Subcutaneous Pump Research Articles

Investigation of miRNA-29b As a Fetal Hemoglobin Inducer in Sickle Cell Disease

Introduction: Therapeutic intervention aimed at inducing fetal hemoglobin (HbF) expression is an effective approach for ameliorating the clinical severity of sickle cell disease (SCD). Hydroxyurea (HU) is the only FDA-approved drug with proven efficacy for inducing HbF in SCD. Recently, DNA methyltransferase (DNMT) inhibitors were shown to reactivate γ-globin gene expression via DNA hypomethylation. However, alternate approaches involve development of small non-coding microRNAs (miR) to silence major repressors of γ-globin transcription. Previous studies from our group showed that miR-29b inhibits DNA methylation by binding the 3' untranslated region of DNMT3A/B (Starlard-Davenport A et al., J Carcinog 12:15; 2013). Subsequent, studies demonstrated that increased levels of miR-29b are associated with high HbF levels in patients with SCD. To gain insights into mechanisms, studies performed in KU812 cells demonstrated DNMT3A/B silencing with ү-globin gene activation. Moreover, miR29b increased HbF expression in erythroid progenitors generated from normal adult CD34 + stem cells (Starlard-Davenport A et al., Br J Haematol 186:91-100; 2019). Therefore, we tested the hypothesis that miR-29b activates γ-globin transcription via DNA hypomethylation in normal and sickle erythroid progenitors and Townes SCD mouse model.Methods: Normal CD34 + cells (n=3) and peripheral blood mononuclear cells (n=2) isolated from SCD patients, were cultured using a two-phase erythroid culturing system. Cells were electroporated with miR-29b mimic (50nM and 100nM) or negative Scrambled (Scr) control on day 8 and collected after 24 h. Erythroid differentiation was assessed using Giemsa staining, and flow cytometry was used to measure the % HbF positive cells (F-cells). Real-time PCR was used to quantify expression of miR-29b, γ-globin, and β-globin genes, and Western blot was performed to measure DNMT, HbF and HbS protein levels. In vivo studies were performed in Townes SCD mice (3 per group) treated for 28 days by continuous infusion with subcutaneous mini-osmotic pumps. The treatment groups included miR-29b (2mg/kg/day and 3mg/kg/day) and corresponding doses of Scr control mimics.Results: We observed erythroid differentiation of untreated normal and SCD erythroid progenitors at day 7, 12, and 14 of culture assessed by Giemsa stain. Treatment with miR-29b increased the ү/ү+β mRNA ratio by 2.5‐fold (p<0.01) and F‐cell levels increased from ~6.0% (Scr) to 15% with miR-29b (100nM); we observed lower DNMT3 mRNA and protein levels after 100nM miR-29b treatment. To confirm HbF induction by miR-29b in sickle progenitors we treated cells on day 8 with 50nM and 100nM miR-29b and observed >85% increase in %F-cells compared to Scr cells. Subsequent miR-29b treatment was conducted for 28 days in Townes SCD mice, which was well tolerated documented by good weight gain and no deaths. There were minimal effects on hematopoiesis with a decrease in total white blood count and an increase in neutrophils. Total hemoglobin, reticulocyte and platelet counts remained stable. By week 4, we observed a 0.5 fold and 2.3-fold (p<0.005) increase in %F-cells at the 2mg/kg and 3 mg/kg miR-29b doses respectively compared to corresponding Scr controls. By week 4, miR29b increased HbF levels 2.1-fold by Western blot, and sickle cell levels under hypoxic conditions decreased 32% (p<0.01).Conclusions: Our findings support the ability of miR-29b to induce HbF in normal and sickle erythroid progenitors without significant toxicity in vitro and in SCD mice in vivo. This research highlights a novel miRNA-based epigenetic approach to induce HbF supporting discovery of new drugs to expand treatment options for SCD. DisclosuresPace: Imara Inc.: Consultancy.

