Levodopa infusion therapies for Parkinson disease.

PURPOSE OF REVIEW: to review recent progress in the development and use of continuous levodopa therapies in Parkinson disease (PD). RECENT FINDINGS: Levodopa/Carbidopa intestinal gel (LCIG) is a continuous levodopa therapy which is widely used in the United States, Europe and other countries and is effective at reducing 'off' time. Recent work has shown that LCIG can be useful in managing dyskinesias and can improve nonmotor symptoms and quality of life. Several studies have shown good long-term effectiveness of LCIG. Recent data support the cost-effectiveness of this treatment strategy. Subcutaneous (SC) delivery of levodopa is a newer strategy that avoids the need for a surgically placed gastric tube. Two different products enabling SC delivery of levodopa are in development: ND0612 and foslevodopa/foscarbidopa. Both have recently been shown to reduce 'off' time in randomized, double-blind trials. Adverse effects of SC levodopa are primarily related to skin reactions at the infusion site. SUMMARY: Continuous levodopa therapies can be used to treat Parkinson disease motor fluctuations that cannot be managed with standard oral therapies. They may also improve nonmotor symptoms, and improve overall quality of life in patients with advanced PD.

Facilitated Subcutaneous Immunoglobulin Treatment Increases the Quality of Life and Decreases the Number of Infections and Hospitalizations in Children with Primary Immunodeficiencies.

INTRODUCTION: Immunoglobulin replacement therapy is an effective lifelong treatment modality used in patients with primary immunodeficiency to prevent and/or reduce the incidence of serious infections. Facilitated subcutaneous immunoglobulin (fSCIG) was developed to combine the advantages of intravenous immunoglobulin (IVIG) and subcutaneous immunoglobulin (SCIG) and is the latest method of immunoglobulin G (IgG) administration. In this study, switching to fSCIG administration in primary immunodeficiency patients receiving regular IVIG or SCIG therapy was evaluated, and serum IgG trough levels, frequency of infections, frequency and duration of hospitalizations, duration of absence from school/work, and quality of life were determined. METHODS: In this study, fifteen patients with primary immunodeficiency who were previously receiving IVIG or SCIG treatment, followed by fSCIG, were evaluated retrospectively. Age, diagnosis, current complications, mean IgG value, frequency of infection, frequency of hospitalization, and duration of absenteeism from school and work were recorded during and before fSCIG treatment. At the beginning of fSCIG treatment, at 6th and 12th months, "The Quality of Life Scale" was also evaluated in patients and parents. RESULTS: The most common indications for initiation of fSCIG treatment were the difficulty of access to the hospital and the long transfusion periods. No systemic adverse reactions were reported except for redness, swelling, and mild pain on the injection site. The median IgG values for the last 1 year were 529.6 mg/dL for IVIG (n = 9), 876.2 mg/dL for SCIG (n = 6) and 856.7 mg/dL for fSCIG (n = 15, all patients) treatment. The frequency of infections and the number of hospitalizations decreased significantly in the fSCIG group compared to both previous treatment modalities. There was a significant increase in the quality of life score of the patients and their families when compared with previous treatment modalities. CONCLUSION: fSCIG is an effective treatment method and is well tolerated in patients with immunodeficiency. It provides stable immunoglobulin levels and excellent protection against infections and offers the patients the possibility of home-based therapy.

Home initiation of apomorphine infusion: lessons from the COVID-19 pandemic and implications for current clinical practice.

Starting Parkinson's disease (PD) patients on subcutaneous apomorphine (APO) infusion is generally undertaken on a hospital day-case basis. During the COVID-19 pandemic, day-case facilities were unavailable. To avoid delays in treatment, a new procedure was developed for initiation of APO therapy in the patient's home. A home initiation protocol was developed and followed for each patient in this analysis. The hospital team worked in collaboration with APO nurses provided by the manufacturer of APO therapies to implement initiation and undertake follow-up. In this analysis, 27 PD patients were initiated onto APO infusion and 21 (77.8%) achieved a therapeutic response. Home initiation of APO infusion can be undertaken successfully and has benefits for both patients and healthcare teams. This protocol will now continue as a standard of care at our centre.

An evaluation of continuous subcutaneous infusions across seven NHS acute hospitals: is there potential for 48-hour infusions?

