EFFECTS OF PLUTONIUM INJECTED SUBCUTANEOUSLY IN THE RAT AND MOUSE. ANL-6823.
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Using the perpendicular injection technique lean diabetic patients may often inject insulin intramuscularly (IM). Guided by ultrasound measurements of the subcutaneous (SC) thickness of the thigh, the aim of the present study was to re-evaluate the absorption kinetics of unmodified insulin from IM and SC injection sites and to evaluate the consequences of IM injection of unmodified insulin for blood glucose control in Type 1 diabetic patients. T50% values (time until 50% of the injected insulin is absorbed from the injection site) of SC injected, radioactively labelled, human unmodified insulin (125I-Actrapid) were 338 +/- 13 (+/- SE) min, 289 +/- 27 min, and 287 +/- 27 min during rest, light physical activity, and strenuous exercise, respectively. Intramuscularly injected unmodified insulin was absorbed faster, T50% 232 +/- 20 min, 113 +/- 13 min, and 112 +/- 5 min during the same levels of physical activity in the same order. When unmodified insulin (Actrapid) was given IM 30 min before breakfast, lunch, and dinner together with intermediate-acting insulin (Protaphane) SC at 2200 h, a more physiological profile of plasma free insulin and a more stable blood glucose profile was obtained than with SC administration into the thigh. The coefficient of variation of blood glucose concentration during the study (3 days each route) was lower with IM than with SC injection of unmodified insulin (33 +/- 4 vs 43 +/- 3%, p less than 0.01). No difference in frequency of hypoglycaemic attacks was found and patients claimed that IM injection was no more painful than SC injection. These data suggest that IM injection of soluble insulin into the thigh is beneficial.
BACKGROUND: Interferons are used in the immune therapy of multiple sclerosis, Kaposi's sarcoma, hepatitis and melanoma based on their antiviral, immunoregulatory and antitumor activities. We report a rare side effect observed during treatment of multiple sclerosis with subcutaneous interferon beta injections. OBSERVATIONS: A 44-year-old patient diagnosed with multiple sclerosis received immune therapy with 6 Mio IU recombinant interferon-beta (IFN-beta) every other day. After 4 years of subcutaneous interferon injections painful indurations appeared directly at and adjacent to the injection sites on the thighs, arms and abdomen. Pain in the thighs made walking almost impossible and required therapy with opiates. After changing to another interferon-beta medication the symptoms improved. Subsequent treatment with doxycycline for 3 weeks was of no additional benefit. CONCLUSIONS: Panniculitis at the injection sites is a rare event but has a significant impact on the quality of life during interferon therapy.
OBJECTIVE: To compare the efficacy, safety and side effects between subcutaneous and intravenous route of erythropoietin administration in Thai hemodialysis patients. DESIGN: Retrospective study. MATERIAL AND METHOD: Retrospective study of hemodialysis patients who switched the route of erythropoietin administration from subcutaneous to intravenous in the Renal Unit Department of Medicine, Bangkok Metropolitan Medical College and Vajira Hospital and Thammasat University was carried out. All patients' information was obtained from the medical records. RESULTS: 60 patients with stable hematocrit level in the last 3 months of the subcutaneous phase who were switched to intravenous route of erythropoietin administration for at least 6 months were recruited The mean hematocrit level of patients in the last 3 months of the subcutaneous period was 30.49+/-4.21%. After switching to the intravenous route for 6 months, the mean hematocrit level was 30.24+/-4.99%. Two patients had to increase the erythropoietin dosage and no side effects were found in the present study. The mean dosage of erythropoietin administered intravenously was not statistically different from the subcutaneous route. There was no correlation between age, sex, cause of renal failure, transferrin saturation, reticulocyte count, C reactive protein and the dosage of erythropoietin, together with the hematocrit level. No other side effects were encountered during the intravenous phase. CONCLUSIONS: This study has shown that the subcutaneous erythropoietin in hemodialysis patients can be changed to the intravenous route in the same dosage with good response and stable hematocrit.