Pharmacokinetics of hydromorphone in dogs after intravenous bolus and delivered subcutaneously with the RxActuator Mini-Infuser® infusion pump

Introduction: There are few therapeutic options to treat moderate pain in dogs on an out-patient basis. The aim of this study was to describe the pharmacokinetics of hydromorphone in dogs following either intravenous (IV) bolus or subcutaneous (SC) infusion via a wearable subcutaneous pump.

Abstract P503: Aldehyde Dehydrogenase 2 Activator 1 Potentiates The Effects Of Empagliflozin, A Sodium-glucose Cotransporter 2 Inhibitor, In Diabetes-mediated Heart Failure With Preserved Ejection Fraction

4-hydroxy-2-nonenal (4HNE), a cellular reactive aldehyde which is significantly increased in diabetic hearts due to decrease in the activity of its metabolizing enzyme, aldehyde dehydrogenase (ALDH)2, contributes to diabetes mellitus (DM)-mediated cardiotoxicity. Therefore, we hypothesize that lowering 4HNE ameliorates heart failure with preserved ejection fraction (HFpEF) in DM. To ameliorate DM mediated HFpEF, we will lower diabetes-mediated oxidative stress-induced 4HNE accumulation as well as augment 4HNE detoxification by activating ALDH2, via pharmacological agents. We induced type-2 DM by feeding high-fat diet (HFD) in ALDH2*2 mutant mice which have intrinsically low ALDH2 activity and thus having increased cardiac 4HNE levels. After 4 months of DM, the mice exhibited features of HFpEF and we treated the diabetic ALDH2*2 mice with vehicle (Veh), empagliflozin (EMP) (3mg/kg/d), a sodium-glucose cotransporter (SGLT) 2 inhibitor to reduce hyperglycemia and Alda-1 (10mg/kg/d), an ALDH2 activator to enhance ALDH2 activity as well as combination of EMP + Alda-1 (E + A), via subcutaneous osmatic pumps. After treating for 2 months, cardiac function was assessed by conscious echocardiography before and after exercise stress. EMP + Alda-1 improved running distance (RD, 231 ± 53 m), ejection fraction after running (EF, 69 ± 5 %), and decreased left atrial area (LA, 3.0 ± 0.2 mm 2 ), cardiomyocyte cross-section area (CA, 251 ± 32 μm 2 ) and myocardial fibrotic area (FA 1.0 ± 0.3 %) in ALDH2*2 mice with diabetic HFpEF compared to EMP (RD 142 ± 53 m; EF 62 ± 5 %; LA 3.5 ± 0.3 mm 2 ; CA 303 ± 55 μm 2 ; and FA 3.2 ± 1.8 %), Alda-1 (RD 183 ± 73 m; EF 68 ± 3 %; LA 3.2 ± 0.2 mm 2 ; CA 288 ± 34 μm 2 ; and FA 2.5 ± 1.2 %) and Veh (RD 52 ± 66 m; EF 55 ± 5.0 %; LA 4.7 ± 0.4 mm 2 ; CA 448 ± 65 μm 2 ; and FA 11 ± 3.5 %). This improvement was exerted by decreasing 4HNE levels as well as attenuating 4HNE-mediated decrease in cardiac liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. In conclusion, our data implicate that ALDH2 activation along with the treatment of hypoglycemic agents may be important strategy to alleviate diabetic HFpEF.