BACKGROUND: Continuous subcutaneous infusions (CSCIs) are commonly used in the United Kingdom as a way of administering medication to patients requiring symptom control when the oral route is compromised. These infusions are typically administered over 24 h due to currently available safety data. The ability to deliver prescribed medication by CSCI over 48 h may have numerous benefits in both patient care and health service resource utilisation. This service evaluation aims to identify the frequency at which CSCI prescriptions are altered at NHS Acute Hospitals. METHODS: Pharmacists or members of palliative care teams at seven acute NHS hospitals recorded anonymised prescription data relating to the drug combination(s), doses, diluent and compatibility of CSCIs containing two or more drugs on a daily basis for a minimum of 2 days, to a maximum of 7 days. RESULTS: A total of 1301 prescriptions from 288 patients were recorded across the seven sites, yielding 584 discrete drug combinations. Of the 584 combinations, 91% (n = 533) included an opioid. The 10 most-common CSCI drug combinations represented 37% of the combinations recorded. Median duration of an unchanged CSCI prescription across all sites was 2 days. CONCLUSION: Data suggests medication delivered by CSCI over 48 h may be a viable option. Before a clinical feasibility study can be undertaken, a pharmacoeconomic assessment and robust chemical and microbiological stability data will be required, as will the assessment of the perceptions from clinical staff, patients and their families on the acceptability of such a change in practice.

Continuous subcutaneous infusion for pain control in dying patients: experiences from a tertiary palliative care center.

BACKGROUND: Continuous subcutaneous infusion (CSCI) via ambulatory infusion pump (AIP) is a valuable method of pain control in palliative care. When using CSCI, low-dose methadone as add-on to other opioids might be an option in complex pain situations. This study aimed to investigate the effects, and adverse effects, of CSCI for pain control in dying patients, with particular interest in methadone use. METHODS: This was an observational cohort study. Imminently dying patients with pain, admitted to specialized palliative inpatient wards and introduced on CSCI, were monitored daily by staff for symptoms (Integrated Palliative Care Outcome Scale - IPOS), sedation (Richmond Agitation and Sedation Scale - RASS), performance status (Eastern Cooperative Oncology Group - ECOG) and delirium (Confusion Assessment Method - CAM). RESULTS: Ninety-three patients with a median survival of 4 days were included. Of the 47 patients who survived ≥3 days, the proportion of patients with severe/overwhelming pain decreased from 45 to 19% (p < 0.001) after starting CSCI, with only a moderate increase in morphine equivalent daily dose of opioids (MEDD). Alertness was marginally decreased (1 point on the 10-point RASS scale, p = 0.001), whereas performance status and prevalence of delirium, regardless of age, remained unchanged. Both patients with methadone as add-on (MET, n = 13) and patients with only other opioids (NMET, n = 34), improved in pain control (p < 0.05 and 0.001, respectively), despite that MET patients had higher pain scores at baseline (p < 0.05) and were on a higher MEDD (240 mg vs.133 mg). No serious adverse effects demanding treatment stop were reported. CONCLUSIONS: CSCI via AIP is an effective way to reduce pain in dying patients without increased adverse effects. Add-on methadone may be beneficial in patients with severe complex pain.

The influence of hospital-based intravenous immunoglobulin and home-based self-administrated subcutaneous immunoglobulin therapy in young children with primary immunodeficiency diseases on their parents' / caregivers' satisfaction.

BACKGROUND: Immunoglobulin replacement has been standard therapy for patients with primary immunodeficiency diseases (PIDD). Intravenous immunoglobin (IVIg) is delivered at the hospital, whereas subcutaneous immunoglobin (SCIg) is used for home-based treatment. The aim of the study was to determine the advantages and disadvantages of IVIg and SCIg in Polish children aged 1-5 years, with PIDD, and the satisfaction of their parents / caregivers regarding immunoglobulin replacement. METHODS: The research involved parents of 23 children with PIDD, aged 1-5 years. All children were given IVIg therapy and after at least 6 months they were switched towards home SCIg therapy for at least 6 months. A questionnaire assessing advantages and disadvantages of preferred types of treatment and the quality of life of PIDD patients' families' lives was used. RESULTS: The research showed that IVIg therapy was better accepted by parents than SCIg therapy (P = 0.034) for the following reasons: It made it possible for the children to receive treatment once per month (60%); it reduced the fear of injecting the children (60%), and it provided better control of the disease through regular visits to the hospital (53.33%). Parents noticed, however, that IVIg had a significant impact on absence at school or work (70%). Parents who preferred SCIg for their children were guided mainly by the smaller number of side effects (40%), and the fact that the treatment did not interfere with parents' work or the children's school (40%). CONCLUSION: The results showed that IVIg therapy was better accepted by parents than SCIg therapy Parents of children with SCIg are less satisfied with their life, and feel anxiety about their children disease, which is related to administering the medicine by themselves.

