Continuous Subcutaneous Infusion Research Articles

Personality and quality-of-life improvement after apomorphine infusion in Parkinson’s disease

Abstract People with Parkinson’s disease with motor fluctuations can be treated by Continuous Subcutaneous Apomorphine Infusion (CSAI) to reduce their symptoms. Nonetheless, factors are lacking to predict patients’ quality-of-life amelioration after CSAI. This pilot study aimed to evaluate associations between personality dimensions and quality-of-life improvement after six months of CSAI. Thirty-nine people with Parkinson’s disease awaiting CSAI were included. Linear regression models between “Temperament and Character Inventory” personality dimensions at baseline and percentage of change in PDQ-39 (Parkinson’s Disease Questionnaire-39) scores after six months of CSAI were realized (n = 35). Temperament and Character Inventory was also compared between patients awaiting CSAI and patients awaiting deep brain stimulation of the sub-thalamic nucleus (n = 39 from the PREDI-STIM study). Higher Reward Dependence scores were associated with a better quality-of-life outcome after six months of CSAI, while Self-Directedness scores were associated with a better quality of life before CSAI (as opposed to Harm Avoidance, Reward Dependence, and Self-Transcendence scores associated with a worse quality of life). Moreover, people with Parkinson’s disease awaiting deep brain stimulation of the sub-thalamic nucleus had similar Temperament and Character Inventory dimensions compared to patients awaiting CSAI. People with Parkinson’s disease with higher Reward Dependence scores at baseline had the best quality-of-life improvement after six months of CSAI. This finding could be used to better prepare and accompany people with Parkinson’s disease during CSAI establishment. Moreover, this result could serve as an orientation factor to second-line treatments.

What was first and what is next in selecting device-aided therapy in Parkinson's disease? Balancing evidence and experience.

Parkinson's disease (PD) progresses with motor fluctuations emerging several years after treatment initiation. Initially managed with oral medications, these fluctuations may later necessitate device-aided therapy (DATs). Globally, various DATs options are available, including continuous subcutaneous apomorphine infusion, deep brain stimulation, levodopa-carbidopa intestinal gel, levodopa-entacapone-carbidopa intestinal gel, and subcutaneous foslevodopa/foscarbidopa infusion, each with its complexities. Hence, matching complex patients with suitable therapy is critical. This review offers practical insights for physicians managing complex PD cases. Balancing evidence and experience is vital to select the most suitable DATs, considering factors like disease stage and patient preferences. Comparative analysis of DATs benefits and risks provides essential insights for clinicians and patients. Treatment sequences vary based on availability, patient needs, and disease progression. Less invasive options like apomorphine are often preferred initially, followed by other DATs if needed. Patient selection requires comprehensive evaluations, including motor function and cognitive status. Follow-up care involves symptom monitoring and adjusting medications. Customized treatment plans are essential for optimizing PD management with DATs.

Ketamine subcutaneous continuous infusion for depressive symptoms at home: A case report beyond pain use.

Ketamine has been widely used in refractory pain as an opioid adjuvant. Evidence suggests that ketamine can also have an essential role in easing depressive symptoms. Its rapid onset of action makes it a valuable choice in palliative care. We present a case of a 70-year-old man with stage IV renal carcinoma and bone metastasis. The main symptoms included neuropathic pain, depression, and a persistent and severe desire for death. We started continuous subcutaneous infusion with morphine 30 mg and ketamine 100 mg/day. The dose of ketamine was incremented to the maximum of 250 mg/day. During the 28-day treatment, we observed an overall improvement in neuropathic pain, depressive symptoms, and other end-of-life psychological aspects of distress. Only minor psychological side effects were identified, which were controlled by using midazolam in the continuous subcutaneous infusion. Some studies have already demonstrated the benefits of ketamine use in alleviating depression, using parental infusion or oral formulas, which are administered in hospice care. Our report enhances the benefit of the subcutaneous route for palliative patients cared for at home.