Standardizing Care for Patients with Insulin Pumps

<h3>Introduction</h3> An increase in the number of patient with subcutaneous insulin pumps was noted in the surgical population. Multiple types of insulin pumps and various levels of patient knowledge were being noted by perioperative staff. <h3>Identification of the problem</h3> The plan of care was found to be inconsistent for these patients and there was no standardized treatment guideline in place to manage practice. <h3>Objectives of project</h3> The objective of this project was to 1) Standardize the perioperative process of insulin pump management, 2) Create a clinical practice guideline specific for this population, and 3) Systematically educate staff of the new process and guideline. <h3>Method</h3> A multidisciplinary team was assembled and the current practice was analyzed to identify gaps. Multiple areas of practice were identified. Monthly meetings were held with leaders from each area contributing to the practice guideline development. <h3>Outcomes</h3> A multidisciplinary clinical practice guideline was developed in conjunction with endocrinology physicians, hospitalists, anesthesiologists, nurses and pharmacists to standardize the process from pre-admission screening to discharge. A new process was created in the electronic medical record to record the patients pump, basal rate and bolus amounts given. Education for staff was developed and distributed hospital wide. <h3>Discussion</h3> This QI project targeted a clinical gap and created a team from nursing, medicine, pharmacy, nutrition, anesthesiology and informatics to standardize practice for a low volume, high risk process. This project ensures that patients with insulin pumps are identified in the pre-screening unit and are assessed for their independence in pump management. <h3>Conclusion and implications</h3> Patients with insulin pumps are now admitted day of surgery with a detailed plan of care from an endocrinologist. Accurate documentation of patient's insulin pump and activity is now standardized. This assists with communication between nursing staff and anesthesia, and aides in promoting positive outcomes for surgical patients. <h3>Future Research</h3> Comparison of glucose levels pre and post practice guideline implementation for effectiveness of change.

Epidemiology of skin event rates among users of pumps for the subcutaneous administration of drugs for chronic conditions

Objective To provide the epidemiology of skin events occurring during long-term administration of medications delivered by continuous subcutaneous infusion pump (CSIP) systems as background rates for the development of novel CSIP treatments to use in community-based settings. Methods Using a United Kingdom general practice database, we conducted a study to assess the rates of skin events among new users of apomorphine and insulin delivered by CSIP in patients with Parkinson’s disease or diabetes, respectively. Skin events included skin infections, skin nodules/localized swelling, dermatitis/eczema, urticaria/erythema, and rash/other non-specific skin eruptions. Results Five hundred and fifty-seven adults (age 30+) were included in this descriptive cohort. The median duration of CSIP use was 17 months among 255 apomorphine users and 41 months among 302 insulin users. By 60 months, ∼40% of both cohorts experienced skin events. Repeated skin events occurred in 11% of the apomorphine cohort and 14% of the insulin cohort at any time during follow-up. The overall skin event rate in the apomorphine cohort was 17 per 1000 person-months (PM) and 13 per 1000 PM in the insulin cohort. The most common skin events in both cohorts were infection and rash/unspecified skin eruptions. The highest rates of skin events occurred soon after apomorphine CSIP initiation (36 per 1000 PM in weeks 1–2 and 50 per 1000 PM in weeks 3–4), with lower rates after 4 weeks. Insulin CSIP users’ skin event rates were consistent over the treatment duration. Conclusions Clinically important skin events are common during long-term administration of medications by CSIP.

Hepatic Arterial Infusion Chemotherapy for Unresectable Intrahepatic Cholangiocarcinoma, a Comprehensive Review.

Cholangiocarcinoma (CCA) is the second most common primitive liver cancer. Despite recent advances in the surgical management, the prognosis remains poor, with a 5-year survival rate of less than 5%. Intrahepatic CCA (iCCA) has a median survival between 18 and 30 months, but if deemed unresectable it decreases to 6 months. Most patients have a liver-confined disease that is considered unresectable because of its localization, with infiltration of vascular structures or multifocality. The peculiar dual blood supply allows the delivery of high doses of chemotherapy via a surgically implanted subcutaneous pump, through the predominant arterial tumor vascularization, achieving much higher and more selective tumor drug levels than systemic administration. The results of the latest studies suggest that adequate and early treatment with the combination approach of hepatic arterial infusion (HAI) and systemic (SYS) chemotherapy is associated with improved progression-free and overall survival than SYS or HAI alone for the treatment of unresectable iCCA. Current recommendations are limited by a lack of prospective trials. Individualization of chemotherapy and regimens based on selective targets in mutant iCCA are a focus for future research. In this paper we present a comprehensive review of the studies published to date and ongoing trials.

Generating Acute and Chronic Experimental Models of Motor Tic Expression in Rats.

