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1.
End-of-Study Results for the Ladder Phase 2 Trial of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration.
Khanani, AM, Callanan, D, Dreyer, R, Chen, S, Howard, JG, Hopkins, JJ, Lin, CY, Lorenz-Candlin, M, Makadia, S, Patel, S, et al
Ophthalmology. Retina. 2021;(8):775-787
Abstract
PURPOSE To report the end-of-study results from the Ladder clinical trial of the Port Delivery System with ranibizumab (PDS) for the treatment of neovascular age-related macular degeneration (nAMD). DESIGN Multicenter, randomized, active treatment-controlled phase 2 clinical trial. PARTICIPANTS Patients diagnosed with nAMD with a documented response to anti-vascular endothelial growth factor treatment who received study treatment (N = 220). METHODS Patients were randomized 3:3:3:2 to treatment with the PDS filled with ranibizumab 10-mg/ml, 40-mg/ml, and 100-mg/ml formulations or monthly intravitreal ranibizumab 0.5-mg injections. MAIN OUTCOME MEASURES End-of-study results for the time to first meeting refill criteria (first refill), mean change from baseline for best-corrected visual acuity (BCVA) and central foveal thickness (CFT), and safety. RESULTS At study end, the mean time on study was 22.1 months (range, 10.8-37.6 months) for all PDS patients. Median time to first refill was 8.7 months, 13.0 months, and 15.8 months, and 28.9%, 56.0%, and 59.4% of patients went 12 months or longer without meeting refill criteria in the PDS 10-mg/ml, 40-mg/ml, and 100-mg/ml treatment arms, respectively. At month 22, the observed mean BCVA change from baseline was ‒4.6 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, ‒2.3 ETDRS letters, +2.9 ETDRS letters, and +2.7 ETDRS letters in the PDS 10-mg/ml, 40-mg/ml, 100-mg/ml, and monthly intravitreal ranibizumab 0.5-mg treatment arms, respectively. At month 22, the observed mean CFT change from baseline was similar in the PDS 100-mg/ml and monthly intravitreal ranibizumab 0.5-mg treatment arms. No new safety signals were detected during the additional follow-up. CONCLUSIONS Over a mean of 22 months on study, vision and anatomic outcomes were comparable between the PDS 100-mg/ml and monthly intravitreal ranibizumab 0.5-mg arms, with a lower total number of ranibizumab treatments with the PDS. The Ladder end-of-study findings were consistent with the primary analysis, and the PDS generally was well tolerated throughout the entire study period. The PDS has the potential to reduce treatment burden in patients with nAMD while maintaining vision.
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2.
Repeat convection-enhanced delivery for diffuse intrinsic pontine glioma.
Bander, ED, Ramos, AD, Wembacher-Schroeder, E, Ivasyk, I, Thomson, R, Morgenstern, PF, Souweidane, MM
Journal of neurosurgery. Pediatrics. 2020;(6):661-666
Abstract
OBJECTIVE While the safety and efficacy of convection-enhanced delivery (CED) have been studied in patients receiving single-dose drug infusions, agents for oncological therapy may require repeated or chronic infusions to maintain therapeutic drug concentrations. Repeat and chronic CED infusions have rarely been described for oncological purposes. Currently available CED devices are not approved for extended indwelling use, and the only potential at this time is for sequential treatments through multiple procedures. The authors report on the safety and experience in a group of pediatric patients who received sequential CED into the brainstem for the treatment of diffuse intrinsic pontine glioma. METHODS Patients in this study were enrolled in a phase I single-center clinical trial using 124I-8H9 monoclonal antibody (124I-omburtamab) administered by CED (clinicaltrials.gov identifier NCT01502917). A retrospective chart and imaging review were used to assess demographic data, CED infusion data, and postoperative neurological and surgical outcomes. MRI scans were analyzed using iPlan Flow software for volumetric measurements. Target and catheter coordinates as well as radial, depth, and absolute error in MRI space were calculated with the ClearPoint imaging software. RESULTS Seven patients underwent 2 or more sequential CED infusions. No patients experienced Clinical Terminology Criteria for Adverse Events grade 3 or greater deficits. One patient had a persistent grade 2 cranial nerve deficit after a second infusion. No patient experienced hemorrhage or stroke postoperatively. There was a statistically significant decrease in radial error (p = 0.005) and absolute tip error (p = 0.008) for the second infusion compared with the initial infusion. Sequential infusions did not result in significantly different distribution capacities between the first and second infusions (volume of distribution determined by the PET signal/volume of infusion ratio [mean ± SD]: 2.66 ± 0.35 vs 2.42 ± 0.75; p = 0.45). CONCLUSIONS This series demonstrates the ability to safely perform sequential CED infusions into the pediatric brainstem. Past treatments did not negatively influence the procedural workflow, technical application of the targeting interface, or distribution capacity. This limited experience provides a foundation for using repeat CED for oncological purposes.