Quality of Life Effects of Continuous Subcutaneous Infusion of Foslevodopa/Foscarbidopa in People with Parkinson’s (P9-3.003)

Quality of Life Effects of Continuous Subcutaneous Infusion of Foslevodopa/Foscarbidopa in People with Parkinson’s (P9-3.003)

Effects of Continuous Subcutaneous Infusion of Foslevodopa/Foscarbidopa on Sleep Dysfunction in People with Parkinson’s (P9-3.005)

Effects of Continuous Subcutaneous Infusion of Foslevodopa/Foscarbidopa on Sleep Dysfunction in People with Parkinson’s (P9-3.005)

Repeated Filling of Elastomeric Pumps for Home-Based Subcutaneous Infusions: A Cost Analysis of 240 Devices.

The use of continuous subcutaneous infusion of drugs using the repeated filling of elastomeric infuser pumps (EIP) has gained clinical recognition for palliative care at home. However, to date, there has been a notable absence of research examining the cost implications associated with the repeated EIP filling procedure. We aimed to evaluate the cost associated to the repeated filling of EIP used in a home-based palliative care team. We conducted an analysis of the cost associated to the repeated filling of 240 EIP (1-day, n = 136; 2-day, n = 102; 7-day, n = 2) (110 patients). The refilling procedure led to a reduction in the utilization of 409 devices, resulting in savings of €4.031. EIP refilling did not result in a decrease in the number of home visits, the duration of each visit, the expenses associated with transportation to patients' residences, or the nurse-to-hour cost. Refilling EIPs reduces costs by reducing the number of devices purchased. No additional cost savings were noted in nursing time, number of home visits and duration, and expenses with transportation. Further cost savings could be realized by training laycarers to refill EIP at home independently. Future research should assess the feasibility of laycarers training programs on performing EIP filling at home.

Continuous Subcutaneous Delivery of rhPTH(1-84) and rhPTH(1-34) by Pump in Adults With Hypoparathyroidism.

Continuous subcutaneous infusion of recombinant parathyroid hormone (rhPTH) through a pump has been proposed as a therapeutic alternative for patients with chronic hypoparathyroidism who remain symptomatic or hypercalciuric on conventional treatment (calcium and active vitamin D) or daily injections of rhPTH(1-84) or rhPTH(1-34). However, the real-world evidence of the outcome of this novel therapy is limited. We report the clinical and biochemical outcomes of 12 adults with hypoparathyroidism (11 women, age 30-70 years, and 1 man, age 30 years) from 3 different clinical sites in the United States who were transitioned from conventional therapy to daily injections of rhPTH(1-84) or rhPTH(1-34) and then switched to continuous administration of rhPTH(1-84)/rhPTH(1-34) via pump therapy. In most patients, mean serum calcium concentrations increased while on PTH pump therapy compared with both conventional therapy (in 11 patients) and single/multiple daily rhPTH injections (in 8 patients). Despite this, 10 patients had lower median 24-hour urinary calcium levels while on PTH pump therapy compared with prior therapy (mean ± SD difference: -130 ± 222 mg/24 hours). All patients reported a qualitative decrease in hypocalcemic symptoms while receiving pump therapy. Three patients had pod failure at least once, and 1 patient developed an infusion site reaction. In this case series of 12 patients with chronic hypoparathyroidism treated with rhPTH(1-84)/rhPTH(1-34) administered via a pump, improvement in clinical and biochemical parameters were observed in the majority of the patients. Our observations indicate benefits of pump administration of rhPTH that warrant further investigation.