Motor tics are sudden, rapid, recurrent movements that are the key symptoms of Tourette syndrome and other tic disorders. The pathophysiology of tic generation is associated with abnormal inhibition of the basal ganglia, particularly its primary input structure, the striatum. In animal models of both rodents and non-human primates, local application of GABAA antagonists, such as bicuculline and picrotoxin, into the motor parts of the striatum induces local disinhibition resulting in the expression of motor tics. Here, we present acute and chronic models of motor tics in rats. In the acute model, bicuculline microinjections through a cannula implanted in the dorsal striatum elicit the expression of tics lasting for short time periods of up to an hour. The chronic model is an alternative enabling the extension of tic expression to periods of several days or even weeks, utilizing continuous infusion of bicuculline via a sub-cutaneous mini-osmotic pump. The models enable the study of the behavioral and neural mechanisms of tic generation throughout the cortico-basal ganglia pathway. The models support the implantation of additional recording and stimulation devices in addition to the injection cannulas, thus allowing for a wide variety of usages such as electrical and optical stimulation and electrophysiological recordings. Each method has different advantages and shortcomings: the acute model enables the comparison of the kinematic properties of movement and the corresponding electrophysiological changes before, during and after tic expression and the effects of short-term modulators on tic expression. This acute model is simple to establish; however, it is limited to a short period of time. The chronic model, while more complex, makes feasible the study of tic dynamics and behavioral effects on tic expression over prolonged periods. Thus, the type of empirical query drives the choice between these two complementary models of tic expression.

Hepatic Arterial Infusion Pumps: What the Radiologist Needs to Know.

Hepatic arterial infusion (HAI) entails the surgical implantation of a subcutaneous pump to deliver chemotherapeutic agents directly to the liver in the setting of primary or secondary liver cancer. The purpose of HAI chemotherapy is to maximize hepatic drug concentrations while minimizing systemic toxicity, facilitating more effective treatment. HAI is used in combination with systemic chemotherapy and can be considered in several clinical scenarios, including adjuvant therapy, conversion of unresectable disease to resectable disease, and unresectable disease. Radiologists are key members of the multidisciplinary team involved in the selection and management of these patients with complex liver disease. As these devices begin to be used at more sites across the country, radiologists should become familiar with the guiding principles behind pump placement, expected imaging appearances of these devices, and potential associated complications. The authors provide an overview of HAI therapy, with a focus on the key imaging findings associated with this treatment that radiologists may encounter. ©RSNA, 2021.

Ontogenetic Oxycodone Exposure Affects Early Life Communicative Behaviors, Sensorimotor Reflexes, and Weight Trajectory in Mice.

Nationwide, opioid misuse among pregnant women has risen four-fold from 1999 to 2014, with commensurate increase in neonates hospitalized for neonatal abstinence syndrome (NAS). NAS occurs when a fetus exposed to opioids in utero goes into rapid withdrawal after birth. NAS treatment via continued post-natal opioid exposure has been suggested to worsen neurodevelopmental outcomes. We developed a novel model to characterize the impact of in utero and prolonged post-natal oxycodone (Oxy) exposure on early behavior and development. Via subcutaneous pump implanted before breeding, C57BL/6J dams were infused with Oxy at 10 mg/kg/day from conception through pup-weaning. At birth, in utero oxy-exposed pups were either cross-fostered (paired with non-Oxy exposed dams) to model opioid abstinence (in utero Oxy) or reared by their biological dams still receiving Oxy to model continued post-natal opioid exposure (prolonged Oxy). Offspring from vehicle-exposed dams served as cross-fostered (in utero Veh) or biologically reared (prolonged Veh) controls. In utero Oxy exposure resulted in sex-dependent weight reductions and altered spectrotemporal features of isolation-induced ultrasonic vocalization (USV). Meanwhile, prolonged Oxy pups exhibited reduced weight and sex-differential delays in righting reflex. Specifically, prolonged Oxy female offspring exhibited increased latency to righting. Prolonged Oxy pups also showed decreases in number of USV calls and changes to spectrotemporal USV features. Overall, ontogenetic Oxy exposure was associated with impaired attainment of gross and sensorimotor milestones, as well as alterations in communication and affective behaviors, indicating a need for therapeutic interventions. The model developed here will enable studies of withdrawal physiology and opioid-mediated mechanisms underlying these neurodevelopmental deficits.

