Real-World Performance of Large Vessel Occlusion Artificial Intelligence-Based Computer-Aided Triage and Notification Algorithms-What the Stroke Team Needs to Know.

PURPOSE: To evaluate the real-world performance of two FDA-approved artificial intelligence (AI)-based computer-aided triage and notification (CADt) detection devices and compare them with the manufacturer-reported performance testing in the instructions for use. MATERIALS AND METHODS: Clinical performance of two FDA-cleared CADt large-vessel occlusion (LVO) devices was retrospectively evaluated at two separate stroke centers. Consecutive "code stroke" CT angiography examinations were included and assessed for patient demographics, scanner manufacturer, presence or absence of CADt result, CADt result, and LVO in the internal carotid artery (ICA), horizontal middle cerebral artery (MCA) segment (M1), Sylvian MCA segments after the bifurcation (M2), precommunicating part of cerebral artery, postcommunicating part of the cerebral artery, vertebral artery, basilar artery vessel segments. The original radiology report served as the reference standard, and a study radiologist extracted the above data elements from the imaging examination and radiology report. RESULTS: At hospital A, the CADt algorithm manufacturer reports assessment of intracranial ICA and MCA with sensitivity of 97% and specificity of 95.6%. Real-world performance of 704 cases included 79 in which no CADt result was available. Sensitivity and specificity in ICA and M1 segments were 85.3% and 91.9%. Sensitivity decreased to 68.5% when M2 segments were included and to 59.9% when all proximal vessel segments were included. At hospital B the CADt algorithm manufacturer reports sensitivity of 87.8% and specificity of 89.6%, without specifying the vessel segments. Real-world performance of 642 cases included 20 cases in which no CADt result was available. Sensitivity and specificity in ICA and M1 segments were 90.7% and 97.9%. Sensitivity decreased to 76.4% when M2 segments were included and to 59.4% when all proximal vessel segments are included. DISCUSSION: Real-world testing of two CADt LVO detection algorithms identified gaps in the detection and communication of potentially treatable LVOs when considering vessels beyond the intracranial ICA and M1 segments and in cases with absent and uninterpretable data.

A novel device for atrial septal defect occlusion (GORE CARDIOFORM).

The GORE CARDIOFORM atrial septal defect (ASD) Occluder (GCA) is composed of a platinum-filled nitinol wire frame covered with expanded polytetrafluoroethylene, making it softer and more conformable compared with nitinol mesh devices. After the ASSURED clinical study confirmed the efficacy and safety of the device, it received U.S. Food and Drug Administration approval and a European conformity mark. Our aim was to understand the learning curve implicated in using the GCA for ASD closure in paediatric and adult patients as well as to study the early outcomes. To this end, a review of ASD device closures with GCA in 4 UK centres was conducted between January 2020 and January 2023. Implantation success was the primary outcome; the secondary outcomes were serious adverse events, including new onset arrhythmia. In all, 135 patients were included, and 128 (95%) had successful ASD device closure with GCA. The median patient age was 49 years, the median defect size was 18 mm, and the median device size was 37 mm. The median follow-up time was 6 months (interquartile range 1-14). One device embolisation occurred, and 15 patients (12% of GCA implantations) developed new onset arrhythmia - this was not related to patient age, defect diameter or device oversizing but was positively associated with device size. With growing experience using GCA, the device can be applied to a wide variety of ASD sizes and morphologies. Given the number of successful implantations with an absence of aortic erosion, as well as the ability to perforate through the device should procedures be required in the left atrium, the GCA device is an important addition for interventionists who close atrial septal defects.

Pharmacokinetics, Metabolism, and Excretion of Intravenous [14C]Difelikefalin in Healthy Subjects and Subjects on Hemodialysis.

