Safety, Tolerability, and Pharmacokinetics of High-Volume Subcutaneous Crenezumab, With and Without Recombinant Human Hyaluronidase in Healthy Volunteers.

Compared with intravenous formulations, subcutaneous (s.c.) formulations of therapeutic monoclonal antibodies may provide increased patient access and more convenient administration options, although historically high-volume s.c. administration (> 10-15 mL) has been challenging. We report results from two phase I studies in healthy participants (GP29523 and GP40201) that evaluated s.c. crenezumab, an anti-Aß monoclonal antibody in development for individuals at risk for autosomal-dominant Alzheimer's disease. GP29523 assessed safety, tolerability, and pharmacokinetics (PK) in 68 participants (aged 50-80 years) who received single ascending doses (600-7,200 mg) of crenezumab or placebo (4-40 mL). GP40201 assessed safety, tolerability, and PK in 72 participants (aged 18-80 years) who received different combinations of dose (1,700-6,800 mg), infusion volume (10-40 mL), and flow rate (2-4 mL/minute), with/without recombinant human hyaluronidase (rHuPH20). There were no serious or dose-limiting adverse events in either study. There were no meaningful differences in pain scores among reference placebo (4 mL), test placebo (4-40 mL), or crenezumab (600-7,200 mg) in GP29523, or across treatments with varying infusion volume, flow rate, dose, or rHuPH20 co-administration or concentration in GP40201. Transient erythema was the most common infusion site reaction in both studies. In GP40201 at volumes of ≥ 20 mL, rHuPH20 co-administration appeared to reduce infusion site swelling incidence, but, in some cases, was associated with larger areas of infusion site erythema. Crenezumab exhibited approximately dose-proportional PK, and s.c. bioavailability was 66% and independent of dose or rHuPH20 co-administration. High-dose, high-concentration, high-volume s.c. crenezumab formulated with/without rHuPH20 was well-tolerated in healthy participants, with an acceptable safety profile.

Treatment of subcutaneous nodules after infusion of apomorphine; a biopsy-controlled study comparing 4 frequently used therapies.

This study aimed to provide clinical evidence for existing treatments of subcutaneous nodules after subcutaneous infusion of apomorphine, using a biopsy-controlled prospective crossover design of four treatments. We demonstrated that dilution of apomorphine significantly improved patient satisfaction, while subcutaneous hydrocortisone reduced nodule size, however with no differences in the histopathology.

Safety and Tolerability of Subcutaneous IgPro20 at High Infusion Parameters in Patients with Primary Immunodeficiency: Findings from the Pump-Assisted Administration Cohorts of the HILO Study.

PURPOSE: To evaluate the safety and tolerability of subcutaneous IgPro20 (Hizentra®, CSL Behring, King of Prussia, PA, USA) administered at high infusion parameters (> 25 mL and > 25 mL/h per injection site) in patients with primary immunodeficiency. METHODS: The Hizentra® Label Optimization (HILO) study was an open-label, parallel-arm, non-randomized study (NCT03033745) of IgPro20 using a forced upward titration design for infusion parameters. Patients experienced with pump-assisted IgPro20 infusions received weekly IgPro20 infusions at a stable dose in the Pump-Assisted Volume Cohort (N = 15; 25-50 mL per injection site) and in the Pump-Assisted Flow Rate Cohort (N = 18; 25-100 mL/h per injection site). Responder rates (percentage of patients who successfully completed ≥ 75% of planned infusions), safety outcomes, and serum immunoglobulin G (IgG) trough levels were evaluated. RESULTS: Responder rates were 86.7% (13/15, 25 mL) and 73.3% (11/15, 40 and 50 mL) in the Volume Cohort, and 77.8% (14/18, 25 and 50 mL/h), 66.7% (12/18, 75 mL/h), and 61.1% (11/18, 100 mL/h) in the Flow Rate Cohort. Infusion compliance was ≥ 90% in all patients in the Volume Cohort and in 83.3% of patients in the Flow Rate Cohort. The number of injection sites (Volume Cohort) and the infusion duration (Flow Rate Cohort) decreased with increasing infusion parameters. The rate of treatment-emergent adverse events per infusion was low (0.138 [Volume Cohort] and 0.216 [Flow Rate Cohort]). Serum IgG levels remained stable during the study. CONCLUSION: Pump-assisted IgPro20 infusions are feasible at 50 mL and 100 mL/h per injection site in treatment-experienced patients, which may result in fewer injection sites and shorter infusion times. TRIAL REGISTRATION: NCT03033745 ; registered January 27, 2017.