Tolerability of Ig20Gly during onboarding in patients with primary immunodeficiency diseases.

BACKGROUND: The subcutaneous immune globulin (SCIG) 20% product, Ig20Gly, was shown to be efficacious and well tolerated in 2 phase 2/3 North American and European studies at infusion volumes up to 60 mL/site and rates up to 60 mL/h/site in patients with primary immunodeficiency diseases. OBJECTIVE: To assess patient experience after switching to Ig20Gly with fast infusion rates and large infusion volumes/site in the North American study. METHODS: In this analysis of the open-label phase 2/3 study in which patients aged ≥2 years received weekly Ig20Gly infusions for up to approximately 1.3 years, tolerability and infusion parameters were assessed throughout the study for all patients and by prestudy treatment regimen (intravenous [IV] switchers or SC switchers). RESULTS: Overall, 61% of patients reached the infusion rate of ≥60 mL/h/site and continued at this rate for 1 or more subsequent infusions; the median infusion number when patients first reached ≥60 mL/h/site was 3. No association was found between higher infusion volumes or rates and increased incidences of local and systemic adverse events (AEs) in the total population and patients younger than 16 years. Infusion parameters and tolerability were generally comparable regardless of the route of prestudy treatment (IV or SC switchers); however, IV switchers experienced lower rates of local AEs than SC switchers and had a slightly higher median infusion volume per site and longer infusion duration vs SC switchers. CONCLUSION: High Ig20Gly infusion rates of at least 60 mL/h/site and volumes ≥60 mL/site were well tolerated during onboarding and throughout treatment, regardless of prestudy treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01218438.

Hyaluronidase-Assisted Resuscitation in Kenya for Severely Dehydrated Children.

BACKGROUND: Dehydration, mainly due to diarrheal illnesses, is a leading cause of childhood mortality worldwide. Intravenous (IV) therapy is the standard of care for patients who were unable to tolerate oral rehydration; however, placing IVs in fragile, dehydrated veins can be challenging. Studies in resource-rich settings comparing hyaluronidase-assisted subcutaneous rehydration with standard IV rehydration in children have demonstrated several benefits of subcutaneous rehydration, including time and success of line placement, ease of use, satisfaction, and cost-effectiveness. METHODS: A single-arm trial assessing the feasibility of hyaluronidase-assisted subcutaneous resuscitation for the treatment of moderately to severely dehydrated individuals in western Kenya was conducted. Children aged 2 months or older who presented with moderately to severely dehydration clinically warranting parenteral rehydration and had at least 2 failed IV attempts were eligible. Study staff received training on standard dehydration management and hyaluronidase infusion processes. Children received all other standards of care. They were monitored from presentation and through discharge, with a 1-week phone follow-up. Predischarge surveys were completed by caregivers, and semistructured interviews with providers were performed. RESULTS: A total of 51 children were enrolled (median age, 13.0 months; interquartile range of 18 months). Fifty-one patients (100%) had severe dehydration. The median length of subcutaneous infusion was 3.0 hours (interquartile range [IQR], 2.95). The median total subcutaneous infusion was 700.0 mL (IQR, 420 mL). Median time to resolution of moderate to severe dehydration symptoms was 3.0 hours (IQR, 2.95 hours). There were no significant complications. CONCLUSIONS: Hyaluronidase-assisted subcutaneous resuscitation is a feasible alternative to IV hydration in moderately to severely dehydrated children with difficult to obtain IV access in resource-limited areas.

Using the MEDiPORT humanoid robot to reduce procedural pain and distress in children with cancer: A pilot randomized controlled trial.

