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The effect of aprotinin on the absorption of subcutaneously injected regular insulin in normal subjects.

The effect of aprotinin on the absorption of regular insulin was assessed in normal man. Ten units of Actrapid insulin were subcutaneously injected together with 1.4 mg aprotinin (i.e., 0.5 ml of Trasylol) or an equivalent volume of physiologic saline (controls) into the thighs of overnight-fasted normal subjects. Aprotinin caused an increase in the rate of insulin entry into the circulation; the absolute amount of insulin that was detected in the circulation during the course of the experiment was also higher. In addition, the onset of the hypoglycemic action of exogenous insulin was significantly accelerated when insulin was administered together with aprotinin. These data suggest that aprotinin increases the absorption rate of subcutaneously injected insulin from its depot into the circulation, possibly by an inhibition of the local degradation of exogenous insulin at the injection site.

Absorption↗

Carcinogenic effect of chronic subcutaneous injections of 2,6-dimethylnitrosomorpholine in Sprague-Dawley rats.

Sprague-Dawley rats received subcutaneous injections of 2,6-dimethylnitrosomorpholine (2,6-DMNM) at 3 different dose levels (1/5, 1/10 or 1/20 LD50) once weekly for life. Up to a 100% rate of tumors of the esophagus was detected in animals which received 1/10 and 1/20 LD50. In addition to tumors of this organ, neoplasms developed at different rates in the lungs and in the liver.

Animals↗

Inducibility of thymic lymphomas in female Hsd: (ICR)BR mice following subcutaneous injection of ethyl- and isopropyl methanesulfonate.

Isopropyl methanesulfonate (IMS), a direct-acting SN1 alkylating agent, induced thymic lymphomas in 29 of 30 female Hsd: (ICR)BR mice by the 139th day following once a week subcutaneous injections at a dose of 10 mumol/mouse. No such neoplasms were observed at the 450th day following 52 once a week subcutaneous injections (20 mumol/mouse) of the borderline SN1/SN2 alkylating agent ethyl methanesulfonate (EMS). Local sarcomas were observed in 2 and pulmonary adenomas in 20 of the 30 EMS-treated mice, 70% of which were alive at the 450th day. Neoplasms were not observed at local or at distant sites other than the thymus gland following treatment with IMS. The results suggest a sensitivity of hemopoietic tissue to the types of DNA lesions induced by IMS.

Animals↗

Morphometric analysis of the collagen changes induced by subcutaneous injection of interferon-gamma after bladder outlet obstruction in the rat.

AIMS: The objective of this study was to examine the effects of interferon-gamma injection on changes in collagen content, after the creation of partial bladder outlet obstruction in the rats. METHODS: A total of 50 Sprague-Dawley female rats were subjected to partial bladder outlet obstruction by using metal rods. The rats were divided into five groups (n = 10 in each group): normal control (N), sham operation (S), bladder outlet obstruction for 4 weeks (BOO), interferon-gamma injection after sham operation (S + IFN), and interferon-gamma injection after bladder outlet obstruction (BOO + IFN). Interferon-gamma was subcutaneously injected (100,000 units per injection, LG chemical Co., Seoul, Korea) daily for 4 weeks in the injection groups, after which all rats were sacrificed. RESULTS: The collagen area percentage (collagen/collagen + muscle) in each bladder, calculated through image analysis, was 40.7 +/- 1.6% in the N, 38.2 +/- 2.0% in the S, 26.6 +/- 3.8% in the S + IFN, 19.9 +/- 2.5% in the BOO, and 12.4 +/- 2.0% in the BOO + IFN group (mean +/- standard error). The difference in the collagen area percentage between the N and S groups (P > 0.05) was not significant, but there were significant differences between the N and S + IFN groups (P < 0.05), between the S and S + IFN groups (P < 0.05), and between the BOO and BOO + IFN groups (P < 0.05). CONCLUSIONS: It appears that interferon-gamma decreases the collagen content in the obstructed rat bladder.