Tissue Response to Subcutaneous Infusion Catheter.

Insulin infusion pump, continuous glucose monitoring (CGM), and insulin infusion set (IIS) have been developed to be increasingly feasible for people with type 1 diabetes (T1D). Several recently approved CGMs are transitioning from 7-day to 10-day wear time without the need for fingerprick recalibration. Nevertheless, studies and improvements on IIS, a critical part of insulin pump therapy, have been limited. In particular, the recommended wear time of IIS is still 2-3 days, which can hardly match the current duration of CGM for potential closed-loop system development. It is generally believed that both the inserted catheter and the subsequent infused insulin drug could induce particular subcutaneous tissue response and skin-related complications at the infusion site. In certain cases, poor glycaemic control, increased risk of hypoglycemia, and serious cosmetic impact on people with diabetes were observed. Skin complication has also been attributed as an important factor resulting users to discontinue insulin pump therapy. This article provides the rare systematic review of IIS induced subcutaneous tissue responses and skin complications, including the impacts from the inserted catheters, the subcutaneous infused insulin, and the adhesive or tape used to immobilize the catheter. The FDA's recommendation for the frequency of IIS change was further discussed. Future studies on this topic are required to further understand the IIS-related problems, and future strategies could be developed accordingly to significantly reduce the incidence of these problems, extend the wear time, and increase the acceptance of insulin pump based therapy.

[The Impact of Prolonged Use of Continuous Subcutaneous Insulin Infusion in the Control of Type-1 Diabetes]. / Impacto do Uso Prolongado da Terapêutica Subcutânea Contínua com Insulina no Controlo da Diabetes Mellitus Tipo 1.

INTRODUCTION: The use of continuous subcutaneous insulin infusion therapy in type 1 diabetes mellitus has increased due to its benefits on glycemic control and on the lifestyle flexibility. The aim of this study was to assess the impact of continuous subcutaneous insulin infusion therapy on glycemic control, body mass index, total daily dose of insulin and complications associated with this therapy, during 20 years of experience in Centro Hospitalar e Universitário de Coimbra. MATERIAL AND METHODS: This retrospective study included patients with type 1 diabetes mellitus who started continuous subcutaneous insulin infusion therapy up until 2005, followed at Centro Hospitalar e Universitário de Coimbra. Glycated hemoglobin A1c, body mass index, total daily dose of insulin and acute complications associated with continuous subcutaneous insulin infusion therapy were evaluated immediately prior to initiation of continuous subcutaneous insulin infusion therapy with follow-up at six months, one year, five, 10, 15 and 20 years. The frequency of acute complications associated with this type of therapy was also evaluated. RESULTS: This study included 20 patients (seven males, 13 females) with mean disease duration up to the start of continuous subcutaneous insulin infusion therapy of 16.1 ± 7.9 years, mean age of onset of continuous subcutaneous insulin infusion therapy of 31.1 ± 8.4 years and follow-up during 13.2 ± 2.3 years. The reasons for initiating pump therapy were: inadequate metabolic control in 15 patients, history of asymptomatic or severe hypoglycemia in four patients, and pregnancy/pregnancy planning in one patient. The previous median of glycated hemoglobin A1c was 9.3% (6.5 - 16.0) and, at six months, decreased to the minimum value of 7.2% (5.3 - 9.8); p < 0.0125. The reduction of glycated hemoglobin A1c remained statistically significant in the first 10 years of follow-up. There was a statistically significant difference in the body mass index variation at 10 years with continuous subcutaneous insulin infusion therapy compared to previous body mass index; 24.7 kg/m2 (18.9 - 31.8) vs 25,5 kg/m2 (18.9 - 38.9), p <0.0125. Daily insulin requirements were reduced from 56.5 U (32.0 - 94.0) to 43.8 U (33.0 - 64.0) (p < 0.0125) at six months and no statistical differences were found in the remaining follow-up. There were two severe episodes of hypoglycemia (incidence 0.0095/patient/year), five episodes of diabetic ketoacidosis (0.0238/patient/year) and no infections at the site of catheter insertion. DISCUSSION: This study shows that continuous subcutaneous insulin infusion therapy improved glycemic control, especially during the first 10 years of follow-up and allowed a significant decrease in total daily dose of insulin in the first six months. The rate of acute complications was low. CONCLUSION: Treatment with continuous subcutaneous insulin infusion therapy seems effective in achieving metabolic control in selected patients with type 1 diabetes mellitus.