BACKGROUND: Subcutaneous port needle insertions are painful and distressing for children with cancer. The interactive MEDiPORT robot has been programmed to implement psychological strategies to decrease pain and distress during this procedure. This study assessed the feasibility of a future MEDiPORT trial. The secondary aim was to determine the preliminary effectiveness of MEDiPORT in reducing child pain and distress during subcutaneous port accesses. METHODS: This 5-month pilot randomized controlled trial used a web-based service to randomize 4- to 9-year-olds with cancer to the MEDiPORT cognitive-behavioral arm (robot using evidence-based cognitive-behavioral interventions) or active distraction arm (robot dancing and singing) while a nurse conducted a needle insertion. We assessed accrual and retention; technical difficulties; outcome measure completion by children, parents, and nurses; time taken to complete the study and clinical procedure; and child-, parent-, and nurse-rated acceptability. Descriptive analyses, with exploratory inferential testing of child pain and distress data, were used to address study aims. RESULTS: Forty children were randomized across study arms. Most (85%) eligible children participated and no children withdrew. Technical difficulties were more common in the cognitive-behavioral arm. Completion times for the study and needle insertion were acceptable and >96% of outcome measure items were completed. Overall, MEDiPORT and the study were acceptable to participants. There was no difference in pain between arms, but distress during the procedure was less pronounced in the active distraction arm. CONCLUSION: The MEDiPORT study appears feasible to implement as an adequately-powered effectiveness-assessing trial following modifications to the intervention and study protocol. ClinicalTrials.gov NCT02611739.

Effectiveness of Continuous Subcutaneous Insulin Infusion on Parental Quality of Life and Glycemic Control Among Children With T1D: Meta-Analysis.

BACKGROUND: Type 1 diabetes (T1D) is one of the most common chronic diseases in childhood. Daily diabetes management poses a major challenge for parents. Intensive insulin therapy using continuous subcutaneous insulin infusion (CSII) or multiple daily injections (MDI) are recommended for patients with T1D, but evidence for their effectiveness on parental quality of life (QOL) and glycemic control among children with T1D is inconclusive. OBJECTIVES: A systematic review was conducted to determine the best available evidence regarding the effectiveness of CSII compared to MDI on parental QOL and glycemic control among children with T1D. METHODS: Studies in English and Chinese from 1978 to March 2015 were identified by searching electronic databases, published references, and unpublished studies. Randomized controlled trials (RCTs) comparing CSII with MDI related to parental QOL and glycemic control (HbA1c) among patients aged 18 years or below with T1D were included. Secondary outcomes were episodes of severe hypoglycemia (SH) and diabetic ketoacidosis (DKA). RESULTS: Seven RCTs were identified. Parental QOL was reported in two studies, with one study reporting no significant improvement in the CSII group and one reporting a significant reduction in diabetes-related worry in the CSII group but increased frequency of stress relating to child medical care in the MDI group. Meta-analysis of seven RCTs involving 220 patients demonstrated that CSII was associated with significant decrease in HbA1c level (MD = -0.24%, 95% CI = -0.41 to -0.07, p = .006) compared to MDI. There were no significant differences in episodes of SH and DKA between the CSII and MDI groups. LINKING EVIDENCE TO ACTION: CSII slightly reduced HbA1c by .24% compared to MDI. Based on two RCTs with small sample sizes, there is insufficient evidence to draw any conclusions on the beneficial effects of CSII compared with MDI on parental QOL among children with T1D. More RCTs with larger samples are needed.

Optimizing the Bioavailability of Subcutaneously Administered Biotherapeutics Through Mechanochemical Drivers.

The subcutaneous route offers myriad benefits for the administration of biotherapeutics in both acute and chronic diseases, including convenience, cost effectiveness and the potential for automation through closed-loop systems. Recent advances in parenteral administration devices and the use of additives which enhance drug dispersion have generated substantial additional interest in IV to SQ switching studies. Designing pre-clinical and clinical studies using SQ mediated delivery however requires deep understanding of complex inter-related physiologies and transport pathways governing the interstitial matrix, vascular system and lymphatic channels. This expert review will highlight key structural features which contribute to transport and biodistribution in the subcutaneous space and also assess the impact of drug formulations. Based on the rapidly growing interest in the SQ delivery route, a number of potential areas for future development are highlighted, which are likely to allow continued evolution and innovation in this important area.

Practical approaches to commencing device-assisted therapies for Parkinson disease in Australia.