BACKGROUND AND OBJECTIVE: Difelikefalin, a selective kappa-opioid receptor agonist, is the first approved treatment for moderate-to-severe pruritus in patients with end-stage renal disease (ESRD) on hemodialysis (HD) in the USA and Europe. The purpose of this open-label study was to investigate the pharmacokinetics and disposition of [14C]difelikefalin following a single intravenous dose in subjects with normal renal function and subjects on HD. METHODS: Twelve adult males (n = 6 healthy subjects; n = 6 subjects on HD) received single intravenous doses of [14C]difelikefalin containing 100 µCi (total doses of 1.7-3.0 µg/kg difelikefalin). Blood, urine, feces, and dialysate samples (when applicable) were collected after dosing. RESULTS: The median time to maximum concentration was similar for HD and healthy subjects, occurring at 5 min post-dose. The mean area under the concentration-time curve (AUC) was approximately 11-fold higher in HD versus healthy subjects; mean plasma half-life was 38.0 h and 2.6 h, respectively. In healthy subjects, 80.5% of the dose was recovered in urine, and 11.3% was recovered in feces. In subjects on HD, 58.8% of the dose was recovered in feces, and 19.5% was recovered in dialysate [for subjects on HD with residual kidney function (n = 3), 11.2% was recovered in urine]. Based on plasma AUClast, parent [14C]difelikefalin was the most abundant analyte in systemic circulation (> 99% of total exposure) for both cohorts. Metabolite profiles in urine and feces suggested minimal metabolism of the parent compound. CONCLUSION: In subjects on HD, difelikefalin total exposure was higher and plasma half-life was longer compared with subjects with intact renal function. Metabolism was low in both healthy subjects and subjects on HD, with unchanged drug representing > 99% of systemic circulation; however, the route of excretion was primarily into urine versus feces in healthy subjects, and feces versus dialysate in subjects on HD. REGISTRATION: ClinicalTrials.gov NCT03947970.

Endosurgical Remodeling of Wide-Necked Bifurcation Aneurysms.

Background: Wide-necked cerebral aneurysms at a bifurcation can be difficult to treat with endovascular techniques despite recent advancements. Objective: We describe a new technique of micro-scaffold remodeling of the aneurysm neck of wide-necked bifurcation aneurysms by placing one or more microcatheters and/or wires in the efferent vessels. We hypothesize that this technique would be a better choice to change the branch angulation, allowing for an improved configuration to stably deploy coils. We present a retrospective case series to illustrate this technique. Methods: 17 wide-necked bifurcation aneurysms in 17 patients were coil embolized using this technique during a 3 year study period. Branch-vessel microcatheters and/or microwires were used to remodel the aneurysm neck and support the coil mass. Statistical analysis of the branch angulation and neck-width changes were performed during treatment. Long-term clinical outcome and follow-up angiography was obtained in 8 patients. Results: Eleven patients had complete occlusion of their aneurysm (Raymond-Roy Class I), and 6 patients had Raymond-Roy Class 2 immediately after treatment. Efferent vessels demonstrated a statistically significant change in angulation with insertion of microcatheters or microwires, while neck width did not change significantly. There were four intraoperative complications and no neurological morbidity in the immediate post-operative period. Complete occlusion was documented for all 10 subjects with long-term follow-up. Conclusions: The micro-scaffold endosurgical remodeling technique is a useful adjunct in treating wide-necked bifurcation aneurysms. By elevating branch vessels away from the aneurysm neck, this technique allows for dense coil packing while decreasing the need for balloon or stent assistance.

Comparison of Complication Rates of Central Venous Catheters Versus Peripherally Inserted Central Venous Catheters in Pediatric Patients.