Results of biosimilar assessing of insulin aspart preparations of Russian and foreign production using the hyperinsulinemic euglycemic clamp method and studying the use of a new ultra-fast-acting Russian biosimilar in pumps

Introduction. Ultra-fast-acting insulin aspart has great potential for improving postprandial glycemia in patients with type 1 and type 2 diabetes mellitus due to its pharmacological characteristics. The development and production of biosimilars are increasing the availability of modern insulins for patients.Aim. To evaluate the comparability of the pharmacokinetics and pharmacodynamics profiles of insulin aspart GP40311 (tested biosimilar of domestic production) and the reference drug (produced in Denmark) under conditions of a hyperinsulinemic euglycemic clamp in healthy volunteers. To evaluate the stability of a new ultrafast-acting biosimilar when used for continuous subcutaneous infusion in insulin pumps.Materials and methods. Double-blind, randomized, crossover study assessing the pharmacokinetics, pharmacodynamics and safety of the tested biosimilar GP40311 of domestic production and the reference drug produced in Denmark, in the form of a solution for intravenous and subcutaneous administration of 100 IU/ml, the study was conducted under conditions of a hyperinsulinemic euglycemic clamp with the participation of 36 healthy volunteers. A study of the stability, dosing accuracy and tendency to catheter occlusion of a domestic drug for continuous subcutaneous infusion was carried out using several types of insulin pumps using the gravimetric method for 72 hours. Dosing accuracy was determined at the minimum and maximum bolus dose, stability was assessed by pH and quantitative insulin content aspart. The quantitative content of insulin and impurities was assessed by high-performance liquid chromatography.Results and discission. The 90% confidence interval for the ratio of geometric mean values of the main parameters of pharmacokinetics (AUCins.0-t and Cins.max) of insulin aspart test and reference drugs corresponded to the acceptable values of 80.00– 125.00%, which indicated their biosimilarity. When assessing PD, the comparability of action parameters is shown. The safety of the study drugs is comparable. Domestic insulin aspart met the specification standards when used for continuous subcutaneous infusion according to physicochemical parameters: pH, quantitative determination of insulin aspart, impurity content. The accuracy of dosing and the absence of occlusions in systems for 72 hours when using the drug in pumps have been established.Conclusion. The study drugs were found to be biosimilar and equally safe. Domestic insulin aspart meets specification standards and can be used in various types of pumps.

Terminal Care in Parkinson's Disease: Real-Life Use of Continuous Subcutaneous Apomorphine Infusion to Improve Patient Comfort.

There are currently no recommendations on the therapeutic management of Parkinson's disease (PD) patients at the end of life. To describe a cohort of patients with PD who benefited from continuous subcutaneous apomorphine infusion (CSAI) initiation at the end of their life as comfort care. This real-life cohort includes 14 PD patients, who benefited from 24-h, low-dose CSAI (0.5-3 mg/h) in the context of terminal care. Patient's comfort (pain, rigidity, and/or ability to communicate) and occurrence of CSAI-related side-effects (nausea/vomiting, cutaneous and behavioral manifestations) were evaluated based on medical records. All patients (age 62-94 years, disease duration 2-32 years) presented with late-stage PD and a compromised oral route. Treatment lasted from a few hours to 39 days. CSAI led to substantial functional improvement, with a good safety profile. Overall clinical comfort was deemed improved by the medical team, the patient, and/or caregivers. CSAI might be a promising approach in PD terminal care, as it reduces motor symptoms and overall discomfort, with an apparent good safety profile. Use of the apomorphine pen, sublingual film or a classic syringe pump might be considered when apomorphine pumps are not available. Larger observational cohorts and randomized controlled trials are needed to establish the efficacy and tolerability of apomorphine in the context of terminal care and more broadly, in an advance care planning perspective.