In Australia 1% of individuals aged over 50 years have Parkinson disease (PD). Guidance for commencing device-assisted therapies (DAT) for PD in Australia was developed based on a review of European recommendations and their relevance to the local clinical setting. An online survey and teleconference discussions were held by a group of eight local movement disorder experts to develop consensus. Referral to a movement disorder specialist and consideration of DAT is appropriate when motor fluctuations cause disability or reduced quality of life, response to treatment is inconsistent or motor fluctuations and dyskinesias require frequent treatment adjustment without apparent benefit and levodopa is required four or more times daily. Three types of DAT are available in Australia for patients with PD: continuous subcutaneous apomorphine; continuous levodopa-carbidopa intestinal gel infusion; and deep brain stimulation. All improve consistency of motor response. The most important aspects when considering which DAT to use are the preferences of the patient and their carers, patient comorbidities, age, cognitive function and neuropsychiatric status. Patients and their families need to be provided with treatment options that are suitable to them, with adequate explanations regarding the recommendations and comparison of potential device-related complications. DAT are best managed, where possible, in a specialist centre with experience in all three types of therapy. Proactive and early management of symptoms during disease progression is essential to maintain optimally motor responses and quality of life in patients with PD.

Identification of drug combinations administered by continuous subcutaneous infusion that require analysis for compatibility and stability.

BACKGROUND: A continuous subcutaneous infusion (CSCI) delivered via syringe pump is a method of drug administration used to maintain symptom control when a patient is no longer able to tolerate oral medication. Several classes of drugs, such as opioids, antiemetics, anticholinergics, antipsychotics and benzodiazepines are routinely administered by CSCI alone or in combinations. Previous studies attempting to identify the most-common CSCI combinations are now several years old and no longer reflect current clinical practice. The aim of this work was to review current clinical practice and identify CSCI drug combinations requiring analysis for chemical compatibility and stability. METHODS: UK pharmacy professionals involved in the delivery of care to palliative patients in hospitals and hospices were invited to enter CSCI combinations comprised of two or more drugs onto an electronic database over a 12-month period. In addition, a separate Delphi study with a panel of 15 expert healthcare professionals was completed to identify a maximum of five combinations of drugs used to treat more complex, but less commonly encountered symptoms unlikely to be identified by the national survey. RESULTS: A total of 57 individuals representing 33 separate palliative care services entered 1,945 drug combinations suitable for analysis, with 278 discrete combinations identified. The top 40 drug combinations represented nearly two-thirds of combinations recorded. A total of 23 different drugs were administered in combination and the median number of drugs in a combination was three. The Delphi study identified five combinations for the relief of complex or refractory symptoms. CONCLUSION: This study represents the first step towards developing authoritative national guidance on the administration of drugs by CSCI. Further work will ensure healthcare practitioners have the knowledge and confidence that a prescribed combination will be both safe and efficacious.

Subcutaneous immunoglobulin for treatment of multifocal motor neuropathy.

INTRODUCTION: Subcutaneous immunoglobulin (SCIg) has been used for treatment of immune neuropathies. METHODS: We evaluated the safety and efficacy of 1.53:1 SCIg to intravenous immunoglobulin (IVIg) in individuals receiving <2 g/kg IVIg per month and 1:1 in individuals receiving 2 g/kg per month for treatment of multifocal motor neuropathy (MMN) in an open-label, 6-month trial. Medical Research Council sum score, grip strength, modified Guy's Upper Limb Neurological Disability score, Health Utility Index Quality of Life score, and immunoglobulin levels were evaluated at baseline and at 3 and 6 months. RESULTS: Eleven men and 4 women, aged 31-82 years, were enrolled. Eleven patients completed the program with minor localized reactions and high satisfaction. Three of 6 patients receiving less than 1.53:1 replacement developed intolerable weakness by month 3, and 1 exited after developing erythema and elevated transaminase levels. CONCLUSION: Patients with MMN tolerate SCIg infusion with maintained strength, but some patients may develop increasing weakness and merit close monitoring. Muscle Nerve 54: 856-863, 2016.

Development of Gendine-Coated Cannula for Continuous Subcutaneous Insulin Infusion for Extended Use.