Introdução: O uso da terapêutica com perfusão subcutânea contínua de insulina na diabetes mellitus tipo 1 é cada vez mais frequente devido aos seus efeitos benéficos no controlo glicémico e na flexibilidade do estilo de vida. Constituiu objetivo deste estudo avaliar o impacto da terapêutica com perfusão subcutânea contínua de insulina no controlo glicémico, índice de massa corporal, dose diária total de insulina e complicações desta modalidade terapêutica durante vinte anos de experiência no Centro Hospitalar e Universitário de Coimbra. Material e Métodos: Estudo retrospetivo que inclui doentes com diabetes mellitus tipo 1 seguidos no Centro Hospitalar e Universitário de Coimbra, que iniciaram terapêutica com perfusão subcutânea contínua de insulina até 2005 e com pelo menos 10 anos de tratamento com terapêutica com perfusão subcutânea contínua de insulina. Avaliou-se a hemoglobina glicada A1c, o índice de massa corporal e a dose diária total de insulina imediatamente antes e seis meses, um ano, cinco, 10, 15 e 20 anos após terapêutica com perfusão subcutânea contínua de insulina a partir dos registos médicos. Avaliou-se ainda a frequência de complicações agudas associadas a este tipo de terapêutica. Resultados: Obtiveram-se dados de 20 doentes (sete homens; 13 mulheres) com duração média de doença até início da terapêutica com perfusão subcutânea contínua de insulina de 16,1 ± 7,9 anos, idade média de início de terapêutica com perfusão subcutânea contínua de insulina de 31,1 ± 8,4 anos e seguimento durante 13,2 ± 2,3 anos. As indicações para colocação de bomba foram: inadequado controlo metabólico em 15 doentes, história de hipoglicemias assintomáticas ou severas em quatro doentes, e gravidez/planeamento de gravidez em um doente. A mediana de hemoglobina glicada A1c prévia foi 9,3% (6,5 - 16,0) tendo diminuído aos seis meses para o valor mínimo de 7,2% (5,3 - 9,8); p < 0,0125. A redução da hemoglobina glicada A1c manteve-se estatisticamente significativa nos primeiros 10 anos de seguimento. Verificou-se uma diferença estatisticamente significativa na variação do índice de massa corporal após 10 anos de seguimento comparativamente com o valor prévio à terapêutica com perfusão subcutânea contínua de insulina; 24,7kg/m2 (18,9 - 31,8) vs 25,5 kg/m2 (18,9 - 38,9), p < 0,0125. As necessidades diárias de insulina foram reduzidas de 56,5 U (32,0 - 94,0) para 43,8 U (33,0 - 64,0) (p < 0,0125) nos primeiros seis meses e não se encontraram diferenças estatísticas no restante seguimento relativamente às necessidades prévias à terapêutica com perfusão subcutânea contínua de insulina. Verificaram-se duas hipoglicemias severas (incidência 0,0095/doente/ano), cinco cetoacidoses diabéticas (0,0238/doente/ano) e nenhuma infeção no local de inserção do cateter. Discussão: Este estudo demonstrou a eficácia da terapêutica com perfusão subcutânea contínua de insulina, que está associada a uma diminuição significativa da hemoglobina glicada A1c sustentada durante 10 anos e a uma redução da dose diária total de insulina, significativa nos primeiros seis meses. A taxa de complicações agudas foi baixa. Conclusão: A evidência sugere que a terapêutica com perfusão subcutânea contínua de insulina é efetivamente vantajosa no controlo metabólico em doentes com diabetes mellitus tipo 1 selecionados.

