Subcutaneous Replacement Research Articles

Efficacy, Safety, and Pharmacokinetics of a 10% Liquid Immune Globulin Preparation (GAMMAGARD LIQUID, 10%) Administered Subcutaneously in Subjects with Primary Immunodeficiency Disease

A multi-center, prospective, open-label study was conducted in primary immunodeficiency disease patients to determine the tolerability and pharmacokinetics of a 10% liquid IgG preparation administered subcutaneously. Forty-nine subjects (3-77 years old) were enrolled. Pharmacokinetic equivalence of subcutaneous treatment was achieved at a median dose of 137% of the intravenous dose, with a mean trough IgG level of 1,202 mg/dL at the end of the assessment period. The overall infection rate during subcutaneous treatment was 4.1 per subject-year. Three acute serious bacterial infections were reported, resulting in a rate of 0.067 per subject-year. A low overall rate of temporally associated adverse events (8%), and a very low rate of infusion site adverse events (2.8%), was seen at volumes up to 30 mL/site and rates ≤ 30 mL/h/site. Thus, subcutaneous replacement therapy with a 10% IgG preparation proved effective, safe and well-tolerated in our study population of subjects with primary immunodeficiency disease.

Immunoglobulin Dosage and Switch from Intravenous to Subcutaneous Immunoglobulin Replacement Therapy in Patients with Primary Hypogammaglobulinemia: Decreasing Dosage Does Not Alter Serum IgG Levels

The impact of reducing immunoglobulin dosage while switching from intravenous to subcutaneous replacement therapy was evaluated. Sixty-five patients with primary hypogammaglobulinemia on stable intravenous replacement therapy were included in a monocentric longitudinal trial. IgG trough levels were measured at baseline and during 1 year following the switch to the subcutaneous route. Mean IgG trough level after 12 months of subcutaneous therapy was increased by 5.4 percent (8.37-8.82 g/l, p=0.3), while immunoglobulin dosage had been reduced by 28.3% (151-108 mg/kg/week, p<0.0001). For the patients with the lowest serum IgG level upon intravenous infusions, serum IgG level rose by 37 percent (5.33-7.33 g/l, p=0.003), while mean immunoglobulin dosage was reduced by 36 percent (170-109 mg/kg/week, p=0.04). The present study shows that sustained serum IgG levels can be achieved after switching towards subcutaneous replacement despite using reduced immunoglobulin doses.

Improvement in Quality of Life Measurements in Newly Diagnosed Patients with Primary Immunodeficiency Receiving Directly Initiated Subcutaneous Replacement Therapy with Vivaglobin

Improvement in Quality of Life Measurements in Newly Diagnosed Patients with Primary Immunodeficiency Receiving Directly Initiated Subcutaneous Replacement Therapy with Vivaglobin

The life situations of patients with primary antibody deficiency untreated or treated with subcutaneous gammaglobulin infusions.

The life situations of 25 patients with hypogammaglobulinaemia were studied before and after the initiation of subcutaneous replacement therapy by using medical records, data registers and questionnaires (a study and a disease-specific questionnaire, the Sickness Impact Profile and the General Health Rating Index). Before treatment, the patients perceived more dysfunctions with regard to ambulation, mobility, emotional behaviour, social interaction, sleep and rest, household management, work and recreation or pastime activities compared with a Swedish reference group (P = 0.0001). A significant increase in the perceived frequency of infections was also seen in untreated patients compared with a group of healthy individuals (P = 0.0001). After 18 months of weekly subcutaneous infusions of an intramuscular gammaglobulin preparation (100 mg/kg), the patients reported a significantly increased, health-related function and improved self-rated health. A significantly higher pre-infusion IgG level was also found.