516 Comparison of intrapartum glycemic management strategies in pregnant women with type 1 diabetes mellitus

Achieving intrapartum maternal euglycemia in women with type 1 diabetes mellitus (T1DM) is critical to reducing the risk of neonatal hypoglycemia. This study sought to compare the maternal and neonatal outcomes among women with T1DM by different intrapartum glycemic control strategies of continuation of subcutaneous insulin pumps versus intravenous insulin infusion. A retrospective cohort study was performed to identify all women with type 1 diabetes mellitus in pregnancy between October 1, 2017 and August 1, 2020 at our tertiary medical center. Medical records were reviewed for sociodemographic, clinical characteristics, and perinatal outcomes. A composite neonatal outcome was created to include one or more of the following outcomes: 1 minute APGAR less than 7, neonatal intensive care unit admission, neonatal hypoglycemia, or respiratory distress. We identified 75 women with T1DM that met inclusion criteria, 27(36%) who remained on their subcutaneous insulin pump and 48(64%) who were transitioned to intravenous insulin infusion intrapartum. Women that continued subcutaneous insulin were more likely to be older (30.5 vs. 28.1, p=0.04), privately insured (85% vs. 15%, p=0.003), multiparous (74% vs. 50%, p=0.042), and have a continuous glucose monitor (CGM) (93% vs. 43%, p<0.001). There was no difference in maternal hypoglycemic events (14.8% vs. 18.8%, p=0.76) or severe hyperglycemia (greater than 300 mg/dL)/development of diabetic ketoacidosis (3.7% vs. 4.2%, p=0.99) in labor between both groups. There was no difference in neonatal composite outcome when adjusted for gestational age at delivery, maternal age, parity, and CGM use for both groups (aOR 0.73, 95% CI 0.12-4.43, p=0.728). Continuation of subcutaneous insulin in the intrapartum period is a reasonable option in women with T1DM given there is no observed difference in maternal or neonatal outcomes when compared to intravenous insulin infusion. Both patient and provider must be comfortable with this intrapartum strategy for glycemic control.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Interleukin-4 repairs wear particle induced osteolysis by modulating macrophage polarization and bone turnover.

Periprosthetic osteolysis remains as a major complication of total joint replacement surgery. Modulation of macrophage polarization with interleukin-4 (IL-4) has emerged as an effective means to limit wear particle-induced osteolysis. The aim of this study was to evaluate the efficacy of local IL-4 delivery in treating preexisting particle-induced osteolysis. To this end, recently established 8week modification of murine continuous femoral intramedullary particle infusion model was utilized. Subcutaneous infusion pumps were used to deliver polyethylene (PE) particles into mouse distal femur for 4 weeks to induce osteolysis. IL-4 was then added to the particle infusion for another 4 weeks. This delayed IL-4 treatment (IL-4 Del) was compared to IL-4 delivered continuously (IL-4 Cont) with PE particles from the beginning and to the infusion of particles alone for 8 weeks. Both IL-4 treatments were highly effective in preventing and repairing preexisting particle-induced bone loss as assessed by μCT. Immunofluorescence indicated a significant reduction in the number of F4/80 + iNOS + M1 macrophages and increase in the number of F4/80 + CD206 + M2 macrophages with both IL-4 treatments. Reduction in the number of tartrate resistant acid phosphatase + osteoclasts and increase in the amount of alkaline phosphatase (ALP) + osteoblasts was also observed with both IL-4 treatments likely explaining the regeneration of bone in these samples. Interesting, slightly more bone formation and ALP + osteoblasts were seen in the IL-4 Del group than in the IL-4 Cont group although these differences were not statistically significant. The study is a proof of principle that osteolytic lesions can be repaired via modulation of macrophage polarization.