Pain Management in Pectus Excavatum Surgery: A Comparison of Subcutaneous Catheters Versus Epidurals in a Pediatric Population.

BACKGROUND: Pectus excavatum is a common chest wall anomaly. Achieving optimal pain control is a priority for adolescents undergoing surgical correction of this condition. Options for pain control include the use of subcutaneous catheters (On-Q® pumps) and epidurals. The objective of this study is to demonstrate the feasibility of using subcutaneous catheters for pain control and to compare them with the use of epidurals during surgical correction of pectus excavatum. MATERIALS AND METHODS: We identified patients who underwent pectus excavatum repair at our institution between January 2010 and August 2016. Patients were divided into two cohorts (epidural or On-Q pump). Patient charts were reviewed for length of stay, pain scores, pain medications, and complications. RESULTS: A total of 124 patients were included. Forty percent of patients used an epidural (n = 50), and 60% had the On-Q pump (n = 74). The average patient age was 15.6 years. The average Haller index was 4.3. The On-Q pump population had a significant decrease in postoperative length of stay (mean [M] = 4.86, standard deviation [SD] = 0.85) compared with the epidural population (M = 5.60, SD = 0.97); P ≤ .001. There was a significant difference observed in pain scores for patients on the epidural (M = 2.91, SD = 1.13) and On-Q pump (M = 3.81, SD = 1.19; P ≤ .001). There was n = 1 wound infection in each group. CONCLUSION: The use of bilateral subcutaneous infusion catheters is a safe and effective method for pain control in patients undergoing surgical correction of pectus excavatum. Even though the degree of pain control is not necessarily superior to epidurals, in this study, the catheters were associated with a shorter postoperative length of stay in this patient population and did not increase the incidence of complications.

Pattern dystrophies in patients treated with deferoxamine: report of two cases and review of the literature.

BACKGROUND: Deferoxamine (DFO) is one of the most commonly used chelation treatments for transfusional hemosiderosis. Pattern dystrophies constitute a distinct entity of retinal disorders that has been occasionally identified in association with deferoxamine. CASE PRESENTATION: We report two cases of bilateral macular pattern dystrophy in transfusion dependent patients undergoing chronic chelation therapy with deferoxamine due to thalassemias. Our patients were evaluated with multimodal imaging and the results are presented. Both patients had normal cone and rod responses in the full-field electroretinogram and continued the prescribed chelation therapy, after hematology consult. The patients were followed up every 3 months for 2 and 4 years respectively for possible deterioration. Their best corrected visual acuity remained stable with no anatomic change on Optical Coherence Tomography findings. CONCLUSION: Multimodal imaging of our patients allowed a better evaluation and possibly earlier detection of the DFO-related changes. Screening and close follow up of patients under chronic chelating therapy is important in order to promptly diagnose and manage possible toxicity either with discontinuation of the offending agent or dose modification.

Safety, efficacy and Management of subcutaneous treprostinil infusions in the treatment of severe pediatric pulmonary hypertension.

