomedical applications. However, since the approval of Gliadel® wafers, little progress has been made in the CNS field, even though brain targeting represents an ever-growing challenge. A thorough assessment of the steps required for successful brain delivery via different administration routes and the consideration of the disease-specific hallmarks are essential to progress in the field. Within this review, we hope to summarize the latest developments, successes, and failures and discuss considerations on designs and strategies for PT in the treatment of CNS disorders. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Background Glucocorticoid-associated osteonecrosis is an intractable condition, making the establishment of preventative strategies of particular importance. Recently various studies using mesenchymal stem cells (MSC) have been conducted. Using a rabbit glucocorticoid-associated osteonecrosis model we administered green fluorescent protein (GFP)-labeled MSC intravenously to investigate their effect on osteonecrosis. Methods A rabbit osteonecrosis model in which methylprednisolone (MP) 20 mg/kg was injected into the gluteus of a Japanese white rabbit was used. Simultaneously with MP, MSC labeled with GFP (GFP-labeled MSC) were injected intravenously. Fourteen days later the animals were killed (MSC(+)/MP(+)/14d), femurs were extracted, and the prevalence of osteonecrosis was determined histopathologically. Also, animals were killed 3 days after simultaneous administration of GFP-labeled MSC and MP (MSC(+)/MP(+)/3d), and western blotting (WB) for GFP was performed of the femur, liver, kidney, lung, blood vessel, and vertebra, in addition to immunohistochemical study of femur. As a control for the histopathological study, animals were killed 14 days after MP administration and intravenous vehicle injection (MSC(−)/MP(+)/14d). For WB, animals were killed 3 days after intravenous GFP-labeled MSC administration and vehicle injection into the gluteus (MSC(+)/MP(−)/3d). Results In MSC(−)/MP(+)/14d osteonecrosis was found in 7 of 10 rabbits (70%), while in MSC(+)/MP(+)/14d, partial bone marrow necrosis was found in only 1 rabbit (12.5%); osteonecrosis was not found in 7 of 8 rabbits (p

We investigated the influence of repeated intravenous administration of dextrans (DEXs) to rats. Seven-week-old Sprague Dawley rats (6 males/group) were given intravenously 10% saline solutions of dextrans (DEXs), 40 kDa or 200–300 kDa, at a dose level of 5 mL/kg/day for 28 days and they were examined histopathologically. Another group (3 males/group) was administered saline in a similar manner and served as the control. Histopathological changes indicating accumulation of DEXs in the mononuclear phagocyte system (MPS) and the liver were noted in the treated groups. The incidence and severity of the findings were molecular weight-dependent, except for the lungs. These results are considered useful in interpreting data from preclinical studies, in which DEXs or their derivatives are administered as test or control substances.

Background: I.v. 0.9% sodium chloride (normal saline) is frequently used to treat ED patients with acute alcohol intoxication despite the lack of evidence for its efficacy. Objective: The study aims to compare treatment with i.v. normal saline and observation with observation alone in ED patients with acute alcohol intoxication. Methods: A single-blind, randomised, controlled trial was conducted to compare a single bolus of 20 mL/kg i.v. normal saline plus observation with observation alone. One hundred and forty-four ED patients with uncomplicated acute alcohol intoxication were included. The study was conducted in one tertiary and one urban ED in Queensland, Australia. Primary outcome was ED length of stay (EDLOS). Secondary outcomes were treatment time, breath alcohol levels, intoxication symptom score, level of intoxication and associated healthcare costs. Results: Both groups were comparable at baseline: blood alcohol content (BAC) was similar between treatment and control groups (0.20 % BAC vs 0.19 % BAC, P = 0.44) as were initial intoxication symptom scores (22.0 vs 22.3, P = 0.90). Both groups had a similar EDLOS (287 min vs 274 min, P = 0.89; difference 13 min [95% CI −37–63]) and treatment time (244 min vs 232 min, P = 0.94; difference 12 min [95% CI −31–55]). Change of breath alcohol levels, intoxication score and level of intoxication were not significantly different between the two groups. Patients in the treatment group had an additional healthcare cost of A$31.92 compared with control. Conclusions: I.v. normal saline therapy added to observation alone does not decrease ED length of stay compared with observation alone. Intoxication symptom scores and general state of intoxication were similar in both groups. The present study suggests that either approach is reasonable, but observation alone might be preferred as it is less resource intensive.