OBJECTIVE: It is important to establish pharmacokinetic or pharmacodynamic differences between novel insulin analogues and human insulin. This study examined the primary metabolic degradation products of insulin glargine (LANTUS) in humans. DESIGN: In this single dose, open-label study, insulin glargine was administered subcutaneously at a dose of 0.6 IU/kg; placebo was administered to one control subject. PATIENTS: Four healthy male subjects, plus one control subject, aged 18-50 years were enrolled in this study. MEASUREMENTS: Following insulin glargine administration, blood glucose levels were clamped at the subjects' fasting concentration for 6 h and the amount of 20% glucose infused to maintain this baseline concentration was recorded. Metabolite profiling was performed in plasma and injection site tissue using HPLC and radioimmunoassay (RIA). Pharmacokinetics were evaluated by RIA of serum and plasma immunoreactive insulin levels. The primary pharmacodynamic measure was the glucose infusion rate (GIR). Safety was evaluated by measuring blood glucose concentrations during the clamp and adverse events were observed by the investigator or reported by the subject. RESULTS: Metabolic profiling revealed a clear pattern: insulin glargine is metabolised by sequential cleavage at the carboxy terminus of the B chain, to yield products M1 and M2, which are both structurally similar to human insulin. These degradation products are present both at the injection site and in plasma. CONCLUSION: Thus, during treatment with a subcutaneous injection of insulin glargine, metabolic degradation is likely to be initiated at the injection site and continued within the circulatory system.
This paper describes systematic studies on the absorption kinetics of exogenous insulin from its subcutaneous tissue depot in 52 male nonobese volunteers (age 20-30 yr). Five experimental protocols were used: effect of changing injection site, effect of temperature change and local massage, effect of aprotinin and human serum, effect of mixing regular insulin with long-acting insulin preparations, and effect of temperature change, muscular exercise, and local massage on the absorption of long-acting insulin preparations. The fastest absorption of insulin occurred at the abdominal injection. Absorption after arm injection was faster than after thigh injection. A hot bath and local massage dramatically increased serum insulin levels in the first 90 min after injection; in contrast, a cold bath delayed absorption substantially. Both aprotinin and the subjects' own blood serum mixed with insulin caused a marked acceleration of the insulin absorption process. Absorption kinetics of two neutral regular insulins (Actrapid and Leo Regular) were virtually identical. Mixing Actrapid with Monotard caused higher serum insulin levels than the mixture of Leo Regular with NPH. A time lag of 5 min between the mixing of Actrapid and Monotard and the injection caused a delayed rise of serum insulin levels; in contrast, this delay could not be observed when Leo Regular and NPH were mixed. Volunteers performed bicycle exercise, applied a hot water bottle to the injection site, or rubbed the injection site 2 1/2 h after injection of long-acting insulin. Accelerated absorption of insulin was only observed after local massage of the injection site of Monotard, Leo NPH, and Mixtard. Local heat had no effect. Exercise caused only an increased absorption of insulin after the Mixtard injection but not after Monotard or NPH injection. These findings have clinical significance and should not be without potential benefit in the attempt to improve metabolic control in insulin-treated diabetic patients.