C-Peptide Reverses Nociceptive Neuropathy in Type 1 Diabetes

We examined the therapeutic effects of C-peptide on established nociceptive neuropathy in type 1 diabetic BB/Wor rats. Nociceptive nerve function, unmyelinated sural nerve fiber and dorsal root ganglion (DRG) cell morphometry, nociceptive peptide content, and the expression of neurotrophic factors and their receptors were investigated. C-peptide was administered either as a continuous subcutaneous replacement dose via osmopumps or a replacement dose given once daily by subcutaneous injection. Diabetic rats were treated from 4 to 7 months of diabetes and were compared with control and untreated diabetic rats of 4- and 7-month duration. Osmopump delivery but not subcutaneous injection improved hyperalgesia and restored the diabetes-induced reduction of unmyelinated fiber number (P < 0.01) and mean axonal size (P < 0.05) in the sural nerve. High-affinity nerve growth factor (NGF) receptor (NGFR-TrkA) expression in DRGs was significantly reduced at 4 months (P < 0.01). Insulin receptor and IGF-I receptor (IGF-IR) expressions in DRGs and NGF content in sciatic nerve were significantly decreased in 7-month diabetic rats (P < 0.01, 0.05, and 0.005, respectively). Osmopump delivery prevented the decline of NGFR-TrkA, insulin receptor (P < 0.05), and IGF-IR (P < 0.005) expressions in DRGs and improved NGF content (P < 0.05) in sciatic nerve. However, subcutaneous injection had only marginal effects on morphometric and molecular changes in diabetic rats. We conclude that C-peptide exerts beneficial therapeutic effects on diabetic nociceptive neuropathy and that optimal effects require maintenance of physiological C-peptide concentrations for a major proportion of the day.

Express Subcutaneous IgG Infusions: Decreased Time of Delivery with Maintained Safety

The aims of the study were to evaluate the safety and feasibility of weekly express subcutaneous replacement IgG self-infusions (E-SCIG, 35 mL/h/syringe driver) in 50 patients and to evaluate their perceptions of the therapy. A total of 4900 E-SCIG infusions at separate infusion sites were given on 1228 treatment occasions. The most commonly reported local tissue reactions were swelling ( n = 37), redness ( n = 25), and soreness ( n = 24). A majority of these patients reported the local reactions as less intense or unchanged compared to those arising from rapid SCIG (20 mL/h) infusions. The patients reported a median score of 16 (visual analogue scale, VAS; 1, not troublesome at all) regarding their overall perceptions of the local reactions. They were positive toward the home therapy regime (median VAS score 96; 100, very positive) and anxious to continue with the E-SCIG infusions (median VAS score 98; 100, very anxious). The E-SCIG method seems to be safe, with few pronounced local reactions, and is appreciated by the patients. Express delivery could also potentially facilitate IgG delivery in a wide variety of diseases, such as autoimmune and autoimmune-like conditions of a neurological or rheumatological character.

Estrogen receptor beta is involved in the anorectic action of estrogen.

Estrogen has been implicated in feeding behavior and adiposity. This study was undertaken to elucidate the mechanism underlying the anti-obesity and anorectic action of estrogen and the role of estrogen receptor (ER) in the central nervous system. Ovariectomy in 8-week-old female Wistar rats induced hyperphagia along with an increase in body weight and abdominal fat accumulation compared to control sham-operated rats. These changes were fully reversed by subcutaneous replacement of estradiol and were abrogated by pair-feeding. Then, the effects of intracerebroventricular infusion of estradiol, alone or in combination with antisense oligodeoxynucleotides (ODN), for ER in ovariectomized rats were examined. The estradiol group showed 10-20% lower daily food intake, and after the 2-week infusion period a 14% reduction in body weight with a similar reduction in abdominal fat compared to the vehicle group. The inhibitory effect of estradiol on food intake and body weight was blocked by co-administration of ER-beta antisense ODN, whereas ER-alpha antisense ODN did not show any influence. These results indicate that ER-beta in the central nervous system is involved in the anorectic action of estrogen.

