Immunization of rats against the Yoshida ascites hepatoma with viable cells injected subcutaneously or intramuscularly.
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The authors tested the efficacy and safety of intermittent high doses of iv deferrioxamine (DFX) on a twice-weekly basis through an externalized venous catheter on 14 thalassemic children who were heavily iron-loaded and poorly or noncomplaint to subcutaneous DFX. The main reasons for their noncompliance were resistance of the child because of severe local reactions or more than one family member affected, with very high burden on the mother to look after all the affected children. There were 9 males and 5 females and their age range was 7-13 years (mean 10.93 +/- 1.9 years). All patients were given a 48-h continuous iv infusion of DFX 200-240 mg/kg/day (approximately 10 mg/kg/h) every 2 weeks, combined with subcutaneous 10-h infusion of DFX 3 days/week. One month after the start of the intermittent high-dose DFX program, the 24 h urinary iron excretion was 29.1-1.50 mg/kg/24 h (mean 69.7 +/- 32.5 mg/kg/24 h). These values dropped significantly to 29-53 mg/kg/24 h (mean 39.8 +/- 7.9 mg/kg/24 h) 1 year after the study (p <.004) and remained almost the same over the second year (mean 39.07 +/- 6.58 mg/kg/24 h). Serum ferritin levels markedly elevated before the start of high-dose chelation fell steadily during iv high-dose DFX therapy. Mean values were 6215.5 +/- 578.3, 3971.5 +/- 321.6, 2507.2 +/- 131.2, and 1866.5 +/- 110 ng/mL at 0, 6, 12, and 24 months, respectively. No serious side effects were reported. Intermittent high-dose DFX therapy combined with 3 days of subcutaneous DFX is safe and effective in reducing iron stores and improving the compliance of these heavily iron-loaded thalassemic children.
The effect of administration of a glutamate-containing protein hydrolysate on the arcuate nucleus of 10-day-old mice was studied by two methods. Arcuate nucleus damage resulted when administration was by a single large subcutaneous dose (100 ml/kg). When the same total dose was administered subcutaneously in five small doses (20 ml/kg) over a period of 8 h, the damage to the arcuate nucleus did not occur. The latter method of administration was to simulate a clinical infusion. The results demonstrate that there is no hazard to the arcuate nucleus w-en glutamate-containing protein hydrolysates are administered by infusion.
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In many countries there is no clear recommendation regarding the preferred route of administration of inactivated influenza vaccines. In a randomised, observer blind study of 720 elderly subjects, a split, trivalent influenza vaccine was significantly more immunogenic for both A strains (H3N2 and H1N1, p = 0.0016 and 0.003, respectively) when given intramuscularly compared to subcutaneously. This difference was due entirely to a gender effect, with females in the intramuscular (IM) group having a significantly greater serological response than females in the subcutaneous (SC) group for both of these strains. Similar results were seen with local adverse effects. These data suggest that vaccination practices that ensure intramuscular injection are required for optimal administration of influenza vaccines in the elderly.
Metrazol administered subcutaneously at a dose of 80 mg . kg-1 elicited genuine minimal seizures (predominantly clonic) in adult, 45- and 25-day-old rats. The same dose of metrazol resulted in long-lasting generalized tonic-clonic seizures in rats aged 15 days and younger. Eighteen-day-old rats represented a transitory stage in which both types of seizures were present: minor seizures at first and then, after a short resting period, major seizures. A different seizure pattern in young rats was not induced by their higher sensitivity to metrazol, but was caused by the level of neural maturation.