We have examined the underlying mechanisms accounting for the enhanced in vitro TNP-specific cytotoxic T-lymphocyte (CTL) response following the parenteral injection of syngeneic hapten-modified lymphoid cells. Augmented CTL activity noted following parenteral injection (iv vs sc) of 2,4,6-trinitrophenol-modified syngeneic spleen cells (TNP-SC) is most apparent when limiting numbers of TNP-modified stimulator cells are used in the in vitro sensitization phase. Enhanced CTL responses seen following sc and iv priming is due to distinct mechanisms. Spleen and lymph node (LN) cells from sc primed mice were found to contain significant levels of radioresistant helper activity upon coculture with either viable normal spleen cells in bulk culture or with thymocytes as the source of precursor CTLs in a limiting dilution assay. The helper activity was found to be mediated by a Lyt 1+2- T cells. In addition, Lyt 2-depleted spleen and LN cells from sc primed BALB/c mice could restore the ability of tolerant spleen cells from 2,4,6-trinitrobenzenesulfonic acid (TNBS)-injected BALB/c mice to generate TNP-specific CTLs. Conversely, Lyt 2-depleted spleen and LN cells from iv primed mice provided no measurable helper activity either in bulk culture or in the limiting dilution assay and did not restore the ability of TNBS-tolerant BALB/c spleen cells to generate TNP-specific CTLs. CTL priming via the iv route was found to be completely antigen specific as iv injection of either 2,4-dinitrophenol (DNP)- or fluorescein isothiocyanatel (FITC)-modified cells caused no enhanced CTL activity. Priming via the sc route exhibited a unique specificity pattern as it was shown that sc injection of both TNP-SC and DNP-SC, but not FITC-SC, resulted in enhanced TNP-specific CTL responses. CTL T-helper (Th)-cell induction via the sc route was correlated with (1) the presence of H-2 I region determinants on the inducer cells as the sc injection of TNP-modified erythrocytes led to no enhanced CTL responses or CTL Th activity (while iv injection of TNP-erythrocytes did lead to enhanced CTL responses without detectable helper activity) and (2) the detection of both hapten-specific T-cell proliferation and Interleukin 2 (IL-2) production upon restimulation in culture. We conclude that the sc injection of TNP-SC leads preferentially to an increase of specific Lyt 1+ helper activity, while iv injection leads preferentially to an apparent expansion of Lyt 2+ prelytic effector CTLs.
Our purpose was to determine the accuracy of increased thyroid activity for diagnosing hyperthyroidism in cats suspected of having that disease during pertechnetate scintigraphy using subcutaneous rather than intravenous radioisotope administration. Increased thyroid activity was determined by two methods: the thyroid:salivary ratio (T:S) and visual inspection. These assessments were made on the ventral scintigram of the head and neck. Scintigraphy was performed by injecting sodium pertechnetate (111 MBq, SQ) in the right-dorsal-lumbar region; static-acquisition images were obtained 20 min after injection. We used 49 cats; 34 (69%) had hyperthyroidism based on serum-chemistry analysis. Using a Wilcoxon's rank-sum test, a significant difference (P < 0.0001) was detected in the T:S between cats with and without hyperthyroidism. Using a decision criterion of 2.0 for the T:S, the test accurately predicted hyperthyroidism in 32/34 cats (sensitivity, 94%; 95% confidence interval (CI), 85-100%) and correctly predicted that hyperthyroidism was absent in 15/15 cats (specificity, 100%; CI, 97-100%). Using visual inspection, the test accurately predicted hyperthyroidism in 34/34 cats (sensitivity, 100%; CI, 99-100%) and correctly predicted that hyperthyroidism was absent in 12/15 cats (specificity, 80%; CI, 56-100%). The positive and negative predictive values were high for a wide range of prevalence of hyperthyroidism. And, the test had excellent agreement within and between examiners. Therefore, detecting increased thyroid activity during pertechnetate scintigraphy by subcutaneous injection is an accurate and reproducible test for feline hyperthyroidism.
The pharmacokinetics of clodronate was studied in rats after single intravenous, intramuscular and subcutaneous doses of a mixture of unlabelled and 14C-labelled disodium clodronate (25 mg/5 muCi/kg). The peak clodronate concentration in plasma was reached within 5 min., and the drug was eliminated with a half-life of about 1.5 hr regardless of administration route. Bioavailabilities after intramuscular and subcutaneous administration were 105% and 89%, respectively. During the 72 hr collection period, the mean share of clodronate recovered from the urine was about 53% of the dose regardless of administration route. Most of the drug was excreted during the first 24 hr. The amount of clodronate in bone (femur) was 186 micrograms/g tissue at 2 hr after intravenous administration, 188 micrograms/g after intramuscular administration and 157 micrograms/g after subcutaneous administration. It is concluded that absorption of clodronate after intramuscular and subcutaneous administration is rapid and good, and that the concentrations of the drug in bone after 2 hr are about the same as after intravenous administration.