Leptin reverses sucrose-conditioned place preference in food-restricted rats

Previous studies have suggested that food restriction can modify performance in the conditioned place preference (CPP) paradigm. In the present study, we tested the hypotheses that food restriction would enhance the development of a CPP to low-calorie sucrose pellets and that peripheral leptin replacement in food-restricted animals would reverse this effect. Using a range of 45-mg sucrose pellets (0–15 pellets) as a reward, we observed that a significant place preference was conditioned in food-restricted, but not ad libitum-fed rats. This CPP was reversed either by treatment of food-restricted rats with the dopamine receptor antagonist α-flupenthixol (200 μg/kg ip) during the training protocol or by chronic subcutaneous replacement of leptin (125 μg/kg/day) that attenuated the food restriction-induced decrease of circulating leptin. We conclude that dopaminergic signaling and the fall of plasma leptin concentrations contribute to the CPP of food-restricted rats. This finding suggests that in addition to metabolic adaptations, hypoleptinemia results in behavioral adaptations during states of energy deprivation.

Maintaining Oral Hydration in Older People; A Systematic Review

Objectives The objective of this review is to present the best available evidence related to: • the factors that increase the risk of poor hydration in older people, • how best to assess older people for risk of inadequate fluid intake, presence and/or risk of dehydration, and • how best to maintain adequate oral fluid intake or hydration, or reverse dehydration, in older people. Criteria for Considering Studies for this Review Types of Participants This review considered all studies that included adults aged over 60 years in an acute care, residential care or community setting. Types of Intervention Interventions of interest were those related to the maintenance of oral hydration in older people, including interventions that ensured optimal fluid intake in older people. This review focussed on oral fluid replacement interventions only. Only oral rehydration management protocols were considered because techniques such as subcutaneous, intravenous and feeding tube fluid replacement are less common in community or nursing home settings. In addition to the management of older adults with inadequate fluid intake, this review also included studies that: 1) identified risk factors for poor fluid intake and dehydration, and 2) evaluated assessment tools to assist in determining fluid intake and fluid status in older people. Studies addressing the ethics of hydration in the terminally ill were excluded as beyond the scope of the review. Types of Outcome Measures The primary outcomes of interest were the measurement of oral fluid intake and those related to the identification of dehydration, the maintenance of oral hydration or the reversal of dehydration. Types of Studies This review considered any randomised control trial that evaluated management strategies to ensure adequate oral fluid intake and maintenance of hydration, or reversal of dehydration, in older people. For the identification of risk factors for dehydration in older people, cohort and case control studies were also included. Studies that evaluated assessment tools for the identification of dehydration in older adults were also considered for inclusion in this review. Results This review has been separated into three categories: risk factors, assessment, and management of dehydration/reduced fluid intake. Risk Factors Few studies have been performed to determine the risk factors for dehydration and/or reduced fluid intake. Age was determined to be a risk factor for dehydration in nursing home residents, but not in older adult emergency admissions. Age as a risk factor for reduced fluid intake yielded contradictory results. Bedridden patients were found to be at higher risk of dehydration, however semi-dependent older adults were found to be at most risk of reduced fluid intake in one study with no correlation in another. It was unclear from present studies if gender was a risk factor for either dehydration or reduced fluid intake. Incontinence was not found to be a risk factor for dehydration in one study but was for decreased fluid intake in another. Mental status was inversely correlated to risk of dehydration but contradictory results were obtained for reduced fluid intake. Reduced speaking ability and evidence of drooling identified patients as being more dependent however this reduced their risk of decreased fluid intake. A single study identified the presence of multiple diseases/medications as risk factors for dehydration. The number of ingestion sessions provided to nursing home residents was also positively correlated with fluid intake. Finally, one study concluded that being an institutionalised older adult led to an increased risk of a significantly lower fluid intake compared to older adults in the community. TRUNCATED AT 600 WORDS

Rapid subcutaneous IgG replacement therapy at home for pregnant immunodeficient women.