OBJECTIVES: The purpose of our study is to compare the rate of central line-associated blood stream infections and venous thromboembolism in central venous catheters versus peripherally inserted central catheters in hospitalized children. There is a growing body of literature in adults describing an increased rate of venous thromboembolisms and similar rates of central line-associated blood stream infection associated with peripherally inserted central catheters versus central venous catheters. It is not known if the rate of central line-associated blood stream infection and venous thromboembolism differs between peripherally inserted central catheters and central venous catheters in children. Based on current adult literature, we hypothesize that central line-associated blood stream infection rates for peripherally inserted central catheters and central venous catheters will be similar, and the rate of venous thromboembolism will be higher for peripherally inserted central catheters versus central venous catheters. DESIGN: This is a cohort study using retrospective review of medical records and prospectively collected hospital quality improvement databases. SETTING: Quaternary-care pediatric hospital from October 2012 to March 2016. PATIENTS: All patients age 1 day to 18 years old with central venous catheters and peripherally inserted central catheters placed during hospital admission over the study dates were included. Central venous catheters that were present upon hospital admission were excluded. The primary outcomes were rate of central line-associated blood stream infection and rate of venous thromboembolism. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 2,709 catheters included in the study, 1,126 were peripherally inserted central catheters and 1,583 were central venous catheters. Peripherally inserted central catheters demonstrated a higher rate of both infection and venous thromboembolism than central venous catheters in all reported measures. In multivariable analysis, peripherally inserted central catheters had increased association with central line-associated blood stream infection (odds ratio of 3.15; 95% CI, 1.74-5.71; p = 0.0002) and increased association with venous thromboembolism (odds ratio of 2.71; 95% CI, 1.65-4.45; p < 0.0001) compared with central venous catheters. CONCLUSIONS: Rates of central line-associated blood stream infection and venous thromboembolism were higher in hospitalized pediatric patients with peripherally inserted central catheters as compared to central venous catheters. Our study confirms the need for further investigation into the safety of central access devices to assist in proper catheter selection.

Duct Stenting Versus Modified Blalock-Taussig Shunt in Neonates With Duct-Dependent Pulmonary Blood Flow: Associations With Clinical Outcomes in a Multicenter National Study.

BACKGROUND: Infants born with cardiac abnormalities causing dependence on the arterial duct for pulmonary blood flow are often palliated with a shunt usually between the subclavian artery and either pulmonary artery. A so-called modified Blalock-Taussig shunt allows progress through early life to an age and weight at which repair or further more stable palliation can be safely achieved. Modified Blalock-Taussig shunts continue to present concern for postprocedural instability and early mortality such that other alternatives continue to be explored. Duct stenting (DS) is emerging as one such alternative with potential for greater early stability and improved survival. METHODS: The purpose of this study was to compare postprocedural outcomes and survival to next-stage palliative or reparative surgery between patients undergoing a modified Blalock-Taussig shunt or a DS in infants with duct-dependent pulmonary blood flow. All patients undergoing cardiac surgery and congenital interventions in the United Kingdom are prospectively recruited to an externally validated national outcome audit. From this audit, participating UK centers identified infants <30 days of age undergoing either a Blalock-Taussig shunt or a DS for cardiac conditions with duct-dependent pulmonary blood flow between January 2012 and December 31, 2015. One hundred seventy-one patients underwent a modified Blalock-Taussig shunt, and in 83 patients, DS was attempted. Primary and secondary outcomes of survival and need for extracorporeal support were analyzed with multivariable logistic regression. Longer-term mortality before repair and reintervention were analyzed with Cox proportional hazards regression. All multivariable analyses accommodated a propensity score to balance patient characteristics between the groups. RESULTS: There was an early (to discharge) survival advantage for infants before next-stage surgery in the DS group (odds ratio, 4.24; 95% confidence interval, 1.37-13.14; P=0.012). There was also a difference in the need for postprocedural extracorporeal support in favor of the DS group (odds ratio, 0.22; 95% confidence interval, 0.05-1.05; P=0.058). Longer-term survival outcomes showed a reduced risk of death before repair in the DS group (hazard ratio, 0.25; 95% confidence interval, 0.07-0.85; P=0.026) but a slightly increased risk of reintervention (hazard ratio, 1.50; 95% confidence interval, 0.85-2.64; P=0.165). CONCLUSIONS: DS is emerging as a preferred alternative to a surgical shunt for neonatal palliation with evidence for greater postprocedural stability and improved patient survival to destination surgical treatment.

Improving Forward Infusion Pressure during Brain Tumor Embolization with the Double Catheter and Coil Technique.

Endovascular embolization or embosurgery of brain tumors can be used to reduce neoplasm vascularity prior to surgical resection. Two challenges with embosurgery relate to insufficient perfusion pressure into the tumor and inadvertent escape of infused agents into parenchymal branches of the adjacent brain. This report describes a multi-catheter and coil technique to improve tumor perfusion and prevent reflux into normal branches.