A randomized, single-centre, cross-over study was designed to compare the bioavailability of two pharmaceutical formulations of recombinant human follicle stimulating hormone (recFSH; Puregon(R)): (i) a dissolved cake injected by a normal syringe; and (ii) a ready-for-use solution injected using a device referred to as Puregon(R)Pen. Twenty-two healthy female volunteers underwent one of two administration sequences: Puregon(R)Pen/syringe or syringe/Puregon(R)Pen, by which they received a single subcutaneous dose of recFSH (150 IU). Endogenous gonadotrophin production had been previously suppressed using an oral contraceptive (Lyndiol(R)). Pharmacokinetic parameters characterizing rate [peak concentration (Cmax) and time of peak concentration (tmax)] and extent [area under the curve (AUC) and clearance (CL)] of absorption were obtained from 20 subjects. After injection with both formulations, serum FSH concentrations reached a peak of 3.4 IU/l at 13 h after injection. The elimination half-life was approximately 34 h, irrespective of formulation. A difference of approximately 18% was found between serum FSH concentrations obtained using the two formulations, which was caused by differences between the anticipated and the actual volume injected with the normal syringe. After correction for injection losses by weighing the amount injected with a normal syringe, the two formulations were found to be bioequivalent with respect to Cmax, AUC and CL. For tmax, bioequivalence could not be proven due to high intra-subject variability and broad absorption peaks of FSH. Both methods were well tolerated, local reactions being generally mild and short-lived.
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In a prospective, randomized, open study 119 consecutive patients with phlebographically verified deep venous thrombosis (DVT) of the leg (36% distal and 64% proximal) were treated either with a low molecular weight heparin (Fragmin, Kabi-Vitrum) subcutaneously (120 anti-FXa U/kg) twice daily or standard heparin (SH) as continuous intravenous infusion (480 IU kg-1 day-1). The Fragmin doses were adjusted to achieve an anti-FXa activity of 0.2-0.4 U/ml before injection and not greater than 1.5 U/ml 4 h after the morning injection. The SH dose was modified to prolong the APTT 2-3 times. Repeat phlebography after 5-7 days showed improvement in 34/45 patients (76%) in the Fragmin group and in 30/49 patients (61%) in the SH group and progress in 2/45 (4%) and 3/49 (6%), respectively. The mean Marder scores decreased from 18.7 +/- 12.1 to 15.7 +/- 12.7 in the Fragmin group and from 16.9 +/- 12.0 to 14.4 +/- 11.8 in the SH group (ns). Two patients in the SH group and none in the Fragmin group had major bleedings. After 22 +/- 7 months follow up 6 rethromboses had occurred in the SH group and 4 in the Fragmin group. Postthrombotic signs and symptoms were similar in both groups. We conclude that two daily sc Fragmin doses seem as effective and safe as continuous SH in the treatment of DVT of the leg.
After bilateral neurotoxic hippocampectomy adult rats received bilateral fetal suspension grafts at the lesion sites. Functional efficacy of fetal grafted tissue was substantially improved by subcutaneous administration of carbachol at a dose of 0.01 mg/kg s.c. The drug caused an almost complete restitution of performance in grafted animals in a Morris water-maze test. The progress of behavioral recovery was studied over 3 months postoperatively. Grafts of fetal hippocampal neurons alone improved lesion-induced spatial learning deficits to a limited degree. These results suggest that peripheral administration of carbachol may be of use in the treatment of central lesions associated with cognitive impairments, allowing or enhancing the development of graft-induced amelioration of behavioral deficits. The data also support the view that grafts of embryonic neural tissue may produce a local opening of the blood-brain barrier allowing drugs which normally act only peripherally to exert central effects. These central effects are probably limited to the graft site because the rest of the brain has a blood-brain barrier which is still intact.
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Several lines of evidence implicate zinc in the pathogenesis of epileptic seizures, and administration of zinc salts has been shown to affect seizure susceptibility. In the present work, we studied the effects of subcutaneous (s.c.) injections of ZnCl2 on seizures induced by intraperitoneal (i.p.) kainic acid (10 mg/kg) in rats and by noise (80-120 dB) in the DBA/2J mouse. Previous administration of zinc salt (20-200 mg/kg) substantially reduced the frequency of noise-induced running fits, clonic and tonic seizures, and deaths in mice, but had no significant effect on the incidence or severity of kainic acid-induced seizures in rats. Together with findings in the literature, our results suggest that zinc plays multiple, sometimes antagonistic roles in seizure development.