BACKGROUND: Continuous intravenous epoprostenol was the first treatment approved for pulmonary arterial hypertension (PAH) but administration through a central venous line carries risks of thrombosis and sepsis, particularly in children. We sought to evaluate the safety, efficacy and management of subcutaneous (SC) treprostinil in children with PAH. METHODS: Fifty-six children (median age 65, range 1-200 months) were treated with SC treprostinil. Clinical status, echocardiography, NT-proBNP, and site pain and infection were evaluated. Right heart catheterization was performed in 54 patients before starting SC treprostinil infusion and was repeated at 6 months in 31 patients. RESULTS: Treatment was well tolerated in 79% of patients. Site pain resistant to simple analgesics occurred in 12 patients (21%), but could be managed in 9/12 children. At 6 months, 3 patients had died, 4 had received a Potts shunt and 1 underwent lung transplantation. Among the 48 treated patients, 40 (83%) showed significant improvement in WHO functional class, 6 minute walk distance, NT-proBNP and pulmonary vascular resistance (p < 0.01 for all parameters). At last follow-up (median 37 months), ten patients had died, 2 underwent a lung transplantation and 8 underwent a Potts shunt. In 30 of the 36 remaining treated patients, improvement of clinical status was sustained. No children developed sepsis and 12 had minor site infections. CONCLUSION: Subcutaneous treprostinil infusion is an effective therapy without serious side effects in children with PAH. Site pain can be managed with simple analgesics in most children.

Safety and Efficacy of Subcutaneous Parenteral Nutrition in Older Patients: A Prospective Randomized Multicenter Clinical Trial.

BACKGROUND: Many patients who cannot tolerate adequate enteral nutrition could benefit from parenteral nutrition support but fail to receive it due to difficult intravenous (IV) access. The objective of this study was to compare the safety and efficacy of subcutaneous (SC) administration of parenteral nutrition with the peripheral IV route. MATERIALS AND METHODS: This was a prospective randomized multicenter study of 121 older hospitalized patients. The primary outcome was the composite end point of major local side effects, defined as local edema, blistering, erythema, phlebitis, cellulitis, unbearable pain, or route failure requiring a switch in route. Secondary outcomes were nutrition parameters, biochemical parameters, clinical outcomes, and safety. RESULTS: The SC route (n = 59) was noninferior to the IV route (n = 61) for major local side effects. Major local side effects trended higher in the IV group ( P = .059). Local edema was more common in the SC group ( P < .05), while route failure was more common in the IV group ( P < .001). Nutrition and biochemical parameters, safety, and clinical outcomes were similar between groups. CONCLUSIONS: The SC route of nutrient administration was better tolerated than the peripheral IV route. SC administration of parenteral nutrition represents a safe alternative to IV nutrition.

Comparison of the Pharmacokinetics of Ketorolac Tromethamine After Continuous Subcutaneous Infusion and Repeat Intramuscular Bolus Injections in Healthy Adult Subjects.

Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug that exhibits analgesic activity with no sedative or anxiolytic properties. Twelve healthy male subjects were enrolled in a study to receive either of 2 treatments over 2 periods in an open-label, randomized, 2-way crossover design: (A) 120 mg of ketorolac tromethamine administered as a continuous subcutaneous infusion over a 24-hour period; or (B) an identical total daily dose administered as 4 intramuscular bolus injections of 30 mg each given every 6 hours (current labeled treatment regimen). The pharmacokinetic and safety profiles were evaluated for both treatments. Both modes of administration have similar values for area under the curve (AUC) and half-life (t1/2 ), suggesting that continuous subcutaneous infusion and repeated intramuscular bolus injections have similar bioavailability. The peak plasma concentration (Cmax ) was 40% lower when ketorolac was administered as a continuous subcutaneous infusion compared with repeat intramuscular bolus injections. The concentration at steady-state (Css ) for continuous subcutaneous infusion was between the Cmax and Ctrough values obtained following the 4 intramuscular injections. Both treatment arms were well tolerated.

Quality of life in Parkinson's disease improved by apomorphine pump: the OPTIPUMP cohort study.