Animals↗

Insulin antibodies do not influence the absorption rate of subcutaneously injected insulin.

The influence of insulin antibodies on absorption rate and plasma free insulin concentrations after subcutaneous injection of insulin, was studied in two groups of insulin-treated diabetic patients, one without insulin antibodies (n = 9) and a second with high plasma concentrations of antibodies (n = 14). Except for antibody concentration there were no differences in clinical variables. During 8 h after the injection of 12 U of iodinated neutral human insulin, residual radioactivity at the injection site, plasma glucose, and free and total insulin were measured. Significant differences in absorption rate of insulin were not found between the groups. Plasma glucose (basal value 16.8 +/- 4.4 SD vs 16.1 +/- 4.2 mmol l-1) and free insulin (basal value 8.3 +/- 1.4 vs 11.4 +/- 2.3 mU l-1, maximum after 90 min 36.9 +/- 19.5 vs 30.5 +/- 18.7 mU l-1) were never significantly different between the groups, nor were areas under the curve for free insulin (191.4 +/- 69.2 vs 170.8 +/- 98.6 mU l-1 h). In the high antibody group a small increase in bound insulin was found.

Adult↗

Level of clodronate in bone after single and repeated subcutaneous injections in rats.

The levels of clodronate in bone and plasma were determined in rats after subcutaneous injection of a mixture of unlabelled and 14C-labelled disodium clodronate as a single dose (25 mg/5 muCi/kg or of 125 mg/25 muCi/kg), and as repeated doses (25 mg/5 muCi/kg) once or five times a week for five weeks. The level of clodronate in bone increased dose-dependently. However, during repeated administration some saturation in bone was observed. The accumulation of clodronate in femur was higher than in ankle. No clear differences in concentration of clodronate in bone could be seen after different dosage schedules when the total doses were the same.

Absorption↗

[Treatment of motor fluctuations in Parkinson's disease with subcutaneous injections of apomorphine].

Sixteen patients with Parkinson's disease and severe motor fluctuations were treated with subcutaneous injections of apomorphine and followed up prospectively for a year. The use of the drug improved the number of daily "off" hours by 52%, while treatment efficacy remained constant for a year without the appearance of tolerance (ANOVA with repeated measurements:p = 0.0002). No severe adverse effect or any justifying treatment discontinuance were recorded. Apomorphine proved a safe and reliable drug for the treatment of motor fluctuations.

Aged↗

Bioactivity and pharmacokinetics of human proinsulin in comparison to human insulin after intravenous and subcutaneous injection.

The hypoglycemic actions of human insulin (1 IU/kg b.w.) and biosynthetic human proinsulin in about equimolar amounts were studied after intravenous and subcutaneous injection in rabbits. Blood samples were taken up to four hours after injection for the determination of blood glucose and immunoreactive levels of both insulin and human C-peptide. For the determination of human C-peptide, serum taken after proinsulin injection was divided into two fractions. One was examined directly by the human C-peptide radioimmunoassay and the other after incubation with a protein-A-sepharose coupled insulin antibody to find "free human C-peptide". Proinsulin in amounts equimolar to 1 IU insulin/kg b.w., exerted a 34% stronger hypoglycemic action after subcutaneous injection than after intravenous administration (area under curve estimation). Proinsulin-induced hypoglycemia did not last longer after intravenous administration than that induced by intravenous insulin. Although subcutaneous proinsulin did not show the same maximum decrease of blood glucose compared to subcutaneous insulin, its action was significantly prolonged (up to 180 min). Specific measurement of free human C-peptide showed no evidence of conversion of proinsulin to insulin and C-peptide.

Animals↗

In vivo ESR studies on subcutaneously injected multilamellar liposomes in living mice.