DDEL-07. A PHASE I STUDY EXAMINING THE FEASIBILITY OF INTERMITTENT CONVECTION-ENHANCED DELIVERY (CED) OF MTX110 FOR THE TREATMENT OF CHILDREN WITH NEWLY DIAGNOSED DIFFUSE MIDLINE GLIOMAS

Convection-enhanced delivery (CED, the infusion of drugs under controlled pressure to the brain parenchyma via targeted micro-catheters, allows accurate anatomical targeting and delivery of higher (therapeutic) drug concentrations through clinically relevant volumes of brain tissue or tumor. Histone deacetylase inhibitors have been found in vitro to be the most active agents against Diffuse Midline Gliomas (DMGs) Using a novel device (implantable subcutaneous pump connected with catheter directly implanted into the pons/thalamus) we are performing a Phase I safety study of repeated infusions of MTX110 (MTX110, Midatech) in a dose escalation manner. Eligible patients include 3–18 years of age with newly diagnosed DMGs following radiation therapy without evidence of hemorrhage or cysts with intact organ function. Patients undergo a tumor biopsy and a single catheter (Spetzler lumbar shunt catheter, Integra, Plainsboro, NJ) is placed stereotactically into the geometric center of the tumor. A second catheter is inserted subcutaneously with the distal tubing connected to the infusion pump, (SynchroMed II (Medtronic)), also inserted subcutaneously. The infusion pump is prefilled with MTX110 and administered using wireless N’Vison Clinical programmer into two 24-hour infusions, consisting of 20 hours of drug infusions at 0.2mL/hr. The pulse is completed 7 days later. This is a dose escalation study with the infusate consisting of gadolinium and MTX110 (30, 60, or 90 microM). The study describing the first use in children of this device for direct-to-tumor drug delivery is open to recruitment (January 2020) and the preliminary data will be available for presentation by June 2020.

Regulation of amyloid‐beta pathology by CNS amylin receptors in APP/PS1 mice

AbstractBackgroundAmylin is a pancreatic amyloid protein, known to regulate glucose homeostasis and satiety through its ability to sensitize insulin and leptin. Importantly, the amylin receptor (AMYR) is expressed throughout the brain, including areas important in both cognition and Alzheimer’s disease (AD) pathology, like the hippocampus. We and others have previously shown that an analogue of amylin, Pramlintide (PRAM), reduces Aβ plaque burden and recuses hippocampal‐dependent cognitive decline in AD‐mouse models. However, the mechanisms underlying the therapeutic benefits of PRAM are not known.MethodAPP/PS1 mice were treated with PRAM, or saline, chronically via a subcutaneous pump for eight weeks. Additionally, a second subcutaneous pump connected to an ICV cannula delivered an AMYR antagonist, AC187 or aCSF during the last four weeks of peripheral treatment. Radial Arm Water Maze was performed at the end of study to measure spatial memory. Soluble‐Aβ1‐42 hippocampal levels were measured via ELISA and APP processing enzymes were evaluated by Western Blot.ResultPreliminary data suggests central blockade of amylin receptors may exacerbate Aβ burden and prevent learning of spatial‐memory tasks; while PRAM treatment showed increased protein expression of certain Aβ degradation enzymes.ConclusionEvaluation of AMYR blockade in AD‐modeled mice has supported a deeper knowledge of amylin signaling in the brain.

It's time: Delivering optimal emergency care of residents of aged care facilities in the era of COVID-19.

It's time: Delivering optimal emergency care of residents of aged care facilities in the era of COVID-19.