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3.
Topical application of highly concentrated water-in-oil emulsions: Physiological skin parameters and skin penetration in vivo - A pilot study.
Binder, L, Klang, V, Sheikh Rezaei, S, Neuer, O, Zhang, Z, Lunter, DJ, Wolzt, M, Valenta, C
International journal of pharmaceutics. 2019;:118694
Abstract
Important aspects in the development of new dermal drug delivery systems are the formulations' physicochemical properties and stability. Moreover, their influence on skin physiology and their penetration performance in vivo are of crucial interest. We have recently developed novel concentrated water-in-oil emulsions based on a non-ionic silicone surfactant; the present study deals with the effect of these formulations on physiological skin parameters of healthy volunteers after repeated application. Variations in skin condition and barrier integrity were investigated using classical biophysical and spectroscopic techniques. After four weeks of continuous treatment, no signs of skin irritation could be observed. Both tested emulsions had a positive effect on skin properties despite their relatively high water content and low lipid content. In vivo tape stripping studies revealed penetrated amounts of the incorporated model drug fluorescein sodium of almost 50% of the applied dose, with a superior performance of emulsions with isopropyl myristate when compared to liquid paraffin. In summary, our study confirmed the suitability of the developed W/O emulsions for pharmaceutic and cosmetic applications.
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4.
Clinical tolerance of corticospinal tracts in convection-enhanced delivery to the brainstem.
Morgenstern, PF, Zhou, Z, Wembacher-Schröder, E, Cina, V, Tsiouris, AJ, Souweidane, MM
Journal of neurosurgery. 2018;(6):1812-1818
Abstract
OBJECTIVE Convection-enhanced delivery (CED) has been explored as a therapeutic strategy for diffuse intrinsic pontine glioma (DIPG). Variables that may affect tolerance include infusate volume, infusion rate, catheter trajectory, and target position. Supratentorial approaches for catheter placement and infusate distribution patterns may conflict with corticospinal tracts (CSTs). The clinical relevance of these anatomical constraints has not been described. The authors report their experience using CED in the brainstem as it relates to anatomical CST conflict and association with clinical tolerance. METHODS In a phase I clinical trial of CED for DIPG (clinical trial registration no. NCT01502917, clinicaltrials.gov), a flexible infusion catheter was placed with MRI guidance for infusion of 124I-8H9, a radioimmunotherapeutic agent. Intra- and postprocedural MR images were analyzed to identify catheter trajectories and changes in T2-weighted signal intensity to approximate volume of distribution (Vd). Intersection of CST by the catheter and overlap between Vd and CST were recorded and their correlation with motor deficits was evaluated. RESULTS Thirty-one patients with a mean age of 7.6 years (range 3.2-18 years) underwent 39 catheter insertions for CED between 2012 and 2017. Thirty catheter insertions had tractography data available for analysis. The mean trajectory length was 105.5 mm (range 92.7-121.6 mm). The mean number of intersections of CST by catheter was 2.2 (range 0-3) and the mean intersecting length was 18.9 mm (range 0-44.2 mm). The first 9 infusions in the highest dose level (range 3.84-4.54 ml infusate) were analyzed for Vd overlap with CST. In this group, the mean age was 7.6 years (range 5.8-10.3 years), the mean trajectory length was 109.5 mm (range 102.6-122.3 mm), and the mean overlap between Vd and CST was 5.5 cm3. For catheter placement-related adverse events, 1 patient (3%) had worsening of a contralateral facial nerve palsy following the procedure with two CST intersections, an intersecting distance of 31.7 mm, and an overlap between Vd and CST of 3.64 cm3. For infusion-related adverse events, transient postinfusion deficits were noted in 3 patients in the highest dose level, with a mean number of 2 intersections of CST by catheter, mean intersecting length of 12.9 mm, and mean overlap between Vd and CST of 6.3 cm3. CONCLUSIONS A supratentorial approach to the brainstem crossing the CST resulted in one worsened neurological deficit. There does not appear to be a significant risk requiring avoidance of dominant motor fiber tracts with catheter trajectory planning. There was no correlation between Vd-CST overlap and neurological adverse events in this cohort.Clinical trial registration no.: NCT01502917 (clinicaltrials.gov).