Ulrika Carlander,1 Dingsheng Li,2 Olivier Jolliet,2 Claude Emond,3,4 Gunnar Johanson1 1Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 2Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA; 3BioSimulation Consulting Inc., Newark, DE, USA; 4Department of Environmental and Occupational Health, School of Public Health, University of Montreal, QC, Canada Abstract: To assess the potential toxicity of nanoparticles (NPs), information concerning their uptake and disposition (biokinetics) is essential. Experience with industrial chemicals and pharmaceutical drugs reveals that biokinetics can be described and predicted accurately by physiologically-based pharmacokinetic (PBPK) modeling. The nano PBPK models developed to date all concern a single type of NP. Our aim here was to extend a recent model for pegylated polyacrylamide NP in order to develop a more general PBPK model for nondegradable NPs injected intravenously into rats. The same model and physiological parameters were applied to pegylated polyacrylamide, uncoated polyacrylamide, gold, and titanium dioxide NPs, whereas NP-specific parameters were chosen on the basis of the best fit to the experimental time-courses of NP accumulation in various tissues. Our model describes the biokinetic behavior of all four types of NPs adequately, despite extensive differences in this behavior as well as in their physicochemical properties. Inaddition, this simulation demonstrated that the dose exerts a profound impact on the biokinetics, since saturation of the phagocytic cells at higher doses becomes a major limiting step. The fitted model parameters that were most dependent on NP type included the blood:tissue coefficients of permeability and the rate constant for phagocytic uptake. Since only four types of NPs with several differences in characteristics (dose, size, charge, shape, and surface properties) were used, the relationship between these characteristics and the NP-dependent model parameters could not be elucidated and more experimental data are required in this context. In this connection, intravenous biodistribution studies with associated PBPK analyses would provide the most insight. Keywords: nondegradable, PBPK, intravenous administration, phagocytosis, rats, nanorods, gold, titanium dioxide, polyacrylamide, polyethylene glycol coating

Purpose:Coring of a medication vial’s rubber stopper has been reported as a major cause of visible particle presence in injectable preparations. In this study, we investigated and quantified visible particle formation caused by coring associated with four potential causal factors.Methods:The factors studied were: nature of the rubber stopper; rubber stopper thickness, type of metal needle bevel used to pierce the stopper, and puncture technique. For each one of 16 different situations, 40 medication vial rubber stoppers were punctured, and the contents filtered. The filters were then examined under optical microscopy and particles present counted and measured.Results:The incidence of particle formation ranged from 0 % to 75 %, depending on the situation. Particle length was on average of 0.98±0.39 mm. The situation that gave the most particles (75 %; 30/40) was obtained when using a short bevelled needle, a 4 mm thick chlorobutyl vial stopper and with a puncture angle of 90°. Whilst a puncture technique reduced particle formation by more than 50 % for the most at risk situation, but without eliminating particle formation (residual formation of 22.5 %; 11/40), the use of a blunt bevelled needle totally eliminated the incidence of visible particle creation. The thickness of the rubber and the nature of the elastomer seemed to be linked to coring incidence, but in lesser proportions.Conclusion:Puncturing the stoppers using a technique with a 45° puncture angle reduced particle formation, but only the use of a blunt metal needle totally eliminated it.

Summary Background Until now there has been no study that directly compares the effect of lansoprazole and pantoprazole administered intravenously on intragastric acidity. The aim of this study is to compare the effect of lansoprazole (30 mg) and pantoprazole (40 mg) administered intravenously on gastric acidity. Material/Methods Helicobacter pylori-negative healthy volunteers were recruited in this open-label, randomized, two-way crossover, single centre study. Lansoprazole at 30 mg or pantoprazole at 40 mg was intravenously administered twice daily for 5 consecutive days with at least a 14-day washout interval. Twenty-four-hour intragastric pH was continuously monitored on days 1 and 5 of each dosing period. Results Twenty-five volunteers completed the 2 dosing periods. The mean intragastric pH values were higher in subjects treated with lansoprazole than those with pantoprazole on both day 1 (6.41±0.14 vs. 5.49±0.13, P=0.0003) and day 5 (7.09±0.07 vs. 6.64±0.07, P=0.0002). Significantly higher percentages of time with intragastric pH >4 and pH >6 were found in the subjects treated with lansoprazole than those with pantoprazole on day 1 (pH >4, 87.12±4.55% vs. 62.28±4.15%, P=0.0012; pH >6, 62.12±4.12% vs. 47.25±3.76%, P=0.0216) and pH >6 on day 5 (76.79±3.77% vs. 58.20±3.77%, P=0.0025). Conclusions Intravenous lansoprazole produces a longer and more potent inhibitory effect on intragastric acidity than does intravenous pantoprazole.