Outcome after transcatheter occlusion of patent ductus arteriosus in infants less than 6 kg: A national study from United Kingdom and Ireland.

OBJECTIVES: This study aimed to report our national experience with transcatheter patent ductus arteriosus (PDA) occlusion in infants weighing <6 kg. BACKGROUND: The technique of transcatheter PDA closure has evolved in the past two decades and is increasingly used in smaller patients but data on safety and efficacy are limited. METHODS: Patients weighing < 6 kg in whom transcatheter PDA occlusion was attempted in 13 tertiary paediatric cardiology units in the United Kingdom and Ireland were retrospectively analyzed to review the outcome and complications. RESULTS: A total of 408 patients underwent attempted transcatheter PDA closure between January 2004 and December 2014. The mean weight at catheterization was 4.9 ± 1.0 kg and mean age was 5.7 ± 3.0 months. Successful device implantation was achieved in 374 (92%) patients without major complication and of these, complete occlusion was achieved in 356 (95%) patients at last available follow-up. Device embolization occurred in 20 cases (5%). The incidence of device related obstruction to the left pulmonary artery or aorta and access related peripheral vascular injury were low. There were no deaths related to the procedure. CONCLUSIONS: Transcatheter closure of PDA can be accomplished in selected infants weighing <6 kg despite the manufacturer's recommended weight limit of 6 kg for most ductal occluders. The embolization rate is higher than previously reported in larger patients. Retrievability of the occluder and duct morphology needs careful consideration before deciding whether surgical ligation or transcatheter therapy is the better treatment option.

Transcatheter Retrieval of Cardiovascular Foreign Bodies in Children: A 15-Year Single Centre Experience.

There has been a rapid increase in the practice of interventional catheter treatment of congenital heart disease. Catheter retrieval of embolized cardiac devices and other foreign bodies is essential, yet no large studies have been reported in the paediatric population. Retrospective 15-year review of all children who underwent transcatheter foreign body retrieval in a tertiary cardiac centre from January 1997 to September 2012. Transcatheter retrieval of foreign bodies from the cardiovascular system was attempted in 78 patients [median age 4 (0.02-16) years and median weight 15 (1.7-74) kg] including 46 embolized devices. Transcatheter retrieval was successful in 70/78 (90%), surgical retrieval was required in 6. In two patients, small embolized coils were left in situ. Gooseneck snare was the most commonly used retrieval device. Median procedure and screening times were 90 (15-316) and 31 (2-161) min, respectively. There were no procedural deaths. Transient loss of foot pulses occurred in 5 and 2 patients required blood transfusion. Transcatheter retrieval of cardiovascular foreign bodies can be performed safely in the majority of children thus obviating the need for surgery. It is essential to have a comprehensive inventory of retrieval equipment and interventional staff conversant with its use.

Epidural analgesia complicated by dural ectasia in the Marfan syndrome.

Patients with the Marfan syndrome are considered to be high risk during pregnancy and warrant a complete multidisciplinary evaluation. One goal is to minimize hemodynamic fluctuations during labor since hypertensive episodes may result in aortic dissection or rupture. Although they may prevent these complications, neuraxial techniques may be complicated by dural ectasia. The case of a parturient with the Marfan syndrome and mild dural ectasia is presented. During attempted labor epidural placement, unintentional dural puncture occurred. A spinal catheter was used for adequate labor analgesia, and a resultant postdural puncture headache was alleviated by an epidural blood patch under fluoroscopic guidance.

Effervescent N-Acetylcysteine Tablets versus Oral Solution N-Acetylcysteine in Fasting Healthy Adults: An Open-Label, Randomized, Single-Dose, Crossover, Relative Bioavailability Study.