Calcifying panniculitis is a rare form of calcinosis cutis belonging to the spectrum of calciphylaxis that has almost invariably been described in patients with severe renal disturbances. We report a patient with osteomalacia without chronic renal failure, who developed calcifying panniculitis following subcutaneous administration of nadroparin-calcium. Light microscopy studies of biopsy specimens revealed multiple foci of microcalcification within the adipose lobules, in the interadipocyte spaces, in connective tissue septa and in the media of small arteries in the subcutis. The patient had an elevated level of intact parathyroid hormone, whereas the calcium-phosphorus product was normal. The lesions slowly resolved upon discontinuation of nadroparin. We conclude that calcifying panniculitis is a rare complication associated with the subcutaneous administration of nadroparin-calcium that may rarely also occur in the absence of renal disturbances. Low molecular weight calcium-containing heparins should probably be used with caution in the presence of hyperparathyroidism.
The aim of this study was to compare the glucodynamic effects of soluble insulin and the rapid acting insulin analogue insulin lispro after subcutaneous (s.c.) and intramuscular (i.m.) injection. Twelve healthy male volunteers (age 26.8 +/- 1.7 years, BMI 23.2 +/- 2.3 kg m(-2); mean +/- SD) participated in this single-centre, open-labelled, euglycaemic glucose clamp study on four different days. Soluble insulin or insulin lispro (0.2 U kg(-1)) were injected s.c. or i.m. into the thigh by syringe. The glucodynamic effects were assessed by registering the glucose infusion rates necessary to maintain blood glucose at 5.0 mmol l(-1) for the subsequent 420 min. Intramuscular injection of soluble insulin led to an earlier peak of metabolic action when compared to s.c. administered soluble insulin (tmax 138 +/- 29 vs 179 +/- 34 min; p < 0.05). The maximal metabolic effect and metabolic activity during the first 2 h after i.m. and s.c. injection of soluble insulin were comparable (GIRmax 9.7 +/- 2.3 vs 7.8 +/- 2.3 mg kg(-1) min(-1); n.s., AUC0-120min 0.60 +/- 0.18 vs 0.50 +/- 0.15 g kg(-1) 120 min; n.s.). Subcutaneous administration of insulin lispro led to a metabolic effect resembling that induced by i.m. application of soluble insulin (tmax 116 +/- 26 vs 138 +/- 29 min; n.s., GIRmax 11.1 +/- 2.3 mg vs 9.7 +/- mg kg(-1) min(-1); n.s.). However, the overall metabolic response during the first 2 h after injection was higher with s.c. insulin lispro (AUC0-120min 0.81 +/- 0.26 vs 0.60 +/- 0.18 g kg(-1) 120 min; p < 0.05). The glucodynamic activity of i.m. applied insulin lispro was comparable to that of lispro s.c.. Following i.m. injection of soluble insulin, the metabolic activity peaked more rapidly than with s.c. administration. In contrast, the metabolic effect of insulin lispro was similar with either route. The time-action profile of i.m. injected soluble insulin lies between that of s.c. applied soluble insulin and insulin lispro.
The effects of subcutaneous administration of three doses of human growth hormone-releasing factor (hGRF-44 NH2 or hGRF) at doses of 100, 300 and 600 micrograms were studied in six normal young men. GH responses obtained with 100 and 300 micrograms were negligible. In contrast, the 600 micrograms dose gave a profile of response comparable in timing and magnitude to that obtained with i.v. hGRF at maximal effect doses (20, 80, 100 micrograms). Plasma immunoreactive hGRF levels (IR-hGRF) were compared after s.c. and i.v. hGRF. Mean maximal plasma concentrations were comparable with s.c. 600 micrograms and i.v. 20 micrograms. Peaks occurred earlier with i.v. hGRF (5 min as opposed to 15 min): however, return to undetectable values was obtained between 90 and 120 min after s.c. or i.v. injections. These data suggest a great loss of the peptide between the subcutaneous space and blood, without delayed absorption. High variability in plasma IR-hGRF concentrations between the subjects after the same s.c. doses was observed.