PURPOSE: An innovative, noninvasive, low-frequency electron spin resonance (ESR) spectroscopy method was applied and adapted to investigate the integrity of multilamellar liposomes from hydrogenated phospholipids after subcutaneous injection in living mice. Moreover, the fate of the injected liposomal preparations was examined, as well as the possibility to achieve a depot effect. METHODS: Highly concentrated solutions of the spin probe 2,2,6,6-tetramethyl-4-trimethylammoniumpiperidine-1-oxyl-iodide (CAT-1; 138 mM) were encapsulated in liposomes. They were characterized by laser diffraction, and the liberation of spin probe was investigated by ESR spectroscopy. RESULTS: Line shape changes allowed the differentiation between encapsulated and released CAT-1 after subcutaneous injection of liposomes. Multilamellar liposomes form a local depot at the site of injection. A sustained release of the spin probe from the depot was monitored by means of ESR. Whereas 40% of the spin probe was released within the first 96 h after administration, 60% remained in intact liposomes under the skin. No depot formation could be observed after injection of CAT-1 solutions, but a fast signal decrease due to systemic distribution and bioreduction of the nitroxide spin probe. CONCLUSIONS: Noninvasive analysis of liposomal integrity in living animals was successfully accomplished using a new L-Band ESR spectroscopy method. The liberation of CAT-1 from liposomes in vitro and in vivo was monitored by changes in the lineshape of ESR spectra and Heisenberg spin exchange. The significance of liposomal integrity for the formation of a localized drug depot effect was proved.

Animals↗

Myalgia and elevated creatine kinase activity associated with subcutaneous injections of diluent.

A 16-year-old boy with short stature and mild primary hypothyroidism received subcutaneous injections of either recombinant human growth hormone or placebo in diluent that contained glycerol and m-cresol as a preservative. While he was receiving the study drug, myalgia developed and serum creatine kinase values were elevated. Both resolved when injections were stopped and recurred when injections of diluent alone were given. The myalgia and elevated creatine kinase activity were apparently caused by a component of the diluent.

Adolescent↗

A comparison of pentosan polysulphate and heparin. II: Effects of subcutaneous injection.

A comparison has been made between the effects of pentosan polysulphate (SP54) and mucosal heparin following subcutaneous injection in man. Unlike heparin, pentosan polysulphate has relatively little effect in vivo as measured by anti-factor Xa clotting assay and none by an anti-Xa amidolytic assay (S-2222). However, pentosan polysulphate is at least as potent as heparin on a weight basis in producing activation of lipoprotein lipase, shortening of the euglobulin clot lysis time and impairing the generation of factor Xa. Our data indicate that pentosan polysulphate has more marked effects in vivo than in vitro, that the action of the drug on clotting is mediated mainly via an At III-independent pathway, and that its effects are not confined to the coagulation system.

Blood Coagulation↗

[Subcutaneous injections and intravenous infusion of sodium salt of heparin in the treatment of thrombosis of deep veins of the lower extremities].

Ninety-four patients with deep vein thrombosis of inferior limbs were randomly allocated to receive sodium heparin either by subcutaneous injections or by continuous intravenous infusion for six days. No significant difference was observed in the therapeutic efficiency as judged by phlebographic examinations and in rate of symptomatic pulmonary embolism between the two groups. There was one instance of major bleeding in the subcutaneous group. Minor bleedings occurred in 10 of the 48 patients treated with subcutaneous heparin and in 13 of the 46 patients receiving intravenous heparin. The results showed that subcutaneous injections of sodium heparin are as effective and safe as continuous intravenous infusion of this drug in the treatment of deep vein thrombosis.

Adult↗

The variability of the absorption of subcutaneously injected insulin: effect of injection technique and relation with brittleness.