The use of slow or rapid, subcutaneous, IgG (SCIG) infusions in pregnant women with primary antibody deficiencies has been described earlier, though only in single-case reports. In this study, we have evaluated the effect of rapid, SCIG infusions during 11 pregnancies in nine women [six women with common variable immunodeficiency (CVID), two with IgG-subclass deficiencies, and one with combined IgA and IgG2 deficiency]. The weekly infusions were given by the women themselves at a dose of 100 mg/kg/week throughout the pregnancy. No adverse systemic reactions or pronounced, local tissue reactions were recorded during or after the more than 400 infusions. The 11 babies were healthy and were born after 38-42 weeks of uneventful gestation. The concentrations of maternal S-IgG at the time of delivery in the four women with CVID ranged from 6.0 to 8.3 g/L, with cord/maternal S-IgG ratios of 1.0-1.5. The IgG subclasses were transferred to the infants. The SCIG home-therapy regime was greatly appreciated by the women.

Subcutaneous Ureteral Replacement: A Canine Model

There are several clinical situations in which extrinsic or intrinsic ureteral diseases necessitate extensive reconstructive surgery. Unfortunately, not all patients are candidates for such surgery (e.g., those with retroperitoneal metastatic disease). Ureteral replacement is indicated in this selected group of patients. A viable option is to establish a ureteral replacement using subcutaneous tubes. Among the problems associated with this method of urine diversion are selecting the proper material for the tubes, the timing of tube replacement, encrustation and occlusion, urine reflux, and renal function. There is an obvious need for an animal model to address these issues. The aim of this study was to establish a reproducible canine model for subcutaneous ureteral replacement, by using a combination of nephrostomy and cystostomy tubes joined together under the skin. The animal study was conducted in 6 dogs. A pigtail nephrostomy and a cystostomy were inserted through a midline abdominal incision and stab wounds in the abdominal wall. A subcutaneous tract was bluntly made toward the nephrostomy incision starting from the cystostomy incision. The nephrostomy was grasped with the clamp and brought through the subcutaneous tunnel to the cystostomy incision. Upon emerging through the cystostomy incision, the tubes were joined and buried under the skin. Intravenous urography at 4-6 weeks postoperatively in 4 dogs showed no deterioration of renal function, but some hydronephrosis was present. Using the technique described in this paper, it is possible to establish a subcutaneous ureteral replacement using nephrostomy and cystostomy tubes in dogs. This model may serve for further research of the various questions associated with subcutaneous ureteral replacement in humans.

Influences of ovariectomy and continuous replacement of 17beta-estradiol on the tail skin temperature and behavior in the forced swimming test in rats.

The effect of ovariectomy and continuous subcutaneous replacement of 17beta-estradiol was examined in female Wistar rats. Tail skin temperature significantly increased in ovariectomized rats 6 days after ovariectomy, and the elevated level was sustained until 21 days after ovariectomy. 17beta-Estradiol at doses of 0.3 and 1.0 microg/body/day suppressed the increases in tail skin temperature. In the forced swimming test, the ovariectomized control rats showed significantly prolonged immobility time in comparison with sham-ovariectomized rats 14 days after ovariectomy. The duration of immobility of ovariectomized rats treated with 17beta-estradiol (0.3, 1.0, 3.0 microg/body/day) or maprotiline (0.6 mg/body/day) was significantly shorter than that of ovariectomized control rats.

Unusual cause of calcinosis cutis

An unusual cause of calcinosis cutis is reported in a 73-year-old woman following subcutaneous fluid replacement, 36 years before consultation. Late secondary infection of the calcium deposits, 35 years after the causative event, was followed by local and systemic symptomatology. Healing was only achieved after wide surgical excision of the involved tissue and skin grafting.