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5.
A novel self-micro-emulsifying delivery system (SMEDS) formulation significantly improves the fasting absorption of EPA and DHA from a single dose of an omega-3 ethyl ester concentrate.
Qin, Y, Nyheim, H, Haram, EM, Moritz, JM, Hustvedt, SO
Lipids in health and disease. 2017;(1):204
Abstract
BACKGROUND Absorption of EPA and DHA from Omega-3-acid ethyl ester (EE) concentrate supplements occurs most efficiently when taken in context of a fatty meal; adequate fat intake is required to release bile salts that emulsify and pancreatic enzymes that digest omega-3-containing lipids in the intestine. Current guidelines recommend reduction in fat intake and therefore there is a need to optimize the absorption of Omega-3 in those consuming low-fat or no-fat meals. To this end, BASF has developed an Absorption Acceleration Technology, a novel self-micro-emulsifying delivery system (SMEDS) formulation of highly concentrated Omega-3-acid EE which enables rapid emulsification and microdroplet formation upon entering the aqueous environment of the gut therefore enhances the absorption. METHODS Two separate single dose, crossover studies were conducted to determine the relative bioavailability of omega-3-acid EE concentrate, either as a novel SMEDS formulation (PRF-021) or as control, in healthy fasted male and female adults at two dose levels (Study 1 "low dose": 630 mg EPA + DHA in PRF-021 vs. 840 mg EPA + DHA in control; Study 2 "high dose": 1680 mg EPA + DHA in PRF-021 vs. 3360 mg EPA + DHA in control). Blood samples were collected immediately before supplementation and at defined time intervals for 48 h. Plasma concentration of total EPA and DHA were determined for pharmacokinetic analysis, area under the curve (AUC) and maximum observed concentration (Cmax) was determined. RESULTS Total EPA plus DHA absorption from SMEDS formulation PRF-021 were 6.4 and 11.5 times higher compared to control in low- and high-dose studies respectively, determined as the ratio of baseline corrected, dose normalized AUC0-24h of PRF-021 over that of control. EPA and DHA individually showed differing levels of enhancement: the AUC0-24h ratio for EPA was 23.8 and 25.7 in low and high dose studies, respectively, and the AUC0-24h ratio for DHA was 3.6 and 5.6 in low and high dose studies, respectively. Cmax was also increased for both EPA and DHA 2.7- to 9.2-fold. CONCLUSION PRF-021 is a novel SMEDS formulation of Omega-3-acid EE demonstrating a marked improvement in absorption of a single dose of EPA and DHA EE under fasted conditions. This allows adequate absorption of Omega-3 from the supplement without the requirement of a high-fat meal.
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6.
Combination therapy with vancomycin-loaded calcium sulfate and vancomycin-loaded PMMA in the treatment of chronic osteomyelitis.
Luo, S, Jiang, T, Yang, Y, Yang, X, Zhao, J
BMC musculoskeletal disorders. 2016;(1):502
Abstract
BACKGROUND Chronic post-traumatic and postoperative osteomyelitis is a refractory disease which results in significant morbidity and mortality. The effect of combination therapy with vancomycin-loaded calcium sulfate and vancomycin-loaded polymethyl methacrylate (PMMA) was unknown. METHODS Fifty-one patients suffering from chronic post-traumatic or postoperative osteomyelitis of the lower extremities were included in the retrospective investigation. The patients were assigned to the study group of the combination therapy with antibiotic-loaded calcium sulfate and antibiotic-loaded PMMA or the control group of the antibiotic-loaded PMMA. Hematological parameters, eradication of infection, rate of infection recurrence and reoperation rate were evaluated during the follow-up. RESULTS The cases were followed up for an average of 24 months (range, 15-48 months) after the first-stage surgical operation. In the study group, all the patients revealed complete calcium sulfate resorption at an average of 6 weeks (range, 30-60 days). In the study group, infection was primarily eradicated in 92.31% (24 of 26) of patients and re-operation rate of 7.69% (2 of 26) after the first-stage surgery. Two patients underwent further surgical operation in the study group. One case achieved infection eradication in the recurrent two cases, with a secondary infection eradication rate of 96.15% (25 of 26). There was no persistent infection in the study group. In the control group, infection was eradicated in 64.00% (16 of 25) of patients and re-operation rate was 36.00% (9 of 25) after the first-stage surgery. Nine patients in the control group underwent further surgical operation. Two case achieved infection eradication in these cases who suffered from persistent or recurrent infection, with a secondary infection eradication rate of 72.00% (18 of 25). There was more re-operation rate in the control group (PMMA group, 9 vs combination therapy group, 2; P = 0.034). CONCLUSION The combination therapy with vancomycin-loaded calcium sulfate and vancomycin-loaded PMMA possibly achieved more effective control of infection in the treatment of osteomyelitis through synergistic effect. The immediate structural stabilization and higher concentration of antibiotic at the local site of infection may be achieved through the combination of biodegradable and non-biodegradable devices in the treatment of chronic post-traumatic and postoperative osteomyelitis. The study was retrospectively registered at 11/16/2016 (TRN: NCT02968693).