A comparison has been made of insulin absorption rate and its variability in healthy subjects (n = 12), matched Type 1 diabetic patients (n = 12), and brittle Type 1 diabetic patients (n = 13) after subcutaneous injection with a standardized injection technique. In each individual 8 U of iodinated neutral human soluble insulin were injected twice, at the fat-muscle boundary. Disappearance of radioactivity was measured for 8 h. Differences in absorption rate could not be demonstrated (T50 207 +/- 30 (+/- SD), 224 +/- 73 and 217 +/- 80 min in the three groups, respectively). Intra-individual variance was similar in the three groups (intra-individual SD of T50 14 +/- 9, 10 +/- 6 and 12 +/- 10%, respectively). Injection with the skinfold technique each patient usually employed, did not alter mean absorption rate or its variability significantly (T50 179 +/- 52 min; intra-individual SD 12 +/- 8%). In a group of Type 1 diabetic patients (n = 26) the absorption rate after deep injection was compared with that after superficial injection. No differences were found (T50 207 +/- 66 vs 236 +/- 66 min). In some of these patients (n = 10) plasma free insulin and glucose concentrations were measured. The increase in free insulin concentrations was significantly different only at some time-points, but insulin curves and plasma glucose concentrations did not differ significantly. Thus neither insulin absorption nor its variability differ between healthy subjects and diabetic patients, between deep and superficial subcutaneous injection, or between stable and brittle diabetic patients.

Absorption↗

Dendritic cells matured with TNF can be further activated in vitro and after subcutaneous injection in vivo which converts their tolerogenicity into immunogenicity.

Dendritic cell (DC) maturation can occur by different types of stimuli. Previously, we described that murine DC matured with tumor necrosis factor (TNF) up-regulate surface MHC and costimulatory molecules but lack cytokine release, and therefore termed them semi-mature DC. These TNF/DC-induced tolerance after intravenous (i.v.) injection in a model of experimental autoimmune encephalomyelitis (EAE). Here, we show that TNF/DC are not terminally differentiated but can still respond to the microbial stimulus lipopolysaccharide. Subcutaneously injected TNF/DC induce an unpolarized T(H)1/T(H)2 response and are not protective in the experimental autoimmune encephalomyelitis model. Although TNF/DC home to the draining lymph node, they remain negative for intracellular cytokine stainings. However, the nonmigrating, endogenous DC started to produce interleukin (IL)-12p40, TNF and little IL-6, IL-10, and MCP-1 in a bystander fashion. Together, DC matured with the inflammatory stimulus TNF remains responsive to further signals in vitro and in vivo. These signals can be provided by pathogens or the subcutaneous injection route, which can convert them from tolerogenic to immunogenic DC. These findings are important for selecting the appropriate injection route of human DC for tumor immunotherapy.

Animals↗

Subcutaneous injection of desmopressin (DDAVP): evaluation of a new, more concentrated preparation.

A more concentrated desmopressin (DDAVP) preparation (40 micrograms/ml), which required small injection volumes (less than 1 ml), was studied in a double-blind trial in 10 healthy volunteers, 12 patients with haemophilia A, and 8 patients with uraemic bleeding. DDAVP was administered by subcutaneous injection at a dose of 0.4 micrograms/kg body weight. In healthy subjects, peak levels of DDAVP ranging from 480 to 638 pg/ml were reached 1 h after the subcutaneous injection and DDAVP was eliminated with a mean half-life of 3.1 h. DDAVP produced a 2.5-fold (3.0-fold) increase of factor VIII:C (factor VIII:Ag) and a 1.9-fold (2.2-fold) increase of von Willebrand factor:Ag (ristocetin cofactor) over baseline levels. Additionally, a 2.1-fold increase of tissue-type plasminogen activator antigen was observed. Factor VIII and von Willebrand factor were rapidly eliminated with a half-life ranging from 1.3 to 5.7 h and from 1.1 to 11.4 h, respectively. In haemophilia A patients, DDAVP produced a 2.3-fold increase of factor VIII:C 1 h after the injection. DDAVP was given on 8 occasions for management of bleeding, and only in 1 patient did a wound haematoma (after herniotomia) occur. In 7 of the 8 patients with uraemia the bleeding time shortened, and in all patients an increase of platelet retention and a decrease of platelet count was observed (p less than 0.05). No serious local or systemic untoward side effects were observed.