Purpose of review To critically examine the mortality rates of septic shock over the last 25 years to determine if significant improvements have been accomplished. Recent findings A gradual and progressive improvement in mortality rates associated with septic shock has been realized over the few decades. These improvements in outcome are quantitatively small but significant and they primarily represent improvements in supportive care, and the recognition that well meaning and seemingly logical treatments have been overused and probably contributed to excess mortality rates in the past. Summary Survival rates for patients in septic shock have gradually improved in critical care units worldwide over the last 25 years. Further improvement will be predicated on the discovery of new therapies to disrupt the underlying pathophysiology of sepsis and the development of improved rapid, diagnostic testing and immune monitoring of individual patients.

Medication errors are commonly encountered in hospital setting. Intravenous medications pose particular risks because of their greater complexity and the multiple steps required in their preparation, administration and monitoring. We aimed to determine the rate of errors during the preparation and administration phase of intravenous medications and the correlation of these errors with the demographics of nurses involved in the process. One hundred patients who were receiving IV medications were monitored by a trained pharmacist. The researcher accompanied the nurses during the preparation and administration process of IV medications. Collected data were compared with the acceptable guidelines. A checklist was filled for each IV medication. Demographic data of the nurses were collected as well. A total of 454 IV medications were recorded. Inappropriate administration rate constituted a large proportion of errors in our study (35.3%). No significant or life threatening drug interaction was recorded during the study. Evaluating the impact of the nurses’ demographic characteristics on the incidence of medication errors showed that there is a direct correlation between nurses’ employment status and the rate of medication errors, while other characteristics did not show a significant impact on the rate of administration errors. Administration errors were significantly higher in temporary 1-year contract group than other groups (p-value < 0.0001). Study results show that there should be more vigilance on administration rate of IV medications to prevent negative consequences especially by pharmacists. Optimizing the working conditions of nurses may play a crucial role.

Objective Various nanoparticles have been designed and tested in order to select optimal carriers for the inhalation delivery of anticancer drugs to the lungs. Methods The following nanocarriers were studied:micelles, liposomes, mesoporous silica nanoparticles (MSNs), poly propyleneimine (PPI) dendrimer-siRNA complexes nanoparticles, quantum dots (QDs), and poly (ethylene glycol) polymers. All particles were characterized using the following methods:dynamic light scattering, zeta potential, atomic force microscopy, in vitro cyto- and genotoxicity. In vivo organ distribution of all nanoparticles, retention in the lungs, and anticancer effects of liposomes loaded with doxorubicin were examined in nude mice after the pulmonary or intravenous delivery. Results Significant differences in lung uptake were found after the inhalation delivery of lipid-based and non-lipid-based nanoparticles. The accumulation of liposomes and micelles in lungs remained relatively high even 24 h after inhalation when compared with MSNs, QDs, and PPI dendrimers. There were notable differences between nanoparticle accumulation in the lungs and other organs 1 and 3 h after inhalation or intravenous administrations, but 24 h after intravenous injection all nanoparticles were mainly accumulated in the liver, kidneys, and spleen. Inhalation delivery of doxorubicin by liposomes significantly enhanced its anticancer effect and prevented severe adverse side effects of the treatment in mice bearing the orthotopic model of lung cancer. Conclusion The results of the study demonstrate that lipid-based nanocarriers had considerably higher accumulation and longer retention time in the lungs when compared with non-lipid-based carriers after the inhalation delivery. These particles are most suitable for effective inhalation treatment of lung cancer.

International audience; Performances of cationic lipid formulations for intravenous gene delivery to mouse lungs have been previously reported. We report in this study that cationic phosphonolipids, when appropriately formulated, can be good synthetic vectors for gene delivery to lung after intravenous administration. One of our reagents, GLB43, was capable of mediating a 500-fold higher expression in the lungs of mice than could be obtained with free pDNA alone (P=0.018). We demonstrate that the most important parameters for cationic phosphonolipid transfection activity after systemic administration are the chemical structure of the cationic phosphonolipid, the lipid to DNA charge ratio and the inclusion of co-lipid in the formulation. We report using a luciferase reporter gene that transfection activity in vivo 24 h after cationic phosphonolipid systemic administration could not be predicted from in vitro analysis. In contrast to in vitro studies, cationic phosphonolipids including the oleyl acyl chains (GLB43) were more effective than its analogue with the myristyl acyl chains (GLB73). Using pathological analysis of animal livers, we demonstrate that the toxicity level was correlated with the lipoplex formulation and the lipid to DNA ratio. Copyright (C) 2000 Elsevier Science B.V.