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7.
The Feasibility of a Completely Automated Total IV Anesthesia Drug Delivery System for Cardiac Surgery.
Zaouter, C, Hemmerling, TM, Lanchon, R, Valoti, E, Remy, A, Leuillet, S, Ouattara, A
Anesthesia and analgesia. 2016;(4):885-93
Abstract
BACKGROUND In this pilot study, we tested a novel automatic anesthesia system for closed-loop administration of IV anesthesia drugs for cardiac surgical procedures with cardiopulmonary bypass. This anesthesia drug delivery robot integrates all 3 components of general anesthesia: hypnosis, analgesia, and muscle relaxation. METHODS Twenty patients scheduled for elective cardiac surgery with cardiopulmonary bypass were enrolled. Propofol, remifentanil, and rocuronium were administered using closed-loop feedback control. The main objective was the feasibility of closed-loop anesthesia defined as successful automated cardiac anesthesia without manual override by the attending anesthesiologist. Secondary qualitative observations were clinical and controller performances. The clinical performance of hypnosis control was the efficacy to maintain a bispectral index (BIS) of 45. To evaluate the hypnosis performance, BIS values were stratified into 4 categories: "excellent," "good," "poor," and "inadequate" hypnosis control defined as BIS values within 10%, ranging from 11% to 20%, ranging from 21% to 30%, or >30% of the target value, respectively. The clinical performance of analgesia was the efficacy to maintain NociMap values close to 0. The analgesia performance was assessed classifying the NociMap values in 3 pain control groups: -33 to +33 representing excellent pain control, -34 to -66 and +34 to +66 representing good pain control, and -67 to -100 and +67 to +100 representing insufficient pain control. The controller performance was calculated using the Varvel parameters. RESULTS Robotic anesthesia was successful in 16 patients, which is equivalent to 80% (97.5% confidence interval [CI], 53%-95%) of the patients undergoing cardiac surgery. Four patients were excluded from the final analysis because of technical problems with the automated anesthesia delivery system. The secondary qualitative observations revealed that the clinical performance of hypnosis allowed an excellent and good control during 70% (97.5% CI, 63%-76%) of maintenance time and an insufficient clinical performance of analgesia for only 3% (97.5% CI, 1%-6%) of maintenance time. CONCLUSIONS The completely automated closed-loop system tested in this investigation could be used successfully and safely for cardiac surgery necessitating cardiopulmonary bypass. The results of the present trial showed satisfactory clinical performance of anesthesia control.
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8.
Targeted delivery of nerve growth factor via encapsulated cell biodelivery in Alzheimer disease: a technology platform for restorative neurosurgery.
Wahlberg, LU, Lind, G, Almqvist, PM, Kusk, P, Tornøe, J, Juliusson, B, Söderman, M, Selldén, E, Seiger, Å, Eriksdotter-Jönhagen, M, et al
Journal of neurosurgery. 2012;(2):340-7
Abstract
OBJECT The authors describe the first clinical trial with encapsulated cell biodelivery (ECB) implants that deliver nerve growth factor (NGF) to the cholinergic basal forebrain with the intention of halting the degeneration of cholinergic neurons and the associated cognitive decline in patients with Alzheimer disease (AD). The NsG0202 implant (NsGene A/S) consists of an NGF-producing, genetically engineered human cell line encapsulated behind a semipermeable hollow fiber membrane that allows the influx of nutrients and the efflux of NGF. The centimeter-long capsule is attached to an inert polymer tether that is used to guide the capsule to the target via stereotactic techniques and is anchored to the skull at the bur hole. METHODS Six patients with mild to moderate AD were included in this Phase Ib open-label safety study and were divided into 2 dose cohorts. The first cohort of 3 patients received single implants targeting the basal nucleus of Meynert (Ch4 region) bilaterally (2 implants per patient), and after a safety evaluation, a second cohort of 3 patients received bilateral implants (a total of 4 implants per patient) targeting both the Ch4 region and the vertical limb of the diagonal band of Broca (Ch2 region). Stereotactic implantation of the devices was successfully accomplished in all patients. Despite extensive brain atrophy, all targets could be reached without traversing sulci, the insula, or lateral ventricles. RESULTS Postoperative CT scans allowed visualization of the barium-impregnated tethers, and fusion of the scans with stereotactic MR images scan was used to verify the intended positions of the implants. Follow-up MRI at 3 and 12 months postimplantation showed no evidence of inflammation or device displacement. At 12 months, implants were successfully retrieved, and low but persistent NGF secretion was detected in half of the patients. CONCLUSIONS With refinement, the ECB technology is positioned to become an important therapeutic platform in restorative neurosurgery and, in combination with other therapeutic factors, may be relevant for the treatment of a variety of neurological disorders. Clinical trial registration no.: NCT01163825.