Improvement of Nutritional Status of Patients with Adenomyosis Combined with Lower Extremity Deep Venous Thrombosis by Combination Therapy

This study aims to explore the effect of a comprehensive treatment scheme comprising conservative surgery, postoperative continuous subcutaneous infusion of gonadotrophin-releasing hormone agonist, rehabilitation training, and rivaroxaban on patients with adenomyosis complicated with lower extremity deep venous thrombosis and to provide a clinical reference. The study results showed that compared to the conventional treatment regimen, patients with adenomyosis combined with lower extremity deep venous thrombosis exhibited significant improvements in uterine function, thrombotic status, and coagulation after the combination therapy. In addition, they demonstrated superior nutritional status and a reduced risk grade for malnutrition. Based on these results, we believe that the combination of conservative surgery, postoperative continuation of gonadotrophin-releasing hormone agonist, rehabilitation, and rivaroxaban has higher clinical value in the treatment of adenomyosis combined with lower extremity deep venous thrombosis than the conventional treatment regimen.

COVID-19 and End of Life in a Quaternary Australian Hospital: Referral for Palliative Care Consultation.

The coronavirus disease 2019 (COVID-19) pandemic resulted in complex physical and psychosocial symptom burden at end of life. The benefit of specialist palliative care input in other disease states has been established, however, there is little evidence on referral patterns to these services in patients dying from COVID-19. This retrospective audit investigated the referral patterns for patients who died from COVID-19 at a quaternary hospital in South Australia (the Royal Adelaide Hospital) over a six-month period in 2022, and whether demographic features or COVID-19 specific factors had an impact on whether these patients received specialist palliative care services (PCS). The second aim was to identify prescription patterns for patients in the last 24 hours of life, and whether this was impacted by referral. Data were obtained from electronic medical records and analyzed using binary logistic regressions for referral to PCS versus no referral based on various predictors. There was no significant difference comparing patient demographics or COVID-19 specific factors with referral to PCS. There was statistical significance between patients who received referral to PCS and those who had a higher oral morphine equivalent daily dose (OMEDD) in the 24 hours before death, as well as the presence of a continuous subcutaneous infusion. Although the cause of this relationship is undetermined, it may represent the prescription patterns of the palliative care physicians during consultation or potentially higher symptom burden prompting referral. There was also a higher proportion of patients who received hydromorphone compared with other opioids, though the OMEDD was consistent with other published literature.

S-adenosylmethionine attenuates angiotensin II-induced aortic dissection formation by inhibiting vascular smooth muscle cell phenotypic switch and autophagy

It is well known that aortic dissection (AD) is a very aggressive class of vascular diseases. S-adenosylmethionine (SAM) is an autophagy inhibitor with anti-inflammatory and anti-oxidative stress effects; however, the role of SAM in AD is unknown. In this study, we constructed an animal model of AD using subcutaneous minipump continuous infusion of AngII-induced ApoE-/-mice and a cytopathic model using AngII-induced primary vascular smooth muscle cells (VSMCs) to investigate the possible role of SAM in AD. The results showed that mice in the AngII + SAM group had significantly lower AD incidence, significantly prolonged survival, and reduced vascular elastic fiber disruption compared with mice in the AngII group. In addition, SAM significantly inhibited autophagy in vivo and in vitro. Meanwhile, SAM also inhibited the cellular phenotypic switch, mainly by up regulating the expression levels of contractile marker proteins [α-smooth muscle actin (α-SMA) and smooth muscle 22α (SM22α)] and down regulating the expression levels of synthetic marker proteins [osteoblast protein (OPN), matrix metalloproteinase-2 (MMP2), and matrix metalloproteinase-9 (MMP9)]. Molecularly, SAM inhibited AD formation mainly by activating the PI3K/AKT/mTOR signaling pathway. Using a PI3K inhibitor (LY294002) significantly reversed the protective effect of SAM in AngII-induced mice and VSMCs.Our study demonstrates the protective effect of SAM on mice under AngII-induced AD for the first time. SAM prevented AD formation mainly by inhibiting cellular phenotypic switch and autophagy, and activation of the PI3K/AKT/mTOR signaling pathway is a possible molecular mechanism. Thus, SAM may be a novel strategy for the treatment of AD.

Nationwide Retrospective Analysis of Combinations of Advanced Therapies in Patients With Parkinson Disease.