International audience; The aim of the present retrospective observational clinical study was to assess the interindividual pharmacokinetic variability of plasma concentrations of amoxicillin or cloxacillin administered in high doses intravenously in critically ill patients, related to renal function or administration method.Four hundred and two plasma concentrations were measured at steady-state with a high performance liquid chromatography technique in 162 patients treated with 100 - 300 mg/kg/day of intravenous amoxicillin or cloxacillin.For both drugs and administration methods, plasma concentrations were significantly higher for patients with creatinine clearance below 60 ml/min, even though doses were adapted for renal impairment. the correlations calculated between plasma concentrations and creatinine level, creatinine clearance or doses were all low. There were fewer outlying drug concentrations in patients receiving continuous rather than intermittent regimens.Our results are in favor of adapting dosages of these beta-lactam antibiotics based on plasma concentrations, especially in cases of renal impairment.

Background: Paclitaxel is one of the most effective anticancer drugs ever developed. To prevent hazards associated with intravenous (IV) administration which include the formation of microbubbles, microbiological contamination and particulate matter, the suppliers recommend that an in-line IV filter should be used during the infusion of the chemotherapeutic agent. Methods: To rule out the possibility that polyethersulfone (PES) membranes retain the paclitaxel during filtration, we carried out specific tests. Paclitaxel retention by PES in-line IV filters was evaluated by a simulated-drug IV infusion and high-performance liquid chromatography analysis. Results: In our model of study, no variation of paclitaxel concentration was revealed before and after filtration using two different filter devices. Conclusions: The results suggest that, under our experimental conditions, paclitaxel concentration in saline solution remains constant before and after filtration. Indeed, our study indicates that the filters analyzed herein, other than preventing hazards associated with IV administration, do not retain paclitaxel, thus avoiding the reduction of the drug concentration and potency during filtration.

Summary Reasons for performing study: The selective COX-2-inhibitor nimesulide is used extra-label in equine veterinary practice as an anti-inflammatory agent. However, there are no data on which to base the rational use of the drug in this species. Objectives: To determine the effective COX selectivity of nimesulide in the horse, and suggest a suitable dosing schedule. Methods: The pharmacokinetics of nimesulide in the horse after oral administration (1 mg/kg bwt), and oral and i.v. administration (1.5 mg/kg bwt) were investigated, effects of feeding status on bioavailability determined, and plasma protein binding of the drug and its principal metabolites measured. Compartmental and noncompartmental pharmacokinetic analyses were performed. The plasma concentration-time profile was used, together with in vitro literature data on nimesulide inhibition of COX isoforms, to determine the effective COX selectivity of nimesulide in the horse, and suggest a suitable dosing schedule. Results and conclusions: The findings suggest that 1.5 mg/kg bwt may produce adequate clinical effects, and the dosing interval should be 12–24 h depending on condition severity. However, at that dose, the concentration in the animal exceeds the in vitro IC50 for both isoforms, so that COX-1/COX-2 selectivity is lost and side-effects due to COX-1 inhibition are a possibility. Nimesulide should therefore be used with caution in equine clinical practice.

The objective of the study was to compare the concentration of lidocaine in different body fluids/tissues after subarachnoid space and intravenous administrations of a lethal dose of lidocaine. Totally 18 dogs were used in the experiment. Six dogs were given subarachnoid anesthesia, another were given an intravenous injection of a dose of 75 mg/kg weight of lidocaine hydrochloride in 5 min and the last 6 dogs were used as the blank control dogs and given a subarachnoid space injection or a femoral artery injection of the same volume of sodium chloride. As soon as its vital signs disappeared, each dog was dissected and the specimen, such as brain, cerebrospinal fluid (CSF) in lateral ventricle, CSF in subarachnoid space, spinal cord (cervical spinal cord, thoracic spinal cord, lumbar spinal cord, and waist spinal cord), heart, lung, liver, spleen, kidney, bile, urine, heart blood, peripheral blood, muscle in injection location, and muscle in no injection location, were collected for analysis of lidocaine immediately. Analysis was performed with gas chromatography-mass spectrometry (GC-MS). From the maximum to the minimum, the order of lidocaine concentration detected in the subarachnoid space-administered dogs was as follows: CSF in subarachnoid space, waist spinal cord, thoracic spinal cord, CSF in lateral ventricle, lumbar spinal cord, cervical spinal cord, lung, kidney, muscle in injection location, heart, brain, spleen, heart blood, liver, peripheral blood, bile, muscle in no injection location, and urine. The order of lidocaine concentration detected in the intravenously administered dogs was as followed: Kidney, heart, lung, spleen, brain, liver, peripheral blood, bile, heart blood, cervical spinal cord, thoracic spinal cord, muscle in injection location, lumbar spinal cord, muscle in no injection location, CSF in subarachnoid space, urine, and CSF in lateral ventricle. The maximum concentration of lidocaine was detected in the subarachnoid space CSF of subarachnoid space-administered dead dogs, while in intravenously injected dead dogs, the maximum concentration of lidocaine was detected in the kidney. Our study provides some useful data for the forensic identification of epidural anesthesia accidents to decide the way the lidocaine enters the body.