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9.
Paclitaxel-eluting balloon angioplasty and cobalt-chromium stents versus conventional angioplasty and paclitaxel-eluting stents in the treatment of native coronary artery stenoses in patients with diabetes mellitus.
Ali, RM, Degenhardt, R, Zambahari, R, Tresukosol, D, Ahmad, WA, Kamar, Hb, Kui-Hian, S, Ong, TK, bin Ismail, O, bin Elis, S, et al
EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology. 2011;:K83-92
Abstract
AIMS: Coronary lesions in diabetics (DM) are associated with a high recurrence following percutaneous coronary intervention (PCI), even after drug-eluting stent (DES) deployment. Encouraging clinical data of the drug-eluting balloon catheter (DEB) SeQuent Please warrant its investigation in these patients. METHODS AND RESULTS Eighty-four diabetic patients (60.8 ± 9.1 years, 76.2% male) were randomised to either the DEB SeQuent Please or the DES Taxus Liberté to compare the 9-month clinical and angiographic outcome of PCI in native coronary arteries. Comparing the DEB vs. the DES the 9-month results (follow-up DEB 39/45 [86.7%], DES 36/39 [92.3%]) are statistically not different at the 0.05 level for the primary endpoint of in-segment (0.37 ± 0.59 mm vs. 0.35 ± 0.63 mm) and in-stent (0.51 ± 0.61 mm vs. 0.53 ± 0.67 mm) late lumen loss, overall and cardiac deaths (2/45 [4.4%] and 3/45 [6.7%] vs. 0), target lesion revascularisation (3/45 [8.9%] vs. 4/39 [10.3%]), the total MACE rate (6/45 [13.3%] vs. 6/39 [15.4%]), and the event free survival after 10.2 ± 3.8 months (Kaplan-Meier analysis, p<0.80, log rank test). CONCLUSIONS The clinical and angiographic outcome of the combination of the drug-eluting balloon SeQuent Please with a cobalt chromium stent compared to the drug eluting Taxus stent are similar.
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10.
Description of Pantera Lux paclitaxel-releasing balloon and preliminary quantitative coronary angiography (QCA) results at six months in patients with coronary in-stent restenosis.
Hehrlein, C, Richardt, G, Wiemer, M, Schneider, H, Naber, C, Hoffmann, E, Dietz, U
EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology. 2011;:K119-24
Abstract
AIMS: Drug-eluting balloons (DEB) have recently emerged as a valuable treatment option for patients with coronary in-stent restenosis (ISR). However, little information exists on results of DEB therapy of in-stent restenosis from drug-eluting stents (DES). METHODS AND RESULTS The Pantera Lux balloon catheter, a novel DEB releasing paclitaxel with a BTHC matrix was studied in a prospective, multicentre first-in-man trial of patients with ISR either from bare metal stents (BMS) or drug-eluting stents (DES). Here we report on the clinical and angiographic follow-up of the first 45 Pantera Lux patients after six months. The mean age (± SD) of the studied ISR patients was 69 ± 9 years (82% males, 18% females). The distribution of BMS and DES in these patients was 53% and 47%, respectively. Success of deployment of the device was 100%. After six months, the major adverse cardiac event (MACE) rate was 7.7% including one post-procedural non-fatal myocardial infarction, one target lesion- and one target vessel- revascularisation (each clinically driven). Angiographic in-stent late lumen loss was 0.03 ± 0.35 mm (BMS: -0.08 ± 0.37 mm, DES: 0.15 ± 0.28 mm) as assessed by an independent angiographic core laboratory. CONCLUSION Treatment of coronary in-stent restenosis with the Pantera Lux paclitaxel-releasing balloon catheter shows very promising preliminary 6-month results, irrespective of whether the initially implanted stent was a bare metal- or a drug-eluting stent.