BACKGROUND: Oral solution N-acetylcysteine (NAC) is an antidote for acetaminophen overdose, but its unpleasant taste and aroma can impede delivery even after the coadministration of antiemetic medications. Flavored effervescent NAC tablets dissolved in water might be a more palatable formulation than oral solution NAC diluted with soft drink. OBJECTIVES: To evaluate the relative bioavailability of these 2 formulations and assess subjective preferences between them. METHODS: Thirty healthy adult volunteers (mean [SD] = 35.2 [9.14] years) were enrolled in this open-label, randomized, single-dose, crossover study, with a 7-day washout period. Volunteers were randomized to receive 11 g effervescent test formulation or the reference product under fasting conditions, after which 19 serial blood samples were collected over 48 hours. Total plasma NAC concentrations were evaluated by LC-MS, and pharmacokinetic parameters were calculated. The 2 formulations were considered bioequivalent if the 90% CIs of log-transformed ratios of pharmacokinetic parameters were within the predetermined bioequivalence range (80%-125%) established by the US Food and Drug Administration. Within 15 minutes of dosing, subjects were also asked to rank formulation attributes on a 5-point hedonic scale, with mean group differences analyzed by Wilcoxon signed rank test. Safety-profile assessment included treatment-emergent adverse events, physical examination, chemistry, and hematology parameters. RESULTS: The concentration-versus-time profiles were similar for the 2 formulations, with mean Cmax of 26.5 µg/mL for effervescent NAC tablets and 28.4 µg/mL for oral solution NAC. The 90% CIs for the pharmacokinetic parameters met the criteria for concluding bioequivalence, and subjects preferred effervescent NAC tablets in terms of taste (P = 0.0247), flavor (P = 0.0082), texture (P = 0.009), and overall likeability (P = 0.0012), but there was no difference for smell (P = 0.0533). All treatment-emergent adverse events were mild, with no differences between the treatment groups. CONCLUSIONS: Data from this study of a single dose of 11 g oral NAC demonstrated that effervescent NAC tablets and oral solution NAC met the regulatory criteria for bioequivalence in fasting healthy adult subjects. Effervescent NAC tablets appear to be a more palatable alternative for treatment of acetaminophen overdose. ClinicalTrials.gov identifier: NCT02723669. (Curr Ther Res Clin Exp. 2016; 83C:1-7) © 2016 Elsevier HS Journals, Inc.

Stenting of the left pulmonary artery after palliation of hypoplastic left heart syndrome.

BACKGROUND: Left pulmonary artery stenosis and hypoplasia is a well-recognized complication following surgical palliation of hypoplastic left heart syndrome. These lesions produce increased after load in a circulation in series so need to be effectively treated. METHODS: Between 2000 and 2011, 86 patients after surgical palliation for hypoplastic left heart syndrome had left pulmonary artery stents implanted. Median age at implantation was 4.7(1.3-15.2) years and median weight was 16.4(9.3-55.2) kg. Uncovered peripheral vascular stents were implanted (median diameter 10(8-15) mm). This is a retrospective review of the incidence of in-stent restenosis over the medium to long term. RESULTS: During primary stenting procedures, there were 2/88(2.3%) major complications of stent migration with no stroke or mortality. Follow-up was for a median period of 4.1(0.5-13.4) years. Follow-up catheter procedures were performed after a median time of 2.3(0.02-9.6) years in 59 patients (68.6%). 55/59(93.2%) had at most mild restenosis (≤10% loss of stent lumen) and 47/59(79.6%) had no evidence of any restenosis at all caused by neointimal in-growth. Freedom from reintervention was 77% at 5 years including stent dilation to compensate for somatic growth. Freedom from reintervention for restenosis was 93% at 5 years. Restenosis was successfully treated with standard balloon angioplasty or restenting. There was only 1/94 (1.1%) major complication in the follow-up catheterizations of stent embolization with successful transcatheter retrieval. CONCLUSIONS: Stenting of the left pulmonary artery after Norwood/Fontan palliation is safe and effective. Stents can be redilated to match somatic growth. The incidence of neointimal proliferation is extremely low and can be addressed by balloon dilation or stent implantation. © 2016 Wiley Periodicals, Inc.

Structure-Specific Liquid Crystal Anchoring Induced by the Molecular Combing of Short Oligonucleotides.