Continuous subcutaneous insulin infusion (CSII) using pumps is a widely used method for insulin therapy in patients with diabetes mellitus. Among the major factors that usually lead to the discontinuation of CSII are CSII set-related issues, including infection at the infusion site. The American Diabetic Association currently recommends rotating sites every 2 to 3 days. This recommendation adds cost and creates inconvenience. Therefore, in order to prevent infections and extend the duration between insertion site changes, we developed a Teflon cannula coated with a combination of gentian violet and chlorhexidine (gendine) and tested its antimicrobial efficacy against different pathogens. The cannulas were coated with gendine on the exterior surface and dried. The efficacy and durability of gendine-coated cannulas were determined against methicillin-resistant Staphylococcus aureus, Staphylococcus epidermidis, methicillin-susceptible S. aureus, Streptococcus pyogenes, vancomycin-resistant enterococci, Escherichia coli, Pseudomonas aeruginosa, Candida albicans, and Candida glabrata using a biofilm colonization method. The cytotoxicity of gendine was assessed against mouse fibroblast cell lines. The gendine-coated cannulas showed complete prevention of biofilm colonization of all organisms tested for up to 2 weeks (P < 0.0001) compared to that with the uncoated control. A gendine-coated catheter against mouse fibroblast cells was shown to be noncytotoxic. Our in vitro results show that a novel gendine cannula is highly effective in completely inhibiting the biofilm of multidrug-resistant pathogens for up to 2 weeks and may have potential clinical applications, such as prolonged use, cost reduction, and lower infection rate.

Long-Term Administration of Neuropeptide Y in the Subcutaneous Infusion Results in Cardiac Dysfunction and Hypertrophy in Rats.

BACKGROUND/AIMS: The purpose of the present study was to clarify whether chronically elevated plasma neuropeptide Y (NPY) might affect heart function and cardiac remodeling in rats. METHODS: Male Wistar rats were administered NPY (85 µg for 30 days) by mini-osmotic pump subcutaneously implanted between the scapulae. Associated indices for heart function, cardiac remodeling and hypertrophy were evaluated. RESULTS: Compared to the sham group, the baseline systolic blood pressure (SBP) in rats administered NPY was significantly increased; cardiac function was significantly decreased, as indicated by reduced ejection fraction (EF), left ventricular end-systolic pressure (LVESP), maximum change velocity of left ventricular pressure in the isovolumic contraction or relaxation period (± dp/dtmax) and increased left ventricular end-diastolic pressure (LVEDP); hematoxylin-eosin (H&E) staining detection displayed enlarged cell areas and a consistent increase in heart-to-body weight ratios (HW/BW) was observed; quantitative real time PCR (qRT-PCR) and Western blot analysis showed markedly increased expressions of ß-myosin heavy chain (ß-MHC), calcineurin (CaN) and phosphorylated p38 proteins, while no changes were found in the expressions of p38 total protein and the phosphorylations of JNK and ERK. CONCLUSION: This study reported for the first time that long-term elevated plasma concentration of NPY could induce cardiac dysfunction and cardiac hypertrophy and this phenomenon could, in part, be mediated by the Ca2+/CaM-dependent CaN pathway and p38 mitogen-activated protein kinase (MAPK) signal pathway in rats.

EuroInf: a multicenter comparative observational study of apomorphine and levodopa infusion in Parkinson's disease.

Subcutaneous apomorphine infusion (Apo) and intrajejunal levodopa infusion (IJLI) are two treatment options for patients with advanced Parkinson's disease (PD) and refractory motor complications, with varying cost of treatment. There are no multicenter studies comparing the effects of the two strategies. This open-label, prospective, observational, 6-month, multicenter study compared 43 patients on Apo (48.8% males, age 62.3 ± 10.6 years; disease duration: 14 ± 4.4 years; median H & Y stage 3; interquartile range [IQR]: 3-4) and 44 on IJLI (56.8% males, age 62.7 ± 9.1 years; disease duration: 16.1 ± 6.7 years; median H & Y stage 4; IQR, 3-4). Cohen's effect sizes (≥0.8 considered as large) were "large" with both therapies with respect to total motor, nonmotor, and quality-of-life scores. The Non-Motor Symptoms Scale (NMSS) with Apo showed moderate improvement, whereas sleep/fatigue, gastrointestinal, urinary, and sexual dimensions of the NMSS showed significantly higher improvement with IJLI. Seventy-five percent on IJLI improved in their quality-of-life and nonmotor symptoms (NMS), whereas in the Apo group, a similar proportion improved in quality of life, but 40% in NMS. Adverse effects included peritonitis with IJLI and skin nodules on Apo. Based on this open-label, nonrandomized, comparative study, we report that, in advanced Parkinson's patients, both IJLI and Apo infusion therapy appear to provide a robust improvement in motor symptoms, motor complications, quality-of-life, and some NMS. Controlled, randomized studies are required.

Single-dose new insulin glargine 300 U/ml provides prolonged, stable glycaemic control in Japanese and European people with type 1 diabetes.