The pharmacodynamics and pharmacokinetics of bupivacaine in solution and in liposome preparations following subcutaneous administration were studied in rats. Multilamellar vesicles entrapping bupivacaine solution were prepared. The local anaesthetic effect was estimated by the tail-flick test in Wistar rats treated with 1 mg bupivacaine in 0.2-mL preparations. Plasma concentrations of bupivacaine were determined by high-performance liquid chromatography. The results showed that both bupivacaine solution and bupivacaine liposomes revealed local anaesthetic effects in the initial tail-flick test (15 min after injection). With bupivacaine liposomes, the duration of action was 5-fold (447+/-28.9 vs 87+/-6.7 min), the maximum possible effect was 2-fold (100+/-0 vs 47.6+/-13%), and the peak plasma concentration (Cmax) was less than one-fifth (0.12+/-0.04 vs 0.65+/-0.04 microg mL(-1)) that with bupivacaine solution. The sensory block effect of bupivacaine solution completely resolved at 90 min, while the plasma concentration of bupivacaine was still more than half the Cmax. Bupivacaine liposomes resulted in a low and relatively constant plasma level (approx. 0.1 microg mL(-1)) and a pronounced local anaesthetic effect throughout the experimental period (> 7 h). In conclusion, bupivacaine liposomes elevated the intensity and prolonged the duration of the local anaesthetic effect of bupivacaine, and suppressed the systemic absorption rate of encapsulated bupivacaine.
Pharmacokinetic models of insulin were examined in order to describe a plasma concentration-time profile after subcutaneous (s.c.) administration of insulin to the patients with insulin-dependent diabetes mellitus (IDDM) or non-insulin-dependent diabetes mellitus (NIDDM). Diabetic subjects were restricted to those with fasting plasma insulin levels around the lowest limit for insulin assay (5 microU/ml). A one-compartment open model with first-order absorption and elimination was appropriate for estimating the plasma concentration-time profile of insulin injected or infused subcutaneously. In the case of continuous s.c. insulin infusion (CSII) for 1 h at the rate of 3 ml/h (2--3 U/ml), the absorption rate constant (Ka), elimination rate constant (Ke), and distribution volume (Vd) were 0.026 +/- 0.001 min-1 (mean +/- SEM; absorption half-life: 27 min), 0.013 +/- 0.005 min-1 (elimination half-life: 53 min), and 1.99 +/- 0.49 L/kg body wt, respectively. These values did not differ significantly from those generated by single bolus s.c. injection of undiluted insulin (40 U/ml). The calculated areas under the plasma insulin concentration-time curves from time zero to infinity ([AUC] 0 infinity) did not differ after each mode of administration, while the [AUC] 0 infinity after CSII was about 32% of that following intravenous bolus injection (P less than 0.01). The following conclusions can be drawn from these results: (1) the plasma concentration-time profile of insulin after CSII or bolus s.c. injection can be analyzed by pharmacokinetic modeling, (2) the absorption kinetics of insulin did ot differ significantly between two modes of s.c. insulin administration in the patients with IDDM or NIDDM, and (3) the insulin after CSII or single bolus s.c. injection seems to be degraded at the s.c. site to the same extent.
Bronchodilating and cardiovascular effects of subcutaneously administered terbutaline, adrenaline 0.01 mg/kg and salbutamol 0.007 mg/kg were compared in a randomized single-blind manner. All drugs produced bronchodilation within 2 minutes and maintained it for 4 hours with terbutaline and adrenaline and for 3 hours with salbutamol. Bronchodilatation elicited by terbutaline was the highest. Increases in heart rate were observed in all especially during the first 30 minutes. All drugs elicited small increases in systolic blood pressure and it was highest with terbutaline from 5 to 240 minutes. Decreases in diastolic blood pressure were observed with all three. Increases in respiratory rate were small and observed within the first 5 to 30 minutes.