A booster dose of a formalin-inactivated, cell culture-propagated Rift Valley fever vaccine (TSI-GSD-200) was administered without significant reactogenicity to 60 volunteers 18 months after they received a three dose primary series. Blood was drawn for serological testing prior to boosting and 10, 49, and 180 days thereafter. Neutralizing antibody response was prompt, being maximum on day 10 and considerably higher than the peak titres obtained on day 42 after the initial series. A marked decline in antibody titres was evident by day 180, as seen for the primary series, but residual titres were substantially higher. The initial series was given in doses of 1.0, 0.5, 0.3, or 0.1 ml and the immune status achieved with these injections was a major determinant of the response to boostering. Secondary responses were highly dependent in magnitude and duration on the prior immune status of the recipient. Evaluation of dose and route of recall inoculation showed 1.0 ml given subcutaneously (SC) to be equivalent to 0.1 ml administered intradermally (ID), though inference should be guarded due to the small sample size. Although 0.1 ml SC dose was inferior to either, it was modestly effective. Intradermal administration of vaccine may be useful for extending the small reserve of vaccine available for use in emergency.
Degradation of human growth hormone (hGH) at the injection site has previously been implicated as the basis for its reduced systemic availability following subcutaneous (SC) administration. The goal of these studies was to develop an animal model which would allow mass balance calculations to (i) quantify the loss at the injection site and (ii) determine the role of the lymphatics in the transport of subcutaneously-administered hGH. The animal model utilized a sheep and enabled simultaneous sampling of blood and collection of either peripheral lymph (via the efferent duct of the popliteal lymph node draining the injection site) or central lymph (via the thoracic lymph duct). In non-lymph cannulated sheep, the systemic availability of hGH following SC dosing was 58.4 +/- 9.1% (mean +/- SEM) relative to an intravenous (IV) control. The availability of hGH decreased to approximately 30-40% when either peripheral or central lymph was collected indicating that a proportion of the dose was transported via the lymph. The fraction of the administered dose collected in peripheral lymph was 61.7 +/- 8.5% (mean +/- SEM), whereas only 8.6 +/- 1.3% was collected in central lymph. These results suggested that loss of hGH within the lymphatics contributed significantly to its reduced systemic availability following SC administration. The total recovery (sum of the systemic availability and the cumulative amount recovered in lymph) of hGH was approximately 93% of the dose in the peripherally-cannulated group indicating that loss at the injection site was minimal.
BACKGROUND: Edema of the mucous membranes lining the airways is a major factor of airway obstruction in asthma. Stimulation of both alpha and beta-adrenergic receptors is thus logically useful to reduce edema through vasoconstriction and to cause smooth muscle relaxation. The aim of this work was to compare the effects of subcutaneous epinephrine vs terbutaline for treating acute attack of asthma in infants. PATIENTS AND METHODS: Fifty-four infants aged less than 30 months admitted for acute asthma attacks were included in this study. None had previous cardiovascular or definite pulmonary disease and none had tachycardia above 200/min. The patients were randomly given subcutaneous epinephrine, 10 micrograms/kg (n = 28) or subcutaneous terbutaline at the same dosage (n = 26). RESULTS: Improvement in accessory muscle use, oxygen saturation, PaO2 and PCO2 was similar in both groups. The respiratory rate was significantly improved after administration of epinephrine (P = 0.05). No adverse effects were seen in either drug. CONCLUSION: Subcutaneous administration of epinephrine is as effective as terbutaline in treating acute attack of asthma in infants. This drug, easy to use and of low-cost, could be the treatment of choice in developing countries.