AIMS: Two single-dose studies were conducted in Japan and Europe to compare the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of new insulin glargine 300 U/ml (Gla-300) and insulin glargine 100 U/ml (Gla-100) in people with type 1 diabetes mellitus. METHODS: In two double-blind, randomized, crossover studies, 18 Japanese participants (aged 20-65 years) and 24 European participants (aged 18-65 years) with glycated haemoglobin levels ≤9.0% (≤75 mmol/mol) received single subcutaneous doses of Gla-300, 0.4, 0.6 and 0.9 U/kg (0.9 U/kg in the European study only), and Gla-100, 0.4 U/kg. A 36-h euglycaemic clamp procedure was performed after each dosing. RESULTS: The serum insulin glargine concentration (INS) and glucose infusion rate (GIR) developed more gradually into more constant and prolonged profiles with Gla-300 than with Gla-100. In support of this, the times to 50% of glargine exposure and insulin activity were longer for all Gla-300 doses than for Gla-100 during the 36-h clamp period, indicating a more evenly distributed exposure and metabolic effect beyond 24 h. Exposure to insulin glargine and glucose utilization were lower with the 0.4 and 0.6 U/ml Gla-300 doses in both studies compared with the 0.4 U/ml Gla-100 dose. Glucose-lowering activity was detected for up to 36 h with all doses of Gla-300. CONCLUSIONS: Single-dose injections of Gla-300 present more constant and prolonged PK and PD profiles compared with Gla-100, maintaining blood glucose control for up to 36 h in euglycaemic clamp settings in Japanese and European participants with type 1 diabetes.

Comparison of arterial pressure and plasma ANG II responses to three methods of subcutaneous ANG II administration.

Angiotensin II (ANG II)-induced hypertension is a commonly studied model of experimental hypertension, particularly in rodents, and is often generated by subcutaneous delivery of ANG II using Alzet osmotic minipumps chronically implanted under the skin. We have observed that, in a subset of animals subjected to this protocol, mean arterial pressure (MAP) begins to decline gradually starting the second week of ANG II infusion, resulting in a blunting of the slow pressor response and reduced final MAP. We hypothesized that this variability in the slow pressor response to ANG II was mainly due to factors unique to Alzet pumps. To test this, we compared the pressure profile and changes in plasma ANG II levels during subcutaneous ANG II administration (150 ng·kg(-1)·min(-1)) using either Alzet minipumps, iPrecio implantable pumps, or a Harvard external infusion pump. At the end of 14 days of ANG II, MAP was highest in the iPrecio group (156 ± 3 mmHg) followed by Harvard (140 ± 3 mmHg) and Alzet (122 ± 3 mmHg) groups. The rate of the slow pressor response, measured as daily increases in pressure averaged over days 2-14 of ANG II, was similar between iPrecio and Harvard groups (2.7 ± 0.4 and 2.2 ± 0.4 mmHg/day) but was significantly blunted in the Alzet group (0.4 ± 0.4 mmHg/day) due to a gradual decline in MAP in a subset of rats. We also found differences in the temporal profile of plasma ANG II between infusion groups. We conclude that the gradual decline in MAP observed in a subset of rats during ANG II infusion using Alzet pumps is mainly due to pump-dependent factors when applied in this particular context.

7th International Immunoglobulin Conference: Immunoglobulin in clinical practice.

Intravenous and subcutaneous immunoglobulins (IVIg and SCIg, respectively) are increasingly used in clinical practice, not only as replacement therapy but also for immunomodulation. Physicians have learned that primary immunodeficiency (PID) patients are susceptible to recurrent respiratory tract infections even when appropriately treated with immunoglobulin (Ig) therapy. Further investigation will establish whether a combined therapeutic approach including Ig dose optimization will prevent progressive lung disease in PID. The wear-off effects observed with IVIg can be minimized by adjusting the dosing regimen. It is also possible to avoid the cyclic wear-off following transition to SCIg administration. Consideration of benefit versus risk with Ig therapy includes evaluating the potential occurrence of thromboembolic and haemolytic events, which may be more frequent when Ig is administered in high doses and in the presence of pre-existing risk factors. The ability to select an administration method from IVIg, SCIg or hyaluronidase-facilitated SCIg infusions provides patient choice and alternatives if one or other administration route is not suitable for a patient. The evolution in indications, applications, and understanding of Ig therapy described here has reinforced the need for robust methods to prioritize Ig use.