Advanced therapies (ATs; deep brain stimulation [DBS] or pump therapies: continuous subcutaneous apomorphine infusion [CSAI], levodopa/carbidopa intestinal gel [LCIG]) are used in later stages of Parkinson disease (PD). However, decreasing efficacy over time and/or side effects may require an AT change or combination in individual patients. Current knowledge about changing or combining ATs is limited to mostly retrospective and small-scale studies. The nationwide case collection Combinations of Advanced Therapies in PD assessed simultaneous or sequential AT combinations in Germany since 2005 to analyze their clinical outcome, their side effects, and the reasons for AT modifications. Data were acquired retrospectively by modular questionnaires in 22 PD centers throughout Germany based on clinical records and comprised general information about the centers/patients, clinical (Mini-Mental Status Test/Montréal Cognitive Assessment, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS], side effects, reasons for AT modification), and therapeutical (ATs with specifications, oral medication) data. Data assessment started with initiation of the second AT. A total of 148 AT modifications in 116 patients were associated with significantly improved objective (median decrease of MDS-UPDRS Part III 4.0 points [p < 0.001], of MDS-UPDRS Part IV 6.0 points [p < 0.001], of MDS-UPDRS Part IV-off-time item 1.0 points [p < 0.001]) and subjective clinical outcome and decreasing side effect rates. Main reasons for an AT modification were insufficient symptom control and side effects of the previous therapy. Subgroup analyses suggest addition of DBS in AT patients with leading dyskinesia, addition of LCIG for leading other cardinal motor symptoms, and addition of LCIG or CSAI for dominant off-time. The most long-lasting therapy-until requiring a modification-was DBS. Changing or combining ATs may be beneficial when 1 AT is insufficient in efficacy or side effects. The outcome of an AT combination is comparable with the clinical benefit by introducing the first AT. The added AT should be chosen dependent on dominant clinical symptoms and adverse effects. Furthermore, prospective trials are needed to confirm the results of this exploratory case collection. This study provides Class IV evidence that, in patients with PD, changing or combining ATs is associated with an improvement in the MDS-UPDRS or subjective symptom reporting.

Glycemic control parameters in children with type 1 diabetes treated with fast-acting insulin aspart domestic biosimilar by continuous subcutaneous infusion

Introduction. Type 1 diabetes (T1D) is a chronic autoimmune disease requiring constant insulin therapy under regular continuous monitoring of glycemic parameters. The use of domestic insulin bioanalogues in CSII therapy is currently not sufficiently covered in the literature.Aim. To evaluate glycemic control parameters in children with T1D treated with the domestic fast-acting insulin aspart biosimilar by CSII.Materials and methods. Retrospective study was carried out on the basis of K.A. Raukhfus center St. Petersburg State Medical and Biomedical Center VMT. Fifty-five children with T1D aged 6 to 17 years (mean age 12 ± 4) were examined, including 29 boys (52.7%, mean age 11 ± 3 years) and 26 girls (47.3%, mean age 13 ± 4 years). Insulin therapy was carried out by systems of CSII Glycemic parameters were monitored by continuous and flash glycemic monitoring systems. The center visits frequency was once a month.Results. During dynamic follow-up after 3 and 6 months, children showed statistically significant (p &lt; 0.05) improvement in glycemic control parameters–decrease in HbA1c level from 8.0 ± 1.8% to 7, 1 ± 1.2% and 6.8 ± 0.6%, increase in TIR from 60.4 ± 20.6% to 71.5 ± 13.0% and 75.9 ± 9.4%, decrease in TAR from 31.1 ± 22.1% to 23.0 ± 12.8% and 20.3 ± 9.3%, decrease in TBR from 9.1 ± 8.2% to 5.8 ± 4.3% and 4.1 ± 1.8%, and decrease in CV from 40.0 ± 9.1% to 33.7 ± 6.7% and 32.5 ± 5.6%.Discussion. The use of domestic biosimilar insulin aspart in insulin pumps iis associated with significant improvement in glycemic control in children and adolescents with T1D. Dynamic observation together with therapeutic education contribute to the maintenance of the achieved parameters at a high level.Conclusions. Therapy with the domestic fast-acting insulin aspart biosimilar by CSII allows achieving target glycemic control in children with T1D.