Adult↗

Insuflon versus subcutaneous injection for cytokine administration in children and adolescents: a randomized crossover study.

Pain is a frequent complication of subcutaneous cytokine injections in children. A randomized crossover trial was conducted to determine the least painful and preferred method of cytokine administration for children and young people. The current standard practice of subcutaneous injection was compared with the use of Insuflon (Maersk Medical, Roskilde, Denmark), a subcutaneous indwelling catheter. Children aged between 1 month-and 18 years undergoing treatment within the oncology/hematology unit of a single tertiary hospital and receiving cytokines were eligible for the study. Twenty children participated in the study, each child receiving both administration methods in random order during sequential cytokine treatment courses. There was a trend toward higher pain scores when using subcutaneous injections for drug administration compared to Insuflon. Seventy-five percent (n = 15) of the children who completed the trial and their families preferred using insuflon for subcutaneous drug administration. Consideration needs to be given, however, to those who refused to enter the study, withdrew, or continued because of a preference for subcutaneous injections. Current practice at the Women's and Children's Hospital is to allow the child and parents to choose their preferred treatment modality for subcutaneous drug administration.

Adolescent↗

Translocation of subcutaneously injected chrysotile fibres: potential cocarcinogenic effect on lung cancer induced in rats by inhalation of radon and its daughters.

Exposure to radon 222 and its daughters has been shown to induce lung cancer in rats. The cocarcinogenic effect of intrapleurally injected mineral fibres in rats which have previously inhaled radon has also been established. The aim of this work was to establish whether a similar process could be induced at a distance from the lungs by subcutaneous injection of chrysotile fibres. Three groups of animals were used: (1) 109 rats which inhaled radon only (dose: 1600 working-level months (WLM]; (2) 109 rats given a subcutaneous injection in the sacrococcygeal region of 20 mg of chrysotile fibres after inhalation of the same dose of radon; and (3) 105 rats injected with fibres only. No mesotheliomas occurred in any of the 3 groups. The incidence of lung cancer was 55% in group 2, 49% in group 1 and 1% in group 3. Statistical analysis using Pike's model showed that the carcinogenic insult was slightly higher in group 2 than in group 1. Electron microscopy analysis of fibre translocation from the injection site showed that less than 1% of injected fibres migrated to the regional lymph-nodes and only about 0.01% to the lungs. After injection, the mean length of the fibres recovered in lung parenchyma increased with time, suggesting that short fibres are cleared by pulmonary macrophages whereas long fibres are trapped in the alveolar walls. Although the high tumour incidence observed in group 1 might have masked the cocarcinogenic effect induced by the fibres, it is possible that this effect can occur only at short distances.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗

A case of non-insulin dependent diabetes mellitus with antiinsulin antibody: effect of subcutaneous injection of human recombinant insulin-like growth factor-I.

We saw a 57-yr-old female non-insulin dependent diabetes mellitus (NIDDM) patient with antiinsulin antibody, in whom insulin-like growth factor-I (IGF-I) was shown to be effective as a blood glucose-lowering agent. Due to the presence of the antibody, the patient suffered from postprandial hyperglycemia and frequent hypoglycemia, which were uncontrollable even by multiple insulin injection therapy. In contrast to insulin injection (0.24 IU/kg body wt) which showed a delayed glucose-lowering effect, subcutaneous injection of recombinant human IGF-I (0.05-0.1 mg/kg body wt) caused a quick fall in plasma glucose levels. Prolongation of the glucose-lowering effect of "rapid-acting" insulin frequently caused subsequent hypoglycemia in this patient, but the effect of IGF-I seemed to have disappeared within the first three hours.

Diabetes Mellitus, Type 2↗