CTNI-25. PHASE IB CLINICAL TRIAL OF CHRONIC CONVECTION-ENHANCED DELIVERY OF TOPOTECAN FOR RECURRENT GLIOBLASTOMA

Abstract OBJECTIVES Convection-enhanced delivery (CED) provides pharmacokinetic advantages over systemic delivery for achieving cytotoxic drug levels into targeted regions of the brain. A major shortcoming of CED has been the need to limit treatment duration because of infection risks associated with external pumps. We engineered a subcutaneously implanted catheter-pump construct for prolonged CED which was successfully tested in a large animal model and then approved by the FDA for a Phase Ib clinical trial with topotecan in patients with refractory glioblastoma (IND 131889). METHODS Five patients with recurrent glioblastoma underwent surgical implantation of a subcutaneous pump and catheter that infused intracerebral topotecan over 30 days. Gadolinium was co-infused as a surrogate tracer and advanced non-invasive radiographic imaging was used to monitor drug distribution and pharmacological effects. Tissue from multiple radiographically-localized regions of each tumor and surrounding brain was procured pre-treatment at the time of catheter implantation and then post-treatment when tumors were surgically resected. Tissue was used for drug level measurements and advanced molecular, genomic and cellular analysis of treatment effects. RESULTS Treatments were successfully completed in all five patients without significant complications. The safety and tolerability of treatment was validated by quality-of-life measures and neurological assessments. Noninvasive imaging demonstrated large and stable drug distribution volumes. Comprehensive tissue analysis demonstrated effective targeting of mitotically active tumor cells while sparing neurons. CONCLUSIONS We engineered a subcutaneously implanted catheter-pump construct for chronic CED that was successfully tested in a Phase Ib clinical trial with topotecan in recurrent glioblastoma patients. Analysis of pre- and post-treatment tissue showed significant anti-tumor activity from topotecan that was not harmful to normal brain. Chronic CED combined with non-invasive real time drug distribution monitoring provides a safe and effective glioma strategy suitable for clinical use.

BouNDless: An active-controlled, randomised, double-blind, double-dummy trial of continuous subcutaneous infusion of levodopa/carbidopa with ND0612 in patients with Parkinson's disease

Objective: ND0612 is a proprietary drug-device combination delivering liquid levodopa/carbidopa (60/7.5mg/mL) via a subcutaneous (SC) infusion pump. This aim of this phase 3 study (NCT04006210) is to confirm the efficacy, safety, and tolerability of continuous levodopa infusion with ND0612 in comparison to oral immediate-release levodopa/carbidopa in patients with Parkinson's disease (PD) experiencing motor complications.

Estrategia terapéutica en el paciente diabético (III). Insulinoterapia

Insulin is the main treatment in type 1 diabetes mellitus and a therapeutic option in type 2 diabetic patient. In gestational diabetes, and other special conditions (for example, diabetes following pancreatectomy), insulin is the treatment of choice, too. In order to make the patient euglycemic the most of the time, we have basal and prandial insulins, as well as prefixed mixtures, which control both fasting blood glucose and postprandial blood glucose. Continuous subcutaneous insulin-infusion pumps, is other therapeutic option for type 1 diabetic patient, whose advantages in selected and trained patients, are metabolic control and to lower the risk of hypoglycemia. Insulin allergy is the only absolute contraindication for this treatment; synthetic insulin is reducing this disorder. Taking into account insulin is metabolized and excreted by liver and kidney, respectively, kidney and liver failure have to be taken into account in insulin dose adjustment. Hypoglycemia is the main adverse effect. Nowadays, local adverse effects caused by subcutaneous administration are less frequent. In diabetic patient, health training is key, mainly in those where insulin is being used.

Advance care planning and syringe drivers in palliative and end-of-life care.

This article discusses the practicalities of syringe drivers (subcutaneous continuous infusion pumps) for symptom control in patients requiring palliative or end-of-life care, which may form part of an advance care plan. It includes a discussion of palliative and end-of-life care, advance care planning, and when a syringe driver might be beneficial for the patient. It also provides step-by-step clinical guidance on setting up a syringe driver.

Cardiac morphological and functional changes induced by C-type natriuretic peptide are different in normotensive and spontaneously hypertensive rats.