Safety and tolerability of long-term apomorphine infusion in advanced Parkinson's disease: an Indian multi-center (APO-IND) experience

Advanced Parkinson’s Disease (APD) is complicated by the emergence of motor and non-motor fluctuations, which are initially predictable and eventually become unpredictable, in part due to erratic gastric absorption and short half of oral levodopa. Attempts to manage such fluctuations with oral dopaminergic drugs often lead to disabling dyskinesias. Continuous Subcutaneous Apomorphine Infusion (CSAI), despite being approved for the treatment of APD since 1993, was approved in India only in 2019. We studied the safety, tolerability and efficacy of CSAI in Indian patients with APD in a registry design to raise local awareness of this important treatment. We conducted a prospective registry-based observational audit at 10 centers across different states of India. Patients with APD, not responding to or with significant side effects from oral dopaminergic therapy, were assessed at baseline and at month 6 and 12 following CSAI infusion. Fifty-one patients completed the study, CSAI significantly reduced the functional impact of dyskinesia (p < 0.01 at 6 months and p < 0.001 at 12 months). There was a significant improvement in the OFF-state from baseline (p < 0.01 at 6 months and p < 0.001 at 12 months) No discernible side effects were observed apart from mild site reaction (n = 7), nausea (n = 7) skin nodules (n = 2). CSAI demonstrated safety, efficacy, tolerability and improved quality of life in patients with APD, as shown in previous studies. Our study highlighted current existing inequalities in treatment availability, lack of awareness, knowledge gap, affordability and cost remains a concern regarding apomorphine use in Indian PD population.

OR34-02 Fasting Pancreatic Polypeptide Predicts Incident Microvascular And Macrovascular Complications Of Type 2 Diabetes

Abstract Disclosure: A.H. Sam: None. A.J. Buckley: None. B.Y. Lam: None. P.R. Bech: None. K. Meeran: None. M.T. Barakat: None. S.R. Bloom: None. G.S. Yeo: None. N.G. Lessan: None. K.G. Murphy: None. Background: Pancreatic polypeptide (PP) is elevated in people with Type 2 Diabetes (T2D) or with increased visceral adiposity, risk factors for arterial disease. PP acts at neuropeptide Y (NPY) receptors with effects demonstrated on body composition, arterial tone, and retinal vasculature. Hypothesis: We hypothesised that addition of PP to established factors would enhance estimates of vascular risk in people with T2D. We further hypothesised that PP might have direct effects in glucose sensitive tissues. Methods: Animal study: Continuous subcutaneous PP infusion for four weeks in a high fat diet mouse model; retinal mRNA obtained using Laser Capture Microdissection and submitted for Ingenuity Pathway analysis. Human study: Fasting PP measured at enrolment in 1478 participants (224 normal glucose tolerance, 224 prediabetes, 1030 T2D) recruited at Imperial College London Diabetes Centre Abu Dhabi; microvascular and microvascular complications of diabetes recorded over median 5.5 (IQR 4.9-5.8) years follow-up. Results: Animal study: PP infusion was associated with changes in retinal gene expression potentially influencing neuronal survival including BMP receptors, TWEAK and TNFR1, and inhibition of upstream regulators including DAP3 and ALKBH1, even with unaltered weight, BP and blood glucose compared with pair-fed controls. Human study: In univariate analysis and adjusting for established factors including age, diabetes duration, BMI, sBP, smoking and HbA1c, log2(PP) was significantly associated with incident retinopathy (64 events; univariate: hazard ratio (HR) 1.39 (1.14-1.68) p &amp;lt; 0.001), adjusted: HR 1.26 (1.04-1.53) p=0.021), incident albuminuria (34 events; univariate: HR 1.48 (1.14-1.93) p=0.003, adjusted: HR 1.61 (1.21-2.14) p=0.001, and incident macrovascular disease (74 events; univariate: HR 1.46 (1.22-1.74) p&amp;lt;0.0001, adjusted: HR 1.32 (1.09-1.61), p=0.005), in individuals with T2D. Addition of PP to fully adjusted models resulted in modest improvements in the c-statistic (retinopathy: 0.74 without PP, 0.77 with PP; albuminuria: 0.65 without PP, 0.70 with PP; macrovascular: 0.72 without PP, 0.74 with PP). Adjusting for glycaemic status, BMI, sex, age and family history, PP was associated with increased hazard of progression to T2D in participants not diabetic at enrolment (HR 1.40 (1.08-1.82), p=0.011). Conclusions: Elevated fasting PP predicts incident vascular complications of diabetes, independent of known risk factors. Tonic elevation of PP in the mouse affects retinal gene expression, influencing pathways which may influence neuronal survival. Our results suggest roles for the PP-fold family of peptides in the pathophysiology of diabetic complications and vascular risk stratification. Presentation: Sunday, June 18, 2023