To investigate the supplement of lost nerve cells in rats with traumatic brain injury by intravenous administration of allogenic bone marrow mesenchymal stem cells, this study established a Wistar rat model of traumatic brain injury by weight drop impact acceleration method and administered 3 × 10(6) rat bone marrow mesenchymal stem cells via the lateral tail vein. At 14 days after cell transplantation, bone marrow mesenchymal stem cells differentiated into neurons and astrocytes in injured rat cerebral cortex and rat neurological function was improved significantly. These findings suggest that intravenously administered bone marrow mesenchymal stem cells can promote nerve cell regeneration in injured cerebral cortex, which supplement the lost nerve cells.

Objective: In chronic obstructive pulmonary disease (COPD) patients with acute respiratory failure (ARF), bronchodilating agents administered by inhalation have, in general, little effect on dynamic hyperinflation and concurrent static intrinsic positive end-expiratory pressure (PEEPi,st). Since in COPD the severely obstructed segments of the lung may not be reached by inhaled medication, we reasoned that drug efficiency may be enhanced by intravenous administration of the agent. Design: Physiological study. Setting: Two four-bed surgical-medical ICUs of a university hospital. Patients: Fourteen COPD patients were studied within 36 h from the onset of ARF. Measurements and results: Static compliance (Cst,rs), minimal (Rmin,rs) and additional (ΔRrs) resistance of the respiratory system, and PEEPi,st were measured before and after intravenous administration of salbutamol. All patients had limitation of air flow before and after salbutamol administration. On average, after salbutamol there was a small, though significant, decrease in Rmin,rs (-9%), ΔRrs (-12%) and PEEPi,st (-8%). Conclusion: The changes in resistance and PEEPi,st after intravenous administration of salbutamol were too small to be of clinical significance.

Akshara Richhariya1, Yi Qian2, Yufan Zhao2, Karen Chung11Amgen Inc, Global Health Economics, Thousand Oaks, CA, USA; 2Amgen Inc, Global Biostatistical Sciences, Thousand Oaks, CA, USAPurpose: Intravenous (IV) zoledronic acid (ZA) is commonly used to delay skeletal complications secondary to bone metastases. However, the time associated with ZA administration may represent a significant burden to healthcare providers and patients. This study assessed the time associated with IV ZA infusion in patients with bone metastases secondary to breast or prostate cancer (BC or PC) in the clinic setting.Methods: Eligible BC or PC patients with bone metastases scheduled to receive IV ZA were observed at seven US-based oncology clinics. Trained observers recorded the time for preinfusion tasks, ZA drug preparation, intravenous infusion, and follow-up activities.Results: Data are reported for 39 patients (BC: 24; PC: 15). Mean administration time was 69 (standard deviation [SD] 42) minutes for all patients combined, 72 (SD 47) minutes for BC, and 65 (SD 33) minutes for PC. Activity times were comparable between tumor types. Mean time for preinfusion tasks (eg, assessment of vital signs, blood draw) and ZA preparation were 12 (SD 20) minutes and 2 (SD 1) minutes, respectively. Mean time required for intravenous infusion (ZA infusion and hydration, when provided) and follow-up activities were 54 (SD 31) minutes and 2 (SD 1) minutes, respectively.Conclusion: Infusion time was the greatest time commitment associated with IV ZA administration, representing 78% of the total time on average. Time for preinfusion activities varied substantially. Overall, the mean time for ZA administration represents a notable time burden for healthcare providers and patients.Keywords: time and motion, bisphosphonates, zoledronic acid, intravenous administration