Inflammation and fibrosis are key mechanisms in cardiovascular remodeling. C-type natriuretic peptide (CNP) is an endothelium-derived factor with a cardiovascular protective role, although its in-vivo effect on cardiac remodeling linked to hypertension has not been investigated. The aim of this study was to determine the effects of chronic administration of CNP on inflammatory and fibrotic cardiac mechanisms in normotensive Wistar rats and spontaneously hypertensive rats (SHR). Twelve-week-old male SHR and normotensive rats were infused with CNP (0.75 μg/h/100 g) or isotonic saline (NaCl 0.9%) for 14 days (subcutaneous micro-osmotic pumps). Echocardiograms and electrocardiograms were performed, and SBP was measured. After treatment, transforming growth factor-beta 1, Smad proteins, tumor necrosis factor-alpha, interleukin-1 and interleukin-6, nitric oxide (NO) system and 2-thiobarbituric acid-reactive substances were evaluated in left ventricle. Histological studies were also performed. SHR showed lower cardiac output with signs of fibrosis and hypertrophy in left ventricle, higher NO-system activity and more oxidative damage, as well as higher pro-inflammatory and pro-fibrotic markers than normotensive rats. Chronic CNP treatment-attenuated hypertension and ventricular hypertrophy in SHR, with no changes in normotensive rats. In left ventricle, CNP induced an anti-inflammatory and antifibrotic response, decreasing both pro-fibrotic and pro-inflammatory cytokines in SHR. In addition, CNP reduced oxidative damage as well as collagen content, and upregulated the NO system in both groups. Chronic CNP treatment appears to attenuate hypertension and associated end-organ damage in the heart by reducing inflammation and fibrosis.

Role of glucosamine in development of diabetic neuropathy independent of the aldose reductase pathway.

Long-term metabolic aberrations contribute to the development of diabetic neuropathy but the precise mechanism or mechanisms remains elusive. We have previously shown that aldose reductase-deficient mice exhibit delayed onset and progression of neuropathy following induction of diabetes, suggesting a role both for downstream metabolites of this enzyme and also for other unrelated pathways. In this study, we have utilized comprehensive metabolomics analyses to identify potential neurotoxic metabolites in nerve of diabetic mice and explored the mechanism of peripheral nerve injury. Aldose reductase knockout and control C57Bl/6J mice were made diabetic by injection of streptozotocin and followed for 8–16 weeks. Diabetic aldose reductase knockout mice exhibited delayed onset of nerve conduction slowing compared to diabetic wild-type mice. The sciatic nerves from aldose reductase knockout mice exposed to 12 weeks of diabetes were used for metabolomics analysis and compared with analyses of nerves from age-matched diabetic wild-type mice as well as non-diabetic aldose reductase knockout and wild-type mice. Neurotoxicity of candidate metabolites was evaluated using cultured Schwann cells and dorsal root ganglion neurons, and further confirmed in vivo. Metabolomics analysis identified elevated glucosamine levels in both diabetic aldose reductase knockout and diabetic wild mice. Exposure to glucosamine reduced survival of cultured Schwann cells and neurons accompanied by increased expression of cleaved caspase 3, CCAT-enhancer-binding homologous protein and mitochondrial hexokinase-I, along with ATP depletion. These changes were suppressed by siRNA to hexokinase-I or the ATP donor, inosine, but not by the antioxidant N-acetylcysteine or the endoplasmic reticulum-stress inhibitor 4-phenylbutyrate. The O-GlcNAcylation enhancer, O-(2-acetamido-2-deoxy-d-glucopyranosylidene) amino N-phenylcarbamate, did not augment glucosamine neurotoxicity. Single dose glucosamine injection into mice caused a reduction of sciatic nerve Na, K-ATPase activity, ATP content and augmented expression of hexokinase-I, which were suppressed by pretreatment with inosine but not with 4-phenylbutyrate. Mice implanted with a subcutaneous pump to infuse glucosamine for 12 weeks developed nerve conduction slowing and intraepidermal nerve fibre loss, recapitulating prominent indices of diabetic neuropathy. While acute glucosamine neurotoxicity is unlikely to contribute substantially to the slowly developing neuropathy phenotype in humans, sustained energy deprivation induced by glucosamine may well contribute to the pathogenesis of diabetic neuropathy. Our data thus identifies a novel pathway for diabetic neuropathy that may offer a potential new therapeutic target.