Subcutaneous Tranexamic Acid at the End of Life in a Patient With Hereditary Hemorrhagic Telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by vascular malformations, which cause frequent bleeding events including epistaxis and gastrointestinal bleeding.1 We describe the management of an 84-year-old woman with HHT who received end-of-life care on a palliative care ward. When the patient was unable to swallow her tranexamic acid tablets, this was converted to a continuous subcutaneous infusion, which was continued for a week until death. She had no significant bleeding events or site reactions. To our knowledge, this case report is the first to describe the palliative management of a patient with HHT at the end of life. This also adds to the current evidence base that subcutaneous tranexamic acid may be a safe and effective alternative to oral administration. Further research is needed to improve understanding of the appropriate patient selection, safety, and efficacy.

Dexmedetomidine use for patients in palliative care with intractable pain and delirium: A retrospective study.

Patients seen by the palliative care team often have difficult and intractable symptoms. The current standard of practice to manage these symptoms is the deeply sedating midazolam continuous subcutaneous infusion for patients who are expected to expire within hours to days. Dexmedetomidine provides sedation but lacks evidence in palliative care use. This study describes continuous subcutaneous infusion of dexmedetomidine's effect on refractory pain and delirium. Retrospective, observational chart review and conducted in accordance with SQUIRE (quality improvement study). Twenty adult patients (18 years of age or older) with metastatic cancer disease admitted to three palliative complex care units of Fraser Health who received continuous subcutaneous infusion of dexmedetomidine between January 2017 to August 31, 2019. Average length of dexmedetomidine use was 9 days (1/3 length of stay). Eight of the 13 patients with pain symptoms exhibited an overall decline in pain. Four of the 6 patients with delirium had an initial decrease in delirium, but it did not last beyond the first day. Despite progressive clinical deterioration, adjunctive medications decreased or remained the same for 53% of as needed medications and 65% for regularly scheduled medications. Forty-five percent of patients had ≥50% days of rousable sedation. Hypotension occurred in 85% of patients. Dexmedetomidine provided benefit in managing intractable pain while allowing patients to remain rousable, but only had a short effect on delirium symptoms.

Continuous Subcutaneous Foslevodopa/Foscarbidopa in Parkinson's Disease: Safety and Efficacy Results From a 12-Month, Single-Arm, Open-Label, Phase 3 Study.