The unconditioned stimulus properties of subcutaneously administered arginine vasopressin (AVP) were examined using place and taste conditioning paradigms. Evidence for an aversive effect of the peptide was found, in general agreement with a previous report, although a high dose of AVP (10 micrograms) was required. Also investigated was the possible role of the dorsal noradrenergic bundle (DNAB) in conditioned taste aversion established by AVP. Although the DNAB has been proposed as one of the central pathways through which AVP exerts a facilitatory effect on conditioned behaviour, destruction of this pontine-forebrain projection with 6-hydroxydopamine did not appear to alter the aversiveness of the drug in the present study. These results replicate the finding that AVP can serve as an aversive stimulus but also indicate that the aversive properties of the peptide may prove to be dissociable from its ability to enhance the retention of learned behaviour.
Thirteen women with symptomatic enlarged leiomyomatous uteri completed 6 months treatment with the gonadotropin releasing-hormone agonist (GnRH-a) buserelin, 600 micrograms daily subcutaneously (s.c.). Seven patients received injections (200 micrograms thrice daily, I-group) and six infusion by pump (50 micrograms.min-(1).2 h-(1). P-group). Residual uterine volumes after 6 months therapy were comparable in both study groups (I-group median 37%, range 23 to 74%; P-group median 49%, range 30 to 69%), as were estradiol levels. Symptoms were well controlled within short time. Six months posttreatment follow-up revealed uterine regrowth to pretreatment dimensions in all but 1 patient with recurrence of symptoms in most women. During therapy, several biochemical indices of bone metabolism were significantly elevated, reflecting an increased bone resorption; they were restored within 3 months after cessation of therapy, except for alkaline phosphatase. Triglycerides and HDL-cholesterol did not change during study; cholesterol was slightly, but significantly elevated after 6 months therapy. GnRH-a buserelin, 600 micrograms daily by s.c. injection or infusion is equally effective in reducing enlarged leiomyomatous uteri. Discontinuation of therapy is followed by uterine regrowth with recurrence of symptoms in most women. The present mode of therapy seems to be beneficial as an adjunct before myomectomy, or in advancing menopause in symptomatic, climacteric women.
It is known that advanced cancer patients may show abnormally low levels of IL-2. The immunotherapy with IL-2 can induce objective tumor regressions, but at present there are no data about the influence of a chronic exogenous IL-2 administration on endogenous secretion of IL-2. This preliminary study was performed to evaluate whether a prolonged IL-2 injection may be able to correct an eventual IL-2 endogenous deficiency in cancer patients. The study included 10 metastatic renal cancer patients, who underwent an immunotherapeutic cycle consisting of IL-2 at 6 million IU/day subcutaneously for 6 days/week for 4 weeks. Serum levels of IL-2 evaluated on venous blood samples collected before and 21 days after the end of IL-2 injection. Before the onset of treatment, abonormally low levels of IL-2 were seen in 6/10 patients. In patients with response or stable disease, mean levels of IL-2 observed 21 days after IL-2 cycle were significantly higher than those seen before therapy, whereas no difference occurred in those who progressed. This preliminary study would suggest that a prolonged subcutaneous injection of low-dose IL-2 may correct an eventual IL-2 endogenous deficiency in advanced cancer patients.