Surface-immobilized oligonucleotides were "combed" by meniscus motion and exposed to a nematic liquid crystal (LC). Although the oligonucleotides were as short as 16 bases, they were apparently oriented by this process and, in turn, successfully biased the orientation of the adjacent LC material. Single-stranded DNA (ssDNA) induced LC orientation in the combing direction, while hybridized double-stranded DNA (dsDNA) rotated the azimuthal LC orientation by ∼30° from the combing direction. The sensitivity of the chiral response to mixed ssDNA/dsDNA surfaces was characterized by employing complementary DNA that was longer than the immobilized DNA, resulting in single-stranded overhangs of various lengths. A rotated LC orientation was observed even when more than 70% of the DNA was single-stranded, and the transition from the rotated to nonrotated response was apparently discontinuous as a function of ssDNA surface coverage. These phenomena represent a sensitive DNA hybridization detection strategy that can potentially comprise a multiplexed assay.

Receptor-Mediated Liposome Fusion Kinetics at Aqueous/Liquid Crystal Interfaces.

Membrane fusion events are essential to cell biology, and a number of reductionist systems have been developed to mimic the behavior of these biological motifs. One such system monitors the DNA hybridization-mediated fusion of liposomes with the liquid crystal (LC) interface by observing changes in LC orientation using a simple optical detection scheme. We have systematically explored key parameters of this system to determine their effects on individual elementary steps of the complex fusion mechanism. The liposome composition, specifically the degree of lipid unsaturation and PE content, decreased the bilayer rigidity, thereby increasing the rate of vesicle rupture under the stress applied by DNA hybridization. In contrast, the presence of cholesterol had the opposite effect on the mechanical properties of the bilayer, and hence of the membrane fusion rates. The accessibility of receptor moieties (i.e., complementary DNA oligonucleotides) affected the fusion kinetics by modulating the rate of hybridization events. DNA accessibility was controlled by systematic variation of the length of the DNA receptor molecules and the thickness of the steric barrier comprised of adsorbed PEGylated lipids. These results provide design rules for understanding the trade-offs between response kinetics and other important system properties, such as nonspecific adsorption. Moreover, these findings improve our understanding of the biophysical properties of membrane fusion, an important process in both natural and model systems used for bioassay and bioimaging applications.

DNA Hybridization-Mediated Liposome Fusion at the Aqueous Liquid Crystal Interface.

The prominence of receptor-mediated bilayer fusion in cellular biology motivates development of biomimetic strategies for studying fusogenic mechanisms. An approach is reported here for monitoring receptor-mediated fusion that exploits the unique physical and optical properties of liquid crystals (LC). PEG-functionalized lipids are used to create an interfacial environment capable of inhibiting spontaneous liposome fusion with an aqueous/LC interface. Then, DNA hybridization between oligonucleotides within bulk phase liposomes and a PEG-lipid monolayer at an aqueous/LC interface is exploited to induce receptor-mediated liposome fusion. These hybridization events induce strain within the liposome bilayer, promote lipid mixing with the LC interface, and consequently create an interfacial environment favoring re-orientation of the LC to a homeotropic (perpendicular) state. Furthermore, the bi-functionality of aptamers is exploited to modulate DNA hybridization-mediated liposome fusion by regulating the availability of the appropriate ligand (i.e., thrombin). Here, a LC-based approach for monitoring receptor (i.e., DNA hybridization)-mediated liposome fusion is demonstrated, liposome properties that dictate fusion dynamics are explored, and an example of how this approach may be used in a biosensing scheme is provided.

On-demand droplet fusion: a strategy for stimulus-responsive biosensing in solution.