Foslevodopa/foscarbidopa, a soluble formulation of levodopa/carbidopa (LD/CD) prodrugs for the treatment of Parkinson's disease (PD), is administered as a 24-hour/day continuous subcutaneous infusion (CSCI) with a single infusion site. The efficacy and safety of foslevodopa/foscarbidopa versus oral immediate-release LD/CD was previously demonstrated in patients with PD in a 12-week, randomized, double-blind, phase 3 trial (NCT04380142). We report the results of a separate 52-week, open-label, phase 3 registrational trial (NCT03781167) that evaluated the safety/tolerability and efficacy of 24-hour/day foslevodopa/foscarbidopa CSCI in patients with advanced PD. Male and female patients with levodopa-responsive PD and ≥ 2.5hours of "Off" time/day received 24-hour/day foslevodopa/foscarbidopa CSCI at individually optimized therapeutic doses (approximately 700-4250mg of LD per 24hours) for 52weeks. The primary endpoint was safety/tolerability. Secondary endpoints included changes from baseline in normalized "Off" and "On" time, percentage of patients reporting morning akinesia, Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Parkinson's Disease Sleep Scale-2 (PDSS-2), 39-item Parkinson's Disease Questionnaire (PDQ-39), and EuroQol 5-dimension questionnaire (EQ-5D-5L). Of 244 enrolled patients, 107 discontinued, and 137 completed treatment. Infusion site events were the most common adverse events (AEs). AEs were mostly nonserious (25.8% of patients reported serious AEs) and mild/moderate in severity. At week 52, "On" time without troublesome dyskinesia and "Off" time were improved from baseline (mean [standard deviation (SD)] change in normalized "On" time without troublesome dyskinesia, 3.8 [3.3] hours; normalized "Off" time, -3.5 [3.1] hours). The percentage of patients experiencing morning akinesia dropped from 77.7% at baseline to 27.8% at week 52. Sleep quality (PDSS-2) and quality of life (PDQ-39 and EQ-5D-5L) also improved. Foslevodopa/foscarbidopa has the potential to provide a safe and efficacious, individualized, 24-hour/day, nonsurgical alternative for patients with PD. ClinicalTrials.gov identifier NCT03781167.

E2730, an uncompetitive γ-aminobutyric acid transporter-1 inhibitor, suppresses epileptic seizures in a rat model of chronic mesial temporal lobe epilepsy.

More than one third of mesial temporal lobe epilepsy (MTLE) patients are resistant to current antiseizure medications (ASMs), and half experience mild-to-moderate adverse effects of ASMs. There is therefore a strong need to develop and test novel ASMs. The objective of this work is to evaluate the pharmacokinetics and neurological toxicity of E2730, a novel uncompetitive inhibitor of γ-aminobutyric acid transporter-1, and to test its seizure suppression effects in a rat model of chronic MTLE. We first examined plasma levels and adverse neurological effects of E2730 in healthy Wistar rats. Adult male rats were implanted with osmotic pumps delivering either 10, 20, or 100 mg/kg/day of E2730 subcutaneously for 1 week. Blood sampling and behavioral assessments were performed at several timepoints. We next examined whether E2730 suppressed seizures in rats with chronic MTLE. These rats were exposed to kainic acid-induced status epilepticus, and 9 weeks later, when chronic epilepsy was established, were assigned to receive one of the three doses of E2730 or vehicle for 1 week in a randomized crossover design. Continuous video-electroencephalographic monitoring was acquired during the treatment period to evaluate epileptic seizures. Plasma levels following continuous infusion of E2730 showed a clear dose-related increase in concentration. The drug was well tolerated at all doses, and any sedation or neuromotor impairment was mild and transient, resolving within 48 h of treatment initiation. Remarkably, E2730 treatment in chronically epileptic rats led to seizure suppression in a dose-dependent manner, with 65% of rats becoming seizure-free at the highest dose tested. Mean seizure class did not differ between the treatment groups. This study shows that continuous subcutaneous infusion of E2730 over 7 days results in a marked, dose-dependent suppression of spontaneous recurrent seizures, with minimal adverse neurological effects, in a rat model of chronic MTLE. E2730 shows strong promise as an effective new ASM to be translated into clinical trials.