OBJECTIVE: To study patients with side effects secondary to the injection of modelants. METHODS: We studied their clinical, serological, histopathological, radiographic, immunoregulatory and fibroblast culture features by standard methods. We studied thirty patients, 24 women, mean age: 38.2 years. Patients had received either mineral oil, guayacol, silicone or a mixture of these substances; some had received unknown material(s). RESULTS: The mean time between the injection and the onset of symptoms was six years (range: 0.1-24 years). All patients had sclerodermatous skin changes, subcutaneous nodules, edema and/or hyperpigmentation at the site(s) of injection(s); five individuals also had skin changes at sites remote from the injection. Thirteen patients had clinical features of an autoimmune disease. Eleven patients gave a history of arthralgias including four that had symmetrical non-erosive polyarthritis. Twenty of 28 patients (71%) had positive anti-nuclear antibodies. We found intracellular spontaneous production of IL-1 (interleukin-1) by patients' macrophages which was almost absent in normal cells (p < 0.001). Silica-stimulated monocytes from patients also secreted more IL-1 than those from normal subjects (p < 0.001) in autologous mixed lymphocyte reaction. Twelve patients had an early proliferative response. At day seven, a decreased proliferative response was seen in 12/19 patients (p < 0.001). Skin fibroblasts from 3/3 patients synthesized 3-to-5-fold more 3H-hyaluronic acid than normal control cells (p < 0.001). CONCLUSIONS: This report confirms the association between the injection of modelants and the development of autoimmune disease (human adjuvant disease, HAD). Our results implicate IL-1 in the amplification of the disease process. The similarities between primary scleroderma and human adjuvant disease now include immunological and connective tissue data. The study of these patients may help to understand the etiopathogenesis of some autoimmune diseases.
This study was done to investigate the effect of indole-3-acetic acid (IAA) administered subcutaneously and by gavage on neutrophil function and cytotoxicity in neutrophils and lymphocytes. A gavage administration resulted in an increase in phagocytic capacity in neutrophils in a dose depended manner for 1 mg, 2 mg, 18 mg, and 40 mg of IAA per kg of body mass, respectively, compared with the control. Similarly, subcutaneous administration of IAA at 2, 18, and 40 mg per kg of body mass promoted a significant rise in phagocytosis by neutrophils. H2O2 production in neutrophils from treated rats by gavage was similar to those receiving subcutaneous IAA treatment, and did not show a significant difference between treatments and control. IAA treatment, whether by gavage or subcutaneous, did not produce an alteration in antioxidant enzyme activities or in glucose-6-phosphate dehydrogenase activity of either neutrophils or lymph nodes. Subcutaneous IAA administration did not alter the neutrophil and lymphocyte death as deduced by unaltered membrane integrity, DNA fragmentation and mitochondrial transmembrane potential, compared with controls. In conclusion, IAA administration either subcutaneously or by gavage could increase the phagocytic capacity by neutrophils and this acid administration did not have prooxidant effects or cytotoxic effects on neutrophils and lymphocytes.
Five Ayrshire cows were given enrofloxacin (5 mg/kg body weight) intravenously (i.v.), intramuscularly (i.m.) and subcutaneously (s.c.). The antimicrobial activity was measured in milk and serum samples using the agar-diffusion technique. High-performance liquid chromatography (HPLC) assay was used to study the extent of metabolism of enrofloxacin to ciprofloxacin. Analysis of the serum concentration-time data was based on statistical moment theory. Mean t1/2 beta of antimicrobial activity in serum was 1.7, 5.9 and 5.6 h after i.v., i.m. and s.c. administration, respectively. Both i.m. and s.c. routes were associated with a marked flip-flop phenomenon. Based on HPLC analysis of serum samples, the half-lives of enrofloxacin and ciprofloxacin were approximately the same. A marked proportion of enrofloxacin was metabolized to ciprofloxacin. The enrofloxacin fraction bound in vitro to serum proteins was 36-45%. About 0.2% of the total enrofloxacin dose was found in milk during the first 24 h and the amount transferred did not depend on the route of administration. Based on the HPLC data, enrofloxacin concentration in milk was parallel to that in serum, while ciprofloxacin was concentrated in milk. After i.v. injection, the peak concentration of enrofloxacin in milk was reached between 0.7 and 1.3 h but occurred much later for ciprofloxacin (tmax 5-8 h). After i.m. and s.c. administration the concentration-time curves for both enrofloxacin and ciprofloxacin in milk were shallow and there were no obvious peaks.