To report on OPTIPUMP, a cohort study, investigating the impact in real-life clinical settings of continuous subcutaneous apomorphine infusion (CSAI) on the quality of life (HRQoL) of patients with Parkinson's disease. OPTIPUMP was a prospective, open-label, observational cohort study involving 30 investigational sites in France. CSAI was proposed as part of routine clinical care to patients aged ≥18 years, in absence of dementia, with a PD diagnosis and based on the presence of motor fluctuations not controlled by oral treatments. The impact of APO-pump on quality of life was evaluated as the difference in PDQ-39 scores between the initiation treatment and the follow-up visit after 6 months' treatment. All adverse events were recorded. Hyper- and hypodopaminergic behavioral tolerance was assessed on the Ardouin Scale of Behavior in Parkinson's Disease. Between September 2011 and January 2013, we enrolled 142 patients: 42 patients were withdrawn due to pump removal (33), death (4), lost of follow-up (4), no available data (1). 100 completed the study. At 6 months, their HRQoL had significantly improved (p = 0.011), as had their total UPDRS score (p < 0.001). Regarding the safety profile, Ardouin scale scores indicated that their hyperdopaminergic behaviors had not increased. CSAI had a favorable impact on HRQoL, with benefits outweighing risks. The analysis of the withdrawn patients highlights the heterogeneity of the use of the pump having an impact on its efficacy and tolerability.

Feasibility of subcutaneous gentamicin and pressurized irrigation as adjuvant strategies to reduce surgical site infection in colorectal surgery: results of a pilot study.

Surgical site infections (SSIs) remain a common and costly morbidity after colorectal surgery. This rate remains high even in the setting of strict adherence to Surgical Care Improvement Project Protocols. The aim of our pilot study was to determine the feasibility and safety of subcutaneous gentamicin injection or pressurized irrigation as adjuncts to reduce SSI. A total of 132 patients who underwent colorectal surgery at the VA North Texas Health Care System were prospectively assigned to a pressurized irrigation group (n = 44), a preincision gentamicin injection group (n = 48), or control (n = 40). The primary objective was to assess safety and feasibility of these strategies. Patient demographics were matched among groups. Univariate and multivariate analyses were performed to identify possible predictions of SSI in this cohort. The rate of SSI in the control group was 25 per cent, 13.5 per cent in the pressurized irrigation group, and 12.5 per cent in the gentamicin group (P = 0.26). Combined, the intervention groups had a 13 per cent SSI versus 25 per cent control (P = 0.09). Operative time was not increased by the interventions and no intraoperative complications specifically related to the interventions were noted. Postoperative complications were not different between groups. Both albumin and body mass index were associated with SSI. Body mass index was and independent predictor of SSI (P = 0.006). In conclusion, this pilot study demonstrates the feasibility of the interventions described. There was no detrimental effect of either intervention. There was trend toward a reduction in SSI in the intervention group, which warrants further investigation.

[Subcutaneous rehydration in patients in terminal phase of dementia]. / Subkutánní rehydratace u pacientu s terminální fází demence.

BACKGROUND: Dehydration among seniors is not rare. It is both medical and nursing problem, leading to many complications. Attention is paid to ways of rehydration among seniors in terminal phase of dementia. Aim to evaluate frequency of complications due to subcutaneous rehydration in patients with terminal phase of dementia and to evaluate nurses opinion in relation to this method of rehydration. METHODS: Observational study has been designed in women psychogeriatric wards, Mental hospital Kromeríz, from June 2012 - December 2013, evaluating frequency of complications due to subcutaneous rehydration - local oedema, local infection, local erythema (60 patients group) and evaluating nurses opinion in relation to this method of rehydration (18 nurses group). METHODS: observation, interview. RESULTS: No complications of subcutaneous dehydration was found in 58 cases (96.6%), in 1 case local oedema (1.7%) and in 1 case (1.7%) local erythema manifested. Nurses reported effortles-sness of subcutaneous rehydration together with sparing of their working time and comfort to a patient in comparison with intravenous rehydration therapy. CONCLUSION: Subcutaneous rehydration seems to be an appropriate method of rehydration in patients with terminal phase of dementia.