Human and porcine regular insulins are equally effective in subcutaneous replacement therapy. Results of a double-blind crossover study in type I diabetic patients with continuous subcutaneous insulin infusion

Human and porcine regular insulins are equally effective in subcutaneous replacement therapy. Results of a double-blind crossover study in type I diabetic patients with continuous subcutaneous insulin infusion

Human and Porcine Regular Insulins Are Equally Effective in Subcutaneous Replacement Therapy: Results of a Double-Blind Crossover Study in Type I Diabetic Patients with Continuous Subcutaneous Insulin Infusion

Semisynthetic human Actrapid insulin (HAI, Novo, Copenhagen) was tested against porcine Actrapid insulin (PAI, Novo, Copenhagen) in 12 type I diabetic patients treated with continuous subcutaneous insulin infusion (CSII). In a double-blind crossover trial each patient received both types of insulin over a 3-wk period, respectively. No significant differences between HAI and PAI were observed in the following parameters: mean blood glucose levels (MBG) of 3-6 measurements per day (129 +/- 5 versus 125 +/- 4 mg/dl, means +/- SEM), mean maximal excursions of blood glucose during the day (107 +/- 6.6 versus 107 +/- 6.9 mg/dl), total daily insulin requirements (sum of basal and premeal insulin doses, 45.7 +/- 1.4 versus 42.7 +/- 1.4 U/day), and a mean of weekly determined hemoglobin A1c values (7.77 +/- 0.13 versus 7.83 +/- 0.14% of total hemoglobin); the frequency of mild hypoglycemic episodes was similar with the two insulins. Thus, under the controlled conditions of CSII, semisynthetic human and porcine regular insulin preparations are of identical efficacy in type I diabetic patients at near normoglycemia.

Role of ovarian hormones in the long-term control of glucose homeostasis. Effects of insulin secretion.

The role of ovarian hormones in the long-term control of B-cell function of in the mouse has been examined. Ovariectomised adult female mice were treated with daily subcutaneous replacement doses of oestradiol (5 microgram/kg), progesterone (1 mg/kg), both hormones combined, or vehicle only for 15 weeks. Ovariectomy caused a 40% increase in plasma glucose concentrations during glucose tolerance tests, a 26% decrease in the plasma insulin response to glucose (2 g/kg IP) and a 32% decrease in the plasma insulin response to arginine (2 g/kg IP) compared with control mice. When islets from ovariectomised mice were incubated for 30 minutes in media containing 28 mmol/l glucose or 2.8 mmol/l glucose with 5 mmol/l arginine, insulin release was reduced by 23% and 31% respectively. Total pancreatic and islet insulin content were each decreased by 36%, and the number of B-cells was decreased by 39% in the ovarietomised mice. These detrimental effects of ovariectomy were partially or totally prevented by the oestradiol and progesterone treatments. The results indicate that ovarian oestrogens and progestogens may play an important role in the long-term maintenance of B-cell competence in the female mouse.

MAINTENANCE OF ADRENALECTOMIZED RATS THROUGH CONCEPTION, PREGNANCY, AND LACTATION.

Maintenance of the reproductive cycle through conception, pregnancy, and lactation was attempted in 231 adrenalectomized rats by subcutaneous replacement therapy with cortisol acetate and/or deoxycorticosterone acetate (DCA). The combination of 100 µg cortisol and 50 µg DCA was not ample for pregnancy maintenance. Saline drinking water (1% NaCl) was insufficient therapy to support pregnancy. Cortisol at 150 or 250 µg and DCA at 250 µg enabled conception and maintenance of pregnancy to occur at 75% and lactation maintenance at 43% of the normal incidence. DCA at 250 µg/day maintained adrenalectomized rats in excellent condition and permitted conception and pregnancy to proceed at a rate equal to the normal control group; however, DCA did not support lactation without the addition of the glucocorticoid. Deoxyribonucleic acid content of the mammary glands was higher in groups receiving cortisol than in the group maintained on DCA.