Complete regression of solid tumors was achieved by plural intravenous (i.v.) administrations of polyethylene glycol (PEG)-modified tumor necrosis factor-alpha (TNF-alpha), prepared by covalently modifying natural human TNF-alpha with N-succinimidyl succinate PEG. The anti-tumor efficacy of PEG-modified TNF-alpha (MPEG-TNF-alpha), in which 56% of the TNF-alpha-lysine residues were coupled with PEG, was compared with that of native TNF-alpha in the Meth-A murine fibrosarcoma model. MPEG-TNF-alpha and native TNF-alpha were given as i.v. injections twice a week for 2 weeks. The anti-tumor activity of MPEG-TNF-alpha was dose-dependent and was far superior to that of native TNF-alpha. Complete regression was observed in 3 of the 8 mice administered native TNF-alpha at the dose of 10,000 JRU (Japan reference unit), but 4 of the 5 remaining mice died during the therapeutic period. At 5,000 JRU of native TNF-alpha, no case of complete regression was observed. By contrast, complete regression was obtained in all 10 mice given 200 JRU of MPEG-TNF-alpha. No side-effects were observed at the dose of 500 JRU of MPEG-TNF-alpha, which was 2.5 times the minimal dose (200 JRU) of MPEG-TNF-alpha required for complete regression in all treated mice. MPEG-TNF-alpha appears to have potential as a candidate anti-tumor therapeutic agent.

Cancer-associated retinopathy (CAR) is a paraneoplastic neuronal degeneration in the retina of a cancer patient and is characterized by the rapid, progressive loss of vision [1]. The CAR has been described to occur with small-cell lung cancer, breast cancer, gynecological cancers, and others, in which the remote effects of cancers may stem from autoimmune responses of serum autoantibodies against both tumor and retinal proteins [2,3]. Pathologically, CAR is the degeneration of photoreceptors, with relative sparing of the inner retina, including ganglion cells, bipolar cells, amacrine cells, and horizontal cells, which are supplied by retinal vessels [1-3]. Although the precise mechanism has not been fully established, CAR may primarily result from autoimmune-mediated apoptosis, which is supported by the lack of inflammatory response to the retinal degeneration of CAR [4,5]. Among those autoantibodies found in sera of patients with CAR, those against the 23-kDa retinal protein recoverin appear to be the most common [1,6]. Recoverin is a cytoplasmic calcium-binding protein that is distributed in photoreceptor cells, bipolar cells, and in a small population of cells in the ganglion cell layer [7]. In CAR, it has been hypothesized that a high titer of autoantibodies are able to cross the blood-retinal barrier (BRB) and penetrate susceptible retinal cells, which is followed by cross-reactivity with particular retinal proteins [1,2]. Binding of the anti-recoverin antibody to recoverin enhances rhodopsin phosphorylation, continuously opens cGMP-gated channels, and increases the intracellular calcium level, which leads to activation of the caspase-dependent apoptotic pathway [5]. It has been already well-established that autoantibodies can enter and kill retinal cells [4,5], whereas it has never been established whether autoantibodies can cross the BRB [8,9]. In addition, although intravitreally injected autoantibodies successfully induced retinal degeneration and dysfunction similar to those of CAR [10,11], the intravitreal autoantibody injection is somehow different from the natural pathogenesis of CAR, in which it is hypothesized that circulating autoantibodies that cross the BRB enter retinal cells to induce cell death. To maintain a stable environment in order to ensure the appropriate activities of retinal neurons, retinal vessels that supply the inner retina form the specialized structure of the BRB [11], which is regulated by modulating both angiogenesis and tight junction formation, as described in our previous findings [12,13]. The BRB is actually located in retinal endothelial cells, whose specific junction molecules are requisite for the maintenance of the barrier function [13,14]. In retinal endothelial cells, tight junction proteins such as zonula occludens (ZO)-1 and occludin are well-characterized, the expressions of which are inversely related to permeability in the BRB [13,15,16]. In a variety of retinal pathologies including uveoretinitis, diabetic retinopathy, or age-related macular degeneration, diverse mechanisms might affect the integrity of the BRB and lead to breakdown [13,14]. Although less is understood about increased vascular permeability and extravasation from the bloodstream in BRB breakdown, it has been proposed that either process may occur to allow for migration through intercellular endothelial tight junctions and for trans-cellular migration through endothelial cells [17,18]. In this study, we demonstrated that intravenously administrated anti-recoverin antibodies could not pass through the BRB and, therefore, do not cause retinal cell death. Moreover, even under the condition of BRB breakdown, anti-recoverin antibodies could not cross the BRB and remained on retinal vessels without retinal cytotoxicity.