A novel strategy is reported for biochemically controlled fusion of oil-in-water (O/W) droplets as an in-solution sensor for biological targets. Inspired by the SNARE complex in cells, the emulsions were stabilized by a combination of phospholipids, phospholipid-poly(ethylene glycol) conjugates, and cholesterol-anchored oligonucleotides. Prior to oligonucleotide binding, the droplets were stable in aqueous media, but hybridization of the oligonucleotides in a zipperlike fashion was shown to initiate droplet fusion. Using image analysis of content mixing of dye-loaded droplets, fusion specificity was studied and optimized as a function of interfacial chemistry. Changing the orientation of the anchored oligonucleotides, using long-chain phospholipids (C18 and C22), and binding a complementary oligonucleotide slowed or even halted fusion completely. Based on these studies, a sensor for the biomarker thrombin was designed using competitive binding of aptamer strands, with droplet fusion increasing as a function of thrombin addition in accordance with a simple binding model, with sensitivity down to 100 nM and with results in as little as 15 min. Future efforts will focus on utilizing this mechanism of content mixing to facilitate highly sensitive detection via modalities such as magnetoresistance or chemiluminescence.

Impact of physical manipulation on in vitro and in vivo release profiles of oxycodone DETERx®: an extended-release, abuse-deterrent formulation.

OBJECTIVE: In vitro: To assess the effect of common crushing techniques on particle size reduction (PSR) and in vitro drug-release kinetics of oxycodone DETERx® (herein DETERx) and of a commercially available oxycodone extended-release (ER) tablet. In vivo: To evaluate the impact of the most effective manipulation method identified in the in vitro study and the effect of chewing on the pharmacokinetics (PK) of DETERx relative to oxycodone solution. DESIGN: In vitro: Mechanical manipulation of dosage forms using common household utensils. In vivo: Open-label, randomized, active-controlled, crossover PK study. SUBJECTS: In vivo: Forty-four healthy male and female volunteers. METHODS: In vitro: DETERx capsule contents and marketed comparator tablets were subjected to manipulation (crushing) using 10 different household utensils. Particle size and dissolution analysis were conducted. In vivo: Subjects were randomly assigned to receive DETERx 40-mg capsules intact, crushed, or chewed or oxycodone solution. Serial blood samples were drawn for PK assessment. RESULTS: In vitro: The utensils used to manipulate DETERx capsule contents were either ineffective in reducing the particle size or produced only a small change in the median particle size and dissolution rate relative to the marketed comparator. In vivo: DETERx intact capsules provided significantly lower Cmax and longer Tmax values than oxycodone solution. Manipulation of DETERx by crushing (using the most effective method established in vitro) or chewing resulted in bioequivalent plasma concentration-time profiles to the intact dosage form. CONCLUSION: These mechanical manipulation and PK studies demonstrated that DETERx beads retained their ER properties after mechanical tampering and chewing by study subjects.

Preclinical gastrointestinal prokinetic efficacy and endocrine effects of the ghrelin mimetic RM-131.

AIMS: The 28 amino acid hormone ghrelin, the natural ligand for the growth hormone secretagogue, or ghrelin receptor (GHR), has diverse physiological functions, including a possible role as a gastrointestinal prokinetic. The synthetic ghrelin mimetic RM-131 is in Phase II clinical trials for treatment of diabetic gastroparesis and other gastrointestinal (GI) disorders. We aimed to determine the relative potency of RM-131, when compared to other GI ghrelin mimetics, to predict efficacy and determine the role of RM-131 in models of inflammatory bowel disease. MAIN METHODS: We evaluated and compared ghrelin, RM-131 and other synthetic ghrelin mimetics for their prokinetic potency in models of gastrointestinal disorders in the rat and we evaluated the endocrine (rats and dogs) and anti-inflammatory effects (mice) of the ghrelin mimetic RM-131. KEY FINDINGS: The pentapeptide RM-131 increased gastric emptying in rodent models of ileus. RM-131 is about 100-fold more potent than human ghrelin and is 600 to 1800-fold more potent, when compared to several investigational ghrelin mimetics tested in clinical trials. RM-131 has anti-inflammatory effects and significantly increases survival and reduces macroscopic markers of tissue damage in a TNBS model of inflammatory bowel disease. RM-131 treatment shows a transient increase in growth hormone levels in Beagle dogs and rats, returning to baseline upon chronic treatment. Significant effects on glucose and insulin are not observed in chronic studies. SIGNIFICANCE: RM-131's potency, efficacy and endocrine profile, are promising attributes for the treatment of diverse functional gastrointestinal disorders in humans.